Term
|
Definition
| Study of the effects of chemicals on cells & organisms |
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Term
|
Definition
| Study of the factors affecting the concentration on the drug at the active site as a function of time (what the body does to the drug) |
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Term
def
Pharmacokinetic process |
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Definition
| ADME - Absorption, Distribution, Metabolism, Excretion |
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Term
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Definition
| The study of how the target cells respond to the delivered concentration of drug (what the drug does to the body) |
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Term
| What are the spectrum of Drug Sizes? (molecular wt) |
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Definition
| Varies from small ions to large proteins |
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Term
| When do drugs have a greater ability to cross biological membranes? |
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Definition
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Term
| How do drugs achieve specificity for target action? |
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Definition
| By targeting receptors that are only expressed on desired cells. |
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Term
| What factors control the concentration of drug at a site at any given time? |
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Definition
| Pharmacokinetic process - ADME. |
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Term
| What are the majority of drug receptors? |
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Definition
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Term
| What are commonly used ligands for receptors? |
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Definition
| Neurotransmitters or hormones. |
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Term
| What happens once a ligand binds its receptor? |
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Definition
| Transduction of the binding to a signal altering the intracellular biochemistry or ionic concentrations to change cellular metabolism. |
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Term
| What are the 4 major receptor classes? |
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Definition
Ligand-gated ion channel
Tyrosine Kinase-linked receptors
G-protein Coupled Receptors
Ligand-activated Transcrption Factors |
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Term
Function:
Ligand-gated Ion Channel |
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Definition
| Change in membrane potential or ionic concentration => cellular effect |
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Term
Function:
Tyrosine Kinase-linked receptors |
|
Definition
| Protein phosphorylation => cellular effect |
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Term
Function:
G-protein Coupled Receptors |
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Definition
Intracellular secondary messanger => cellular effect
or
Intracellular secondary messanger => protein phosphorylation => cellular effect. |
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Term
| Function: Ligand-activated Transcription Factors |
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Definition
| Nucleus activation => mRNA => protein => cellular effect |
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Term
| Which receptor type is used by >50% of the currents drugs used? |
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Definition
| G Protein-Coupled Receptors |
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Term
| Besides receptors, what else can be used as drug sites of action? (drug targets) |
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Definition
| other cell components s.a. phospholipids, DNA, enzymes, etc. |
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Term
| Which receptor site works fastest? |
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Definition
| Ligand-gated ion channel : milliseconds |
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Term
| Which receptor site works slowest? |
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Definition
| Ligand-activated Transcrption Factors: hours |
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Term
| How fast do Tyrosine Kinase-linked receptors & G-protein Coupled Receptors work? |
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Definition
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Term
| What are the only 2 post-synaptic drug action site? |
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Definition
| Post-synaptic adrenoreceptors => trigger biological responses Non-adrenergic post-synaptic autoreceptors => modulate actions of post-synaptic adrenergic receptors |
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Term
| What 2 presynaptic receptors do drugs work on? |
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Definition
Pre-synaptic autoreceptors => limit further NE secretion when there's an abundance in the synaptic cleft
Non-adrenergic presynaptic receptors => modulate actions of the pre-synaptic adrenergic receptors |
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Term
| What 3 OMPs are used as drug target sites? |
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Definition
Pre-synaptic NE transporter
The calcium channel
SNAP proteins involved in vesicular exocytosis |
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Term
| What drug action site is a target for cocaine? |
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Definition
| Presynaptic NE transporter |
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Term
| What drug action site is a target for Ca2+ channel blockers? |
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Definition
|
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Term
| What 3 drug action sites have to do with vesicles? |
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Definition
Secretory vesicle/plasma fusion process
Vesicular DA transporter
(SNAP OMPs involved in vesicular exocytosis) |
|
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Term
| What presynaptic enzyme can be a target for drugs? |
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Definition
| Tyrosine Hydroxylase => rate limiting enzyme for neuronal NE synthesis |
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Term
| What is the drug target site aimed at intrecaellular organelles? |
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Definition
| Inhibition of mitochondrial MAO => increase presynaptic NE |
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Term
| What 2 things can drugs add to the synaptic cleft as an action? |
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Definition
Exogenous NE (or similar agonist)
Receptor antagonist |
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Term
|
Definition
1) Post-synaptic adrenoreceptors
2) Pre-synaptic auto receptors
3) Non-adrenergic post-synaptic receptors
4) Non-adrenergic presynaptic receptors
5) Presynaptic NE transporter
6) Secretory vesicle/plasma membrane fusion process
7) Tyrosine Hydroxylase
8) Ca2+ Channel
9) Vesicular Dopamine Transporter
10) SNAP proteins
11) Inhibition of mitochondrial MAO
12) Add exogenous NE (or other agonists)
13) Add receptor antagonists. |
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Term
Function:
Nicotinic acetyl choline receptor |
|
Definition
| gates a sodium channel to produce depolarization in skeletal muscle |
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Term
| Function: Muscarinic acetylcholine receptor |
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Definition
| activate biochemical pathway to increase intrecellular Ca2+ in smooth muscles |
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Term
Function:
β-adrenergic receptor |
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Definition
| Binds epi & activates an increase in cAMP in many cell types |
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Term
Function:
Insulin receptor |
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Definition
| Activate recruitment of GLUT4 glucose transporter molecules to the plasma membrane of many cells |
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Term
Function:
Glucocorticoid receptor |
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Definition
| translocates from cytoplasm to nucleus to turn on transcription of specific genes |
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Term
| How does the anti-tumor drug adriamycin inhibit transcription? |
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Definition
| Intercalation into the DNA minor groove |
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Term
| How do statins inhibit cellular cholesterol biosynthesis? |
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Definition
| Bind to HMG-CoA reductase |
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Term
| Where does α1-adrenoreceptor signal? |
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Definition
| Arteriolar smooth muscle =>contraction |
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Term
| What signal molecule is released from a sympathetic nerve terminal in α1-adrenergic stimulation? |
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Definition
|
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Term
| What does the singal molecule, NE, bind to in α1-adrenergic stimulation? |
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Definition
| Arteriolar smooth muscle plasma membrane α1-adrenoreceptor |
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Term
| What does NE binding to α1-adrenoreceptor do to the receptor? |
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Definition
| Induces a conformational change in the receptor protein. |
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Term
| What does the conformational change of the α1-adrenoreceptor allow? |
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Definition
| Intracellular part of the receptor to catalyze the exchange of GDP with GTP on α subunit of Gq |
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Term
| What happens once the α subunit of Gq is phosphorylated to GTP in α1-adrenergic signaling pathway? |
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Definition
Allows: Gq βγ subunits dissociate
Activates: Phospholipase Cβ to breakdown PIP2 => releases IP3 & DAG |
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Term
|
Definition
| gated channel to release intracellular Ca2+ |
|
|
Term
| What activates PKC (Protein Kinase C)? |
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Definition
|
|
Term
| What does activated PKC do? |
|
Definition
| Allows entry of extracellular Ca2+ => muscle contraction. |
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Term
| What does it mean that binding of ligands to receptor is controlled by mass action? |
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Definition
| Increasing ligand concentration produces more binding, but there is a limit - a saturation point beyond which there is no further binding. |
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Term
| What is the equilibrium equation for drug & receptor? |
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Definition
|
|
Term
| What is the equation for the equilibrium dissociation constant for drug & receptor? |
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Definition
|
|
Term
| What is kon?
What is koff? |
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Definition
k on = forward rate constant
k off = reverse rate constant |
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|
Term
| What does magnitude of response of a drug depend on? |
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Definition
| binding of receptors, therefore response=max response when [DR] = [R]total (when all DR is formed) |
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Term
Equation
Response/Max Response |
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Definition
|
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Term
| When isn't binding of DR:response 1:1? |
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Definition
| Signaling systems where downstream effects are amplification. |
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Term
| How is Kd similar to Km in kinetics? |
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Definition
| Just like Km = concentration where 1/2 receptors are occupied, Kd = concentration where 1/2 receptors are occupied. |
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Term
What plot types are used for plotting over a larger concentration range?
Why would we need to do this? |
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Definition
logarithmic plots
to compare drugs |
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Term
|
Definition
| a ligand that binds to a receptor to directly activate a signaling pathway. |
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Term
|
Definition
| stablize receptor in a particular conformation |
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Term
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Definition
| measure of the maximum response obtained with the highest concentrations of the agonist. |
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Term
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Definition
| Measure of the concentration of agonist required to achieve 50% of maximum response |
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Term
| What is EC50 usually equivalent to? |
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Definition
|
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Term
| What is used to compare 2 agonists for the same receptor? |
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Definition
|
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Term
|
Definition
| Comparison of EC50 values for 2 or more agonists.
It compares the concentrations needed for 50% response. |
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Term
| When does a drug have greater potency? |
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Definition
| When EC50 is smaller, i.e. smaller concentration is needed to get desired response. |
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Term
|
Definition
| drugs that produce an effect with lower efficacy than the standard full agonists. |
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Term
| How can compounds such as atropine with zero efficacy be useful? |
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Definition
| Can antagonize the binding & therefore the biological actions of agonists. |
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Term
|
Definition
| an agent that binds to a receptor but cannot produce the conformational change necessary to trigger the downstream events. |
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Term
| What response is seen when an antagonist is bound by itself? |
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Definition
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Term
def
competetive antagonist |
|
Definition
| an antagonist that binds reversibly therefore can be competed away by higher agonist concentrations. |
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Term
|
Definition
| when an antagonist binds to its receptor, it "blocks" further binding of an agonist => hindering ability to activate receptor. |
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Term
|
Definition
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Term
| What happens to the concentration-response curve for an agonist with increasing concentrations of competitive antagonist? |
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Definition
| EC50 gets pushed to the right, but there's no change in efficacy. |
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|
Term
| What is the equation for the response for competitive antagonism? |
|
Definition
|
|
Term
def
non-competitive antagonist |
|
Definition
| antagonist that either inactivate the receptor molecules or else act on a downstream site |
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Term
| What happens to the concentration-response curve for an agonist with a non-competitive antagonist? |
|
Definition
| decrease efficacy.
no effect on EC50 |
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Term
| Will increasing concentrations of agonist overcome a non-competitive antagonist? |
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Definition
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|
Term
| What is the equation for the response for non-competitive antagonism? |
|
Definition
|
|
Term
|
Definition
Since enzymes can amplify a signal, not 100% of the receptors need to be used to produce max response.
The remaining unoccupied receptors are the spare receptors. |
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Term
| What is the advantage to spare receptors? |
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Definition
| activation at low concentrations with faster turn off. |
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Term
|
Definition
produces a response opposite that of an agonist.
(unlike antagonist when alone produces no response) |
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Term
|
Definition
diffusion rate.
(it's fairly constant for sm. ligands) |
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Term
| What determines the magnitude of KD? |
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Definition
|
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Term
| What happens when koff is small? |
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Definition
| KD is small => high affinity binding |
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Term
| What happens when koff is large? |
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Definition
| KD is large => low affinity binding |
|
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Term
| When will there be a faster release of ligand when concentration drops? |
|
Definition
|
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Term
|
Definition
|
|
Term
|
Definition
| Non-competitive Antagonist |
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Term
|
Definition
|
|
Term
| How can you change the potency, efficacy, and/or change an agonist to an antagonist? |
|
Definition
| Changing substituent groups around the core structure of a compound. |
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|
Term
| How are congeners produced? |
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Definition
| Adding on longer hydrocarbon chains. |
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Term
| How are analogs produced? |
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Definition
| A substitution of an esteric linkage. |
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Term
| What are analogs often useful in producing? |
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Definition
| Longer-lived version of an endogenous compound. |
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Term
| What is the predominant mechanism of how drugs cross membranes? |
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Definition
|
|
Term
| What do drugs need for passive diffusion? |
|
Definition
| Enogh lipid solubility to pass through the lipid portion of cell membranes |
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|
Term
| What is the driving force for movement in passive diffusion? |
|
Definition
| concentration gradient across the membrane |
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Term
| What are the 5 other mechanisms (besides passive diffusion) that drugs may cross the membrane? |
|
Definition
1) Ion channels
2) skeletal muscle capillary fenestrations
3) active pumps or co-transporters
4) facilitated diffusion carriers
5) cellular endocytosis |
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|
Term
| What equation is used to calculate the pH? |
|
Definition
|
|
Term
| -What is the Henderson-Hasselbalch equation? |
|
Definition
| pH = pKa + log (unprotonated/protonated) |
|
|
Term
| Where do acids accumulate? |
|
Definition
|
|
Term
| Where do bases accumulate? |
|
Definition
|
|
Term
| Are acids or bases absorbed from the stomache? |
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Definition
| Acids. They are trapped by the more alkaline plasma, where bases are trapped to the acidic stomache. |
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Term
| What drug types are NOT effected by pH? |
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Definition
|
|
Term
| What 3 routes of administration give immediate effect? |
|
Definition
Sublingual
Inhalation
Intravenous |
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|
Term
| How fast does oral administration take effect? |
|
Definition
|
|
Term
| Which 2 administration routes take effect in minutes to hours? |
|
Definition
|
|
Term
| How long before topical agents take effect? |
|
Definition
|
|
Term
| What route of administration has the most variable effect? |
|
Definition
| Intramuscular - minutes to days. |
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|
Term
| Which 3 routes of administration are more convenient? |
|
Definition
|
|
Term
| Which 2 drug administration routes avoid 1st pass metabolism? |
|
Definition
|
|
Term
| What is the alternative to oral administration? |
|
Definition
|
|
Term
| Which administration route allows for the most control? |
|
Definition
|
|
Term
| Which administration route could be given in a long-term depot? |
|
Definition
|
|
Term
| Which 3 routes of administration must be given in small amounts? |
|
Definition
Sublingual
Topical
Subcutaneous |
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|
Term
| Which 2 routes of administration are irreversible? |
|
Definition
|
|
Term
| What is the disadvantage to oral administration? |
|
Definition
|
|
Term
| Besides small quantity, what is a disadvantage to topical administration? |
|
Definition
|
|
Term
| What is the disadvantage to inhalation administration? |
|
Definition
| Gas, vapor, or small particles are needed. |
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|
Term
| Why is first pass metabolism a disadvantage? |
|
Definition
| Blood from stomach & intestines flows first thru the liver => significant amount of a drug could be chemically altered (perhaps inactivated) before it reaches the systemic circulation. |
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Term
|
Definition
| measure of the percent or fraction of the orally administered dose of a drug that enters systemic circulation. |
|
|
Term
| How do drugs compensate for low bioavailability? |
|
Definition
|
|
Term
| How do you monitor drug therapy? |
|
Definition
| Determine Volume of Distribution (Vd) for the drug and relate it to the concentration in the blood. |
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Term
| How do you determine the Volume of Distribution (Vd) |
|
Definition
1) Administer known amount of drug IV
2) Take blood samples intermittently & measure [drug].
3)Plot log concentration vs. time
4) Extrapolate straight line back to t=0 |
|
|
Term
| **What is the equation for Vd? |
|
Definition
| Vd = (amount administered)/([t=0]) |
|
|
Term
| What does the distribution phase depend on? |
|
Definition
Distribution out of plasma & therefore lipid solubility.
Elimination from body |
|
|
Term
| What does the elimination phase depend on? |
|
Definition
|
|
Term
|
Definition
| The apparent volume of plasma that would have yielded the extrapolated concentration at t=0 upon dose administration |
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|
Term
| When is the drug entirely in the plasma for an IV dose? |
|
Definition
|
|
Term
|
Definition
|
|
Term
| What 2 properties of a drug determine it's Vd? |
|
Definition
1) Lipid solubility: high lipid solubility => low plasma concentration => large Vd
2) Binding to plasma proteins: high binding => trapping of drug in blood => low Vd |
|
|
Term
Vd value range
>40 liters
5-10 literss |
|
Definition
>40: highly lipid soluble
5-10: highly charged/bound to plasma protein |
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|
Term
| What 2 places do highly lipid soluble drugs have access to that other drugs don't? |
|
Definition
1)Liver cells - access to CYP450
2) CNS |
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|
Term
| How are CNS drugs usually excreted? |
|
Definition
|
|
Term
| Why does blood flow from the stomach to the liver? |
|
Definition
| To protect us from lipid soluble compounds in the diet from becoming CNS toxic |
|
|
Term
| Why do drugs extensively plasma bound have slower elimination? |
|
Definition
| Renal & Hepatic excretion depends on free, unbound drug. |
|
|
Term
| What is an advantage to extensively bound plasma drugs? |
|
Definition
| They act like a depot. As the small amount of free drug is eliminated, bound drug unbinds and replenishes. |
|
|
Term
| When can plasma binding drugs have DDI? |
|
Definition
| When there's another plasma bound drug competing for plasma proteins. |
|
|
Term
|
Definition
Vd = 1400 mg/(40 mg/L)
= 35 L |
|
|
Term
| What is the purpose of drug metabolism? |
|
Definition
| To convert non-polar molecules not excreted by the kidney to polar metabolites which can be excreted by the kidney. |
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Term
|
Definition
| Enzymatic reactions involving oxidation, reduction or hydrolysis. |
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|
Term
|
Definition
| biosynthetic reactions where a functional group is attached to the drug molecule. |
|
|
Term
| Can Phase II Metabolism preceed Phase I? |
|
Definition
|
|
Term
| Do all compounds have to go thru both Phase I & Phase II metabolism? |
|
Definition
| No. Can go thru, I, II or both. (if both, I usually preceeds II, but isn't necissary) |
|
|
Term
| How is drug metabolism controlled? |
|
Definition
Chronic exposure => faster metabolism
or
Substrates can induce metabolism |
|
|
Term
With chronic exposure, how long before maximum induction of metabolism is reached?
to return to normal levels? |
|
Definition
| Same for both: several days to a week |
|
|
Term
| What can cause inhibition and toxic accumulation of a drug? |
|
Definition
| If drugs metabolized by CYP3A4 are co-administered and are therefore competitive => inhibition of eachother's metabolism. |
|
|
Term
| What contributes to individual variations in metabolism? |
|
Definition
|
|
Term
| Why can other P450 isoforms increase in activity when one P450 substrate induces it's own metabolism? |
|
Definition
|
|
Term
| How are most drugs eliminated from the body? |
|
Definition
| Renal excretion, liver metabolism, or a combination. |
|
|
Term
| What is the most important organ for excretion of drugs and/or their metabolites? |
|
Definition
|
|
Term
| Via what other bodily fluids may drugs be excreted? |
|
Definition
| Bile, sweat, saliva, exhaled air, milk |
|
|
Term
| What is the ultrafiltrate of the kidney, allowing small molecules & water to pass thru, but retaining cells & large molecules in the blood? |
|
Definition
|
|
Term
| Which molecules are not reabsaorbed by the renal loops & tubules & are therefore excreted? |
|
Definition
|
|
Term
| What are the 3 factors of renal excretion? |
|
Definition
1) Glomerular Filtration
2) Tubular Secretion (active)
3) Tubular Reabsorption (passive) |
|
|
Term
| How does golmerular filtration affect drug excretion? |
|
Definition
Only allows passage of free drug
Increased filtration rate increases rate of elimination |
|
|
Term
| How can tubular secretion affect drug elminiation? |
|
Definition
| It can select certain drugs & actively transport them against a concentration gradient, even if protein bound. |
|
|
Term
| How does tubular reabsorption affect elimination? |
|
Definition
Enhanced lipid solubility favors reabsorption
Urine pH affects drug reabsorption - same as in the gut
Slow renal flow favors reabsorption |
|
|
Term
| When is biliary excretion an option? |
|
Definition
High molecular wt.
glucouronidated drugs |
|
|
Term
| How can urinary excretion be increased in cases of overdose of a weak acid or base? |
|
Definition
|
|
Term
| How do you cause urinary alkalinization? |
|
Definition
| IV administration of sodium bicarbonate. |
|
|
Term
| How do you cause urinary acidification? |
|
Definition
| administer ammonium choloride. |
|
|
Term
| What is the range of pKa when urinary acidification or alkalinization will work? |
|
Definition
|
|
Term
| What can provide active secretion of compounds from CSF to blood? |
|
Definition
|
|
Term
| When is hepatic drug metabolism useful? |
|
Definition
| Nonpolar compounds, since urinary excretion doesn't work well due to reabsorption. |
|
|
Term
|
Definition
| Dependence of rate of a process on the exponent of the drug concentration |
|
|
Term
| What is the rate equation of a drug? |
|
Definition
| Rate = Constant * [Drug]n |
|
|
Term
| What does is mean if n=0 in the rate equation (i.e. Rate = Constant)? |
|
Definition
| The process is not dependent on drug concentration and proceeds at a constant rate per unit of time. |
|
|
Term
| What does it mean if n=1 in the rate equation (i.e. rate = constant*[Drug])? |
|
Definition
| The rate is directly dependent on the drug concentation. This means that a constant percent is lost per unit of time. |
|
|
Term
| What 2 process are zero order? |
|
Definition
1) Drug Administration
2) Drug elimination in overdose |
|
|
Term
| What is the equation for rate of drug input? |
|
Definition
Rate of Drug input = f(D/T)
f= bioavailability (functional absorption)
D/T = Drug given/time i.e. 24 mg/hr, etc. |
|
|
Term
| What 2 processes are first order? |
|
Definition
1) Drug metabolism under ordinary circumstances
2) Renal Excretion |
|
|
Term
| Why is drug metabolism under normal circumstances a first order process? |
|
Definition
| The plasma concentrations of most metabolized drugs are typically below Km for the metabolic enzyme. |
|
|
Term
| How is renal excretion a first order process? |
|
Definition
| The amount of drug excreted is directly proportional to the plasma drug concentration assuming a constant number of liters are being filtered per time. |
|
|
Term
Why is elimination first order or zero order under normal conditions?
Why? |
|
Definition
| First Order since it's determined by hepatic metabolism and/or renal excretion - both of which are first order. |
|
|
Term
| Why is alcohol usually zero order elimination? |
|
Definition
| Amounts of EtOH ingested is in the gram range (as opposed to the mg grange) therefore saturating the metabolizing system so it operates at Vmax. |
|
|
Term
| When is Km of EtOH exceeded? |
|
Definition
| 3 beers or 3 oz of whiskey |
|
|
Term
| What is Vmax for EtOH elimination? |
|
Definition
| 9 g/hr (3/4 of one beer per hour) |
|
|
Term
| What is the graph test for a zero order process? |
|
Definition
| Straight-line behavior when concentration data is plotted on a normal (non0logarithmic) graph. |
|
|
Term
| What is the graphic test for first order processes? |
|
Definition
| Straight-line behavior when concentration data is plotted on a logarithmic graph. |
|
|
Term
| When in EtOH is first order behavior seen? |
|
Definition
| When blood levels are below 10 mg/dl. |
|
|
Term
| What in the rate of drug input is adjusted when there is incomplete absorption of metabolism of a drug? |
|
Definition
| Increase D & then multiply by f so that f(D) = amount of drug actually reaching the systemic circulation. |
|
|
Term
| What equation is used to determine elimination in 1st order kinetics? |
|
Definition
| Michaelis-Menten Equation |
|
|
Term
| What is the Michaelis-Menten Equation? |
|
Definition
|
|
Term
| What does the non-logarithmic plot of first order processes look like? |
|
Definition
|
|
Term
| When is elimination rate fastest? |
|
Definition
| Lg. amount of drug in the body. |
|
|
Term
|
Definition
| Time required for amount to decrease to ½ of the starting amount |
|
|
Term
| Are there half-lifes in zero order kinetics? |
|
Definition
|
|
Term
| What is assumed normal in a t½ value? |
|
Definition
| normal liver & kidney function |
|
|
Term
| What happens to t½ if there is kidney impairment? |
|
Definition
|
|
Term
| **What is the equation relating the first order elimination constant to t½? |
|
Definition
|
|
Term
| What does it mean that t½ & ke are inversely related? |
|
Definition
| As t½ increases, ke decreases & vice versa. |
|
|
Term
| What does ke help approximate? |
|
Definition
| The % of drug lost per unit of time. |
|
|
Term
| How is therapeutic dosing determined? |
|
Definition
| maximum plasma level below toxic, but above minimally effective level |
|
|
Term
| What is the equation used to maintain a constant concentration for a therapeutic steady state? |
|
Definition
| Csteady state = (f*dose)/(intervaldosing*clearance)
f=functional availability (bioavailability) |
|
|
Term
| What is the rate of drug output equation? |
|
Definition
| Rate of Drug Output = X ke
or = C*Vd*ke
X = amount of drug in the body |
|
|
Term
| What equation is used to estimate the total body amount of drug? |
|
Definition
X = C*Vd
C= blood concentration
Vd= Volume of Distribution |
|
|
Term
| What determines the amount of drug remaining from the previous day? |
|
Definition
|
|
Term
| When is steady state for drug accumulation achieved (aka plateau principle)? |
|
Definition
| When rate of input = rate of output. |
|
|
Term
| **What is the equation of steady state (input rate = output rate)? |
|
Definition
| f(D/T) = css*Vd*ke
or
f(D/T) = css*Vd*(0.7/t1/2)
or
f(D/T) = css*clearance
css= steady state avg. concentration |
|
|
Term
| How can amplitude of fluctuations in steady state be reduced? |
|
Definition
| Decreasing Dose & Dose Interval |
|
|
Term
| What completely removes the fluctuations of the steady state? |
|
Definition
|
|
Term
| What is the equation that approximates how long until steady state can be achieved? |
|
Definition
|
|
Term
| What controls accumulation kinetics? |
|
Definition
|
|
Term
| What is used when 4*t½ is too long of a time to achieve steady state? |
|
Definition
| Loading Dose - dose given to immediately achieve steady state concentration |
|
|
Term
| **What is the equation for Loading Dose? |
|
Definition
|
|
Term
| How is steady state maintained after a loading dose is administered? |
|
Definition
|
|
Term
| For saftey reasons, how are most Loading Doses given? |
|
Definition
|
|
Term
| Is loading dose dependent on elimination? |
|
Definition
|
|
Term
| **What is the equation for clearance? |
|
Definition
|
|
Term
| Does clearance apply to zero order processes? |
|
Definition
|
|
Term
| What is the equation of total body clearance? |
|
Definition
| CLtotal = Σ CLorgans that eliminate |
|
|
Term
| What is the equation for maintenance dose in steady state? |
|
Definition
| Dosemaintanence = CL*csteady state |
|
|
Term
|
Definition
1) Liver 160 mg/ml, Kidney 40 mg/ml
2) 180 mg/ml: 160 Liver, 20 Kidney |
|
|
Term
| How do we obtain an Area Under the Curve (AUC)? |
|
Definition
| Plotting plasma concentation-time curve on linear axes and integrating the area under the curve. |
|
|
Term
| How is clearance calculated using AUC? |
|
Definition
|
|
Term
| What is the equation for oral bioavailability? |
|
Definition
|
|
Term
| Drug V is administered at 4 x 1 mg tablets every 4 hours. t½ = 1 day. How long will it take the patient to reach steady state? |
|
Definition
|
|
Term
| Drug V is administered to another patient at 2 x 1 mg tablets every 4 hours. How long will it take for this patient to reach steady state? |
|
Definition
|
|
Term
| You decide that 4 days is too long to reach steady state for your patient. How much do you give your patient recieving 4 x 1 mg tablets every 4 hours? |
|
Definition
| 4 mg/4 hr = 24 mg/day
f(D/T) = css*Vd*ke
24 mg/day = css*Vd*(0.7/1 day)
34.3 mg = css*Vd = Loading Dose |
|
|
Term
Data for metoprolol"
Oral availability: 38%
Clearance: 63 L/hr/70kg
Vd: 290 L/70kg
t½ = 3.2 hr
Target Concentration: 25 ng/mL
What is the maintenance dosing rate? |
|
Definition
f(D/T) = css*CL
.38(D/T) = (25 ng/mL)*(63 L/hr/70kg)*(1000mL/L)*(mg/1000 µg)
(D/T) = 4.1 mg/hr or 100 mg/day |
|
|
Term
| Patient has been hospitalozed with cardiac arrythmia that has been treated using an IV infusion rate of 20 mg/hr of Drug X (t½ = 5 hr). Kidney problems change t½ to 10 hr. What will happen to the steady state blood level of the patient if they continue to recieve 20 mg/hr dosage? |
|
Definition
Steady state will double.
f(D/T) = css*Vd*(0.7/t½)
css = [f(D/T)*t½]/[Vd*0.7] so if t½ doubles, css doubles. |
|
|
Term
| If the therapeutic steady state level of Drug X is 100 µg/ml, and toxicity becomes evident at 150 µg/ml, how long from time of change in renal function will it take for signs of toxicity to manifest? |
|
Definition
10 hr (one half life).
Steady state increases from 100 to 200 µg/ml. Therefore in one half life (10 hr), the level increases to 150 µg/ml where signs of toxicity become evident. |
|
|
Term
| If the therapeutic steady state level of Drug X is 100 µg/ml, and toxicity becomes evident at 150 µg/ml. What happens to the level after 2 half-lives? |
|
Definition
|
|
Term
| Suppose that in the previous patient, the plasma level was at 200 µg/ml before the treating physician figured out that the t½ had doubled. How do we treat this patient to get the plasma level back to 100 µg/ml and then maintain the correct steady state? |
|
Definition
First, stop administering the drug. If we wait 1 half life of 10 hr, the drug concentration will be at 100 µg/ml.
To maintain this level, we must decrease the input rate from the original 20 µg/ml to half of that to compenstate for the doubling of the half life (i.e. 10 µg/ml). |
|
|
Term
| Why does decreased cardiac output affect hepatic metabolism? |
|
Definition
| decreased cardiac output => decreased hepatic blood flow. |
|
|
Term
| Which drugs are most affected by decreased cardiac output? |
|
Definition
| Those affected by first pass metabolism |
|
|
Term
| What are the 2 effects all drugs have? |
|
Definition
|
|
Term
| What increases the chance of a DDI? |
|
Definition
| The more medications a person is on |
|
|
Term
| Why is there no standard dose for all people? |
|
Definition
| People vary genetically, ht, wt, age, sex, body fat, etc. |
|
|
Term
| What age is drug metabolism rate low? |
|
Definition
| infants/neonates therefore infants should not be treated as small adults |
|
|
Term
| What age is a decline in renal function seen? |
|
Definition
|
|
Term
| Why is nephrotoxicity an issue with AMGs? |
|
Definition
| AMGs are renally eliminated, so toxic levels can be incurred if nephrotoxicity isn't monitored. |
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
Same as potentiation
3+4>7 |
|
|
Term
| What is used to test candidate compounds as potential drugs? |
|
Definition
| Population studies in animals & healthy human volunteers |
|
|
Term
|
Definition
| use matched grouped of animals or humans to study responses at various dose levels to determine tolerated doses & toxic doses |
|
|
Term
def
Phase II & III double-blinded clinical trials |
|
Definition
| measure effective and lethal doses (in animals) & efficacy (in humans). Responses are usually measured using a quantal response (all or nothing). |
|
|
Term
| What 2 curves can be plotted in a population study? |
|
Definition
| Effective Dose & Lethal Dose |
|
|
Term
|
Definition
| Effective Dose that 50% of participants will observe a quantal response. |
|
|
Term
|
Definition
| The lethal dose of 50% of the population |
|
|
Term
| How is the Therapeutic Index (TI) calculated? |
|
Definition
|
|
Term
| What does the TI tell us? |
|
Definition
Separation of dose from effect to toxicity.
Low TI = narrow window
Large TI = wide window |
|
|
Term
| What are the 4 problems with TI? |
|
Definition
| 1) Animals are used to avoid killing human patients => uncertain applicability
2) In human studies, toxic dose is used instead of lethal dose
3) ED50 isn't a realistic dose. ED99 would be better, but isn't possible in clinical trials.
4) ED & LD are assumed parallel, though not always true. |
|
|
Term
| What is the goal when designing a drug regimen? |
|
Definition
| Maintain drug concentration in therapeutic window. |
|
|
Term
| When is it necessary to monitor drug levels? |
|
Definition
| When there is significant toxicity whose threshold level is close to the therapeutic window, or in life-threatening situations where optimal plasma levels must be maintained. |
|
|
Term
| What must be done special while monitoring drugs that are highly bound to plasma proteins? |
|
Definition
| Ask lab to determine level of FREE drug, not bound, since free drug is what interacts to cause action. |
|
|
Term
| When monitoring drug levels, when should blood samples be taken? |
|
Definition
| At the trough, just before the next dose is administered. |
|
|
Term
|
Definition
the chemical alteration of xenobiotics within the body.
This may involve rearrangement of chemical bonds, incorporation or loss of atoms or molecules, or some combination. |
|
|
Term
|
Definition
| any compound normally foreign to living systems |
|
|
Term
| What 3 things can cause xenobiotic biotransformation? |
|
Definition
Enzymatic processes
Non-enzymatic processes
Rearrangements |
|
|
Term
| What usually metabolizes drugs and/or xenobiotics that are analogues of physiological substances? |
|
Definition
| Specific enzymes normally responsibile for the disposition of these compounds. |
|
|
Term
| What can metabolize drugs and/or xenobiotics that have no edogenous counterparts? |
|
Definition
| Enzyme systems that exhibit broad substrate specificity |
|
|
Term
| What are the 3 reasons drug biotransformation is necessary? |
|
Definition
1) Highly polar drugs are generally poorly absorbed & poorly transported across membranes.
2) Metabolism results in the transformation to more polar, hydrophilic compounds more readily excreted
3) Metabolic transformation facilitates elmination and may result in inactivation |
|
|
Term
| What is the principal organ of drug metabolism (tho nearly all tissues have some capacity)? |
|
Definition
|
|
Term
| What 4 "portals of entry" have significant capacity for drug metabolism? |
|
Definition
|
|
Term
| How much capacity for xenobiotic metabolism do the kidneys have? |
|
Definition
|
|
Term
| What 3 things contribute to the first pass effect restricting bioavailability of some oral drugs? |
|
Definition
1) Oral drugs absorbed from sm. intestine are transported to the liver via the portal system and extensively metabolized prior to systemic circulation.
2) With some drugs, extensive metabolism also occurs in the intestinal mucosa
3) To a lesser extent, microorganisms can also metabolize drugs and contribute to the first pass effect. |
|
|
Term
| What are the 3 subcellular localizations of drug-metabolizing enzymes? |
|
Definition
1) smooth ER
2) cytoplasm
3) mitochondria |
|
|
Term
| What occurs in Phase I metabolism? |
|
Definition
| Oxidation, Reduction, Hydrolysis => metabolite becomes more polar and possibily more readily excreted or ready for additional metabolism. |
|
|
Term
| What occurs in Phase II metabolism? |
|
Definition
| Conjugation of sm., endogenous substrate with functional groups already present on the drug or with those that are added/revealed by Phase I metabolism. |
|
|
Term
| What 2 compartments are P450s found in? |
|
Definition
|
|
Term
| Are P450s usually Phase I or Phase II metabolism enzymes? |
|
Definition
|
|
Term
|
Definition
| a system where a flavoprotein is coupled to a hemoprotein terminal oxidase |
|
|
Term
| What is the flavoprotein in the CYP450 system? |
|
Definition
| NADPH CYP450 oxidoreductase |
|
|
Term
| What is the hemoprotein terminal oxidase in the CYP450 system? |
|
Definition
|
|
Term
| What does the CYP450 system require as a source of reducing equivalents? |
|
Definition
|
|
Term
| What type of environment is the CYP450 system in? |
|
Definition
| lipid environment. (therefore a membrane protein) |
|
|
Term
| How is CYP450 identified? |
|
Definition
| Distinct optical spectrum, due to thiol ligan to heme moiety |
|
|
Term
| How many genes, gene families, & subfamilies are there of CYP450? |
|
Definition
>600 genes
18 human gene families
44 subfamilies |
|
|
Term
CYP450 Catalytic Cycle
[image] |
|
Definition
1) e-
2) O2
3) e-
4) H2O
5) [image] |
|
|
Term
| What is the nomenclature system regarding CYP450? |
|
Definition
CYP#Letter#
CYP - CYP450
1st # - Gene Family
Letter - Gene Subfamily
2nd # - Individual Gene |
|
|
Term
| What is the nomenclature for a P450 pasudogene? |
|
Definition
| P450 name followed by a P |
|
|
Term
|
Definition
| defective gene that doesn't produce a functional protein. |
|
|
Term
| How are psaudogenes formed? |
|
Definition
| As relics of gene duplications where one of the copies has degenerated and lost its function. |
|
|
Term
| Why are CYP450s capable of catalyzing a wide variety of monooxygenase reactions? |
|
Definition
| broad substrate specificity as individual proteins & as a super-family of enzymes. |
|
|
Term
| What are the 7 reactions cyp450 can do? |
|
Definition
1) Dealkylation & Deamination
2) Dehalogenation
3) Desulfuration
4) Epoxidation
5) Hydroxylation
6) N-oxidation
7) Sulfur oxidation |
|
|
Term
| What 2 types of molecules can P450 hydroxylate? |
|
Definition
Aliphatic (non-aromatic cyclic or acyclic)
Aromatic |
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
def
dealkylation and deamination |
|
Definition
| removal of an HX group or an amino group (-NH2), where X is OR, NR2, SR |
|
|
Term
|
Definition
| A) Hydroxylamines
R2NH -> R2N-OH
B) N-oxides
R2N -> R2N-O |
|
|
Term
|
Definition
|
|
Term
|
Definition
RX -> ROH
X = F, Cl, Br, I, At, Uus |
|
|
Term
|
Definition
|
|
Term
| Which CYP familes are involved in drug metabolism? |
|
Definition
|
|
Term
| Which CYP450 is involved in the biotransformation of almost all drugs? (also significant to poor bioavialability of drugs) |
|
Definition
|
|
Term
| What metabolism are the other CYP450 families important for? |
|
Definition
| Endogenous compunds s.a. setroids & FA |
|
|
Term
| What additional proteins are needed by Flavin-Containing monooxygenases (FMOs)? |
|
Definition
|
|
Term
| What monooxygenase reactions do FMOs catalyze? |
|
Definition
|
|
Term
| What do FMOs require that CYP450s also require? |
|
Definition
|
|
Term
| Where are FMOs localized in the cell? |
|
Definition
|
|
Term
| What do FMOs prefer to oxidize over hydroxyl amines & N-oxides? |
|
Definition
| oxidation of secondary & tertiary amines & S-oxidation |
|
|
Term
| How many FMO gene products are there in mammals? |
|
Definition
|
|
Term
| How are CYP450s & FMOs similar? |
|
Definition
1) ER localization
2) require NADPH
3) same overall rxn
4) broad substrate specificity
5) multigene family |
|
|
Term
| How are CYP450s & FMOs different? |
|
Definition
1) P450s are also in mitochondria
2) FMOs have no accessory protein
3) FMOs prefer oxidation of secondary & tertiary amines vs. primary amines
4) FMO catalyzes S-oxidation
5) FMOs have of 5 genes while P450 has >600
6) Catalytic cycle differences in order |
|
|
Term
| What can FMOs do to thiols? |
|
Definition
| form a S-S bridge to connect them |
|
|
Term
| What does FMO do to tertiary amines? |
|
Definition
|
|
Term
| What does FMO do to hydrazines? |
|
Definition
| forms 2 ractive intermediates |
|
|
Term
| What does FMO do to sulfides? |
|
Definition
|
|
Term
FMO Catalytic Cycle
[image] |
|
Definition
| 1) NADPH + H+
2) O2
3) OX (X is the xenobiotic substrate)
4) NADP+ + H2O |
|
|
Term
| What do the Phase II metabolism conjugation reactions involve? |
|
Definition
| High-energy intermediates & transferases |
|
|
Term
| How many steps are there to the glucuronidation pathway? |
|
Definition
|
|
Term
| What occurs in setps 1 & 2 in the glucuronidation pathway? |
|
Definition
| glucose activation/oxidation to UDPGA |
|
|
Term
| What occurs in step 3 of the glucuronidation pathway? |
|
Definition
|
|
Term
| What are the 4 glucuronides can be formed in glucuronidation pathway? |
|
Definition
| C-, O-, N-, S-glucuronidation |
|
|
Term
| How many steps are there in the Sulfate Conjugation Pathway? |
|
Definition
|
|
Term
| What occurs in steps 1 & 2 in the sulfate conjugation pathway? |
|
Definition
| sulfate activation of PAPS |
|
|
Term
| What occurs in step 3 of the sulfate conjugation pathway? |
|
Definition
|
|
Term
| What are the 2 elements that can sufate conjugate? |
|
Definition
|
|
Term
| How many steps are there in the Glutathione Conjugation Pathway? |
|
Definition
|
|
Term
| What are the 4 steps in the GSH Conjugation Pathway? |
|
Definition
1) GST (transferase)
2) GGT (gamma-glutamyl transpeptidase)
3) DP (dipeptidase)
4) NAT (n-acetyltransferase) |
|
|
Term
| What are 3 examples of gSh conjugation rxns? |
|
Definition
CDNB (removes Cl)
DEM (removes double bond)
epoxides (open ring)
-adds an SG |
|
|
Term
| What 3 factors affect drug metabolism? |
|
Definition
Induction
Inhibition
Genetic polymorphisms |
|
|
Term
| When might a person have increased de novo synthesis of CYP450? |
|
Definition
| exposure to certain drugs & environmental pollutants. |
|
|
Term
| What does increased CYP450 (induction) cause? |
|
Definition
| increased biotransformation & therefore decrease in the availability of drug, possibly increased toxicity (if metabolized active). |
|
|
Term
| How does CYP induction occur thru the pregnane X receptor (PXR)? |
|
Definition
| nuclear receptor-mediated signal transduction |
|
|
Term
| What occurs as a result to inhibition of drug biotransformation enzymes? |
|
Definition
| elevated levels of the parent drug, prolonged effects, increased toxicity |
|
|
Term
| Due to genetics, how are people classified based on their metabolic capacity? |
|
Definition
|
|
Term
| Which metabolism category puts a patient at a higher risk for adverse effects? |
|
Definition
|
|
Term
def
Pharmacogenetics/Pharmacogenomics |
|
Definition
| the study of genetically controlled variations in drug response, and includes both genetic polymorphisms & rare genetic defects that alter an individual's drug response |
|
|
Term
|
Definition
| a Mendelian or monogenetic trait that exists in the population in at least 2 phenotypes, neither of which is rare |
|
|
Term
|
Definition
| an organism's observable characteristics or traits |
|
|
Term
|
Definition
| the genetic makeup of a cell, an organism, or an individual |
|
|
Term
def
extensive (fast) metabolism |
|
Definition
| phenotype of persons that metabolize substances quickly |
|
|
Term
def
Poor (slow) metabolizer |
|
Definition
| phenotype of persons that metabolize substances slowly |
|
|
Term
def
SNPs (single nucleotide polymorphism) |
|
Definition
a DNA sequence variation occurring when a single nucleotide — A, T, C or G — in the genome differs between members of a biological species or paired chromosomes in an individual.
variant sequence has a frequency of at least 1% in the population |
|
|
Term
|
Definition
a DNA sequence variation occurring when a single nucleotide — A, T, C or G — in the genome differs between members of a biological species or paired chromosomes in an individual.
variant sequence has a frequency of less than 1% in the population |
|
|
Term
| What are the 3 patterns of genetic polymorphisms? |
|
Definition
Additive
Autosomal Recessive
Austosomal Dominant |
|
|
Term
| What pattern of genetic polymorphism is most common? |
|
Definition
|
|
Term
def
Additive (Co-dominant) |
|
Definition
There is no domination of one allele over the other.
AA - Dark skin
Aa - Tan skin
aa - White skin
(an example only, not for real) |
|
|
Term
|
Definition
Normal allele dominates over mutant allele
AA - black skin
Aa - black skin
aa - white skin
(example only, not for real) |
|
|
Term
|
Definition
mutant allele dominates over normal allele
AA - black skin
Aa - white skin
aa - white skin
(example only, not for real) |
|
|
Term
| What cytosolic enzyme is affected by acetylation polymorphism? |
|
Definition
| N-acetyltransferase-2 (NAT2) |
|
|
Term
| What cytosolic enzyme is affected by acetylation polymorphism? |
|
Definition
| N-acetyltransferase-2 (NAT2) |
|
|
Term
| What 2 enzymes catalyze acetylation? |
|
Definition
|
|
Term
|
Definition
| Yes (originally thought not) |
|
|
Term
| What does NAT2 catalyze acetylation of? |
|
Definition
| lg. # of drugs & environmental chemicals s.a. procainamine, caffeine, and 4-aminobiphenyl (bladder carcinogen) |
|
|
Term
| Is there ethnic variation in regards to acetylation polymorphism? |
|
Definition
| considerable variation. Slow acetylators accounting for <10% to >90% in certain groups |
|
|
Term
| What 3 clinically important consequences are associated with slow acetylation? |
|
Definition
1) more prone to polyneuropathy during isoniazid treatment
2) more likely to develop hemolytic anemia in sulfa drug Tx
3) higher incidence of bladder cancer in those exposed to arylamine carcinogens |
|
|
Term
| What do fast acetylators need to achieve a desired effect? |
|
Definition
|
|
Term
| What controls human acetylation polymorphism? |
|
Definition
| 4 major alleles at a single autosomal gene locus on chromosome 8 |
|
|
Term
| How many of the 4 alleles controlling human acetylation polymorphism encode for slow activity? |
|
Definition
|
|
Term
| Is fast or slow activity dominant in acetylation? |
|
Definition
|
|
Term
| Since fast acitivity is dominant, how many slow alleles must a person have to be a slow acetylator? |
|
Definition
|
|
Term
|
Definition
|
|
Term
| What metabolizes isomiazid? |
|
Definition
|
|
Term
|
Definition
|
|
Term
| What is the dose required of debrisoquine to lower bp? |
|
Definition
| variable throughout the population |
|
|
Term
| Why is there variation in debrisoquine metabolism? |
|
Definition
| variation in the ability to hydroxylate debrisoquine to 4-hydroxydebrisoquine |
|
|
Term
| What metabolizes debrisoquine? |
|
Definition
|
|
Term
| What is the population frequency for debrisoquine metabolism? |
|
Definition
| bimodal: extensive or poor |
|
|
Term
| What is the phenotypic variation among ethnic groups for debrisoquine metabolizers? |
|
Definition
| Poor metabolizers: as high as 12% in Caucasians or as low as 1% in Arabic populations |
|
|
Term
| Do poor or extensive metabolizers of debrisoquine have higher plasma concentrations of debrisoquine? |
|
Definition
|
|
Term
| What controls hydroxylation of debrisoquine? |
|
Definition
| 2 alleles at a single autosomal gene locus on chromosome 22 |
|
|
Term
| What alleles have been identified in poor metabolizers of debrisoquine? |
|
Definition
|
|
Term
| What is noted about CYP2D6 levels in poor metabolizers of debrisoquine? |
|
Definition
|
|
Term
| Why are genetic differences in CYP2D6 importanat? |
|
Definition
| a number of drugs are metabolized by this enzyme |
|
|
Term
| When is CYP2D6 polymorphism clinically important? |
|
Definition
1) drug metabolized by it
2) widely used drug
3) narrow therapeutic window |
|
|
Term
|
Definition
|
|
Term
| Why is ADH polymorphism important? |
|
Definition
| Each ADH allele encodes for a different isoenzyme. Each isoenzyme has it's own kinetic properties which all vary greatly in Km & Vmax |
|
|
Term
| What 2 enzymes are needed in methyl conjugation? |
|
Definition
| thiomethyltransferase & thiopurine methyltransferase |
|
|
Term
| What drugs are methy transferases important in metabolizing? |
|
Definition
|
|
Term
| What happens if there's decreased methyltrasferase activity while using chemotherapeutic agents s.a. 6-mercaptopurine & azathiopurine? |
|
Definition
| drug induced myelosuppression |
|
|
Term
|
Definition
|
|
Term
| Is poor metabolism of mephenytoin recessive, dominant, or co-dominant? |
|
Definition
|
|
Term
| What ethnic group is at an increased risk for poor mephenytoin metabolism? |
|
Definition
|
|
Term
| What enzyme is responsible for mephenytoin hydroxylation? |
|
Definition
|
|
Term
|
Definition
| catalyzes oxidation of polycyclic hydrocarbon |
|
|
Term
| What are substrates for CYP1A1? |
|
Definition
| environmental toxins, potential carcinogens, & certain drugs |
|
|
Term
| What determines genetically controlled variability of CYP1A1? |
|
Definition
| variation in inducibility of AHH activity |
|
|
Term
| What does AHH activity induction require? |
|
Definition
| intracellular receptor protein, Ah receptor |
|
|
Term
| What determines the presence of the Ah receptor? |
|
Definition
| polymorphism at the Ah locus |
|
|
Term
| What happens once the inducing agent binds to the Ah cytosolic receptor? |
|
Definition
| inducer-receptor complex gains chromatin-binding properties & binds to regulatory elements upstream of CYP1A1 on chromosome 15 |
|
|
Term
| What does the inducer-receptor complex binding of regulatory elements upstream of CYP1A1 on chromosome 15 do? |
|
Definition
| activation of gene transcription & induction of CYP1A1 |
|
|
Term
| Is CYP1A1 induction also bimodal? |
|
Definition
|
|
Term
| What explains the interindividual susceptibility to potential carcinogens & other environmental pollutants that have been associated with cancer risk? |
|
Definition
| the differences in induction od CYP1A1 |
|
|
Term
|
Definition
| Aryl Hydrocarbon Hydroxylase |
|
|
Term
| What is the most common DNA sequence variations? |
|
Definition
|
|
Term
| Are SNPs more stable than repeated sequences? |
|
Definition
| yes (therefore have lower mutation rate) |
|
|
Term
| How often in the human genome as bases polymorphic? |
|
Definition
| 1/100 bases (40-200 SNPs) |
|
|
Term
| How have SNPs been used to etimate tribal migration & divergence of wthnic groups? |
|
Definition
| SNPs have been found to segregate together |
|
|
Term
| What are the 2 main classes of cells in the nervous system? |
|
Definition
|
|
Term
| Are there more glia or nerve cells? |
|
Definition
|
|
Term
| What are the 2 subcategories of glia cells? |
|
Definition
|
|
Term
| What 3 cells are considered macroglia? |
|
Definition
1) oligodendrocytes
2) Schwann cells
3) astrocytes |
|
|
Term
Function
Oligodendrocytes & Schwann cells |
|
Definition
| produce myelin & insulate never cell axons (saltatory conduction) |
|
|
Term
|
Definition
| act as scavengers - remove debris after cell death |
|
|
Term
| How do glial cells promote signaling b/w neurons? |
|
Definition
| accumulating or metabolizing neurotransmitters |
|
|
Term
|
Definition
1) guide migrating neurons
2) neuronal progenitors in some brain regions (hippocampus) |
|
|
Term
| What cells regulate the properties of the presynaptic terminal at the nerve-muscle synapse? |
|
Definition
|
|
Term
|
Definition
|
|
Term
| What do glial cells synthesize & release for neuronal survival? |
|
Definition
|
|
Term
| What 3 physical supports do glial cells have? |
|
Definition
1) neuron support
2) structure to brain
3) separate & insulate neuronal groups/synaptic connections |
|
|
Term
| What are the main signaling units of the nervous system? |
|
Definition
|
|
Term
| What are the 4 parts of a neuron? |
|
Definition
1) cell body (soma)
2) dendrites
3) axon
4) presynaptic terminals |
|
|
Term
|
Definition
| metabolic center containing nucleus & ER |
|
|
Term
|
Definition
| tree-like processes with extensive arborization to recieve incoming signals |
|
|
Term
| What receptors are available on dendrites? |
|
Definition
| ionotropic neurotransmitter receptors (glutamatergic) & voltage gated Ca2+ channels |
|
|
Term
|
Definition
| recieve signal & propagate electrical signal to the soma |
|
|
Term
|
Definition
| output unit for the neuron |
|
|
Term
|
Definition
|
|
Term
| What receptors do axons use to convey action potentials? |
|
Definition
| voltage-gated Na+ channels |
|
|
Term
| Where are action potentials initialized? |
|
Definition
|
|
Term
| Where are presynaptic terminals found on a neuron? |
|
Definition
| at the end of the dividing branches of the axon |
|
|
Term
Function
presynaptic terminals of the neuron |
|
Definition
| "classical" neurotransmitter biosynthesis (package to synaptic vesicles & exocytosis) |
|
|
Term
| How do neurons connect with eachother? |
|
Definition
|
|
Term
| What parts of the 2 neurons can be synaptically connected? |
|
Definition
1) axo-dendritic
2) axo-somatic
3) axo-axonic |
|
|
Term
| Why is it important to understand the steps involved in synaptic transmission? |
|
Definition
| each of these steps can be targeted for pharmocological intervention |
|
|
Term
| How many steps are involved in synaptic transmission? |
|
Definition
|
|
Term
Synaptic transmission
Step 1 |
|
Definition
| Neuron synthesizes neurotransmitter from precursor & stores in vesicles |
|
|
Term
Synaptic transmission
Step 2 |
|
Definition
| Action potential travels down axon & depolarizes pre-synaptic nerve terminal |
|
|
Term
Synaptic transmission
Step 3 |
|
Definition
| Membrane depolarization activates voltage-dependent Ca2+ channels => Ca2+ to enter pre-synaptic nerve terminal |
|
|
Term
Synaptic transmission
Step 4 |
|
Definition
| Increased cytosolic Ca2+ => vesicle fusion with plasma membrane => neutrotransmitter release to synaptic cleft |
|
|
Term
Synaptic transmission
Step 5 |
|
Definition
Neurotransmitter crosses synaptic cleft & binds to:
1) ionotropic receptors => change in permeability or membrane potential
or
2)metabotropic receptors => cascade to activate other ion channels |
|
|
Term
Synaptic transmission
Step 6 |
|
Definition
Signal termination via:
1) degrading transmitter via enzymes in cleft
or
2) transmitter recycled to presynaptic cell by reuptake transporters |
|
|
Term
Synaptic transmission
Step 7 (continuation of 6) |
|
Definition
| Signal termination also via enzymes that degrade post-synaptic cell signaling molecule |
|
|
Term
|
Definition
| 1)Neurotransmitter synthesized & packaged
2) action potential down axon
3) Ca2+ channels activated my membrane depolarization
4) increased Ca2+ => vesicle fusion => neurotransmitter release to synaptic cleft
5)Neurotransmitter binds to:
a) ionotropic receptor => Δ permeability & membrane potential
b) metabotropic receptor => cascade => Δ permeability
6)Signal termination by:
a) enzyme degradation in synaptic cleft
b) recyled via reuptake transporters in presynaptic cell
7)Signal termination via enzymes degrading postsynaptic signaling molecules |
|
|
Term
| What are the 2 borad categories of small molecule neurtransmitters? |
|
Definition
1) aa (amino acids)
2) biogenic amines |
|
|
Term
Function
aa as neurotransmitters |
|
Definition
| primary excitatory & inhibitory neurotransmitters in CNS |
|
|
Term
Function
biogenic amines as neurotransmitters |
|
Definition
| primary modulatory neurotransmitters in CNS |
|
|
Term
| What neurotransmitter structural category (aa or biogenic amines) do Ach, adenosine, NO, & peptide neurotransmitters fall into? |
|
Definition
|
|
Term
| How is NO an atypical neurotransmitter? |
|
Definition
| made on demand & released by diffusion (not by synaptic vesicles) |
|
|
Term
| Where are peptide neurotransmitters of hte brain typically found? |
|
Definition
| co-localized with classical neurotransmitters |
|
|
Term
| How are peptide neurotransmitters synthesized? |
|
Definition
| from large precursors & cleaved via specific proteases |
|
|
Term
| Where in the nerve are peptide neurotransmitters synthesized? |
|
Definition
| In the soma & are transported down the axon |
|
|
Term
| Which aa do most neurons in the brain use as the neurotransmitter to mediate fast excitatory synaptic transmission? |
|
Definition
|
|
Term
| How does glu mediate fast synaptic transmission? |
|
Definition
| activating ligand gated ion channels (ionotropic receptors) of AMPA & NMDA |
|
|
Term
| What happens when glu activated the ionotropic receptors? |
|
Definition
| depolarize membrane via Na+ & Ca2+ passage down electrochemical gradients |
|
|
Term
| What receptors mediate inhibitory neurotransmission? |
|
Definition
| GABA or glycine activation of other ionotropic receptors |
|
|
Term
| How do GABA & glycine mediate inhibitory neurotransmission? |
|
Definition
| hyperpolarize the membrane via movement of Cl- down its gradient |
|
|
Term
| What determines the output of a neuron? |
|
Definition
| The sum of its inhibitory & excitatory parts |
|
|
Term
Function
metabotropic G protein-coupled receptors |
|
Definition
| modulating the properties of the neurons themselves => modulates hoe they integrade fast synaptic activity |
|
|
Term
|
Definition
| heterotrimeric proteins that couple receptor activation with various effector mechanisms |
|
|
Term
| What mediates the actions of G protein coupled receptors? |
|
Definition
| a variety of second messanger systems s.a. cAMP-PKA system. |
|
|
Term
| What in the properties of the second messenger systems allows for pharmalogical intervention at numerous places? |
|
Definition
| the biological complexity within the signaling pathway |
|
|
Term
| How can G protein coupled receptors add additional layers of complexity? |
|
Definition
| Same neurotransmitter interacts with multiple metabotropic receptors that have different second messanger affects |
|
|
Term
| What happens when you stimulate Gαs?
Gαq?
Gαi/o? |
|
Definition
| Gαs: increased AC
Gαq: increased PLCβ
Gαi/o: decreased AC |
|
|
Term
| What G receptor do β adrenergic receptors stimulate? |
|
Definition
|
|
Term
| What G receptor do α1 adrenergic receptors stimulate? |
|
Definition
|
|
Term
| What G receptor do α2 adrenergic receptors stimulate? |
|
Definition
|
|
Term
| What G receptor do D1 & D5 DA receptors stimulate? |
|
Definition
|
|
Term
| What G receptor do D2, D3, & 4 DA receptors stimulate? |
|
Definition
|
|
Term
| What G receptor do M1, M3, & M5 muscarinic acetylcholine receptors stimulate? |
|
Definition
|
|
Term
| What G receptor do M2 & M4 muscarinic acetylcholine receptors stimulate? |
|
Definition
|
|
Term
| What 2 neurotransmitters can function as fast neurotransmitters & slow neuromodulatory neurotransmitters? |
|
Definition
|
|
Term
| What 2 receptor types are stimulated by Glu? |
|
Definition
| ionotropic & metabotropic |
|
|
Term
| What 2 recptor types are stimulated by Ach? |
|
Definition
|
|
Term
|
Definition
| ligand gated ion channels at neuromuscular juntion |
|
|
Term
|
Definition
| G protein coupled receptors |
|
|
Term
| What are the 5 monoamine small molecule neurotransmitters? |
|
Definition
1) DA
2) Epi
3) NE
4) Serotonin
5) Histamine |
|
|
Term
| What are the 2 drug targets for monoamines? |
|
Definition
1) Vesicular storage
2) Reuptake/Catabolism |
|
|
Term
| How are catecholamines synthesized? |
|
Definition
Tyr => L-Dopa => DA => NE => Epi
(True Love Does Not Exist) |
|
|
Term
| What are the 4 enzymes needed in catecholamine synthesis? |
|
Definition
1) Tyrosine hydroxylase
2) Decarboxylase
3) DA β Hydroxylase
4) PNMT |
|
|
Term
| What do many psychoactive drugs taret? |
|
Definition
| G protein coupled receptors directly |
|
|
Term
| Where do sympathetic preganglionic neurons arise from? |
|
Definition
| thoracic & lumbar segments of the SC |
|
|
Term
| Where do sympathetic preganglionic neurons project to? |
|
Definition
| postganglionic neurons in ganglia near the SC |
|
|
Term
| Where do the parasympathetic ganglia generally lie? |
|
Definition
| close to organs they innervate |
|
|
Term
| Where do parasympathetic preganglionic neurons arise from? |
|
Definition
| nuclei in the branstem & sacral segments of SC |
|
|
Term
| Are parasympathetic preganglionic generally long or short? |
|
Definition
|
|
Term
| Do parasympathetics generally project onto long or short postganglionic neurons? |
|
Definition
|
|
Term
| What are the primary neurotransmitters of DRG? |
|
Definition
| Glu, substance P, peptides |
|
|
Term
| What are the primary neurotransmitters of somatic motor neurons? |
|
Definition
|
|
Term
| What are the primary neurotransmitters of the preganglionic neuron? |
|
Definition
|
|
Term
| What are the primary neurotransmitters of the postganglionic neuron? |
|
Definition
|
|
Term
| What are the 3 major organizational motifs of the CNS cellular organization? |
|
Definition
1) Long-tract neurons
2) Local circuit neurons
3) Single-source divergent neurons |
|
|
Term
Function
Long-tract neurons |
|
Definition
| act as relay b/w periphery & higher CNS |
|
|
Term
| Where do long-tract neurons recieve their signal from? |
|
Definition
| convergent signals from many different neurons |
|
|
Term
| Where do long-tract neurons synapse? |
|
Definition
| divergent signal on many downstream neurons |
|
|
Term
Function
Local circuit neurons |
|
Definition
|
|
Term
| What is the local ciruit neuronal structure? |
|
Definition
| complex, arranged in layers, with inhibitory & excitatory neurons |
|
|
Term
Function
Single source divergent neurons |
|
Definition
| innervate thousands of neurons (usually in cerebral cortex) |
|
|
Term
| Where do signle-source neurons typically originate from? |
|
Definition
|
|
Term
| Where do dopaminergic single source divergent neurons arise from? |
|
Definition
| substantia nigra & ventral tegmental area |
|
|
Term
| Where do dopaminergic single source divergent neurons project to? |
|
Definition
Substantia Nigra => Striatum
Ventral Tegmental Area => cerebral cortex |
|
|
Term
Function
dopaminergic single source divergent neurons |
|
Definition
| initiation of movement & brain reward pathway |
|
|
Term
| Where do cholinergic single source divergent neurons arise from? |
|
Definition
| nucleus basalis, peduculopontine nucleus, & medial septal nuclei |
|
|
Term
| Where do cholinergic single source divergent neurons project to? |
|
Definition
| widely throughout the brain |
|
|
Term
Function
cholinergic single source divergent neurons |
|
Definition
| maintain sleep-wake cycle & regulate sensory transmission |
|
|
Term
| Where do noradrenergic single source divergent neurons arise from? |
|
Definition
|
|
Term
| What do the noradrenergic single source divergent neurons innervate? |
|
Definition
|
|
Term
Function
noradrenergic single source divergent neurons |
|
Definition
|
|
Term
| Where do serotonergic single source divergent neurons arise from? |
|
Definition
|
|
Term
| Where do serotonergic single source divergent neurons project to? |
|
Definition
| diencephalon, basal ganglia, and via the basal forebrain to the cerebral hemispheres, cerebellum, & SC |
|
|
Term
Function
serotonergic single source divergent neurons |
|
Definition
|
|
Term
| What are the 2 major divisions of the efferent portion of the nervous system? |
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
| unconscious innervated structures of periphery |
|
|
Term
| Where does control of the somatic nervous system originate? |
|
Definition
| mortox cortex via corticospinal tracts |
|
|
Term
| Where do all synapses of the somatic nervous system occur? |
|
Definition
| within CNS (therefore motor neurons run from CNS to skeletal muscles uninterrupted) |
|
|
Term
| Are somatic motor neurons usually myelinated or unmyelinated? |
|
Definition
|
|
Term
| That is the neurotransmitter for skeletal muscle? |
|
Definition
|
|
Term
| What happens to skeletal muscles if their innervation is lost? |
|
Definition
|
|
Term
| Where does control of the autonomic nervous system originate? |
|
Definition
| hypothalamous, limbic system, & brain stem that integrate at the peripheral ganglia b/w CNS & neuroeffector junction. |
|
|
Term
| What happens to smooth muscles & glands in the absence of functional autonomic innervation? |
|
Definition
|
|
Term
| What are the 2 major portions of the autonomic nervous system? |
|
Definition
Parasympathetic
Sympathetic |
|
|
Term
| What is the PS comprised of? |
|
Definition
| autonomic output of the cranial nerves & sacral portion of the SC |
|
|
Term
| What is the neurotransmitter at all ganglionic & neuroeffector junctions of the PS? |
|
Definition
|
|
Term
| What is the SS comprised of? |
|
Definition
| autonomic output of the thoracic & lumbar portions of the SC |
|
|
Term
| When is Ach the neurotransmitter in SS? |
|
Definition
| sympathetic ganglia, adrenal medulla, & few sympathetic neuroeffector junctions |
|
|
Term
| What is the neurotransmitter dominant at the neuroeffector junctions of the SS? |
|
Definition
|
|
Term
Which of the autonomic system is "rest & digest"?
"fight or flight"? |
|
Definition
|
|
Term
| What could be regarded at the 3rd component of the ANS? |
|
Definition
|
|
Term
| Where is the enteric nervous system found? |
|
Definition
|
|
Term
| What modulates the intrinsic activity of the enteric nervous system? |
|
Definition
|
|
Term
| What outputs does the enteric nervous system have? |
|
Definition
| cholinergic & NANC (non-adrenergic, noncholinergic) |
|
|
Term
| What are the primary neurotransmitters of the enteric nervous system? |
|
Definition
| peptides, purines, & other substances (NO) |
|
|
Term
| What do peptides, purines, & other substances function as in cholinergic & adrenergic neurons? |
|
Definition
|
|
Term
|
Definition
| any neuron in CNS or periphery that liberates Ach as it's transmitter |
|
|
Term
| What is the primary signal for all neurons leaving the CNS? |
|
Definition
|
|
Term
| What receptor type do all Ach originating from CNS synapse on initially? |
|
Definition
|
|
Term
| When are muscarinic Ach receptors used? |
|
Definition
| In SS sweat glands & PS AFTER they initially synapse on a nictotinic Ach receptor |
|
|
Term
| Where is Ach synthesized? |
|
Definition
| cytoplasm of cholinergic nerve terminals |
|
|
Term
| What 2 substrates are used to form Ach? |
|
Definition
|
|
Term
| What enzyme catalyzes Ach synthesis? |
|
Definition
| ChAT (choline acetyltransferase) |
|
|
Term
| Where is ChAT synthesized? |
|
Definition
| cell body of neuron & transported down axon |
|
|
Term
| Why is the rate of Ach synthesis dependent on choline? |
|
Definition
| aceytl CoA is produced via mitochondria in the nerve, choline is selectively pumped into the nerve. |
|
|
Term
| What amine type is choline? |
|
Definition
|
|
Term
|
Definition
| contents of a single vesicle of Ach |
|
|
Term
| How does Ach end up in vesicles? |
|
Definition
| packaged into vesicles in nerve terminal |
|
|
Term
| What singals Ach vesicles to fuse with the membrane & be relesed to synapse? |
|
Definition
| Terminal becomes excited by action potential => Ca2+ channels activated => Ca2+ influx |
|
|
Term
| What can effect Ca2+-dependent Ach release? |
|
Definition
| Any Ca2+ antagonist interfering with permeability of Ca2+ |
|
|
Term
def
MEPP (mini end plate potential) |
|
Definition
| Sm. transient depolarization of the motor end plate via spontaneous release of individual quanta NOT cauing an AP |
|
|
Term
| Why are graded responses in Ach release needed in the heart, visceral organs, or glandular tissue? |
|
Definition
1) Single AP doesn't provide maximal response
2) released Ach must diffuse more widely due to less organized neuromuscular junction |
|
|
Term
| What is the postsynaptic cholinoreceptor for Ach? |
|
Definition
|
|
Term
| What enzyme degrades Ach? |
|
Definition
| AChE (acetylcholinesterase) |
|
|
Term
| What does the cholinergic mediated response depend on? |
|
Definition
| Ach binding postsynaptic AchR |
|
|
Term
| How do presynaptic receptors play a role in neurotransmission? |
|
Definition
|
|
Term
|
Definition
| By effects of agonists (muscarine & nicotine) & effects of antagonists (atropine & s-tubocurarine) |
|
|
Term
| What does the flexibility of Ach allow it to bind to? |
|
Definition
|
|
Term
| What does the flexibility of Ach allow it to bind to? |
|
Definition
|
|
Term
| What on all cholinoreceptors allows the + charged Ach to orient over the binding site? |
|
Definition
|
|
Term
| Why do Ach analogs tend to have preference over receptor type/subtype? |
|
Definition
|
|
Term
What stimulates muscarinic receptors (mAch)?
What blocks mAch? |
|
Definition
Stimulates: Ach
Blocks: atropine |
|
|
Term
|
Definition
| alkaloid isolated from Amanita muscaria mushroom |
|
|
Term
| What 5 locations does muscarine mimic Ach? |
|
Definition
1) visceral smooth muscle GI, LUT, uterus, bronchi
2) heart/vasculature
3) secondary glands
4) CNS
5) autonomic ganglia (primary cholinoreceptor is nicotinic, tho) |
|
|
Term
|
Definition
| an alkaloid from the leaves of atopine belladonna |
|
|
Term
|
Definition
| all cholinoreceptors that are activated by muscarine & blocked by atropine. They traverse the membrane 7 times. |
|
|
Term
|
Definition
|
|
Term
|
Definition
| mAchR predominant in the heart |
|
|
Term
|
Definition
| mAchR predominant in secretory signals |
|
|
Term
|
Definition
| a liquid alkalois isolated from tobacco |
|
|
Term
| What are the 4 cholinoreceptor sites where nicotine acts as an agonist? |
|
Definition
1) Neuromuscular junction of somatic muscles
2) all autonomic ganglia on dendrites of post-ganglionic neurons
3) CNS
4) adrenal medulla |
|
|
Term
| What happens when nictotine binds to AchR in low concentrations? |
|
Definition
| stimulation followed by recovery |
|
|
Term
| What happens when nictotine binds to AchR in high concentrations? |
|
Definition
| stimulation followed by depression |
|
|
Term
| What causes the depression seen in high nicotine concentrations after stimulation? |
|
Definition
| sustained depolarization of receptor membrane due to ionic channels being kept open |
|
|
Term
def
depolarization blockade |
|
Definition
| effect of large nicotine cocentrations |
|
|
Term
| What blocks the stimulatory action of nicotine? |
|
Definition
|
|
Term
|
Definition
|
|
Term
def
nicotinic AchR (nAchR) |
|
Definition
cholinoreceptor stimulated by nicotine & blocked by d-turbocurarine
They are pentameric complexes that span the membrane several times. |
|
|
Term
| What are mAchR coupled with to transduce signals & cellular responses? |
|
Definition
|
|
Term
| Which mAchR's are coupled through Gi? |
|
Definition
|
|
Term
|
Definition
| increased K+ conductance => inhibitory to cellular activity
decreased cAMP => decreased AC |
|
|
Term
| What are the 3 subunits of the G protein? |
|
Definition
|
|
Term
| What subunit of G protein is responsible for it's function? |
|
Definition
|
|
Term
| When does the G protein α subunits dissociate from the βγ subunits? |
|
Definition
|
|
Term
| When does G protein α subunit rejoin βγ subunits? |
|
Definition
| After GTP hydolyzed to GDP by α subunit |
|
|
Term
| Which mAchR's are coupled through Gq? |
|
Definition
| Odd mAchR's (M1, M3, & M5) |
|
|
Term
|
Definition
| increase cytosolic calcium => stimulatory to cellular activity
(via phospolipase C activation => conversion of PIP2 to PIPG3 & DAG => intracellular stroage release of calcium) |
|
|
Term
| What is formed when nictotinic receptors are bound to agonists? |
|
Definition
| conformational change to a poor allowing Na+, K+, & Ca2+ permeability |
|
|
Term
| Why is it possible to selectively block nitotinic receptors either at autonomic ganglia or neuromuscular junction? |
|
Definition
| Though both nAchR's, there are subtle differences at the binding sites. |
|
|
Term
| Why does synaptically released Ach have a very short half life? |
|
Definition
| presence of cholinesterases |
|
|
Term
|
Definition
| hydrolyze ester linkage of Ach => choline & acetic acid |
|
|
Term
|
Definition
| cholinergic/effector cell membranes & RBC membranes |
|
|
Term
| Why is AchE so rapid to degrade Ach? |
|
Definition
| to limit duration of action of Ach at cholinergic junctions |
|
|
Term
| Where are pseudocholinesterases found? |
|
Definition
|
|
Term
Function
pseudocholinesterases |
|
Definition
| less selective hydrolyzation of esters |
|
|
Term
| Why is Ach relatively ineffective as a drug? |
|
Definition
| it's rapidly metabolized in plasma |
|
|
Term
| What are the 2 primary sites that Ach interacts contained on AchE? |
|
Definition
| anionic site & esteratic site |
|
|
Term
| What attracts the Ach to AchE? |
|
Definition
| the (-) charge of anionic site draws in the (+) charge of quaternary amine of Ach => orients Ach over esteratic site for ester link hydrolysis |
|
|
Term
| What releases choline from Ach in AchE? |
|
Definition
| enzyme transfer of acetyl group to serine residue |
|
|
Term
| What causes acetic acid release from AchE after choline leaves? |
|
Definition
|
|
Term
| What happens to the free choline after Ach breakdown by AchE? |
|
Definition
| pumped back into nerve terminal or diffused away |
|
|
Term
| What are the common pre-synaptic AchR's? |
|
Definition
|
|
Term
|
Definition
| regulate evoked release of Ach (feedback inhibition) i.e. prevent excessive Ach release |
|
|
Term
| Why can low doses of atropine produce a paradoxical bradycardia? |
|
Definition
| presynaptic AchR's = mAchR's. mAchR's are blocked by atropine => less feedback inhibition of presynaptic Ach release |
|
|
Term
Function
presynaptic nAchR at neuromuscular junction |
|
Definition
| stimulatory for Ach release to maintain Ach release during periods of intense neuromuscular transmission |
|
|
Term
Pharmacologic sites of action at cholinergic synapses
[image]
|
|
Definition
| 1) Ach synthesis
2) Ach storage
3) Prevent nerve terminal activation
4) Interfer with Ca2+ influx to nerve terminal via Ca2+ antagonists (NOT Ca2+ channel blockers)
5) Exocytosis modification
6) AchR Action
7) AchE inhibition |
|
|
Term
| How do drugs affect Ach synthesis? |
|
Definition
| Inhibit the rate-limiting step (choline uptake to nerve terminal) |
|
|
Term
| How do drugs affect Ach storage? |
|
Definition
| Prevent Ach packaging into secretory vesicle |
|
|
Term
|
Definition
| blocks rate-limiting step of Ach synthesis |
|
|
Term
|
Definition
| Inhibit Ach vesicle formation |
|
|
Term
| What can prevent activation of nerve terminal? |
|
Definition
|
|
Term
| What interfers with Ca2+ influx to nerve terminal? |
|
Definition
| hypermagnesia (or other Ca2+ antagonists, NOT Ca2+ channel blockers) |
|
|
Term
| What inhibits Ach exocytosis? |
|
Definition
|
|
Term
| What activated Ach exocytosis? |
|
Definition
|
|
Term
|
Definition
| agents that occupy cholinesterase Ach binding sites |
|
|
Term
def
reversible indirect Ach agonist |
|
Definition
indirect Ach agonist agents metabolized or removed from binding site within minutes-hours
or they are simple, competitive inhibitors of Ach binding |
|
|
Term
def
irreversible indirect Ach agonist |
|
Definition
| indirect Ach agonist agents that have stable covalent binding to esterases & remain on the AchE receptor for hours-days |
|
|
Term
| What is an example of an irreversible indirect Ach agonist? |
|
Definition
|
|
Term
| Patient has primary axillary hyperhydrosis (excessive sweating) that has not responded to topical treatment. What agent may be appropriate for this patient. |
|
Definition
|
|
Term
| When can botox be used pharmacologically? |
|
Definition
| strabismus, torticollis, wrinkles, possibly migranes |
|
|
Term
|
Definition
|
|
Term
| What competitively blocks mAchR's? |
|
Definition
|
|
Term
| What are muscarinic receptors couple with to produce downstream effects? |
|
Definition
|
|
Term
| Which mAchR's couple with Gq? |
|
Definition
|
|
Term
| Which mAchR's couple with Gi? |
|
Definition
|
|
Term
| Effect
mAchR activation of Gq? |
|
Definition
| increase cytosolic calcium => stimulatory |
|
|
Term
| Effect
mAchR activation of Gi? |
|
Definition
| increase potassium conductance & decrease AC => inhibitory |
|
|
Term
| Do muscarinic agents (agonist & antagonist) show selectivity for mAchR's? |
|
Definition
|
|
Term
| What is muscarinic activity of the CNS associated with? |
|
Definition
|
|
Term
| What account for the majority of CNS agonists? |
|
Definition
| quaternary amines that don't cross the BBB |
|
|
Term
| What is the prototype anti-muscarinic drug? |
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
| delirium, hallucinations,coma, death |
|
|
Term
| What are the 3 ways aropine is administered? |
|
Definition
| PO, parenterally, topically |
|
|
Term
|
Definition
| natural alkaloid (from Atropa belladonna- same as atropine) |
|
|
Term
| Why is scopolamine given thru an adhesive patch for motion sickness? |
|
Definition
| topical absorption is very effective |
|
|
Term
| What metabolizes both atropine & scopolamine? |
|
Definition
|
|
Term
| How are atropine & scopolamine both excreted? |
|
Definition
|
|
Term
MOA
atropine & scopolamine |
|
Definition
| competitive antagonists of mAchR |
|
|
Term
| How is scopolamine different from atropine in effects? |
|
Definition
| produces 100x greater CNS depression => anxiolytic, hypnotic, anti-motion sickness, & amnestic effects |
|
|
Term
| What mediates atropine & scopolamine effects on CNS? |
|
Definition
| their muscarinic blocking action at cholinoceptive sites in brainstem & cortex |
|
|
Term
| How were the amnestic effects of scopolamine used as an advantage? |
|
Definition
| In preoperative medication or childbirth |
|
|
Term
| Is delirium & hallucinations also seen with scopolamine? |
|
Definition
| yes, but unlike atropine where it's only seen in toxic levels, they can be seen at therapeutic dose levels with scopolamine |
|
|
Term
| What is atropine used for clinically? |
|
Definition
| alleviate motor Sx of Parkinson's |
|
|
Term
| What synthetic muscarinic antagonist is used to alleviate Parkinson's Sx? |
|
Definition
| Benztropine (you Park your Benz) |
|
|
Term
|
Definition
|
|
Term
| What are the atropine SE? (think mnemonic) |
|
Definition
Red as a beet
Dry as a bone
Blind as a bat
Mad as a hatter
Hot as a hare |
|
|
Term
| What autonomic innervation does the eye recieve? |
|
Definition
|
|
Term
| What is controlled by the PS in the eye? |
|
Definition
1) sphincter pupillae of iris
2) ciliary muscle controling lens shape |
|
|
Term
What of the PS in the eye are mAchR agonist therapeutic targets?
mAchR antagonist therapeutic targets? |
|
Definition
agonist: sphincter pupillae of iris
antagonist: ciliary muscle of lens |
|
|
Term
| What synthetic mAchR agonist is used to cause miosis? |
|
Definition
|
|
Term
|
Definition
|
|
Term
| Can Carbamylcholine bind only to mAchR? |
|
Definition
| no, it can also bind nAchR |
|
|
Term
| Why is Carbamylcholine only employed as a topical mitoic agent? |
|
Definition
| too much of a widespread activity |
|
|
Term
| What is special about Carbamylcholine? |
|
Definition
Not broken down by cholinesterases
(note: is this done by something else, or does this lead to a long lasting effect?) |
|
|
Term
| What in the eye is controlled by SS? |
|
Definition
| radially oriented fibers of the iris |
|
|
Term
| When PS & SS of the iris are stimulated, what occurs? |
|
Definition
| both cause contraction => opposition to eachother |
|
|
Term
Effect
mAchR agonist in the eye |
|
Definition
|
|
Term
| How can mAchR agonists in glaucoma cause reduced intraocular pressure? |
|
Definition
| enhance drainage of intraocular fluid via canal of Schlemm |
|
|
Term
| What natural teritary amine is used for topical glaucoma miotic effect? |
|
Definition
|
|
Term
| Which AchR do pilocarpine work on? |
|
Definition
|
|
Term
| Why might pilocarpine be used to treat salivary disfunction or dry mouth? |
|
Definition
|
|
Term
Effect
mAchR antagonist in the eye |
|
Definition
|
|
Term
| Why isn't atropine used for mydriasis? |
|
Definition
|
|
Term
| What topical mAchR antagonist is shorter-acting and therefore more suitable for mydriasis effect? |
|
Definition
|
|
Term
|
Definition
|
|
Term
Effect
Contraction of lens ciliary muscle |
|
Definition
| increase lens convexity => focus of near objects |
|
|
Term
| What do cholinergic agonists do to vision focusing? |
|
Definition
|
|
Term
| What do cholinergic antagonists do to vision focusing? |
|
Definition
|
|
Term
| Why is atropine not given in glaucoma? |
|
Definition
| can lead to dangerous increase of pressure in the eye |
|
|
Term
|
Definition
| paralysis of ciliary muscle by mAchR antagonist => blurred near vision (focus in distance only) |
|
|
Term
| What is the typical SE of tropicamide? |
|
Definition
|
|
Term
| What mAchR receptors does the heart possess that decreased cellular activity when stimulated? |
|
Definition
|
|
Term
| Where is muscarinic action on the heart directed? |
|
Definition
|
|
Term
| What does M2 activation in the heart do? |
|
Definition
1) slows HR
2) decreased force of contraction
3) suppresses AV conduction |
|
|
Term
| What major effects does Ach have on atrial pacemaker cells? |
|
Definition
| 1) AP => shortened due to increased K+ permeability, or threshold may not even be met.
2) diastolic depolarization phases of cycle => steeper slope caused by hyperpolarization |
|
|
Term
| What causes the negative ionotropic action of Ach on atrial tissue? |
|
Definition
| shortened AP duration since it shortens the release & influx of Ca2+ => weaker contraction |
|
|
Term
| When are vascular Ach responses the most prominent pharmacological effect? |
|
Definition
|
|
Term
| What mAchR receptors are avilable in vasculature? |
|
Definition
|
|
Term
Effect
mAchR binding in vasculature |
|
Definition
|
|
Term
| When the M3 is bound in the blood vessel, what does the increase in incracellular calcium cause? |
|
Definition
| EDRF (endothelial-derived relaxing factor) to be realeased & diffuse to smooth muscle |
|
|
Term
|
Definition
|
|
Term
| How is EDRF (NO) derived? |
|
Definition
| calcium stimulated NO synthase |
|
|
Term
| What happens to BP & HR when mAchR is activated in vasculature? |
|
Definition
| decreased BP w/ reflex tachycardia |
|
|
Term
| When are Ach effects ONLY seen in the vasculature? |
|
Definition
| low doese IV administration (since Ach is metabolized so quickly in the plasma) |
|
|
Term
| Is reflex tachycardia seen in low dose Ach IV administration? |
|
Definition
| yes, due to dilation of the blood vessels |
|
|
Term
| What happens when high does of Ach is administered IV? |
|
Definition
| cardiac depression through Ach action on M2 receptors |
|
|
Term
| What happens if you give extra high IV dose of Ach? |
|
Definition
| Complex results due to cadiac stimulation via SS nAchR => NE release |
|
|
Term
| Why would cardiac stimulation be prominant if atropine is given prior to Ach administration? |
|
Definition
| mAchR are blocked, but nAchR are not. The only nAchR's not coupled with mAchR's are SS => cardiac stimulation |
|
|
Term
| Why does atropine, if administered alone, typically produce prominent tachycardia, but have no effect on BP? |
|
Definition
| BP is regulated by factors outside of AchR and atropine would have no effect on them. |
|
|
Term
| Why does atropine cause skin to become red, warm, & dry? |
|
Definition
Redness is due to vasodilation via reflex mechanism
Warm & dry is due to the blocking of sweat |
|
|
Term
| Why is atropine toxicity more likely to cause death in young children? |
|
Definition
| They are less capable to handle hyperthermic effects |
|
|
Term
| Why is atropine given after a MI? |
|
Definition
| to treat sinus bradycardia |
|
|
Term
| What effect does mAchR agonists have on GI smooth muscle from lower esophagus to rectum? |
|
Definition
| increased tone & motility |
|
|
Term
| What are the only muscles in the GI that relax due to mAchR agonists? |
|
Definition
| sphincter muscles (except lower esophageal sphicter which contracts) |
|
|
Term
| Which mAchR's mediate GI Ach effect? |
|
Definition
|
|
Term
|
Definition
| synthetic quaternary amine |
|
|
Term
|
Definition
| Tx of GI or urinary stasis, esp. post-partum or post-op. |
|
|
Term
| How is bethanechol similar to Carbamylcholine? |
|
Definition
| not metabolized by cholinesterases (or pseudocholinesterases) |
|
|
Term
| Why can't you give bethanechol when there's a mechanical GI or urinary obstruction? |
|
Definition
| will caused increased pressure of the lumen and may cause perforation |
|
|
Term
| What AchR do bethanechol work on? |
|
Definition
|
|
Term
| Why may atropine be used to treat mild diarrhea? |
|
Definition
|
|
Term
| Why was atropine previously used to treat peptic ulcer/gastric reflux? |
|
Definition
| contriction on esophogeal sphincter & decrease in HCl secretion of stomach |
|
|
Term
| Why shouldn't atropine be used to treat peptic ulcer? |
|
Definition
| decreased GI motility will keep acids in the stomach, even tho will slow some HCl secretion |
|
|
Term
|
Definition
|
|
Term
|
Definition
| spasmolytic of GI (decrease spasms) => hypermotility Tx |
|
|
Term
| Would atropine or propantheline be DOC for GI hypermotility? |
|
Definition
| propantheline b/c its a quaternary amine (they're better in GI, biliary, & urinary spasm Tx) |
|
|
Term
| What muscle of the bladder is stimulated by mAchR to faciliate urination? |
|
Definition
|
|
Term
Effect
mAchR antagonist on bladder |
|
Definition
|
|
Term
| What direct mAchR agonist is used to promote micturation (urination)? |
|
Definition
|
|
Term
| What indicrect mAchR agonist (i.e. AchE inhibitor) is also selective for promoting micturation (& GI motility)? |
|
Definition
|
|
Term
| What atropine SE are men with prostatic hyperplasia particularly sensitive to? |
|
Definition
|
|
Term
| What 2 mAchR antagonist variants are specifically for urge incontinence & post-op bladder spasms? |
|
Definition
|
|
Term
| What metabolizes oxybutynin? |
|
Definition
|
|
Term
| What metabolizes Tolterodine? |
|
Definition
|
|
Term
Structure
Oxybutynin & Toterodine |
|
Definition
|
|
Term
Effect
mAchR agonists on uterus |
|
Definition
| very sm. increase in tone/contractions |
|
|
Term
Effect
mAchR agonist in lung |
|
Definition
| bronchiolar smooth muscle contraction |
|
|
Term
| What mAchR receptors are in the lungs? |
|
Definition
|
|
Term
| What patients are especially sensitive to bronchiolar constriction of mAchR agonists? |
|
Definition
|
|
Term
|
Definition
| synthetic quaternary amine |
|
|
Term
| What mAchR's do methacholine show preference for? |
|
Definition
|
|
Term
| What is methacholine used for? |
|
Definition
Perviously: tachycardia
Currently: Aerosol form for Dx of bronchial airway hyper-reactivity in subclinical asthma |
|
|
Term
| Why does methacholine have a longer duration of action than Ach? |
|
Definition
| not metabolized by pseudocholinesterase & slowly degraded by AchE |
|
|
Term
| Why was atropine formerly smoked as afolk remedy? |
|
Definition
| mAchR antagonist => bronchial dilation |
|
|
Term
| What mAchR antagonist structure is preferred to cause bronchial dilation? |
|
Definition
|
|
Term
| What 2 quarternary amines are administered via aerosol to Tx emphysema & chronic bronchitis? |
|
Definition
1) ipratropium
2) tiotropium |
|
|
Term
| How is tiotropium different from ipratropium? |
|
Definition
| longer half-life & less antagonistic activity on M2 receptors |
|
|
Term
Effect
mAchR agonists on glands |
|
Definition
|
|
Term
| Why are mAchR agonists used to treat dry mouth? |
|
Definition
| increase salivary secretion |
|
|
Term
| What mAchR agonist (previously discussed) is used for salivary & sweat gland stimulation? |
|
Definition
|
|
Term
| What recently approved synthetic mAchR agonist is also used for Tx of dry mouth? |
|
Definition
|
|
Term
| What mAchR receptors does cevimeline show selectivity for? |
|
Definition
|
|
Term
| What metabolizes cevimeline? |
|
Definition
|
|
Term
| Why was atropine formerly used in preanesthetic medication? |
|
Definition
| eliminate the increased secretions associated with their irritant actions |
|
|
Term
| Patient was brought to ER after hallucinations & then collapsing while drinking a gin & tonic prepared by husband. Exam reveals non-responsive 45 yo woman with flushed appearance, dilated pupils, & absence of bowel sounds. What is the source of her intoxication? |
|
Definition
|
|
Term
|
Definition
| naturally occuring alkaloid, lipid-soluble teritary amine |
|
|
Term
| Since it's lipid soluble, where in a pregnany woman is nicotine found? |
|
Definition
across the placenta, in milk secretion
(plus throughout the body, including CNS) |
|
|
Term
| Why can nicotine activation lead to depolarizing blockade? |
|
Definition
|
|
Term
|
Definition
1) intense autonomic stimulatio thru ganglia
2) CNS excitation with convulsions followed by depression
2) eventual skeletal muscle paralysis |
|
|
Term
| When is nicotine used pharmacologically? |
|
Definition
1) Tx of nicotine withdrawl
2) Improved cognition in Alzheimer's patients
3) Reduce Parkinson's incidence |
|
|
Term
| What allows for selective nAchR therapeutic manipulation? |
|
Definition
| different nicotinic subtypes at different locales |
|
|
Term
| What drug was the first partial nAchR agonist to be approved by FDA? |
|
Definition
|
|
Term
|
Definition
| aid in smoking cessasion by reducing pleasurable effects & cravings for tobacco |
|
|
Term
| Where is varenicline eliminated? |
|
Definition
|
|
Term
|
Definition
| negative neuropsychiatric SE |
|
|
Term
| Patient is an African American 48 yo male experiencing irritability & insomnia. Formerly a heavy smoker (2 packs/day) but quit "cold turkey." Vital signs: tachycardia & hypertension. PE shows patient to be anxious & sweating. What is the basis for his complaint? How could he be treated. |
|
Definition
Undergoing nicotine withdrawl
Could be given nictotine or varenicline |
|
|
Term
| Why are nAchR at the nmj given agonists as an adjunct to general anesthesia? |
|
Definition
| to produce controlled skeletal muscle relaxation |
|
|
Term
| Why would nAchR agonists be given in mechanical ventillation, electroconvulsive therapy, or during an endoscopy? |
|
Definition
MV: suppress endogenous breathing
ECT: suppress muscle contractions
E: facilitate intubation |
|
|
Term
| What are the 2 drug classification of skeletal muscle blocking drugs? |
|
Definition
1) Competitive antagonists
2) Depolarizing blockers (agonists) |
|
|
Term
Function
nAchR competitive agents |
|
Definition
| act as competitive antagonists at the nAchR on the motor end plate |
|
|
Term
Effect
nAchR competitive antagonist |
|
Definition
| reduce number of available nAchR for Ach to interact with => less responsive to nerve released Ach |
|
|
Term
| What are nAchR competitive antagonists competitive with? |
|
Definition
|
|
Term
| What can reverse the block caused my nAchR competitive antagonists? |
|
Definition
| increased amounts of Ach in synaptic cleft |
|
|
Term
| What can be used to increase Ach in the synpatic cleft to override nAchR competitive antagonists? |
|
Definition
anticholinesterase drugs
tetanic stimulation of motor nerves |
|
|
Term
| What 2 anticholinesterases can be used to increase Ach in the synpatic cleft to override nAchR competitive antagonists? (may be needed to reverse blockade when prolonged effects are delaying post-op recovery) |
|
Definition
|
|
Term
| Why is atropine often given prior to neostigmine when it's employed for blockade reversal? |
|
Definition
| nAchR are the receptors needing unblocked, so when Ach is increased, we don't want extra stimulation of mAchR, thus atropine block. |
|
|
Term
| How do AMG antibiotics affect nAchR competitive antagonists? |
|
Definition
| Lead to longer paralysis since AMG reduces cytosolic calcium. |
|
|
Term
Structure
d-turbocurine (curare) |
|
Definition
| naturally occuring alkaloid |
|
|
Term
| What is the most common SE in d-TC? |
|
Definition
| BP drop, but gradual recovery by 10 min. |
|
|
Term
| What causes the Bp drop in d-TC use? |
|
Definition
1) autonomic ganglionic blockade => decreased SS tone to vasculature
2) release of histamine from mast cells by direct action => decreased vascular resistance |
|
|
Term
|
Definition
|
|
Term
| Where is d-TC metabolized/excreted? |
|
Definition
metabolized - liver
excreted - kidney (40% unchanged excretion) |
|
|
Term
| What synthetic agent is a potent isomer of former agent atracurium? |
|
Definition
|
|
Term
| Why does the nAchR competitive agonist cisatracurium have only mild hypotensive action? |
|
Definition
|
|
Term
| How is cisatracurium inactivated? |
|
Definition
|
|
Term
| Why can cistracurium be safely used in hepatic and renal failure patients? |
|
Definition
| not totally dependent on renal or hepatic excretion (since spontaneous breakdown & short half life) |
|
|
Term
What breakdown product of cisatracurium can cross the BBB?
Why? |
|
Definition
| laudanosine - it's lipid soluble |
|
|
Term
| Why has cisatracurium (the cis isomer of atracurium) replaced atracurium? |
|
Definition
| more potent therefore less drug is needed => less laudanosine produced |
|
|
Term
| What nAchR competitive antagonist is selective for nmj & has a long duration of action? |
|
Definition
doxacurium
(no longer used) |
|
|
Term
| What nAchR competitive antagonist has the shortest duration of action? |
|
Definition
Mivacurium
(no longer used) |
|
|
Term
| What are the 3 steroid-based nAchR competitive antagonists? |
|
Definition
1) Pancuronium
2) Vecuronium
3) Rocuronium |
|
|
Term
| Which steriod-based nAchR competitive antagonist has a long duration & is eliminated by the kidneys? |
|
Definition
|
|
Term
| Which steroid-based nAchR competitive antagonist has the fastest onset? |
|
Definition
|
|
Term
| How is vercuronium different from pancuronium? |
|
Definition
| intermediate duration of action & eliminated by liver to bile |
|
|
Term
| Why does pancuronium produce tachycardia? |
|
Definition
| has some additional antagonistic activity at M2 receptors |
|
|
Term
| How is rocuronium eliminated? |
|
Definition
|
|
Term
| What 6 things can potentiate the competitive nmj blocking agents? |
|
Definition
1) general anesthetics
2) AMG
3) electrolyte imbalance
4) polypeptide Abx
5) advanced age
6) pathologies |
|
|
Term
| What is the nAchR depolarizaing blocking agent? |
|
Definition
|
|
Term
| Where is succinylcholine a long-lasting agonist? |
|
Definition
| nmj (some rapid onset & very short duration at most AchR) |
|
|
Term
| What metabolizes succinylcholine? |
|
Definition
|
|
Term
| What is succinylcholine metabolized to? |
|
Definition
|
|
Term
What happens if a patient is heteozygous for atypical pseudocholinesterases?
homozygous? |
|
Definition
heterozygous: degrade succinylcholine slowly
homozygous: unable to hydrolyze succiylcholine at all => renal excretion becomes only route of drug termination |
|
|
Term
| How is biodegradation of succinylcholine resumed to normal in patients homo- or hetero- zygous for atypical pseudocholinesterases? |
|
Definition
| administration of plasma containing normal pseudocholinesterases |
|
|
Term
| Why aren't BP changes detected in succinylcholine administration? |
|
Definition
1) histimine released => BP change
2) mild ganglionic stimulation => mask of histamine effect |
|
|
Term
| Why can succinylcholine lead to cardiac arrest? |
|
Definition
| it can produce significant release of potassium into blood (hyperkalemia) |
|
|
Term
| When is succinylcholine usually administered? |
|
Definition
| to assist in intubation after anesthesia via relaxing of the laryngeal muscles |
|
|
Term
| Why is succinylcholine only used in emergency situations of intubation need in children? |
|
Definition
| reports of cardiac arrest |
|
|
Term
|
Definition
| potent nAchR agonist at nmj => sustained binding since metabolism occurs at nmj. This leads to 2 phases on pharmacologic response |
|
|
Term
| When can succinylcholine cause phase I depolarizing blockade? |
|
Definition
| single dose/short infusion |
|
|
Term
| When can succinylcholine cause phase II? |
|
Definition
| longer infusions or re-administered in frequent intervals => sustained paralysis |
|
|
Term
| When does phase I nicotinic nmj junction with polarizing agents occur? |
|
Definition
| within seconds following IV administration |
|
|
Term
| What is phase I nicotinic nmj junction with polarizing agents |
|
Definition
| gradual depolarization of the motor end plate |
|
|
Term
| What is phase I nicotinic nmj junction with polarizing agents |
|
Definition
| gradual depolarization of the motor end plate |
|
|
Term
| What does succinycholine do to cause motor end plate depolarization? |
|
Definition
| opens Na+ & K+ channels as Ach opens them as well, but succinylcholine causes slower distribution to the synapse => membrane potential decreases past threshold => Ach threshold is blocked (therefore blockage of nmj) |
|
|
Term
| What causes muscle fasiculations in upper thorax, limnbs & neck after succinylcholine amdinistration? |
|
Definition
| direct action on motor end plate occuring asynchronously as each fiber reaches threshold as it's depolarized |
|
|
Term
| How are fasciculations avoided in succinylcholine use? |
|
Definition
| Prior treatment with low-dose non-depolarizing agent s.a. rocuronium (but then increased doses of succinylcholine will be needed) |
|
|
Term
| What would intensify phase I deploarizing blockade? |
|
Definition
1) stimulation of motor nerves
2) administration of neostimine or edrophonoium
(i.e. further reduction of membrane potential) |
|
|
Term
| What is the pharmacological antagonist for phase I depolarizing blockade? |
|
Definition
|
|
Term
| How is succinylcholine overdose treated? |
|
Definition
| ventilation breathing supposrt until effects wear off |
|
|
Term
| What happens to the membrane potential in phase II blockade? |
|
Definition
| repolarizes, though transmission failure still present |
|
|
Term
| How does phase II blockade resemble competitive antagonism? |
|
Definition
| tetanic stimulation of motor nerve will result in improved but weak muscular contractions & tone |
|
|
Term
| What will neostigmine or endrophonium do during phase II bloackade? |
|
Definition
| breathing & normal tonus can be partially restored |
|
|
Term
|
Definition
unclear
may be due to block of channel pore by drug or due to gradual accumulation of metabolite of succinylcholine that may act as a competitive antagonist |
|
|
Term
| Why is phase II associated with mixed/dual blockade? |
|
Definition
| not all end plates reach phase II at the same time |
|
|
Term
Structure
all skeletal muscle relaxants |
|
Definition
|
|
Term
| How must all skeletal muscle relaxants be administered? |
|
Definition
| parenterally (usually IV) |
|
|
Term
| Do skeletal muscle relaxants cross the BBB? |
|
Definition
|
|
Term
| Why is use of nAchR nmj blockage by itself during surgery unethical? |
|
Definition
| they provide no anesthetic effect |
|
|
Term
| What are the 5 most sensitive muscles in decending order (most to least) to nAchR nmj blockage? |
|
Definition
1) digits
2) neck & limbs
3) abdomen
4) thorax
5) diaphragm |
|
|
Term
| How are nAchR nmj relaxant agents chosen? |
|
Definition
| duration of action & safety |
|
|
Term
| Which 2 nAchR muscle relaxants are long duration? |
|
Definition
|
|
Term
| Which nAchR muscle relaxant has massive histamine realease? |
|
Definition
|
|
Term
| What 3 nAchR muscle relaxants have no histamine release? |
|
Definition
Pancuronium
Rocuronium
Vercuronium |
|
|
Term
| Which 2 nAchR muscle relaxants have no significant adverse effects? |
|
Definition
|
|
Term
| Which nAchR muscle relaxant causes hyperkalemia? |
|
Definition
|
|
Term
| What nAchR muscle relaxant causes CNS excitement? |
|
Definition
|
|
Term
| Which nAchR muscle relaxant causes tachycardia? |
|
Definition
|
|
Term
| Which nAchR muscle relaxant causes weak ganglionic blockade? |
|
Definition
|
|
Term
| How are the effects of skeletal muscle relaxants monitored? |
|
Definition
| transdermal stimulation of nerves to hand & record evoked twitches |
|
|
Term
| Which 2 nAchR muscle relaxants have rapid onset? |
|
Definition
Rocuronium
Succinylcholine |
|
|
Term
| Which nAchR muscle relaxant has a very short duration of action? |
|
Definition
|
|
Term
| What nAchR muscle relaxant is eliminated by spontaneous breakdown? |
|
Definition
|
|
Term
| Which nAchR muscle relaxant is eliminated by pseudochoinesterase? |
|
Definition
|
|
Term
| What 2 nAchR muscle relaxants are eliminated mostly by liver/bile? |
|
Definition
|
|
Term
| What 3 nAchR muscle relaxants have intermediate duration of action? |
|
Definition
Cisatracurium
Rocuronium
Vercuronium |
|
|
Term
| What 2 nAchR muscle relaxants have small histadine release? |
|
Definition
Cisatracurium
succinylcholine |
|
|
Term
| What 2 nAchR muscle relaxants are mainly eliminated by the kidney? |
|
Definition
|
|
Term
| 7 yo girl has been admitted thru ER with intense abdominal pain & vomiting. PE reveals RLQ tenderness. Abdominal ultrasonography is consistent with appendicitis. Which skeletal muscle relaxant would be appropriate as an adjunct to general anethesia? |
|
Definition
| Any except succinylcholine (don't give to children) |
|
|
Term
| What are the non-cholinergic muscle relaxant? |
|
Definition
|
|
Term
|
Definition
| blocks Ca2+ from sarcoplasma reticulum of skeletal muscle |
|
|
Term
| What are 2 uses of dantolene? |
|
Definition
1) spasticity type diseases
2) as an adjunct to anesthesia to treat malignant hyperthermia since no effect on Ach release |
|
|
Term
| What are the 3 components of the membrane potential change from postganglionic cell bodies? |
|
Definition
1) rapid short-duration spike - EPSP (excitatory post synaptic potential)
2) hyperpolarization -IPSP (inhibitory post synaptic potential)
3) 1+ slower EPSPs of low magnitude |
|
|
Term
| What component of the membrane potential change of postganglionic cell bodies is responsible for ganglionic transmission by inducing depolarization to fire APs? |
|
Definition
|
|
Term
| What mediates the first high EPSP? |
|
Definition
|
|
Term
| What 2 drugs can block the first EPSP? |
|
Definition
|
|
Term
|
Definition
Several mechanisms:
1) DA released from accessory cells
2) Ach stimulation of M2 receptors |
|
|
Term
|
Definition
| control/prevent excessive neurotransmission thru the ganglia |
|
|
Term
| What mediates the slower later EPSPs? |
|
Definition
| M1 receptors & peptide co-transmitter receptors |
|
|
Term
Receptor Affecting Peak/Low
[image] |
|
Definition
1) N
2) M2
3) M1 & Peptides |
|
|
Term
| What were the first effective drugs to treat hypertension? |
|
Definition
| ganglionic blocking drugs |
|
|
Term
| What is a classic ganglionic blocker that is effective in HTN treatment? |
|
Definition
| hexamethonium (not really used) |
|
|
Term
| What autonomic transmission is blocked by ganglionic blockers? |
|
Definition
|
|
Term
| What SE is particularly marked in ganglionic blockers? |
|
Definition
|
|
Term
| Why aren't ganglionic blockers used reeally anymore in anti-HTN Tx? |
|
Definition
| newer agents that are more selective |
|
|
Term
| What is the only ganglionic blocker still on the market? |
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
| block access for Ach to active site on AchE |
|
|
Term
|
Definition
| precent breakdown of Ach => magnifying Ach response |
|
|
Term
| What must be intact & functional for anticholinesterases to work? |
|
Definition
|
|
Term
| What are the 3 classes of anticholinesterases? |
|
Definition
|
|
Term
def
reversible anticholinesterase |
|
Definition
| agents that bind non-covalently to AchE active site or are slowly hydrolyzed by AchE => temporary inhibition |
|
|
Term
def
irreversible anticholinesterase |
|
Definition
| agents that form extremely stable covalent bonds with AchE esteratic site with long half lives (hours to days) => prolonged duration of action => sustained actions of Ach release |
|
|
Term
| What are the 8 reversible anticholinesterases? |
|
Definition
1) physostigmine
2) neostigmine
3) pyridostigmine
4) endrophonium
5) donepezil
6) tacrine
7) rivastigmine
8) galantamine |
|
|
Term
| What are the 4 irreversible anticholinesterases? |
|
Definition
1) echothiophate
2) malathion
3) parathion
4) sarin |
|
|
Term
|
Definition
| irreversible anticholinesterases |
|
|
Term
| Which 2 reversible anticholinesterases are hydolyzed slowly by AchE? |
|
Definition
|
|
Term
|
Definition
|
|
Term
| Fo what AchR does physostigmine act on it's AchE? |
|
Definition
|
|
Term
| What is the clinical use of physostigma? |
|
Definition
|
|
Term
|
Definition
|
|
Term
| What metabolizes physostigmine? |
|
Definition
| ester hydrolysis in plasma |
|
|
Term
Structure
Neostigmine & pyridostigmine |
|
Definition
| synthetic quaternary amines |
|
|
Term
Function
neostigmine & pyridostigmine |
|
Definition
AchE inhibitor
agonist for nAchR (due to charged amine) |
|
|
Term
| Though anticholinesterases need functional release of Ach to function, why would neostigmine (&pyridostigmine) still have some function (though muted)? |
|
Definition
|
|
Term
| Due to it's charged form, what are neostigmine & pyridostigmine used to treat? |
|
Definition
|
|
Term
| Does neostigmine have CNS effect? |
|
Definition
| No sicne it's a quarternary amine |
|
|
Term
| What are the clinical applications of neostigmine? |
|
Definition
1) augment GI/UT motility
2) reverse skeletal muscle blockade by competitive antagonists
3) Tx of myasthenia gravis |
|
|
Term
| What metabolizes neostigmine? |
|
Definition
|
|
Term
| Why does seostigmine need large oral does compared to parenteral dosage? |
|
Definition
|
|
Term
|
Definition
| skeletal muscle weakness that gradually becomes more intense thru the day & thru the years => eventually life threatening |
|
|
Term
|
Definition
| autoimmune disease where AB occupy nAchR on motor end plate |
|
|
Term
| How do anticholinesterases help myasthenia gravis patients? |
|
Definition
| improve strength of contraction |
|
|
Term
|
Definition
| synthetic quaternary amine |
|
|
Term
| What is the duration of action for edrophonium? |
|
Definition
|
|
Term
| How is edrophonium used clinically? |
|
Definition
| Dx of myasthenia gravis (excercise til muscle weakness present then administer edrophonium, if +, muscle stregth will resume for 5 min) |
|
|
Term
| How does pyridostigmine differ from neostigmine? |
|
Definition
| longer duration of action |
|
|
Term
| Why may a myasthenic patient become weaker during course of anticholinesterase therapy? |
|
Definition
1) exacerbation of disease
2) inadequate blood levels of anticholinesterase agent (myasthenic weakness)
3) overdose/toxic level (cholinergic crisis) |
|
|
Term
| What causes cholinergic crisis? |
|
Definition
| motor end plate is excessively stimulated by accumulating Ach & by direct action of neostigmine on motor end plast nAchR => membrane resting potential to be depolarized beyond threshold => depolarizing blockade & muscle weakness |
|
|
Term
| What will antagonize the muscle weakness in cholinergic crisis? |
|
Definition
| nerve stimulation or cholinergic agonist |
|
|
Term
| What is given to differentiate myasthenic weakness from cholinergic crisis? |
|
Definition
|
|
Term
| What effets would be seen by edorphonium in myasthenic weakness vs. cholinergic crisis? |
|
Definition
MW: improved muscle contraction
CC: intensified muscle weakness |
|
|
Term
| Why is edrophonium given over any other anticholinesterase to test b/w myasthenic weakness & cholinergic crisis? |
|
Definition
|
|
Term
| When might a person with myathenia gravis not benefit from anticholinesterase Tx? |
|
Definition
| If they are among the unlucky who have congenital mutations in nAchR |
|
|
Term
| Which anticholinesterase has FDA approval for prophylaxis against nerve gas exposure? |
|
Definition
|
|
Term
| What 4 anticholinesterases are used in Alzheimer's Tx? |
|
Definition
Donepezil
Tacrine
Rivastigmine
Galantamine
(Don'T foRGet) |
|
|
Term
| Why isn't tacrine used anymore? |
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
longer duration => once daily dosing
milder SE w/o hepatotoxicity |
|
|
Term
| What metabolizes donepezil? |
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
| slow metabolism by cholinesterase & less DDI |
|
|
Term
|
Definition
| synthetic teritary alkaloid |
|
|
Term
| What Alzheimer drug is NOT a anticholinesterase? |
|
Definition
|
|
Term
|
Definition
|
|
Term
| Why are irreversible anticholinesterase referred to as organophosphates? |
|
Definition
| they all contain a reactive phosphate group & some organic substitution |
|
|
Term
| When are irreversible anticholinesterase actually irreversible (i.e. no slow hydrolysis)? |
|
Definition
| if organic radical is an isopropyl substitution |
|
|
Term
| Why are organophosphids well absorbed through mucous membranes & skin? |
|
Definition
|
|
Term
| What is the only irreversible anticholinesterase used medically today? |
|
Definition
|
|
Term
| Why is echothiophate considered atypical? |
|
Definition
| polar & stable in aqueous solution |
|
|
Term
Effect
topical irreversible anticholinesterase on eye |
|
Definition
|
|
Term
| What does chronic use or irreversible anticholinesterase topically on the eye cause? |
|
Definition
|
|
Term
| What are the 2 most widely used organophosphates? |
|
Definition
|
|
Term
|
Definition
|
|
Term
| When are malathion & parathion activated as anticholinesterases? |
|
Definition
| once bio-activated by liver |
|
|
Term
| Why is malathion used for home & garden insecticides & parathion is reserved for farming & other professional uses? |
|
Definition
| malathion is effectively detoxified by metabolism in mammals, parathion is not. |
|
|
Term
| How can malathion be used topically? |
|
Definition
|
|
Term
| Which insecticide is sprayed aerially to control mosquitos? |
|
Definition
|
|
Term
| How are all organophosphates excreted? |
|
Definition
|
|
Term
| What irreversible anticholinesterase poses the greatest threat of widespread poisoning? |
|
Definition
|
|
Term
| What causes death in anticholinesterase toxicity? |
|
Definition
any number of toxic SE (usually depends on route & rate of absorption)
1) CV collapse
2) asphyxia due to:
a) bronchoconstriction & secretion
b) paralysis of resp. muscles
3) CNS depression/coma |
|
|
Term
| What are the 6 toxic SE of anticholinesterases? |
|
Definition
1) Increased GI motility
2) Hypotension
3) Bronchial constriction & secretion
4) Involuntary micturition
5) CNS stimulation => convulsions => CNS depression/coma
6) muscle fasicluations followed by depolarizing blockade/paralysis |
|
|
Term
| What are the 3 parts of organophosphate poisoning Tx? |
|
Definition
1) decontamination (prevent further eposure)
2) atropine to control mAchR action
3) give an agent to promote regeneration of AchE s.a. pralidoxime |
|
|
Term
|
Definition
| binds anionic AchE site & phosphate moiety of organophosphate => permits bonds to be broken |
|
|
Term
| What happens if water is added to the organophosphate-AchE complex? |
|
Definition
| complex becomes "aged" and regeneration by pralisoxime will not occur |
|
|
Term
| Can pralidoxime reach the CNS? |
|
Definition
| no, it's a quaternary amine |
|
|
Term
| Patient is a 35 yo male admitted to ER with abdominal craming & vomiting. He was found slumped over a tractor in a fruit orchard. PE reveals him to be minimally responsive & shows cyanosis with marked resp. distress & hyperactive bowel sounds. He has bilateral miosis with extensive lacrimation & salvation with evidence of urinary incontinence. What is the problem? How should it be treated? |
|
Definition
| Organophosphate toxicity. Tx by decontamination, atropine, & pralidoxime. |
|
|
Term
MOA
pyridostigmine prophylaxis for nerve gas exposure |
|
Definition
| it binds to same site on AchE as organophosphate. If bound, then organophosphate can't bind. It won't protect DURING organophophate exposure, but once removed from exposure, pryidostigmine will be hydrolyzed off, preserving AchE function & therefore life |
|
|
Term
|
Definition
| the study of the harmful effects of chemicals on biological systems |
|
|
Term
|
Definition
| any substance that can cause death, disease, or injury |
|
|
Term
| What are the 4 routes of poison entry to the body? |
|
Definition
1) oral
2) inhalation
3) parenteral
4) dermal |
|
|
Term
| How are poisons classified? |
|
Definition
Under borad headings s.a.
irriants
systemics
corrosives
gases
or by chemical structure s.a.
acids
bases
organic solvents
heavy metals
etc. |
|
|
Term
|
Definition
| any substance in the environment as a consequence of human activity |
|
|
Term
|
Definition
| locally, systemically, or both |
|
|
Term
| What determines time before posion effect is noticed/duration & intensity? |
|
Definition
1) dose
2) age
3) personal habits
4) genetics
5) route of administrationWhe |
|
|
Term
| What is the leading cause of all poisons in the U.S.? |
|
Definition
|
|
Term
|
Definition
| ADME of toxins, toxic doeses of therapeutic agents, and their metabolites |
|
|
Term
|
Definition
| the injurious effects of these substances on vital functions |
|
|
Term
| When will a chemical produce a toxic effect on a biological system? |
|
Definition
| when it reaches a critical concentration in traget tissue |
|
|
Term
|
Definition
| dose of a chemical required to produce death in 50% of organisms exposed to it |
|
|
Term
|
Definition
| dose producing desired parmacological effect in 50% of individuals |
|
|
Term
Equation
Therapeutic index |
|
Definition
|
|
Term
| In general, what route of exposure leads to the most rapid & greatest effect? |
|
Definition
|
|
Term
|
Definition
| single exposure or multiple exposures over a 24 hr period |
|
|
Term
|
Definition
| multiple exposures over 24 hr to 3 month period |
|
|
Term
|
Definition
| muliple exposures over period of 3 months or more |
|
|
Term
def
non-cumulative poisons |
|
Definition
readily cleared by the body & doesn't cause permanent irreversible damage at low doses
(total dose not important, so long as individual doses are small) |
|
|
Term
|
Definition
| accumulate in the body or cause irreversible damage where total exposure is critical |
|
|
Term
|
Definition
| rate of drug elimination is independent of of drug concentration |
|
|
Term
| How are drugs usually eliminated, first or zero order kinetics? |
|
Definition
|
|
Term
| When do drugs become zero order? |
|
Definition
|
|
Term
| What causes the change from first order to zero order kinetics in overdose situations? |
|
Definition
|
|
Term
| What happens at saturation? |
|
Definition
| processes are functioning at maximum & therefore limits rate of drug removal |
|
|
Term
| Equation
ke (zero order rate constant) |
|
Definition
| ke = (A0-A)/t
A0 = amount of drug at time 0
A = amount of drug at any other given time |
|
|
Term
| When will zero order kinetics yield a straight line? |
|
Definition
|
|
Term
| When will we see zero order kinetics with toxic agents? |
|
Definition
higher doses
(first order at low doses & mixture in between) |
|
|
Term
| What everyday substances (as examples) observe first order kinetics below saturation & zero order kinetics above? |
|
Definition
|
|
Term
| What are some examples of heavy metals? |
|
Definition
lead
murcury
arsenic
cadmium
chelators |
|
|
Term
|
Definition
| metals that are not metabolized & so pose a significant threat since they stay in the body for long periods of time |
|
|
Term
| What do heavy metals combine with in the body to exert their toxic effect? |
|
Definition
| essential aa residues of enzymes => inhibition of catalytic activity |
|
|
Term
| What are the sources of lead exposure? |
|
Definition
Environmental (water, air, soil, food)
Household (crayons, toys, paint, etc)
Occupational (miners, spray painters, etc) |
|
|
Term
Sx
Acute Inorganic Pb poisoning |
|
Definition
Severe GI
Progresses to: CNS (stupor/convulsions to coma/death) |
|
|
Term
| Why is Dx of acute inorganic Pb poisoning difficult? |
|
Definition
| Sx ~ appendicitis, peptic ulcer, pancreatitis |
|
|
Term
Sx
Chronic inorganic Pb poisoning |
|
Definition
Weakness, anorexia, nervousness, tremor, wt. loss, headache, GI
(recurrent abdominal pain & extensor muscle weakness w/o sensory disturbances => Pb poisoning possibility) |
|
|
Term
| What is the most characteristic finding in chronic inorganic Pb poisoning? |
|
Definition
|
|
Term
| How do you confirm Dx of inorganic Pb poisoning? |
|
Definition
1) measure blood level
2) ID abnormalities of porphyrin metabolism |
|
|
Term
| What usually causes organic Pb poisoning? |
|
Definition
| tetraethyl or tetramethyl Pb in gasoline |
|
|
Term
| Why is organic Pb readily absorbed thru skin & RT? |
|
Definition
| highly volatile & lipid soluble |
|
|
Term
| What has diminished organic Pb in environment? |
|
Definition
| phase-out of leaded gasoline |
|
|
Term
|
Definition
acute CNS disorders
few hetatological abnormalities
rapidly progressing => hallucinations, insomnia, headache, & irritability |
|
|
Term
| Where in the body does inorganic Pb distribute to after absorption? |
|
Definition
| soft tissues (primarily kidney & liver) => redistribution to bone, teeth, & hair => eventually 95% found in bone |
|
|
Term
| What is most circulating inorganic Pb associated with? |
|
Definition
|
|
Term
What is the half life of Pb in blood?
in bone? |
|
Definition
blood: 1-2 mo.
bone: 20 yr. |
|
|
Term
| What are tetraethyl & tetramethyl lead metabolized to by the liver? |
|
Definition
| trialkyl Pb & inorganic Pb |
|
|
Term
| What is trialkyl Pb responsible for? |
|
Definition
|
|
Term
| Where are trialkyl & inorganic Pb excreted? |
|
Definition
|
|
Term
| What is the primary screening procedure for Pb poisoning? |
|
Definition
| FEP test (RBC protoporphyrin will be increased due to inhibitionof ferrochelatase by Pb) |
|
|
Term
| What happens due to Pb inhibition of several enzymes in heme biosynthesis? |
|
Definition
| elevated urinary prophyrin |
|
|
Term
| How does Pb cause anemia? |
|
Definition
| inhibiting hemoglobin synthesis in bone marrow & increasing fragility of RBC |
|
|
Term
Heme metabolism
Succinyl CoA + Glycine -> ?
What enzyme is used? |
|
Definition
| δ-Aminolevulinate synthase is used to produce δ-Aminolevulinate |
|
|
Term
Heme metabolism
δ-Aminolevulinate -> ?
What enzyme is used? |
|
Definition
| δ-Aminolevulinate dehydratase is used to produce Prophobiliongen |
|
|
Term
Heme metabolism
Prophobilinogen -> ?
Which enzymes are used? |
|
Definition
| Porphobilinogen deaminase & uroporphyrinogen III cosynthase are used to produce Uroporphyrinogen III |
|
|
Term
Heme metabolism
Uroporphyrinogen III -> ?
What enzyme is used? |
|
Definition
| Uroporphyrinogen decarboxylase is used to produce Coproporphyrinogen III |
|
|
Term
Heme metabolism
Coproporphyrinogen III -> ?
What enzyme is used? |
|
Definition
| Coproporphyrinogen oxidase is used to produce Protoporphyrun IX |
|
|
Term
Heme metabolism
Protoporphyrin IX -> ?
What enzyme is used? |
|
Definition
| Ferrochelatase + Fe2+ are used to produce heme |
|
|
Term
| What 2 enzymes in heme metabolism does Pb have an effect on for sure? |
|
Definition
| δ-Aminolevulinate dehydratase & Ferrochelatase |
|
|
Term
| What 2 enzymes in heme synthesis does Pb probably have an effect on? |
|
Definition
| δ-Aminolevulinate synthase & Coproporphyrinogen oxidase |
|
|
Term
| What happens to δ-Aminolevulinate as a consequence of Pb? |
|
Definition
| it's excreted in the urine |
|
|
Term
| What happens to coproporphyrinogen as a result of Pb? |
|
Definition
|
|
Term
| What happens to protoporphyrin IX as a consequence of Pb? |
|
Definition
|
|
Term
|
Definition
1) orevent further exposure & provide supportive measures
2) Tx of seizures with diazepam
3) Tx of cerebral edema w/ mannitol & dexamethasone
4) Maintain fluid & electrolyte balance
5) initiate chelation therapy asap |
|
|
Term
| What are the 3 forms of Hg? |
|
Definition
elemental
inorgangic
organic |
|
|
Term
| Which form of Hg is more completely absorbed through GI? |
|
Definition
|
|
Term
| Which Hg form is poorly absorbed thru GI, but is quite volatile & can be absorbed thru the lungs? |
|
Definition
|
|
Term
Which organic Hg is most dangerous?
Why? |
|
Definition
| methylmercury - more completely absorbed thru GI |
|
|
Term
| Where, after distribution, is Hg concentration the highest? |
|
Definition
|
|
Term
| What does Hg bind to in the body? |
|
Definition
|
|
Term
|
Definition
|
|
Term
| Which Hg is more predominant in CNS? |
|
Definition
|
|
Term
| How are patients with acture Hg intoxication being exposed? |
|
Definition
| inhalation of Hg vapor (occupational exposure) |
|
|
Term
|
Definition
chest pain
SOB
metallic taste
N/V
=> acute kidney damage
if survives, severe gingivitis & gastroenteritis occur
Severe cases: muscle tremor & psychopathology develop |
|
|
Term
Sx
Chronic Hg intoxication |
|
Definition
mouth/GI disorders w/ Sx of renal insufficency
gingivitis, discolored gums, loose teeth
enlarged salivary glands
Tremor of digits, arms, & legs
altered handwriting
ocular changes (Hg deposition in lens)
personality change |
|
|
Term
| Where are organ toxicity most present in Hg poisoning? |
|
Definition
|
|
Term
| Why is Hg very corrosive? |
|
Definition
| ability to precipitate protein on contact |
|
|
Term
|
Definition
| removal from exposure & chelation with dimercaprol |
|
|
Term
|
Definition
| Oral penicillamine or N-acetylpenicillamine (chelation) |
|
|
Term
| How is Hg chelation success monitored? |
|
Definition
|
|
Term
| What are 4 the chemical forms of arsenic? |
|
Definition
elemental
inorganic
organic
asine gas |
|
|
Term
| When is arsenic used medically? |
|
Definition
| only in certain tropical diseases |
|
|
Term
| What are the 2 inorganic arsenic forms that cause major toxiological effects? |
|
Definition
primary: trivalent
pentavalent |
|
|
Term
| Why does pentavalent also have toxicologic effects? |
|
Definition
| uncoupler of oxidative phosphorylation |
|
|
Term
| How do trivalent arsenics produce toxological effects? |
|
Definition
| act as sufhydryl reagents => inhibition of SH-sensitive enzymes |
|
|
Term
|
Definition
| closes sulfhydryl ring by connecting to both S in the enzyme complex |
|
|
Term
|
Definition
stabilization of patient & prevention of further absorption.
chelation with dimercaprol followed bby penicillamine |
|
|
Term
| What contributes to cadmium (Cd) exposure? |
|
Definition
cigarette smoking
<5% of Cd is recycled in environment => pollution |
|
|
Term
| What is the half life of Cd? |
|
Definition
|
|
Term
| Why are smokers at an increased risk to Cd posioning? |
|
Definition
| build up sm. amounts of Cd/year due to cigarettes + Cd has an extremely long half life (prone to accumulation) |
|
|
Term
|
Definition
no effective Tx established
stabilization & prevention of further absorption
Chelation with calcium disoodium (never with dimercaprol => mobilizaes Cd causes it to concentrate in kidney & dissociates from chelator) |
|
|
Term
def
heavy metal antagonists |
|
Definition
|
|
Term
|
Definition
| desined to bind to heavy metals & prevent or reverse binding of metals to cellular molecules |
|
|
Term
| How are chelators flexible? |
|
Definition
| 2+ electronegative groups that for stable covalent bonds with cationic metal |
|
|
Term
| How is binding b/w chelator & metal ion accomplished? |
|
Definition
|
|
Term
| What are the common donor atoms for electron supply on the chelator? |
|
Definition
|
|
Term
| What 4 things does chelating effectiveness depend on? |
|
Definition
1) affinity for heavy metal
2) affinity for essential metals in body
3) distribution of metal & chelator in body
4) ability of chelator to mobilize metal |
|
|
Term
| What are the desirable propertirs of a good chelating agent? |
|
Definition
| 1) water solubility
2) resistance to metabolism
3) ability to distribute to same sites as metal
4) ready excretion of chelation complexes
5) can function at physiological pH
6) complexes are less toxic than free metal
7) low affinity for Ca2+ & Zn2+
8) high affinity for metal
9) minimal inherant toxicity
10) absorbed orally |
|
|
Term
| What are the 4 chelators used? |
|
Definition
1) Dimercaprol
2) EDTA
3) penicillamine
4) desferoxamine mesylate |
|
|
Term
| What are the propterties of dimercaprol? |
|
Definition
colorless oily liquid with offensive odor
readily absorved IM |
|
|
Term
| When is dimercaprol contraindicated? |
|
Definition
| liver disease or severe renal disease |
|
|
Term
|
Definition
Cardiovascular (HTN, tachycardia)
headache
fever in children
etc.
N/V |
|
|
Term
| Why do congeners of dimercaprol have less SE? |
|
Definition
| more water soluble & therefore confined to extracellular space |
|
|
Term
| When is EDTA an efficient chelator? |
|
Definition
|
|
Term
| What limits the clinical usefulness of EDTA? |
|
Definition
| chelation of essential calcium |
|
|
Term
| When in EDTA contraindicated? |
|
Definition
Hg poisoning
renal disease |
|
|
Term
| How is invivo calcium binding circumvented with EDTA? |
|
Definition
| addition of calcium-disodium |
|
|
Term
| How is penicillamine formed? |
|
Definition
| degradation of penicillin |
|
|
Term
| Why is the D isomer of penicillamine preferred over the L isomer? |
|
Definition
|
|
Term
| What is penicillamine most used to Tx? |
|
Definition
| Pb, Hg, & Cu poisoning (Wilson's disease since Cu chelation) |
|
|
Term
| When are SE seen in penicillamine |
|
Definition
only in chronic use
(allergic rxn, leukopenia, eosinophilia, nephrotoxicity) |
|
|
Term
| What is deferoxamine mesylate isolated from? |
|
Definition
|
|
Term
| When is deferoxamine mesylate used? |
|
Definition
iron toxicity (possibly aluminium toxicity as well)
only use when severity of poisoning justifies it, since it's toxic as well |
|
|
Term
| When is deferoxamine mesylate contraindicated? |
|
Definition
|
|
Term
|
Definition
diarrhea
HTN
cataract formation |
|
|
Term
10 yo boy living near pigment manufacturing plant presents with burning snesation in glove and stocking distribution with sever bilateral arm & leg weakness. He presents with hyperpigmentation & thickening of skin over pamls & soles. He is in the habit of eating paint.
Neurological exam reveals decreased senation, decreased motor stregeth, absent tendon reflexes, & wasting in arms & legs.
Arsenic levels elevated in blood, urine, & hair.
What should be used for Tx? |
|
Definition
| penicillamine or oral DMSA |
|
|
Term
| When do neurological Sx predominate over GI Sx in arsenic poisoning? |
|
Definition
|
|
Term
5 yo boy brought to medical clinic b/c of sudden, vigorous vomiting with no previous nausea. Mother states he's been behaving stragely & been irritable. Child complains of weakness in hands & feet. Boy lives in an old house recently renovated. He's had episodes of abdominal pain in the past.
PW shows pallor, lethary, foot drop, retinal strippling, lines in gum, wasting of muscles of hands with motor weakness.
Labs show hyperchromatic, microcytic anemia with casophilic strippling, hyperuricemia, increased urinary coproporphyrin & aminolevulinic acid, elevated blood Pb.
X-rays show increased density at metaphysis
Edema of the brain & peripheral nerve segmental demyelination present
Acid fast intranuclear bodies in renal tubluar cells, hepatocytes, & osteoclasts.
What Tx is indicated? |
|
Definition
sepatation from source of exposure
IM chelation with CaEDTA or DMSA orally, dimercaprol |
|
|
Term
28 yo male, professor of chemistry, come to ER complaining of acute retosternal & epigastric pain & frequent vomiting of blood-tinged material. He admits to a suicide attempt thru ingestion of several teaspoons of mercurium bichloride. On arrival he had a bloody, diarrhetic bowel movement.
PE shows hypotenstion, tachycardia, pallor, cold & clammy skin, whitish tongue, & confused demeanor. Patient was oliguric & dyspneic, exhibited moderate abdominal tenderness & grayish discoloration of buccal mucosa.
Lab showed elevate serum creatinine & BUN. tubular casts in urine analysis. Markedly increased fractional excretion of sodium & elevated serum hemoglobin levels
He has acute tubular necrosis, acute irritative colitis with mucosal necrosis with sloughing & hemorrhage.
What Tx is indicated? |
|
Definition
Specific chelation therapy with dimercaprol & siccomer.
Supportive management of acute tubular necrosis |
|
|
Term
| What are the properties of carbon monoxide (CO)? |
|
Definition
| colorless, tasteless, odorless, non-irritating |
|
|
Term
| What are the major sources of CO? |
|
Definition
| automobile exhause, charcoal fires, gas furnaces, methylene chloride |
|
|
Term
|
Definition
| It combines with Hb at O2 binding sites to form carboxyhemoglobin (unable to transport O2 from lungs to tissue)
Hb affinity for CO is >200x that of Hb for O2
therefore CO is dangerous at LOW levels |
|
|
Term
| What tissues are most affected by CO poisoning? |
|
Definition
|
|
Term
| How do Sx of CO poisoning vary? |
|
Definition
|
|
Term
|
Definition
| headache, weakness, N/V => loss of muscular control, collapse, unconsciousness & death |
|
|
Term
| Why are the cardiac & resp. systems affected by CO? |
|
Definition
|
|
Term
|
Definition
| 1) remove from source of exposure
2) maintain respiration
3) may need to administer O2 |
|
|
Term
| Why is it important to remove indivudual from exposure & maintain respiration (besides the obvious) in CO poisoning? |
|
Definition
| Once removed from exposure, CO readily dissociated from COHb via expiration |
|
|
Term
| What are the cources of cyanide (CN)? |
|
Definition
occupational chemicals (fumigants, cleaners, rubber, etc)
produced in fired involving N-containing plastics
Home environment (silver polish, insecticides, fruit seeds) |
|
|
Term
| How soon after inhalation of toxic doses of CN as Sx seen? |
|
Definition
|
|
Term
|
Definition
Sm dose: giddiness, headache, palpitations, N/V => increased dose: ataxia, convulsions, soma, death
very lg dose: collapse & death almost immediately |
|
|
Term
|
Definition
Abruptness of Sx onset
Odor of bitter almonds on breath |
|
|
Term
|
Definition
| CN bings to ferric iron in cytochrome oxidase of mitochondra => inhibits cellular respiration => cytotoxic hypoxia |
|
|
Term
|
Definition
| Administer amyl nitrite or sodium nitrite to produce methemeoglobin from hemoglobin [Fe(II) to Fe(III)].
This provides a large pool of Fe(III) for CN to bind to
Tx of induced hypoxia via O2 inhalation |
|
|
Term
| What are the sources of methanol? |
|
Definition
| industrial chemical (anitfreeze, paint remover) |
|
|
Term
| How does MeOH removal compare to EtOH? |
|
Definition
| MeOH is more slowly oxidized |
|
|
Term
| What are the 2 MeOH products responsible for MeOH toxicity? |
|
Definition
| MeOH -> fomaldehyde -> formic acid |
|
|
Term
|
Definition
~ to those with EtOH
Severe GI cramps, vomiting, acidosis, cardiac depression
early: vision disturbances (blurred, dilated pupils)
resp. & circulatory failure => coma, delirium, death
(protracted blondness can be premanent, even if recovery occurs) |
|
|
Term
| What causes blindness in MeOH toxicity? |
|
Definition
| formaldehyde by damaging retinal cells |
|
|
Term
| What causes cadiac Sx & is a systemic acidifier in MeOH toxicity? |
|
Definition
|
|
Term
| What is the key to survaval of MeOH poisoning? |
|
Definition
|
|
Term
|
Definition
keep patient warm
protect patient eyes from light
correct acidosis by administration of sodium bicarbonate
continuously monitor blood pH & gases
may administer EtOH since both are metabolized by EtOH dehydrogenase, but with a higher affinity for EtOH |
|
|
Term
| Where is the major source of ethylene glycol? |
|
Definition
| antifreeze (major component) |
|
|
Term
| What metabolizes ethylene glycol? |
|
Definition
|
|
Term
| What does EtOH dehydrogenase metabolize Ethylene glycol to? |
|
Definition
|
|
Term
| Why does oxalate cause severe renal injury & failure? |
|
Definition
|
|
Term
| What causes acidosis in ethylene glycol intoxication? |
|
Definition
| formic acid production (just like MeOH) |
|
|
Term
Tx
Ethylene glycol intoxication |
|
Definition
gastric lavage
correct acidosis with sodium bicarbonate
administration of EtOH to compete for EtOH dehydrogenase & slow metabolism of ethylene glycol
hemodialysis |
|
|
Term
| How much of acetaminophen (APAP) is absorbed from GI? |
|
Definition
| 100% absorbed (& rapidly) |
|
|
Term
| How soon after APAP administration is plasma concentration peak seen? |
|
Definition
|
|
Term
| What is the half life of APAP? |
|
Definition
|
|
Term
| What is APAP metabolized to? |
|
Definition
primarily: glucuronide
sulfate conjugates |
|
|
Term
|
Definition
24-48 hr: pallor, N/V
2-4 d: heptaic damage observed |
|
|
Term
| Why is early diagnosis of APAP toxicity critical? |
|
Definition
| it's metabolized during 1st pass metabolism (must monitor LFT) |
|
|
Term
|
Definition
majority: gluronidated
sm amount: hydroxylated by CYP450 => conjugation to GSH & excreted |
|
|
Term
| What happens to GSH levels in massave APAP doses? |
|
Definition
| depletion => hydroxylated metabolite binding to tissue => necrosis |
|
|
Term
|
Definition
| N-Acetylcysteine (asministration of sulfhydryl compound to maintain hepatic GSH or act as an alternative target for hydroxylated APAP metabolite) |
|
|
Term
| What is one of the major causes of accidental poisoning in children under 5? |
|
Definition
|
|
Term
| What is the source of most vitamin toxicities? |
|
Definition
| chronic use of vitamins over many years |
|
|
Term
|
Definition
|
|
Term
| Which vitamins are most likely to cause overdose? |
|
Definition
| fat soluble (A & D more prominent, E & K rarely seen) |
|
|
Term
| What is the main source of "multivitamin" toxicity? |
|
Definition
|
|
Term
A 29 yo mechanic brought to ER after complaining of persistent headache, nausea & dizziness. He has been working indoors all day bc of the cold weather & felt tired, dizzy, & nauseated. He has otherwise been in good health.
PE reveals tachycardia & patient is lethargic & disoriented.
Labs reveal carboxyhemaglobin concentraion of 38%
What Tx should be administered? |
|
Definition
| 100% oxygen until carboxyhemoglobin concentration <5%. |
|
|
Term
6 yo boy is brought to ER b/c of severe vomiting. Patient was with his father in the garage when he drank some antifreeze. On arrival, the boy started having tonic-clonic seizures.
PE reveals tachycardia, no fever, hypotension, & the patient was hyperventilating & experiencing convulsions.
Labs reveal leukocytosis, ethylene glycol in blood, metabolic acidosis w/ elevated osmolar & anion gap, hyponatremia & hyperkalemia. BUN & creatinine were normal. ECG showed premature ventricular beats.
Chest x ray showed no evidence of bronchoaspiration of ethylene glycol.
What Tx should be administered? |
|
Definition
administration of EtOH to saturate EtOH dehydrogenase.
administer pyridoxine, folate, & thiamine to counteract effecs of toxic metabolites
Treat convulsions with diazepam & monitor vital signs.
hemodialysis if necessary |
|
|
Term
|
Definition
| general classification for poisons designed to kill various pests (plant & animal) |
|
|
Term
def
chlorinated hydrocarbon insecticides |
|
Definition
| group of fat-soluble, low molecular wt., stable compounds with low water solubility |
|
|
Term
| Why do chlorinated hydrocarbon insecticides s.a. DDT have poor biodegradability? |
|
Definition
|
|
Term
|
Definition
| interfering with inactivation of sodium channel => alteration of sodium & potassium transport across axonal membranes => rapid repetitive firing in most neurons |
|
|
Term
|
Definition
| support physiological function |
|
|
Term
| What is the primary short-term effect of DDT? |
|
Definition
|
|
Term
| What insecticides have largely replaced chlorinated hydrocarbon insecticides? |
|
Definition
| organophosphorus insecticides |
|
|
Term
| Why are organophosphorus insecticides uned even though they persist in the environment? |
|
Definition
| extrememely low carcinogenic potential (though much higher acture toxicity in humans - need only sm. dose to be lethal in children) |
|
|
Term
| What organophosphorus insecticide is the most frequent pesticide invilved in fatal poisoning? |
|
Definition
|
|
Term
| How are organophosphorus insecticides absorbed? |
|
Definition
|
|
Term
MOA
organophosphorus insecticides |
|
Definition
| inhibition on AchE by phosphorylating the esteric site |
|
|
Term
Sx
organophosphorus insecticide poisoning |
|
Definition
Sx of persistent Ach hyperstimulation (muscarinic, nicotinic, CNS)
death
delayed neurotoxicity in some substances |
|
|
Term
MOA
carbamates insecticides |
|
Definition
| inhibit AchE by carbamoylation of esteratic site |
|
|
Term
Sx
carbamate insecticide poisoning |
|
Definition
| ~organophosphorus insecticide poisoning |
|
|
Term
| Why are carbamate insecticides less toxic than organophosphorus insecticides? |
|
Definition
| they easily dissociate fro enzyme => shorter duration of action |
|
|
Term
| Why are carbamates thought to have little negative environmental impact? |
|
Definition
| nonpersistent in the environment |
|
|
Term
| Which pesticides persist in the environment? |
|
Definition
| cholorinated hydrocarbons & organophosphorus insecticides |
|
|
Term
| Which is the only pesticide to bioaccumulate? |
|
Definition
| cholorinated hydrocarbons |
|
|
Term
| What pesticides do not accumulate in animals? |
|
Definition
|
|
Term
| What are herbicides used for? |
|
Definition
| control many broad-leaf woody plants |
|
|
Term
|
Definition
|
|
Term
| Why don't herbicides accumulate in animals? |
|
Definition
| readily excreted (though slowly metabolized) |
|
|
Term
| What is the half life of herbacides? |
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
high dose: ventricular fibrillation
loe dose: neuromuscular involvement |
|
|
Term
| Why are the 2 bipyridyl herbacides? |
|
Definition
|
|
Term
| What are the 3 primary sites of damage due to paraquat toxicity? |
|
Definition
lungs, liver, & kidneys
(lung fibroblast widespread proliferation) |
|
|
Term
|
Definition
| redox cycling in cells to generate lg. amount of ROS => change in regulation of cell function => necrosis |
|
|
Term
| What is the main environmental pollutant caused by plastic, flame retardant, etc thru the 70s & still persists today? |
|
Definition
|
|
Term
| What are the characteristics of PCBs? |
|
Definition
| very lipophilic, highly stable, poorly metabolized |
|
|
Term
| Why does PCB bioaccumulate in the food chain? |
|
Definition
| very resistant to environmental degradation |
|
|
Term
| What is the major source of human exposure to PCB? |
|
Definition
|
|
Term
| What mechanisms may be imployed by chamical interactions? |
|
Definition
1) alteration of absorption
2) protein binding effects
3) biotransformation alteration
4) excretion effects on any number of interacting toxicants
5) ADME |
|
|
Term
| What can happen to the effects when 2+ chemicals ineract together? |
|
Definition
1) additive (10+2=12) - assume to be the case
2) synergistic (10+2=20)
3) potentiation (10+0=20)
4) antagonistic (10+2=5) |
|
|
Term
| What is an antagonist to coumarin poisoning? |
|
Definition
|
|
Term
def
physiological antagonism |
|
Definition
| drugs that stimular antagonistic physiological mechanisms |
|
|
Term
| Why is physiological antagonism not used clincally? |
|
Definition
little clinical value & may decrease survival:
-difficult to titrate-duration of action may differ |
|
|
Term
| When are DDI of importance? |
|
Definition
| When margin of safety for a drug is small |
|
|
Term
| What increases lielihood of DDI? |
|
Definition
|
|
Term
|
Definition
1) physical interaction
2) plasma protein binding
3) competition for enzzymes/excretion
4) induction/inhibition of metabolizing enzymes |
|
|
Term
| What legal & uncontrolled substances are often overlooked for potential DDI? |
|
Definition
|
|
Term
| What DDI are caused by EtOH? |
|
Definition
induction of CYP450
competition for CYP450
CNS effects |
|
|
Term
| What DDI are caused by caffeine? |
|
Definition
Inducer/sunstrate for microsomal metabolizing enzymes
potential harm with common medication interactions |
|
|
Term
| What DDIs are caused by tobacco? |
|
Definition
induction of metabolizing enzymes
decrease effect of common drugs |
|
|
Term
| Which CYP450 enzyme is a major culprit of DDI? |
|
Definition
|
|
Term
| What are the 3 major sources of problems in geriatric toxicology? |
|
Definition
1) altered physiology
2) altered drug metabolism
3) polypharmacy |
|
|
Term
| Where are age-related changes seen in drug disposition? |
|
Definition
|
|
Term
| What 4 considerations should be taken into account when perscribing for elderly patients? |
|
Definition
1) dose adjustments
2) progress monitoring
3) individualize therapy
4) benefit:risk ratio |
|
|
Term
def
activation (bioactivation) |
|
Definition
| metabolic ranx of a xenobiotic in which the product is more toxic than the substrate |
|
|
Term
|
Definition
| various short-lived, highly reactive intermediates in the reduction of oxygen |
|
|
Term
|
Definition
| chemicals that can add alkyl groups to DNA => mispairing of bases or chromosome breaks |
|
|
Term
|
Definition
| binding of toxicants or their reactive metabolites to endogenous molecules to produce stable adducts |
|
|
Term
|
Definition
| metabolic rxn or sequence of rxns that reduces the potential for adverse effects of a xenobiotic |
|
|
Term
|
Definition
| molecules that have unpaired electrons |
|
|
Term
|
Definition
| tripeptide, γ-glutamyl-Lcysteinylglycine (involved in many detoxification rxns in cells since resistant to proteases) |
|
|
Term
def
reactive intermediates |
|
Definition
| chemical compunds, produced during the metabolism of xenobiotics that are more chemically reactive than the parent compund => greater adverse effect potential |
|
|
Term
def
bioactivation vs. detoxification |
|
Definition
| drug metabolism rxns can function as both detoxification & bioactivation mechanisms |
|
|
Term
| What is GSH role in drug metabolism? |
|
Definition
| involved in many detoxification rxns in cells since it's resistant to proteases |
|
|
Term
| What are the 5 mechanisms of bioactivation? |
|
Definition
1) bioactivation to stable, toxic metabolites
2) biotransformation to reactive, electrophilic metabolits
3) biotransformation to free radicals
4) formation of reduced oxygen metabolites
5) metabolic derangements |
|
|
Term
30 yo man brought to ER in stuporous state with nausea, protracted vomiting & malaise. Over-treated himself with Tylenol (APAP) with up to 30 pills/day to relieve pain/discomfort with a whiplast neck injury a week ago.
PE shouw jaundice & asterixis. Patient was slightly confused & dehydrated. Retinal exam was normal
Labs showed markedly elevated serum transaminases, bilirubin, creatinine & BUN. Mild hypoglycemia & metabolic acidosis. Serum APAP levels were in toxic range.
Liver biopsy reveals over coagulative necrosis. Cells are shrunken & pyknotic with marked presence od nrutophils.
What TX should be administered? |
|
Definition
N-acetylcysteine to replace GSH levels & supportive Tx.
Liver transplant may be considered in severe case |
|
|
Term
| Why is the bioactivation of xenobiotics to stable, toxic metabolites limited? |
|
Definition
| few chemicals are stable & toxic |
|
|
Term
| What 2 toxins are stable? |
|
Definition
|
|
Term
| How common are xenobiotics metabolized to reactive, electrophile metabolites? |
|
Definition
|
|
Term
| What principle do reactive electrophiles use to interact with cellular nucleophiles? |
|
Definition
| Pearson's principle of hard & soft acids & bases |
|
|
Term
|
Definition
|
|
Term
|
Definition
|
|
Term
| According to Pearson's principle, what do hard electrophiles interact preferentially with? |
|
Definition
|
|
Term
| According to Pearson's principle, what do soft electrophiles interact preferentially with? |
|
Definition
|
|
Term
def
hard base (nucleophile) |
|
Definition
donor atom/molecule that:
1) high electronegativity
2) low polarizability
3) difficult to oxidize
(i.e. amino groups) |
|
|
Term
def
soft base (nucleophile) |
|
Definition
a donor atom/molecule that:
1) low electronegativity
2) high polarizability
3) easy to oxidize
(i.e. thoil group of GSH & cycteine) |
|
|
Term
def
hard acid (electrophile) |
|
Definition
an acceptor atom/molecule:
1) high positive charge
2) sm. size
3) lacks unshared electrons in valence shell
(i.e. alkyl carbonium ion) |
|
|
Term
def
soft acid (electrophile) |
|
Definition
an acceptor atom/molecule that:
1) low positive charge
2) relatively lg. size
3) contains unshared electron pairs in valence shell
(i.e. michael acceptors) |
|
|
Term
| What toxins have reactive, electrophilic metabolites? |
|
Definition
| APAP, bromobenzene, benzo(a)pyrene, 2-acetylaminofluorine, nitrosamines, trichloroethylene) |
|
|
Term
| Which of the reactive electrophile examples produce soft electrophiles? |
|
Definition
|
|
Term
| Which of the reactive electrophile examples produce soft/hard electrophiles (usually epoxides)? |
|
Definition
bromobenzene, benzo(a)pyrene
GSH conjugation when nephrotoxic |
|
|
Term
| Which of the reactive electrophile examples produce hard electrophiles? |
|
Definition
| 2-acetylaminofluorine & nitrosamine |
|
|
Term
| What metabolizes bromobenzene, benzo(a)pyrene, 2-acetylaminofluorene, & nitrosamine to their reactive electrophile conformation? |
|
Definition
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|
Term
| What elements can carry a free radical? |
|
Definition
|
|
Term
| What are the 3 ways free radicals can be induced? |
|
Definition
one electron oxidation
one electron reduction
homolytic s-bond cleavage |
|
|
Term
Rxn
one electron oxidation |
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Definition
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Term
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Definition
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|
Term
Rxn
homolytic s-bond cleavage |
|
Definition
|
|
Term
| What are the 2 ways free radicals can be propagated? |
|
Definition
Abstraction of H atoms (H·)
Addition |
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Term
Rxn
Abstraction of H atoms |
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Definition
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|
Term
|
Definition
|
|
Term
| What are the 3 ways free radicals can be terminated? |
|
Definition
Dimerization back to neutral
Disproportionation
Rxn with anti-oxidant |
|
|
Term
Rxn
Dimerization back to neutral |
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Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
| R· + Antiox -> RH + Antiox· -> neutral |
|
|
Term
| What metabolizes carbon tetrachloride to a free radical? |
|
Definition
|
|
Term
|
Definition
| 1) HO2· (perhydroxyl radical)
2) H+ + O2-· (superoxide anion)
3) H2O2 (hydrogen peroxide)
4) HO· (hydroxy radical) |
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Term
|
Definition
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Term
|
Definition
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Term
|
Definition
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|
Term
|
Definition
|
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Term
|
Definition
|
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Term
|
Definition
|
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Term
|
Definition
|
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Term
|
Definition
|
|
Term
| What intracellular nonenzymatic rxn forms ROS? |
|
Definition
|
|
Term
| How does Paraquat produce ROS? |
|
Definition
Via redox cycling.
A free radical is formed & the extra electron is donated to oxygen to reform the parent compound |
|
|
Term
| What is the quinone protective mechanism from ROS? |
|
Definition
| DT-diaphorase (enzyme that skips the ROS step, and allows for 2 electron reduction) |
|
|
Term
| How do nitro anions cause ROS? |
|
Definition
| they form free radicals & are recycled back to the parent species via the formation of ROS |
|
|
Term
def
metabolic derangements |
|
Definition
| xenobiotic acts by being metabolized to an inhibitor of the metabolic pathway or may produce a depletion of a metabolic intermediate/coenzyme |
|
|
Term
| What is depleted by galactosamine? |
|
Definition
|
|
Term
| What is depleted by ethionine? |
|
Definition
| ATP (& many others)via antagonizing methionine to form S-adenosylethionine => liver damage |
|
|
Term
| What is depleted by fructose? |
|
Definition
| ATP via rapid metabolism to fructose 1-P => hepatotoxicity |
|
|
Term
|
Definition
toxicity of fluoracetate
the process by which a toxicant similar in structure to an endogenous substrate is incorporated into the same metabolic pathway as the endogenous substrate => transformation to a toxic/lethal product |
|
|
Term
| What is fluoroacetate (which simulates acetate) converted into? |
|
Definition
|
|
Term
| What is inhibited by fluoracetate? |
|
Definition
|
|
Term
|
Definition
|
|
Term
|
Definition
| 3 ring ether with 2 C & an O |
|
|
Term
|
Definition
| N-R where N has 6 valence electros therefore an electrophile |
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Term
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Definition
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|
Term
A 67 yo pharmacologist was stung on the hand and forehead by bees. In less than 5 min, the sites were inflamed & developed lg. swelling. He felt restless & itchy all over. In the next 5-10 min., his entire body was bright red, skin was itchy & he developed hives. Soon his sight was blurred & he was feeling dizzy. In his medical cabinet there were antihistaminic, anticholinergic & adrenergic classes.
What drugs shoul be taken for immediate relief of his anaphylaxis?
What would be DOC? |
|
Definition
Adrenergics (to increase BP & improve breathing to prevent anaphylactic shock)
DOC: Epi (can be self-injected IM for rapid action) |
|
|
Term
| What are the adrenergics? |
|
Definition
| catecholamines s.a. NE & Epi |
|
|
Term
| What is the main neurotransmitter of sensory neurons? |
|
Definition
|
|
Term
| What is the main neurotransmitter of presynaptic neurons? |
|
Definition
|
|
Term
| What is the main neurotransmitter of postsynaptic neurons? |
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Definition
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|
Term
| What are the co-trasnmitters used in addition to the principal transmitters? |
|
Definition
|
|
Term
| What peptidergic cotransmitter is used in cholineric neurons? |
|
Definition
| VIP (vasoactive intestinal polypeptide) |
|
|
Term
| What peptidergic cotransmitter is used in adrenergic neurons? |
|
Definition
|
|
Term
|
Definition
|
|
Term
| What type of cell are adrenergic neurons? |
|
Definition
| multipolar cells w/ long axon & characteristic "beaded" terminal nerve endings |
|
|
Term
| What is the functional unit of the neuron? |
|
Definition
|
|
Term
| Where in the adrenergic neuron is the highest concentration of NE? |
|
Definition
|
|
Term
| Where is NE synthesized in the adrenergic neuron? |
|
Definition
| all regions => transported by vesicle to terminals by fast axoplasmic transport |
|
|
Term
| Why is it important to know that adrenergic neurons display fast transport? |
|
Definition
| Fast transport can be blocked by such drugs as colchicine & vinca alkaloids via inhibition of polymerization of microtubules/microfilaments |
|
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Term
|
Definition
|
|
Term
| What is contained in adrenergic varicosities? |
|
Definition
| lg # of vesicles storing NE (500-2000) |
|
|
Term
| What is the range of synaptic clefts from adrenergic nerve endings to their target organs? |
|
Definition
| small (10-20 nm vas deferens, SA node) to large (100-500 nm lg blood vessels, GI smooth muscle) |
|
|
Term
| When will adrenergic neurons produce faster & greater response? |
|
Definition
| more narrow synaptic junctions |
|
|
Term
| What are the 5 major events of the "life" of NE? |
|
Definition
1) storage
2) release
3) action
4) inactivation
5) recycling |
|
|
Term
|
Definition
Tyrosine -> L DOPA -> DA -> NE (-> Epi)
[true love does not exist] |
|
|
Term
| What is the end product of catecholamine synthesis in CNS? |
|
Definition
|
|
Term
| What is the end product of catecholamine synthesis in sympathetic neurons? |
|
Definition
|
|
Term
| Where is Epi the end product of catecholamine synthesis? |
|
Definition
|
|
Term
| What enzyme converts Tyrosine -> L DOPA? |
|
Definition
| tyrosine hydroxylase (TH) |
|
|
Term
| What enzyme converts L DOPA -> DA? |
|
Definition
|
|
Term
| What enzyme converts DA -> NE? |
|
Definition
|
|
Term
| What enzyme converts NE -> Epi? |
|
Definition
|
|
Term
| Where are the catecholamine synthesis enzymes TH, DD & DBH synthesized & transported to? |
|
Definition
| adrenergic nerve cell bodies & transported to nerve endings (where much of NE synthesis is carried out) |
|
|
Term
| What is the rate limiting enzyme of catecholamine synthesis? |
|
Definition
|
|
Term
| What 2 mechanisms regulate NE synthesis by TH activation regulation? |
|
Definition
1) phosphorylation of existing enzyme
2) induction or synthesis of new TH |
|
|
Term
| What balances the increased rate of NE release in enhanced frequency of sympathetic nerve impulses? |
|
Definition
| increased rate of NE synthesis via phosphorylation of TH |
|
|
Term
| What balances the increased rate of NE release in chronic activation of sympathetic nervous system (daily exercise, long exposure to cold, stress, etc)? |
|
Definition
| increased rate of NE synthesis via increasing synthesis of TH |
|
|
Term
| What does it mean that DBH is a vesicular enzyme? |
|
Definition
| ~75% of the enzyme is located in the membranes of storage granules & remaining in the soluble contents of the vesicles |
|
|
Term
| Why is the concentration of DBH used as an idication of sympathetic nerve activity of a patient? |
|
Definition
|
|
Term
| Where can PNMT mostly be found? |
|
Definition
| chromaffin cells of adrenal gland |
|
|
Term
| Why is PNMT found in the chromaffin cells of the adrenal gland? |
|
Definition
| It's where NE is methylated to form Epi |
|
|
Term
| What is the methyl donor to form Epi? |
|
Definition
|
|
Term
| What incudes PNMT in the adrenal medulla? |
|
Definition
|
|
Term
| How can glucocorticoids perfuse the adrenal medulla? |
|
Definition
| via adrenal cortical sinusoids |
|
|
Term
| What mechanism type is used to store NE & DA? |
|
Definition
| voltage & pH dependent mechanism |
|
|
Term
| What co-factors are required by VMAT (vesicular monoamine transporter) for NE & DA storage? |
|
Definition
|
|
Term
|
Definition
| vesicular pump for NE & DA storage |
|
|
Term
| What are the 2 types of VMAT? |
|
Definition
|
|
Term
| What do VMAT 1 & 2 transport? |
|
Definition
| 5-HT (serotonin), histamine & catecholamines |
|
|
Term
| Where is VMAT 1 mostly found? |
|
Definition
| periphery (esp. endocrine cells) |
|
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Term
|
Definition
| CNS (esp. neuronal cells) |
|
|
Term
| What molecule is NE to be found in association with within storage vesicles? |
|
Definition
|
|
Term
| Besides ATP, what is also found in the NE vesicle? |
|
Definition
| DBH, acidic proteins (chromogranins), ascorbic acid, Ca2+, etc. |
|
|
Term
| What cells in the adrenal medulla store Epi? |
|
Definition
| cells that have induced PNMT (in a similar way NE is stored) |
|
|
Term
| What are the only places chromogranins are found? |
|
Definition
1) adrenal medullary secretion granules
2) adrenergic nerve synaptic vesicles
3) endocrine tissues |
|
|
Term
| What is chromogranin A a marker for? |
|
Definition
| tumors of tissues containing chromogranins => over-expression & secretion of chromogranin A |
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Term
|
Definition
|
|
Term
| What channels open following adrenergic memebrane depolarization? |
|
Definition
| Ca2+ => extracellular Ca2+ to enter neurons |
|
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Term
| What does increased [Ca2+] at the mouth of Ca2+ channels of adrenergic neurons allow? |
|
Definition
| docked vesicles to exocytose via association of complex machinery |
|
|
Term
| What is released with NE? |
|
Definition
| everything contained in it's vesicle (DBH, chromogranins, ATP, ascorbic acid, etc) |
|
|
Term
| What happens to substances of high molecular wt. in the extracellular space? |
|
Definition
| uptaken into storage granules |
|
|
Term
| What are the 4 types of Ca2+ channels? |
|
Definition
P, T, N, L
(Pity Those who Never Love) |
|
|
Term
| Where are T Ca2+ channels found? |
|
Definition
|
|
Term
| Where are N Ca2+ channels found? |
|
Definition
| neuron (inc. sympathetic neurons!) |
|
|
Term
| Where are L Ca2+ channels found? |
|
Definition
| muscle, endocrine, exocrine glands |
|
|
Term
| Where are P Ca2+ channels found? |
|
Definition
| cerebellar Purkinje neurons |
|
|
Term
| What 2 Ca2+ channels are found in sympathetic neurons? |
|
Definition
Mostly: N
soma may contain some: L |
|
|
Term
| What happens to the cytosolic [Ca2+] after massive influx? |
|
Definition
| goes from 100-200nM to over 10,000nM |
|
|
Term
| Why is the massice rise of [Ca2+] transient? |
|
Definition
| Ca2+ channels rapidly close & mechanisms regulate the intracellular Ca2+ via pumps & buffers to bring [Ca2+] back to basal levels in a few seconds |
|
|
Term
| what action does NE have of the presynatpic nerve after its release in the synaptic cleft? |
|
Definition
| inhibitory to its own release |
|
|
Term
| What specific adrenergic receptor is responsible for NE feedback inhibition? |
|
Definition
|
|
Term
| How do α2 receptors turn off subsequent NE release? |
|
Definition
| either decrease in cAMP or inhibition of Ca2+ entry |
|
|
Term
| What adrenergic receptors are located postsynaptically? |
|
Definition
|
|
Term
| Why is it useful to know that α1 receptors differ from α2 receptors? |
|
Definition
| They have their own agonists and therefore can be used as pharmacologic targetrs (i.e. α2 agonists are useful in controlling high BP) |
|
|
Term
| What are the 3 paths NE can take once it's released into the synapse? |
|
Definition
1) diffusion
2) extraneuronal uptake
3) neuronal uptake via NET |
|
|
Term
|
Definition
| liver vis capillaries or lymphatics => metabolized by COMT & MAO |
|
|
Term
| How can NE be uptaken by effector cells? |
|
Definition
| via extraneuronal uptake (Uptake2) which is specific for catecholamines |
|
|
Term
| What inhibits Uptake2 of NE? |
|
Definition
| supra-physiological amounts of estrogens & corticosteroids |
|
|
Term
| What metabolizes NE in the effector cells? |
|
Definition
|
|
Term
| What does COMT metabolize NE to in the effector cells? |
|
Definition
| inactive nor-metanephrine |
|
|
Term
| What is the fate of inactive nor-metanephrine? |
|
Definition
| diffuse out of effector cell & either be eliminated in urine or further metabolized in liver by MAO |
|
|
Term
| How much of NE released into the synapse diffuse or are uptaken by effector cell? |
|
Definition
|
|
Term
| What happens to the 70% of NE not uptaken by the effector cell nor diffused? |
|
Definition
| taken back up into the releasing nerve terminals |
|
|
Term
| What pump is needed for reuptake (Uptake1) of NE? |
|
Definition
| amine pump NET (NE transporter) |
|
|
Term
| Does NET uptake other catecholamines? |
|
Definition
|
|
Term
| Is the synthetic catecholamine isoproterenol (Iso) transported by NET? |
|
Definition
|
|
Term
| What other function does NET have (for amines & other drugs)? |
|
Definition
| concentrate other amines & drugs (i.e. a variety of drugs can rapidly & effectively block NET) |
|
|
Term
| What antidepressants are known to block NET? |
|
Definition
|
|
Term
| What 2 enzymes metabolize NE? |
|
Definition
monoamine oxidase (MAO
catcechol-o-methyl transferase (COMT) |
|
|
Term
|
Definition
| nerve terminal (mitochondrial outer membrane), brain, liver, interstinal mucosa, & neuronal tissue |
|
|
Term
| Why is there MAO in nerve terminals? |
|
Definition
| to regulate NE content in cytosol |
|
|
Term
|
Definition
| effector cells & liver (NOT brain or neuronal cells) |
|
|
Term
| Does MAO or COMT metabolize NE first? |
|
Definition
either
MAO first in nerve terminal -> COMT in liver
or
COMT first in effector cells -> MAO liver |
|
|
Term
| What catecholamine products are found excreted in the urine? |
|
Definition
| mixture of catacholatimes, COMT NE & Epi products, MAO products, and COMT & MAO products |
|
|
Term
| What is the primart pathway of NE metabolism? |
|
Definition
| inactivation by COMT then oxidation by MAO |
|
|
Term
| What is the the metabolic pathway of Epi? |
|
Definition
|
|
Term
| How do the metabolic products differ if MAO or COMT metabolizes NE (or Epi) first? |
|
Definition
| they don't. they lead to the same end products if are metabolized by both (but individual products differ) |
|
|
Term
| What are the 2 end products of MOA & COMT metabolism together? |
|
Definition
|
|
Term
| What are the 2 types of adrenergic receptors? |
|
Definition
|
|
Term
Fuction
α receptor agonists |
|
Definition
contraction/excitation
(except in intestinal smooth muscle, pre-synaptic nerve terminals, platelets & brain where it inhibits) |
|
|
Term
Function
β receptor agonists |
|
Definition
relaxation/inhibition
(except in the heart & kidney where it stimulates) |
|
|
Term
| Can organs/cells have α & β receptors, or only one or the other? |
|
Definition
|
|
Term
| Can both α & β receptors be activated simultaneously, or only one or the other? |
|
Definition
| some adrenergic agoniss can stimulate both simulateneously |
|
|
Term
| Since both α & β receptors can be on a cell & both can be activated by the same agonists, what determines the final response? |
|
Definition
| dominance of receptor type & adrenergic agonist used. |
|
|
Term
| What are the 2 α receptors? |
|
Definition
|
|
Term
| Where are α1 receptors found? |
|
Definition
| postsynaptic smooth muscles of blood vessels, salivary glands, pancreas, internal sex organ, etc. |
|
|
Term
|
Definition
| presynaptic sympathetic nerve terminals, blood platelets & CNS |
|
|
Term
| What are the potencies of the 2 α agonists that affect only α1? |
|
Definition
| Phenylephrine (PE) > methoxamine |
|
|
Term
| What are the potencies of the 3 α agonists that affect only α2? |
|
Definition
| Clonidine > α-methyl-NE >> oxymetazoline |
|
|
Term
| What are the potencies of the 3 α aginists that affect α1 & α2? |
|
Definition
|
|
Term
| What are α & β receptors coupled with? |
|
Definition
|
|
Term
| What are the 2 β receptor types? |
|
Definition
|
|
Term
| What are the potencies of the 4 β agonists on β1 receptors? |
|
Definition
| Isoproterenol (Iso) > Epi > NE >>> Phenylephrine (PE) |
|
|
Term
| What are the potencies of the 4 β agonists on β2 receptors? |
|
Definition
|
|
Term
| What adrenergic receptors does DA activate? |
|
Definition
| none, it activates DA receptors (distinct from adrenergic α & β receptors) |
|
|
Term
| Where are the major effects of DA exerted? |
|
Definition
| CNS (therefore a lg # of antipsychotic & neuroleptic drugs target DA receptors) |
|
|
Term
| What are the 2 types of DA receptors? |
|
Definition
|
|
Term
| What are the 2 DA receptor subtypes in the D1 family? |
|
Definition
|
|
Term
| What are the 3 DA receptor subtypes in the D2 receptor family? |
|
Definition
|
|
Term
|
Definition
|
|
Term
| Where are D1 family receptors found? |
|
Definition
Mainly CNS (striatum, hypothalamus, hippocampus)
also: smooth muscle cells of blood vessels (esp. renal vasculature) |
|
|
Term
| What does D1 stiumlation do to the periphery? |
|
Definition
| vasodilation, natriuresis & diursis |
|
|
Term
|
Definition
| inhibits cAMP, blocks Ca2+ channels & opens K+ channels |
|
|
Term
| Where are D2 receptors found? |
|
Definition
| sympathetic ganglia, sympathetic nerve terminals & CNS (pituitary gland, substantia nigra, frontal cortex, medulla, hypothalamus, etc) |
|
|
Term
| What does stimulation of D2 family receptors do to the periphery? |
|
Definition
| hypotention, bradycardia, vasodilation |
|
|
Term
| What are the 2 DA agonists? |
|
Definition
|
|
Term
| What is the potency of the DA agonist DA on DA receptors & adrenergic receptors? |
|
Definition
|
|
Term
| What is the potency of the DA agonist fenoldopam on DA receptors & adrenergic receptors? |
|
Definition
|
|
Term
| What are the 3 ways DA produces cardiovascular actions? |
|
Definition
1) releasing NE from adrenergic neurons
2) interacting with α & β adrenergic receptors
3) interacting with specific DA receptors |
|
|
Term
|
Definition
| Increase HR, contraction, & cardiac output |
|
|
Term
| What is the main mechanism DA uses to increase HR, contraction & cardiac output? |
|
Definition
| activation of β receptors via NE release from sympathetic neurons in the heart |
|
|
Term
| Why is it important to know the relative potency of the neutrotransmitter at each receptor? |
|
Definition
| better prediction of the effects on the organ/organ system |
|
|
Term
| What with an amine that is indirectly acting on adrenergic receptors response look like? |
|
Definition
|
|
Term
| What receptor mediates all actions on the heart? |
|
Definition
|
|
Term
| Function
β1 agonist in the heart |
|
Definition
1)increased HR
2)increased contractile force
3)increased conduction
4)decreased cardiac efficency
5)arrhythmia induced |
|
|
Term
| What cells do β1 agonists bind to when affecting HR? |
|
Definition
| pacemaker cells of SA node |
|
|
Term
| What does activation of pacemaker cells of SA node via β1 agonists do to increase HR? |
|
Definition
| => more rapid diastolic depolarization & increase of frequency of APs via accelerating potassium leak in the diastolic interval decreasing threshold time for depolarization |
|
|
Term
| How can β1 agonists produce a decrease in HR (counterintuitive)? |
|
Definition
| if amine involved also causes an increase in BP (s.a. NE or PE) => vagus reflex activation can override direct action of amine on HR to decrease BP |
|
|
Term
| What cells with β1 receptors are activated to increae contractile force of the heart? |
|
Definition
|
|
Term
| How does activation of β1 agonists on myocardial cells increase contractile force? |
|
Definition
| => increase Ca2+ influx with each AP => greater force of contraction |
|
|
Term
| How is conduction of the heart increased by β1 agonists? |
|
Definition
velocity of impulse transfer from SA to AV nodes is increased
refractory period of AV node is decreased |
|
|
Term
| Which 2 β1 agoinsts are more likely to cause arrhythmias?
Why? |
|
Definition
NE & Epi bc they cause increase in BP too
BP increase => greater workload on heart => greater possibility of arrythmia
(further enhanced by general anesthetics) |
|
|
Term
| What adrenergic receptor mediates the kidney vascular beds? |
|
Definition
|
|
Term
| Effect
α1 agonist in the kidney vascular beds |
|
Definition
vasoconstriction with Epi & NE
slight vasodilation with Iso |
|
|
Term
| What adrenergic receptor is seen in skeletal muscle vascular beds? |
|
Definition
|
|
Term
Effect
PE & NE on skeletal muscle vascular beds
due to what receptor? |
|
Definition
| vasocontriction due to α1 |
|
|
Term
Effect
Epi on skeletal muscle vascular beds
due to what receptors? |
|
Definition
| vasodilation at lower concentration, but vasoconstriction at higher concentrations
Epi has higher affinity for β2 receptors than α1 receptors.
At low concentrations, β2 receptors are activated => vasodilation
At high concentrations, both α1 & β2 are activated, but the α1 receptors mediate the response. |
|
|
Term
Effect
Iso on skeletal muscle vascular beds
due to what receptors? |
|
Definition
| vasodilation due to β2 receptors |
|
|
Term
| What adrenergic receptor mediates the liver & spanchnic area vascular beds? |
|
Definition
| α1 (+ sm. β receptor component) |
|
|
Term
Effect
Epi & NE on liver & spanchnic area vascular beds |
|
Definition
vasocontriction: higher concentrations of Epi & NE
vasodilation: lower concentration of Epi |
|
|
Term
Effect
NE, Epi, & Iso on coronaries
due to what receptors? |
|
Definition
| vasodilation due to β2 receptors |
|
|
Term
| What is also a contributor to vasodialtion of the coronaries? |
|
Definition
| adenosine on smooth smuscles of coronaries during exercise |
|
|
Term
| Whaat adrenergic receptor mediates effect of pulmonary circulation? |
|
Definition
| Both α & β receptors, but α receptors dominate |
|
|
Term
Effect
Epi & E on pulmonary circulation |
|
Definition
| some relatively weak vasoconstriction |
|
|
Term
| What adrenergic receptors are seen in the α cells on the pancreas? |
|
Definition
|
|
Term
| What adrenergic receptors are seen in the β cells on the pancreas? |
|
Definition
|
|
Term
Effect
α cell β receptor agonist in pancreas |
|
Definition
| stimulation of glucagon secretion |
|
|
Term
Effect
β cell α receptor agonist in pancreas |
|
Definition
| inhibition of insulin secretion |
|
|
Term
|
Definition
| systolic increase, diastolic decrease => little to no change in overall BP |
|
|
Term
Effect
low [Epi] on cardiac output |
|
Definition
|
|
Term
Effect
low [Epi] on total peripheral resistance |
|
Definition
| decreased (due to vasodilation in skeletal muscle) |
|
|
Term
Effect
NE & higher [Epi] on BP |
|
Definition
| increase of both systolic & diastolic pressure => increased BP |
|
|
Term
Effect
NE & higher [Epi] on total peripheral resistance |
|
Definition
| increased (due to vasoconstriction in skeletal muscle) |
|
|
Term
|
Definition
| sm. increase in systolic, lg. decrease in diastolic => decrease in BP |
|
|
Term
| When can Iso cause decrease in cardiac output? |
|
Definition
| if vasodilation is too extreme => decrease in venous return |
|
|
Term
Effect
Iso on total peripheral resistance |
|
Definition
| decreased (due to vasodilation in skeletal muscle) |
|
|
Term
| What adrenergic receptors mediate the broncial smooth muscle? |
|
Definition
|
|
Term
| Effect
β2 agonist on bronchial smooth muscle |
|
Definition
| bonchodilation (thus β2 agonists are used in asthma) |
|
|
Term
| What adrenergic receptors mediate the iris radial muscle? |
|
Definition
|
|
Term
| Effect
α1 agonist on iris radial muscle |
|
Definition
| contraction => mydriasis (thus α1 agonists are used in opthalmology) |
|
|
Term
| What adrenergic receptors are in GI smooth muscle? |
|
Definition
|
|
Term
| Effect
α1 & β2 agonists in GI smooth muscle together |
|
Definition
| relaxation (tho sphincter muscles may contract) |
|
|
Term
| Why do α1 agonists cause relaxation in GI smooth muscle? |
|
Definition
| hyperpolarization => prevention of pacemaker potentials reaching threshold for AP => relaxation |
|
|
Term
| What adrenergic receptors are in bladder smooth muscle? |
|
Definition
|
|
Term
| What adrenergic receptors are dominant in the bladder detrussor muscle? |
|
Definition
|
|
Term
| Effect
β2 on bladder detrussor muscle |
|
Definition
|
|
Term
| Where are α1 receptors concentrated in the bladder? |
|
Definition
|
|
Term
| Effect
α1 agonists in the trigone region of the bladder |
|
Definition
|
|
Term
| What adrenergic receptors are in uterus smooth muscle? |
|
Definition
|
|
Term
Effect
NE on uterus smooth muscle |
|
Definition
|
|
Term
Effect
Epi on uterus smooth muscle |
|
Definition
|
|
Term
| Effect
β2 agonist on uterus smooth muscle |
|
Definition
| relaxation (thus β2 agonists are used to delay premature labor) |
|
|
Term
| What adrenergic receptors are dominant in spleen smooth muscle? |
|
Definition
|
|
Term
| Effect
α1 agonist in spleen |
|
Definition
| contraction => blood expulsion |
|
|
Term
| What adrenergic receptors are dominant in the vas deferens & seminal vesicles? |
|
Definition
|
|
Term
| Effect
α1 agonist in vas deferens & seminal vesicle smooth muscle |
|
Definition
|
|
Term
| How does an α1 agonist lead to contraction in vas deferens & seminal vesicles? |
|
Definition
| => membrane depolarization => AP generation => contraction |
|
|
Term
| What intracellular response is seen in β receptor activation? |
|
Definition
| increased cAMP => hyperglycemia, hyperlactemia, increase in FFA & overall increase in caloigenic effect |
|
|
Term
| Do Epi & NE readily cross the BBB? |
|
Definition
|
|
Term
| What CNS manifestation can EPI (& NE to a lesser extent) produce if given systemically? |
|
Definition
| resp. stimulation, restlessness & anxiety |
|
|
Term
| How do Epi & NE cause CNS manifestations? |
|
Definition
unclear
either direct action on CNS or indirect result of systemic effects |
|
|
Term
| Where is the CNS do neurons contain NE? |
|
Definition
|
|
Term
| Are there adrenergic receptors & NET in the CNS? |
|
Definition
|
|
Term
| What type of drugs are indirect-acting adrenergics? |
|
Definition
|
|
Term
| What are the 3 phenylethylamines? |
|
Definition
1) tyramine
2) amphetamine
3) ephedrine |
|
|
Term
| How do indirectly-acting adrenergic drugs (sympathomimetic) agents work? |
|
Definition
| releasing NE from sympathetic neurons (do NOT directly stimulate adrenergic receptors) => NE action on α & β receptors |
|
|
Term
| How do indirectly-acting adrenergic drugs cause release of NE? |
|
Definition
|
|
Term
| How do we know that NE is released by a non-exocytotic process via indirectly-acting adrenergic drugs? |
|
Definition
| Ca2+ not required and DBH & other NE vesicle contents are not released |
|
|
Term
|
Definition
| dose-dependent increase in BP, HR, & other NE effects for several minutes |
|
|
Term
| How does tyramine produce it's effect? |
|
Definition
accumulated by adrenergic neurons by NET => NE release from synaptic vesicles => NE diffusion out of nerve terminal
it also delays oxidation of NE in nerve terminal b/c it's a substrate of MAO |
|
|
Term
| How is tyrosine formed naturally? |
|
Definition
| product of decarboxylation of tyrosine (occurs in aged cheeses & some wines) |
|
|
Term
| Why can't tyramine be a drug? |
|
Definition
| When ingested in foods, it's oxidized by MAO to inactive product in gut mucosa & liver |
|
|
Term
| When can tyramine effects by profoundly potentiated, even life threatening? |
|
Definition
| when foods are administered with tyramine while on MAO inhibitors |
|
|
Term
| How do amphetamine & ephedrine differ from tyramine? |
|
Definition
| Same mechanism, same high affinity for MAO, just are not metabolized by MAO (therefore can be used as stong sympathomimetic drugs) |
|
|
Term
| What prevents MAO metabolism of amphetamine & ephedrine? |
|
Definition
|
|
Term
| What phenylethylamines can penetrate the BBB? |
|
Definition
|
|
Term
| What CNS effects are seen when amphetamine & ephedrine penetrate the BBB? |
|
Definition
| arousal - restlessness, remor, reduction of fatigue, loss of appetite (by release of NE and/or DA) |
|
|
Term
| What is the duration of action of amphetamine & ephedrine? |
|
Definition
|
|
Term
Effect
acute overdose of amphetamine & ephedrine |
|
Definition
confusion & anxiety
elevated BP
angina
cardiac arrhythmia
psychotic behavior (therefore supervise carefully) |
|
|
Term
| What develops in chronic amphetamine use? |
|
Definition
|
|
Term
|
Definition
phenomenon of rapid tolerance via lg doses of amphetamine
(BP response decreases over time with each subsequent dose) |
|
|
Term
| Why does tachyphylaxis occur? |
|
Definition
| gradual depletion of NE storage => decrease of NE release |
|
|
Term
Do NE & Epi injections demonstrate tachyplaxis?
Why? |
|
Definition
| no since they act directly on receptors and don't affect NE storage |
|
|
Term
| How does ephedrine differ from amphetamine? |
|
Definition
| ephedrine has some minor direct effects on adrenergic receptors |
|
|
Term
| Is ephedrine used as a drug? |
|
Definition
| not in the U.S., but psudoephedrine is used as an OTC decongestant |
|
|
Term
| What is the most important use of adrenergic drugs? |
|
Definition
|
|
Term
| How do anti-hypertensives decrease BP? |
|
Definition
| interefere with sympathetic neurotransmission at different steps to reduce release/action of NE => decreased sympathetic tone in vascular smooth muscle & in heart => decreased BP |
|
|
Term
| What are the 5 anti-ATN drugs? |
|
Definition
1) α-methyl tyrosine
2) Reserpine
3) Guanethidine
4) Clonidine
5) Methyldopa |
|
|
Term
| How does α-methyl tyrosine exhert it's antihypertensive effects? |
|
Definition
| TH inhibition (competes with tyrosine => inhibition of of L DOPA formation) |
|
|
Term
| What was the clinical use of α-methyl tyrosine? |
|
Definition
| pheochromocytoma to reduce catecholamines prior to surgical removal |
|
|
Term
| Why is α-methyl tyrosine no longer used? |
|
Definition
| produces renal damage via crystallization |
|
|
Term
| How does reserpine exert impairment to both autonomic nervous system & CNS? |
|
Definition
reduces NE storage by blacking NE carrier of synaptic vesicles => blacking of NE transport & permitting NE to accumulate in cytosol for metabloism by MAO => decreased adrenergic function in ANS
may also impair DA transport by synaptic vesicles => decreased adrenergic effect in CNS |
|
|
Term
| What 2 other non-adrenergic transmitters can be depleated by reserpine? |
|
Definition
| depletion of 5-HT from serotonergic neurons & histamine from platelets |
|
|
Term
| How long do the effects of reserpine last? |
|
Definition
| up to a week or more after the last dose |
|
|
Term
parasympathetic SE
reserpine |
|
Definition
miosis
excessive salivation
gastric hypersecretion
peptic ulceration
hyperperistalsis
diarrhea
bradycardia
hypotension |
|
|
Term
| Why is the SE profile for reserpine so extensive? |
|
Definition
| doesn't impair parasympathetic function |
|
|
Term
|
Definition
depression (=> suicide)
tremors |
|
|
Term
|
Definition
| alkaloid from snakeroot plant |
|
|
Term
|
Definition
|
|
Term
| What was one of the first synthetic anti-HTN medication? |
|
Definition
|
|
Term
|
Definition
| lower bp, HR, 7 renin secretion |
|
|
Term
|
Definition
1) uptaken to the sympathetic neuron by NET => blockage of NET (acute)
2) blocks exocytosis of NE & therefore transmission (acute)
3) with continued exposure, decreases NE stores (chronic) |
|
|
Term
| How is guanethidine used clinically? |
|
Definition
|
|
Term
| What is clonidine highly specific for? |
|
Definition
|
|
Term
| What is the rank of potency of α2 vs. α1 receptors for clonidine, α-methyl NE, NE, & phenylephrine? |
|
Definition
clonidine > α methyl NE > NE >>>> phenylephrine
α2 receptors α1 receptors |
|
|
Term
|
Definition
|
|
Term
| What adrenergic receptors does clonidine act on? |
|
Definition
| α2 receptors of CNS & imidazoline receptors |
|
|
Term
| Effect
clonidine on α2 receptors |
|
Definition
| reduce sympathetic outflow |
|
|
Term
Effect
clonidine on imidazoline receptors |
|
Definition
| decrease sympathetic outflow |
|
|
Term
|
Definition
| dizziness, nausea, impotense, dry mouth |
|
|
Term
| What SE are seen in sudden withdrawl of clonidine after long-term use? |
|
Definition
hypertensive crisis (due to over activity of sympathetic nerves)
Sx include:
nervousness, headache, tachycardia, hypotension, sweating, etc. |
|
|
Term
| What special Tx can clonidine or it's related agents be used for clinically? |
|
Definition
reduce intraoccular pressure
analgestic effects to help with withdrawl |
|
|
Term
| What other antihypertensive does methyldopa's MOA resemble? |
|
Definition
|
|
Term
| What is methyldopa metabolized to? |
|
Definition
|
|
Term
| Where is α-methyl NE stored? |
|
Definition
| in synaptic vesicles of adrenergic neurons => releasesame way NE is released |
|
|
Term
| How does α-methyl NE differ from NE? |
|
Definition
| much lower affinity for β receptors than NE |
|
|
Term
| Which α receptor does α-methyl NE have a much higher affinity for? |
|
Definition
|
|
Term
|
Definition
| reduce sympathetic nerve impulse activity in medulla via activation of α2 receptors
reduce renal vascular resistance |
|
|
Term
| What anti-depressants affect the adrenergic system? |
|
Definition
|
|
Term
| What are 3 examples of TCAs? |
|
Definition
1) imipramine
2) desipramine
3) amitryptyline |
|
|
Term
|
Definition
| block NET => enhanced NE action |
|
|
Term
| Which TCA is the most potent NET inhibitor & a weak 5-HT transport inhibitor? |
|
Definition
|
|
Term
| Which TCA inhibits 5-HT & NE equally well, but 20x less potent than desipramine? |
|
Definition
|
|
Term
| What other receptors can be blocked by TCAs at higher concentrations? |
|
Definition
|
|
Term
|
Definition
tremor
insomnia
blurred vision
orthostatic hypotension |
|
|
Term
| What 2 abusive drugs use adrenergic receptors? |
|
Definition
|
|
Term
|
Definition
| reversibly binds to NET, completely blocking the uptake of NE & Epi => marked enhancement of NE & Epi response |
|
|
Term
|
Definition
CNS stimulation (followed by depression-like action)
local anesthetic action (via nerve conduction block), but NOT at the same concentrations for NE & Epi potentiation |
|
|
Term
| How are amphetamines used clinically? |
|
Definition
|
|
Term
|
Definition
CNS arousal
suppress appetite & sleep |
|
|
Term
SE
chronic amphetamine overdose |
|
Definition
|
|
Term
|
Definition
restlessness
tremor
reduction of fatigue
loss of appetite |
|
|
Term
Sx
acute overdose
amphetamines |
|
Definition
severe confusion & anxiety
increased BP
angina
arrythmia
other adrenergic effects |
|
|
Term
| What are 3 amphetamines used to treat ADHD? |
|
Definition
1) methamphetamine
2) dextroamphetamine
3) adderall |
|
|
Term
| What ADHD amphetamine is the most abused? |
|
Definition
| methamphetamine (ritalin) aka crystal meth |
|
|
Term
| What are 2 potent β2 agonists that cause relaxation of cronchial smooth muscle? |
|
Definition
|
|
Term
| What 2 drugs are used to treat asthma, chronic bronchitis, nasal decongestant & mydriasis? |
|
Definition
|
|
Term
| Why isn't Iso used to Tx asthma? |
|
Definition
| risk of cardiac stimulation => need more selective β2 agonists |
|
|
Term
| What are the 2 cardiovascular emergencies? |
|
Definition
| Anaphylactic shock & Circulatory shock |
|
|
Term
| What 3 adrenergics are used to treat anaphylactic shock? |
|
Definition
1) Epi
2) NE
3) PE (parenteral) |
|
|
Term
| What 2 adrenergics are used to treat circulatory shock? |
|
Definition
1) NE
2) metaraminol (limited usefulness; may worsen condition) |
|
|
Term
| Why is local anesthetic often mixed with Epi or PE? |
|
Definition
| to decrease removal rate from injection site & increase duration of action |
|
|
Term
| What adrenergic agents are used to maintain blood pressure in spinal anesthesia? |
|
Definition
| Epi, PE, methoxamine, NE, etc. |
|
|
Term
| What adrenergic is used to treat urticaria (hives)? |
|
Definition
|
|
Term
| What 2 adrenergics are used as a nasal degongestant? |
|
Definition
|
|
Term
| What 2 adrenergics are used to cause mydriasis? |
|
Definition
1) PE
2) Ephedrine (topical) |
|
|
Term
| What 2 adrenergics are used to stimulate the CNS? |
|
Definition
1) amphetamine
2) methamphetamine |
|
|
Term
| What are the 2 isomer types of the adrenergic agonist dobutamine? |
|
Definition
|
|
Term
Function
L isomer Dobutamine |
|
Definition
| α agonist & weak β1 agonist |
|
|
Term
Function
D isomer Dobutamine |
|
Definition
| α1 antagonist & potent β1 agonist |
|
|
Term
| Since Dobutamine comes as a racemic mixture of both L & D isomers, what is the overall effect of Dobutamine? |
|
Definition
|
|
Term
| When is dobutamine used clinically? |
|
Definition
| actue management of heart failure to improve cardiac output |
|
|
Term
Function
adrenergic antagonists |
|
Definition
| inhibit action of NE, Epi & other adrenergic agonists at receptor level => inhibits responses of effector organs |
|
|
Term
|
Definition
| decrease in BP due to decrease in vascular resistance => reflex tachycardia & increase in cardiac output |
|
|
Term
| Which α receptor can exaggerate the effects of α antagonists? |
|
Definition
|
|
Term
| Why do α2 antagonists exaggurate α agonist effects? |
|
Definition
| enhanced NE in cardiac tissues => stimulation of β1 receptors |
|
|
Term
| How do α2 antagonists increase NE release in heart (& blood vessels)? |
|
Definition
| they "disinhibit" sympathetic drive to periphery => increased sympathetic outflow and NE release in heart & blood vessels |
|
|
Term
| What ate the 3 α antagonist groups? |
|
Definition
1) Haloalkylamines
2) Imidazolins
3) Qunazolins |
|
|
Term
What α antagonist type are phenoxybenzamine?
prazosin?
phentolamine? |
|
Definition
phenoxybenzamine: haloalkylamine
phentoalmine: imidazolin
prazosin: quanzolin |
|
|
Term
| Which type of α agonists are more popular clinically? |
|
Definition
|
|
Term
|
Definition
a noncompetitive irreversible α adrenergic antagonist.
It forms a covalent bond b/w α receptors & drug |
|
|
Term
| What are the "other" actions of phenoxybenzamine? |
|
Definition
| blocks neuronal & extraneuronal uptake of NE |
|
|
Term
| Why is phenoxybenzamine considered non-specific? |
|
Definition
| It blocks receptors for 5-HT, Ach, & histamine too |
|
|
Term
| What is the clinical use of phenoxybenzamine? |
|
Definition
management of Sx associated with pheochromocytoma & severe HTN
Use 1-3 weeks prior to operation to control exaggerated actions of catecholamines released from the tumor
Tx for peripheral vascular disease (Raynaud's syndrome) |
|
|
Term
|
Definition
| competitive reversive α antagonist |
|
|
Term
| How is phentolamine used clinically? |
|
Definition
HTN control in patients with pheochromocytoma
hypertensive crisis following abrupt withdrawl of clonidine or tyramine containing foods when on an MAO inhibitor |
|
|
Term
|
Definition
| slective antagonist of α1 (about 1000x greater affinity for α1 than α2) |
|
|
Term
| What is the clinical use for prazoin? |
|
Definition
HTN
congestive cardiac failure |
|
|
Term
| Why is prazoin used in congestive cardiac failure? |
|
Definition
| reduces preload & afterload |
|
|
Term
| What is the half life of prazoin? |
|
Definition
|
|
Term
| What is the duration of action of prazoin? |
|
Definition
|
|
Term
| What is the advantage of doxazoin over prazoin (newer α1 blocker)? |
|
Definition
| longer half life (10 hr) therefore longer duration of action (~20 hr) |
|
|
Term
| What are the 3 α1 subtypes? |
|
Definition
|
|
Term
| What are the 3 α3 subtypes? |
|
Definition
|
|
Term
| What are the most important adrenergic agents clinically? |
|
Definition
|
|
Term
| What 2 β antagonists are among the most perscribes Rx every year? |
|
Definition
|
|
Term
| What are β blockers used clinically for Tx of? |
|
Definition
HTN
angina
arrythmias
prevention of 2nd heart attack
MI
migranes
tremors
EtOH withdrawl
anxiet
glaucoma
etc. |
|
|
Term
| What synthetic β blocker is the classical prototype β antagonist that all others are compared to? |
|
Definition
|
|
Term
|
Definition
| selective β antagonist without any agonist activity |
|
|
Term
| Why is propranolol only used in times of sympathetic elevation (exercise/stress)? |
|
Definition
| it has little cardiovascular effect alone (compared to α antagonists), but has great effect in times of stress |
|
|
Term
|
Definition
| decrease HR & cardiac output (β1)
reduced sinus rate & slowed conduction
increased peripheral resistance (β2) => initial increase in BP (followed by normalization via vagus)
release of renin from juxtaglomerular apparatus (β1)
decrease peripheral manifestations of hyperthyroidism
reduce intraoccular pressure
anxiety management
prophylaxis of migranes |
|
|
Term
| What β blocker has complication when reducing intraoccular pressure in glaucoma and occular HTN? |
|
Definition
|
|
Term
| Why are β blockers used as anxiolytics? |
|
Definition
| anxiety is caused by increased activity of SS |
|
|
Term
MOA
β blocker prophylaxis of migranes |
|
Definition
| block CNS β receptors => vasodilation |
|
|
Term
| When should β blocker NOT be used (b/c the worsen the condition)? |
|
Definition
asthma
congestive heart failure
Raynaud's syndrome
diabetes |
|
|
Term
| What DDI is important to remember when dealing with β blockers? |
|
Definition
| β blockers + Ca2+ channel blockers = AV block |
|
|
Term
| Why must β blockers be withdrawn gradually after prolonged use? |
|
Definition
| To avoid withdrawl Sx, which include MI |
|
|
Term
| When can selective β blockers be non-selective? |
|
Definition
|
|
Term
| What 7 β blockers are non-selective (i.e. blocks both β1 & β2)? |
|
Definition
1) Propranolol
2) Carteolol
3) Levobunolol
4) Nadolol
5) Pindolol
6) Timolol
7) Penbutolol |
|
|
Term
| What is the only non-selevtive β blocker to be a full partial agonist? |
|
Definition
pindolol
(slight acitivity with carteolol, timolol, penbutolol) |
|
|
Term
| What is the only non-selective β blocker with membrane stabalizing capability? |
|
Definition
propranolol
(slight activity with pindolol) |
|
|
Term
| What are the 5 cardio selective β blockers (i.e. β1)? |
|
Definition
1) Acebutolol
2) Atenolol
3) Betaxolol
4) Esmolol
5) Metoprolol |
|
|
Term
| What is the only cardio-selective β blocker with slight partial agonist activity? |
|
Definition
|
|
Term
| What are the 2 cardio-selective β blockers with slight membrane stablilization? |
|
Definition
|
|
Term
|
Definition
| cardiospecific β blocker for β1 |
|
|
Term
|
Definition
decrease cardiac force of contraction & HR
vasodilation
decrease in peripheral resistance |
|
|
Term
| What is the classic α & β blocking agent? |
|
Definition
|
|
Term
| How does labetolol compare in potency to other α & β blockers? |
|
Definition
1/3 as potent as propranolol
1/10 as potent as phentolamine |
|
|
Term
| Is labetolol more selective for α or β adrenergic receptors? |
|
Definition
|
|
Term
| Is labetelol a selective or non-selective β blocker? |
|
Definition
|
|
Term
| Does labetolol have any partial agonist activity or membrane stabilization like other β blockers? |
|
Definition
|
|
Term
| What does membrane stabilization mean? |
|
Definition
| local anesthetic-like action |
|
|
Term
| What α receptor does labetelol have little affinity for? |
|
Definition
| pre-synaptic α2 receptors |
|
|
Term
| How does labetelol have cocaine-like action? |
|
Definition
| blocks NE neuronal uptake |
|
|
Term
|
Definition
| lower peripheral vascular resistance w/o major change of HR or CO (sum of effects of α & β blockers) |
|
|
Term
| When is labetelol used clinically? |
|
Definition
HTN
HTN w/ angina
preop management of patients with pheochromocytoma |
|
|
Term
|
Definition
|
|
Term
| What are the ABCs of emergency medicine? |
|
Definition
Airway
Breathing
Circulation
(implies nothing's more important than making sure the patient has an airway) |
|
|
Term
| How is airway-breathing of a poisoned patient assessed/restored? |
|
Definition
1) remove obstruction
2) intubate early
3) ventilate if necessary
4) ABG to assess:
a) oxygenation
b) ventilation
c) acid-base status |
|
|
Term
| How is circulation of a poisoned patient assessed/restored? |
|
Definition
1) Obtained BP & pulse
2) Cardiac monitoring & cardioversion
3) Fluids
4) 12 lead EKG asap
5) Vasopressors |
|
|
Term
| What are the "Other C's"? |
|
Definition
|
|
Term
| What do the ABCs help with in emergency medicine? |
|
Definition
|
|
Term
What 4 substances are immediately given to all ER patients with altered mental status?
Why? |
|
Definition
1) Oxygen
2) Glucose (in case of diabetic shock)
3) Naloxone (in case of narcotic OD)
4) Thiamine (in case it's Wernicke's) |
|
|
Term
| What patient's would NOT get naloxone if altered mental status? |
|
Definition
1) opiod dependent w/o apnea/severe resp. depression
2) Hx of speedball abuse
3) agitated/seizing
4) pregnant & opiod dependent |
|
|
Term
| What is flumazenol used for clinically? |
|
Definition
|
|
Term
| Why isn't flumazenol used regularly? |
|
Definition
| can precipitate benzo withdrawl |
|
|
Term
| What is done after a patient is stablized? |
|
Definition
Disrobe patient and do a thourough PE (always starting with vital signs)
check for:
trauma
odors
burns/tracks
bullae
**neuro exam |
|
|
Term
| What Hx is obtained from the patient? |
|
Definition
complete Hx:
HPI & PMH
(though, you will need to confirm with friends, family, police, paramedics since ~50% of the time it's inaccurate) |
|
|
Term
| What happens if your poisoned patient is tachycardic? |
|
Definition
| It's not very specific, but gives a general area of where to start looking |
|
|
Term
| What happens if your poisoned patient is bradycardic? |
|
Definition
| It's very specific and narrows the list of substances significantly, down to 4 main substances (+ some other rare substances) |
|
|
Term
| What are the 4 drugs you think of poisoning when your patient is bradycardic? |
|
Definition
| 1) β blocker
2) Ca2+ channel blocker
3) clonidine (α2 agonist)
4) digoxin (for digitalis [cardiac glycosides made from foxgloves plants]) |
|
|
Term
| Besides cold exposure, what is the number one cause of hypothermia? |
|
Definition
|
|
Term
| What are the 2 common causes of hyperthermia? |
|
Definition
1) ecstacy
2) anticholinergics (no sweat) |
|
|
Term
| What drugs can cause both hypothermia & hyperthermia depending on the season (no body temp regulation)? |
|
Definition
|
|
Term
| What drugs can cause HTN in OD? |
|
Definition
| same as tachycardic (usually stimulants of some kind) |
|
|
Term
| What 2 drugs should you think of when your patient is hypotensive? |
|
Definition
1) opiates
2) sedative hypnotics |
|
|
Term
| What does hyperventilation tell you about a patient? |
|
Definition
| It's very non-specific, but it could indicate metabloic acidosis |
|
|
Term
| How helpful is it to notice miosis in a patient? |
|
Definition
| Very - tends to be more specific |
|
|
Term
| What drugs should you think of when you have a miotic patient? |
|
Definition
1) opiates
2) cholinergics |
|
|
Term
| How helpful is it to notice mydriasis in a patient? |
|
Definition
| Not so helpful, unless dramatic |
|
|
Term
| What drugs should you think of if your patient has dramatic mydriasis? |
|
Definition
|
|
Term
| How specific is nystagmus in a poisoned patient? |
|
Definition
| Not too specific, but you do think of sedative hypnotics |
|
|
Term
| What drugs cause rotational nystagmus? |
|
Definition
|
|
Term
| What odor is smelled with heavy metals? |
|
Definition
|
|
Term
| What happens if you smell bitter almonds? |
|
Definition
|
|
Term
Toxidrome
Anticholinergics
(Pulse, BP, Resp., Temp., Bowel Sounds) |
|
Definition
Pulse: ↑
BP: ↑
Resp.: ↑
Temp: ↑
Bowel Sounds: ↓ |
|
|
Term
Toxidrome
Anticholinergics
(Skin, Mental Status, Pupils, Other) |
|
Definition
Skin: dry, red, hot (as a bone, as a beet, as a hare)
Mental Status: altered
Pupils: mydriasis
Other: urinary retention |
|
|
Term
Toxidrome
Sympathomimetic
(Pulse, BP, Resp., Temp., Bowel Sounds) |
|
Definition
Pulse: ↑
BP: ↑
Resp.: ↑
Temp: ↑
Bowel Sounds: normal |
|
|
Term
Toxidrome
Sympathomimetic
(Skin, Mental Status, Pupils, Other) |
|
Definition
Skin: sweaty
Mental Status: altered
Pupils: mydriasis
Other: bruxism |
|
|
Term
Toxidrome
Cholinergic
(Pulse, BP, Resp., Temp., Bowel Sounds) |
|
Definition
Pulse: ↓
BP: normal
Resp.: normal
Temp: ↓
Bowel Sounds: ↑ |
|
|
Term
Toxidrome
Cholinergic
(Skin, Mental Status, Pupils, Other) |
|
Definition
Skin: sweaty
Mental Status: normal
Pupils: miosis
Other: fasciulations, weakness, odors |
|
|
Term
Toxidrome
Opioids
(Pulse, BP, Resp., Temp., Bowel Sounds) |
|
Definition
Pulse: ↓
BP: ↓
Resp.: ↓
Temp: ↓
Bowel Sounds: ↓ |
|
|
Term
Toxidrome
Opioids
(Skin, Mental Status, Pupils, Other) |
|
Definition
Skin: sweaty
Mental Status: ↓
Pupils: miosis
Other: track marks |
|
|
Term
| What 5 options do ED doctors have to decrease further absorption in a poisoned patient? |
|
Definition
1) skin/eye decontamination
2) gut decontamination
3) activated charcoal
4) cathartics
5) whole bowel irrigation |
|
|
Term
| What is the #1 decontamination rule? |
|
Definition
| Protect yourself & your staff |
|
|
Term
| How is eye decontamination done? |
|
Definition
| iirgate with copious amounts of saline |
|
|
Term
| How is skin decontamination done? |
|
Definition
Begin with wounds and you can use:
water
mild soap
50/50 detergent/corn starch
dilute bleach |
|
|
Term
| How do you decontaminate GI tract from a corrosive substance? |
|
Definition
Children: 4oz water only
Adults: 8oz water, then go to ED |
|
|
Term
|
Definition
|
|
Term
| Though Ipecac is not really used anymore, when should you NOT use it for sure? |
|
Definition
<1 yr
CNS depression (vomiting unconscious child = bad)
corrosive agent (burns on the way down & up) |
|
|
Term
|
Definition
| placement of lg. bore orogastric tube into stomach & pump 2+ L saline |
|
|
Term
| When is gastric lavage used clinically? |
|
Definition
1) patients who have come to ED within 1 hr of ingestion
2) patients who have ingested copious amounts of a sunbstance |
|
|
Term
| Why isn't gastric lavage used more frequently? |
|
Definition
| risk of airway blockage & aspiration |
|
|
Term
| When is gastric lavage contraindicated? |
|
Definition
1) unprotected airway
2) ingestion of corrosive substance |
|
|
Term
| What is your "friend" when trated poisons ingested? |
|
Definition
|
|
Term
|
Definition
1) direct absorption of material
2) interrupt enterohepatic recirculation
3) gut dialysis |
|
|
Term
| When in charcoal contraindicated? |
|
Definition
1) certain substances s.a. hydrocarbons & metals (Fe, Li) that don't bind to it
2) corrosive agents
3) intestinal obstruction |
|
|
Term
| When would multiple doses of charcoal be needed? |
|
Definition
| drugs that have enterohepatic recirculation |
|
|
Term
| Why is sorbitol given when charcoal is administered? |
|
Definition
| to move the charcoal (bound to poison) through the stomach and out |
|
|
Term
|
Definition
|
|
Term
def
whole bowel irrigation |
|
Definition
|
|
Term
| When would you do a massive bowel irrigation? |
|
Definition
| When charcoal won't work, body packers |
|
|
Term
| When is whole bowel irrigation contraindicated? |
|
Definition
|
|
Term
| Why are drugs that cause concretions "annoying"? |
|
Definition
| Can cause prolonged intoxication |
|
|
Term
| What lab diagonostic tests can be done to help with deciding on a toxicant? |
|
Definition
1) EKG
2) UA
3) few bedside tests |
|
|
Term
| How do you calculate the anion gap? |
|
Definition
| AG = Na - (HCO3 + Cl)
with normal ~ 12 |
|
|
Term
| What is the mnemonic for an increaed anion gap? |
|
Definition
|
|
Term
|
Definition
MeOH
Uremia
Diabetes
Paraldehyde/phenformin
Iron/isoniazid
Lactate
Ethylene Glycol
Salicylates
(anything that causes lactic acidosis) |
|
|
Term
| What are the 2 causes of decreased anion gap? |
|
Definition
|
|
Term
| How do you calculate osmolality? |
|
Definition
| Os = 2Na + (Glucose/18) + (BUN/2.8) |
|
|
Term
| How do you calculate the osmolol gap? |
|
Definition
OG = measured os - calculated os
normal ~ 10 |
|
|
Term
| What sm. osmols can increase the osmolal gap? |
|
Definition
|
|
Term
| Why are drug screens unreliable? |
|
Definition
| not necessarily specific or sensitive for what was the poison |
|
|
Term
| How are drugs of abuse drug screened? |
|
Definition
|
|
Term
| Why are urine drug tests unreliable? |
|
Definition
| Just say what the patient has used, not necessarily why they're there today |
|
|
Term
| What drug screens are more useful? |
|
Definition
|
|
Term
| What tox screen method is the "gold standard" (very sensitive & specific)? |
|
Definition
|
|
Term
| How is xray helpful in Dx of a toxicant? |
|
Definition
| some toxicants are radiopaque |
|
|
Term
|
Definition
| enhanced elimation where drugs that are weak acids or weak bases can be trapped alkalinization or acidification (not reccomended) of urine |
|
|
Term
| Why is hemodialysis not used frequently? |
|
Definition
| only a small list of drugs can be removed this way (sm. molecular wt., low protein binding, sm. volume of distribution s.a. salicylates, MeOH, Li, ethylene glycol) |
|
|
Term
| When would you use hemoperfusion? |
|
Definition
| when a substance meets the criteria for hemodialysis, but is highly protein bound |
|
|
Term
|
Definition
| pump charcoal cartridge thru blood |
|
|
Term
| What are the 2 "bread & butter" antidotes? |
|
Definition
1) N-acetylcysteine => acetaminophen
2) Naloxone => opiates |
|
|
Term
| When is sodium bicarbonate given in OD situations? |
|
Definition
|
|
Term
| What is the antidote for digoxin? |
|
Definition
|
|
Term
| What toxins do you think of in house fires? |
|
Definition
|
|
Term
| What intoxicant are you thinking for a patient passed out with a needle in their arm? |
|
Definition
|
|
Term
| What is the antidote for an opioid? |
|
Definition
|
|
Term
| What toxicant are you thinking if someone's hands are blue & their blood is brown? |
|
Definition
| some type of oxidant s.a. methemoglobulinemia |
|
|
Term
| What is the antidote for methemoglobulimemia? |
|
Definition
|
|
Term
| What is the antidote for ethylene glycol poisoning (antifreeze)? |
|
Definition
| either EtOH or a chemical blocker antizol |
|
|
Term
| What is the anitdote for a rattlesnake bite? |
|
Definition
|
|
Term
| Why is hematopoiesis necessary? |
|
Definition
| short life span of blood cells => need for continuous replacement |
|
|
Term
|
Definition
| significant reduction in functional red cell mass with consquent reduction in oxygen carrying capacity |
|
|
Term
| What are the 3 causes of anemia? |
|
Definition
1) blood loss
2) reduced RBC production
3) production of abnormal RBCs or precursor cells |
|
|
Term
| What 9 cells are formed by hematopoiesis? |
|
Definition
1) RBCs
2) eosinophils
3) basophils
4) ganulocytes
5) monocytes
6) platelets
7) B cells
8) T cells
9) NK cells |
|
|
Term
| What plays a role in synthesis of mature cells in hematopoiesis? |
|
Definition
| GFs & cell-cell interactions |
|
|
Term
| Where is erythropoietin synthesized? |
|
Definition
proximal tubular cells of kidney
(sm. amount made in liver) |
|
|
Term
| Why is erythropoietin glycosylated? |
|
Definition
| to prolong half life (it is not essential) |
|
|
Term
|
Definition
1) Reulation of proliferation of committed progenitors (CFU-E), maturation of erythroblasts, & release of reticulocytes
2) Synergistic with IL-3 & GM-CSF to expand BFU-E population
3) promote release of maturer reticulocytes into circulation from bone marrow
4) prevent anemia |
|
|
Term
| When will a patient have a rapid increase of erythropoietin? |
|
Definition
|
|
Term
| How does erythropoietin promote maturation of committed progenitors? |
|
Definition
| binds to membrane surface receptor of bone marrow cells |
|
|
Term
| What are myeloid GFs aka? |
|
Definition
| colony-stimulating GFs (CSFs) |
|
|
Term
|
Definition
| glycoproteins that stimulate proliferation & differentiation of several types of hematopoietic precursor cells & enhance the function of mature leukocytes. |
|
|
Term
| What are the 4 human CSFs? |
|
Definition
1) GM-CSF (granulocyte/macrophage)
2) M-CSF (macrophage)
3) G-CSF (granulocyte)
4) IL-3 |
|
|
Term
| What synthesizes GM-CSF & IL-3? |
|
Definition
|
|
Term
| What synthesizes GM-CSF, G-CSF, & M-CSF? |
|
Definition
| monocytes, fibroblasts, & endothelial cells |
|
|
Term
|
Definition
1) stimulate colony formation of most hematopoietic cell lines
2) synergistic with GM-CSF to increase neutrophils, monocytes & eosinosinophils
3) synergistic with erythropoietin to expanf BFU-E compartment & stimulate CFU-E proliferation
4) influence function of eosinophils & basophils |
|
|
Term
|
Definition
1) synergistic with IL-3 to stimulate colony formation & proliferation of granulocytes, monocytes/macrophages, & megakaryocytes
2) synergistic with erythropoietin to promote formation of BFU-E
3) increases phagocytic & cytotoxic potential of mature granulocytes, but reduces motility & clearance from circulation
4) increases cytotoxicity of eosinophils & leukotriene synthesis |
|
|
Term
|
Definition
1) stimulate granulocyte colony formation
2) synergistic with GM-CSF to simulate granulocyte/macrophage colonies & with IL-3 to induce formation ot megakaryocytes
3) induce release of granulocytes from marrow
4) enhance phagocytic & cytotoxic activities of mature granulocytes |
|
|
Term
|
Definition
1) stimulate monocyte/macrophage colony formation alone & synergistically with GM-CSF & IL-3
2) induce synthesis of G-CSF & IL-1
3) enhance production of IFN & TNF
4) enhance function of monocytes & macrophages |
|
|
Term
| How is erythropoietin administered for therapeutic purposes? |
|
Definition
|
|
Term
| How is erythropoietin used clinically? |
|
Definition
1) anemia due to chronic renal failure
2) transfusion-dependent patients undergoing hemodialysis
3) anemia in patients with progressive renal failure (not requiring dialysis)
4) other anemias
5) preop to increase RBCs to allow storage of larger volumes of blood for autologous transfusion |
|
|
Term
| Do I hate learning about hematopoiesis? |
|
Definition
yes!
(i hope someone reads this card, bc its true) |
|
|
Term
| What is the half life of patients on erythropoietin in chronic renal failure for IV administration? |
|
Definition
|
|
Term
| When is peak plasma concentration seen in SC injection of erythropoietin |
|
Definition
|
|
Term
| Why must dose of erythropoietin be titrated? |
|
Definition
| to avoid excessively rapid increase in hematocrit early in therapy or a rise in hematocrit above 36% during maintenance |
|
|
Term
| Why might a patient need iron supplements in addition to erythropoietin? |
|
Definition
| erythropoietin requires adequate iron stores |
|
|
Term
SE
erythropoietin toxicity |
|
Definition
increase of RBC => HTN & thrombotic phenomena
possible mild allergic rxn |
|
|
Term
| How is erythropoietin SE avoided? |
|
Definition
| raising hematocrit slowly & closely monitoring BP |
|
|
Term
| What internal cell singals occur in the kidney to produce more erythropoietin? |
|
Definition
| Gs stimulation -> increase AC -> increase cAMP -> activation of Kinase A -> activation of phosphoproteins -> stimulation of mRNA production of erythropoietin |
|
|
Term
| What are the 4 major areas meyloid GFs (CSFs) are used clinically? |
|
Definition
1) restoration of normal hematopoiesis in patients with malignancies or non-neoplastic diseases that interfere with marrow production
2) reduction in the morbidity of chemotherapy by diminishing duration of severe neutropenia
3) augmentation of host defenses against inf.
4) adjunct role in chemotherapy to improve cytotoxicity against tumor cells & promote cell maturation |
|
|
Term
|
Definition
site of injection: local induration
site of infusion: thrombophlebitis
fever, myalgia, fatigue, rash, GI Sx, bone pain (common, but dose dependent)
pericarditis, pleuritis, pleural effusions, & pulmonary emboli (dose-limiting)
G-CSF associated with: mild/moderate bone pain, vasculitis & worsening of psoriasis
may have ongogenic potential |
|
|
Term
Hematopoietic GFs
[image] |
|
Definition
1) GM-CSF/IL-3
2) Erythropoietin
3) GM-CSF/G-CSF
4) GM-CSF/M-CSF |
|
|
Term
A 60 yo woman presents with stage IV ovarian cancer. The standard of care Tx is cytoreductive surgery followed by administration of systemic chemotherapy.
1st line therapy consists of carboplatin in combination with paclitaxel. The drugs are given via IV infusion. The "madir" occurs b/w days 10-14.
What can be done to mitigate leukopenia & anemia? |
|
Definition
| Administration of one of the CSFs to promote maturation of the progenitive cells. |
|
|
Term
An obese woman of child bearing age with fertility issues presents for couseling. Blood tests show hemoglobin values <130 g/L.
Example questions: Which follow up tests would you order & what are the likely causes of her anemia? How could this anemia be treated? What impact would be had on a developing fetus if left untreated?
What is this case study illustrating (the only actual question answered on card)? |
|
Definition
| It's important to understand the etiology of an anemia before any Tx is delivered or prognosis. |
|
|
Term
| What is the most common cause of nutritional anemia? |
|
Definition
|
|
Term
| What is the characteristic result of severe iron deficiency? |
|
Definition
| microcytic, hypochromic anemia secondary to reduction in synthesis of Hb |
|
|
Term
| Why does iron deficiency have effects besides those on RBCs? |
|
Definition
| Iron is a required group in many other proteins. |
|
|
Term
| Besides its affect of RBCs, what other effects might occur in iron deficiency? |
|
Definition
| altered muscle metabloism independent of the effect on oxygen delivery via blood |
|
|
Term
| What are the 3 causes of iron0deficiency anemia? |
|
Definition
1) inadequate dietary iron
2) blood loss
3) interference with iron absorption |
|
|
Term
| What is the cause of most nutritional iron deficiency in the U.S.? |
|
Definition
blood loss
1) by the GI
2) by the uterus |
|
|
Term
| How is iron found in the body? |
|
Definition
1) in essential iron containing compounds
2) stored (excess) |
|
|
Term
| Where is 70% of the iron in our body found? |
|
Definition
|
|
Term
| What is the storage form of iron? |
|
Definition
|
|
Term
| How much is ferritin found (molecules or aggregates)? |
|
Definition
| either individual molecules or aggregated form |
|
|
Term
| How many atoms of iron can each ferritin molecule bind? |
|
Definition
|
|
Term
|
Definition
|
|
Term
| Where is hemosiderin predominately found? |
|
Definition
reticuloendothelial system in liver
(some in muscle) |
|
|
Term
| What is the plasma protein for iron transport? |
|
Definition
|
|
Term
| What regulates sysnthesis of transferrin receptors & ferritin? |
|
Definition
iron supply
1) when high, sysnthesis of transferrin receptors are reduced & ferritin production is increased
2) if low, tranferrin receptors are increased and ferritin production is decreased |
|
|
Term
| Why is dietary intake or realease from body stores the primary determinant of iron content in cells? |
|
Definition
| low body turnover of iron |
|
|
Term
Where does each stage of Fe absorption pathway occur?
[image] |
|
Definition
1) intestinal lumen
2) mucosa
3) blood
4) tissue |
|
|
Term
| What determines iron requirements? |
|
Definition
| Obligatory physiological losses & need for growth |
|
|
Term
| Why do females require more iron/day than males? |
|
Definition
|
|
Term
| When do females need 4x the normal amount of iron/day? |
|
Definition
| last 2 trimesters of pregnancy |
|
|
Term
| When else might a patient need 4x the daily dose of iron? |
|
Definition
| infants (due to rapid growth) |
|
|
Term
| What are the dietary sources of iron? |
|
Definition
Good: organ meats, egg yolk, oyster, certain dried beans & fruit
Poor: dairy, non-green vegetables |
|
|
Term
| What is the most readily bioavailable form of iron? |
|
Definition
| heme iron (but non heme iron is the majority of dietary iron) |
|
|
Term
| What helps the absorption of nonheme iron? |
|
Definition
|
|
Term
| How does ascorbate increase nonheme iron absorption? |
|
Definition
| 1) complexing with iron
2) reducing Fe3+ to Fe2+ |
|
|
Term
| What are the 2 options of iron deficiency Tx? |
|
Definition
1) Oral iron therapy
2) parenteral iron therapy |
|
|
Term
|
Definition
| nausea, epigastric discomfort, abdominal cramps, constipation, diarrhea (dose related) |
|
|
Term
| How are oral iron therapy SE avoided? |
|
Definition
| taking tablets with meals |
|
|
Term
| When might an iron deficient patient recieve parenteral iron therapy? |
|
Definition
1) cannot tolerate or absorb oral iron
2) chronic blood loss
(since iron stores are repleated more rapidly than by oral therapy) |
|
|
Term
| How are Vit B12 & folic acid deficiencies interconnected? |
|
Definition
| Vit B12 is needed for folic acid to work => deficiency of either results in decreased synthesis of methionine & S-adenosylmethionine => interference with protein synthesis & methylation rxns |
|
|
Term
| What does Vit B12 complex with in the stomach in order to be absorbed? |
|
Definition
|
|
Term
| What secretes IF in the stomach? |
|
Definition
|
|
Term
| What plasma protein transports Vit B12? |
|
Definition
|
|
Term
| What happens to excess Vit B12? |
|
Definition
| stored in liver or excreted in urine |
|
|
Term
| What is the source of Vit B12? |
|
Definition
|
|
Term
| Why is Vit B12 deficiency rare? |
|
Definition
| It would take 3-4 yrs to develop b/c of liver storage |
|
|
Term
| What does absorption of folate require? |
|
Definition
| transport & a pteroyl-γ-glutamyl carboxypeptidase associated with intestinal muscoal membranes |
|
|
Term
| Where does most absorption of folate occur? |
|
Definition
|
|
Term
| What form are folates transported to tissus? |
|
Definition
|
|
Term
| How are folates uptaken into cells? |
|
Definition
| receptor mediated endocytosis |
|
|
Term
| What are the sources of folates? |
|
Definition
| almost all foods, esp. green vegetables, liver, yeast, and some fruit (tho cooking can destroy up to 90% of folate content in foods) |
|
|
Term
| What 2 systems are effected by Vit B12 deficiency? |
|
Definition
| hematopoietic and nervous systems |
|
|
Term
| Why is hematopoiesis sensitive to Vit B12 deficiency? |
|
Definition
| due to its high rate of cell turnover which means it requires high reates of DNA synthesis |
|
|
Term
| What does insufficient Vit B12 do to DNA synthesis & eventually cell maturation? |
|
Definition
| results in highly abnormal DNA => inability of maturing cells to complete nuclear divisions (tho cytoplasmal maturation occurs normally) => production morphologically abnormal cells that die during maturation (most profound effect is in producing abnormally large RBCs - megaloblastic anemia) |
|
|
Term
| What causes for Vit B12 deficiencies? |
|
Definition
| malabsorption due to deficiency in IF or in absorption of IF-B12 complex |
|
|
Term
| How is Vit B12 deficiency treated? |
|
Definition
| parenteral injections of Vit B12 (usually lifelong do to incurable syndromes) |
|
|
Term
| How is Vit B12 deficiency diagnosed? |
|
Definition
| serum measurement of Vit B12 &/or methylmalonic acid |
|
|
Term
| What causes folic acid deficiency? |
|
Definition
| inadequate dietary intake |
|
|
Term
| Who often develops folic acid deficiencies? |
|
Definition
Elderly
Poor
Diets lacking vegetables, eggs & meat
Alcoholics & other patients with liver disease |
|
|
Term
| Does megaloblastic anemia differentiate b/w Vit B12 or folate deficiencies? |
|
Definition
|
|
Term
Tx
folic acid deficiencies |
|
Definition
| 1) proper diagonosis so you don't treat for folic acid deficiency when it's more rare Vit B12 deficiency
2) folate therapy |
|
|
Term
| What does folate therapy do in Vit B12 deficiency? |
|
Definition
| relieves the megaloblastic anemia, but doesn't alter neurological defects due to the Vit B12 deficiency |
|
|
Term
| When can Cu deficiency occur (very rare)? |
|
Definition
intestinal bypass surgery, parenteral nutrition, malnourished infants, Zinc overdose
(NOT usually seen in those with hypocupremia) |
|
|
Term
|
Definition
| decrease activity of Cu-dependent enzymes due to decreased Cu transport (NO hematological abnormalities) |
|
|
Term
|
Definition
leukopenia (esp. granulocytopenia)
anemia |
|
|
Term
| When is Cu therapy indicated? |
|
Definition
| with low plasma [Cu], leukopenia & anemia |
|
|
Term
| What is Cu deficiency usually comorbid with? |
|
Definition
| other nutritional deficiencies |
|
|
Term
| Can humans have Cobalt (Co) deficiency? |
|
Definition
|
|
Term
| When is Co therapy beneficial? |
|
Definition
|
|
Term
| What is Co effect on the body? |
|
Definition
| inhibit enzymes in oxidative metabolism => tissue hypoxia => erythropoietin increase |
|
|
Term
| What happens in Co intoxication? |
|
Definition
depress erythropoiesis
in children: cyanoisis, coma, death |
|
|
Term
| When can oral therapy with pyridoxine Vit B6 increase hematopoiesis? |
|
Definition
| hereditary or acquired sideroblastic anemia |
|
|
Term
| What characterizes sideroblastic anemia? |
|
Definition
| impaired Hb synthesis & accumulation of iron in mitochondria of erythroid precursor cells. |
|
|
Term
| What causes hereditary sideroblasic anemia? |
|
Definition
| x-linked recessive trait (variable penetrance & expression) |
|
|
Term
| What causes acquired sideroblastic anemia? |
|
Definition
number of drugs
inflammatory states
neoplastic disorders
preleukemic syndromes |
|
|
Term
| What rare syndromes can be seen due to riboflavin deficiency? |
|
Definition
spontaneous red-cell aplasia
hypoproliferative anemia |
|
|
Term
| When is riboflavin administration reported to be beneficial? |
|
Definition
| correcting red-cell aplasia in patients with protein depletion |
|
|
Term
|
Definition
| anemia effecting RBC precursors |
|
|
Term
|
Definition
| process that maintains the integrity of the circulatory system after vascular damage |
|
|
Term
|
Definition
| adhere to damages endothelium to form platelet plug |
|
|
Term
|
Definition
|
|
Term
|
Definition
| clots form upon the conversion of fibrinogen to fibrin & adds to the platelet plug |
|
|
Term
|
Definition
|
|
Term
def
thrombolysis/fibrinolysis |
|
Definition
| process of fibrin digestion by plasmin |
|
|
Term
|
Definition
|
|
Term
| What is converted to plasmin? |
|
Definition
|
|
Term
| What do endothelial cells synthesize & secrete in response to injury to convert plasminogen to plasmin? |
|
Definition
| t-PA (tissue plasminogen activator) |
|
|
Term
|
Definition
| cleave fibrin & dissolve clot |
|
|
Term
| What are the 3 major classes of anticoagulant drugs (blood thinners)? |
|
Definition
1) Indirect Thrombin Inbitors
2) Parenteral direct Thrombin Inhibitors
3) Oral Anticoagulants |
|
|
Term
MOA
Indirect Thrombin Inhibitors |
|
Definition
| interaction with separate proteins AT III (antithrombin III) & Xa |
|
|
Term
| What 2 drugs are indirect thrombin inhS? |
|
Definition
1) heparin
a) LMW
b) HMW
2) fondaparinux |
|
|
Term
|
Definition
| heterogeneous mixture of sulfated mucopolysaccharides |
|
|
Term
|
Definition
| degrade thrombin & factor X when bound to heparin |
|
|
Term
| What are the 3 targets of heparin? |
|
Definition
1) IXa
2) Xa
3) IIa (thrombin) |
|
|
Term
| How is heparin used clinically? |
|
Definition
1) venous thrombosis
2) pulmonary embolism
3) acute MI
4) during cardiopulmonary bypass in surgery
5) unstable angina |
|
|
Term
| Why is heparin used for venous thrombosis, pulmonary embolism & acute MI? |
|
Definition
|
|
Term
| What is the clinical application of fondaparinux? |
|
Definition
| thromboprophylaxis of patients undergoing hip/knee durgery (to prevent pulmonary embolism & deep vein thrombosis) |
|
|
Term
| How is heparin therapy monitored? |
|
Definition
| by aPTT (activated partial thromboplastin time) |
|
|
Term
|
Definition
1) bleeding
2) heparin induced thrombocytopenia |
|
|
Term
| What are the 3 parenteral direct thrombin inhibitors? |
|
Definition
1) Hirudin
2) Bivalrudin
3) Aragatroban |
|
|
Term
| Which of the parenteral direct thrombin inhibitors is irreversible? |
|
Definition
|
|
Term
| What is the target of the parenteral direct thrombin inhibitors? |
|
Definition
|
|
Term
| When is hirudin used clinically? |
|
Definition
| heparin-induced thrombocytopenia |
|
|
Term
| What must be monitored while a patient is on hirudin? |
|
Definition
|
|
Term
| What is bivalirudin used for clinically? |
|
Definition
| alternative to heparin in patients undergoing coronary angioplasty |
|
|
Term
| What is aragatroban used for clinically? |
|
Definition
| alternative to hirudin for prophylaxis/Tx of patients with or at risk of developing haparin0induced throbmocytopenia |
|
|
Term
| When should parenteral direct thrombin inhibitor use be closely monitored? |
|
Definition
| renal failure => can accumulate and cause bleeding |
|
|
Term
Sx
parenteral direct thrombin inhibitor toxicity |
|
Definition
| antihirudin Ab => paradoxical increase in aPTT (i.e. must monitor aPTT daily) |
|
|
Term
| What are the 2 oral anticoagulants (oral direct thrombin inhibitors)? |
|
Definition
1) Warfarin
2) Next generation |
|
|
Term
|
Definition
| synthetic derivative of coumarin (found in plants) |
|
|
Term
| What is the bioavailability & half life of warfarin? |
|
Definition
BioA: 100%
Half life: 36 hr (long) |
|
|
Term
| How does warfarin compare to heparin? |
|
Definition
|
|
Term
|
Definition
| inhibits Vit K-dependent synthesis of biologically active forms of the calcium-dependent clotting factors & a regulatory factor => no clot formation |
|
|
Term
| What are the calcium-dependent clotting factors? |
|
Definition
|
|
Term
| What regulatory protein does warfarin inhibit synthesis of? |
|
Definition
|
|
Term
|
Definition
| block γ-carboxylation of glutamate residues in coagulation factors => incomplete coagulation factor molecules biologically inactive |
|
|
Term
| What are the 4 targets of warfarin? |
|
Definition
VII
IX
X
Prothrombin II
Protein C |
|
|
Term
| How is warfarin used clinically? |
|
Definition
1) prevent progression/recurrence of acute deep vein thrombosis/pulmonary embolism following initial heparin course
2) prevent venous thromboembolism in patients undergoing ortho/gyn surgery
3) prevents systemic embolization in patients with acute MI, prosthetic heart valves, or chronic atrial fibrillation |
|
|
Term
| In what patients should warfarin never be used? |
|
Definition
|
|
Term
| When should warfarin be used with caution? |
|
Definition
congenital coagulation factor deficiency
thrombocytopenia
hepatic/renal insufficiency |
|
|
Term
| What defines the therapeutic range for oral anticoagulant therapy? |
|
Definition
| international normalized ratio (INR) |
|
|
Term
|
Definition
| patients PT(prothrombin time)/mean of normal PT for lab |
|
|
Term
|
Definition
| progression/recurrance of a thrombotic effect |
|
|
Term
| When are patients more likely to form warfarin resistance? |
|
Definition
|
|
Term
| What does increasing the INR increase the risk of? |
|
Definition
|
|
Term
| What 2 drugs is warfarin anticoagulation effect decreased? |
|
Definition
|
|
Term
| What 2 drugs is warfarin anticoagulation effect augmented? |
|
Definition
|
|
Term
| What are the 3 next generation oral anticoagulants? |
|
Definition
1) Pradaxa
2) Rivaroxiban
3) Apixaban |
|
|
Term
| What are the targets of the next generation oral anticoagulants? |
|
Definition
Rivaroxaban & Apixaban: Xa
Pradaxa: IIa (thrombin) |
|
|
Term
| What are the 2 advantages of apixaban? |
|
Definition
reduce risk of :
1)stroke in patients with atrial fibrillation (a-fib)
2)major bleeding |
|
|
Term
| What are the 2 advantages of pradaxa? |
|
Definition
reduce risk of:
1) stroke & 2) systemic embolism in patients with a-fib |
|
|
Term
| What are the 2 advantages of rivaroxaban? |
|
Definition
reduce risk of:
1) intracranial & 2) fatal bleeding |
|
|
Term
| What are the 2 advantages of all next generation oral anticoagulants over warfarin? |
|
Definition
1)no monitoring needed
2)less DDI |
|
|
Term
| What 2 next generation oral anticoagulants lower stroke risk in a-fib? |
|
Definition
|
|
Term
| What 2 next generation oral anticoagulants reduce risk of bleeding? |
|
Definition
|
|
Term
| Do any of the oral anticoagulants have a antidote? |
|
Definition
|
|
Term
Function
fibrinolytic drugs |
|
Definition
| rapid lysis of thrombi by catalyzing activation of plasmin |
|
|
Term
def
t-PA (tissue plasminogen activator) |
|
Definition
| endogenous serine protease that is a poor plasminogen activator in the absence of fibrin |
|
|
Term
| How does t-PA activate plasminogen? |
|
Definition
| binds fibrin via lysine binding sites at amino terminus => activation of plasminogen |
|
|
Term
| What controls t-PA clearance? |
|
Definition
|
|
Term
| What is the half life of t-PA? |
|
Definition
|
|
Term
| What produces streptokinase? |
|
Definition
|
|
Term
|
Definition
| cofactor for the cleavage plasminogen to form free plasmin |
|
|
Term
| How does streptokinase induce cleavage of plasminogen to plasmin? |
|
Definition
| form stable complex with plasminogen to expose active site |
|
|
Term
| When is t-PA used clinically? |
|
Definition
1) lysing thrombi during Tx of acute MI
2) pulmonary embolism
3) severe deep vein thrombosis |
|
|
Term
| How do recominant mutant varients of t-PA differ from native t-PA? |
|
Definition
|
|
Term
Sx
Fibrinolytic drug toxicity |
|
Definition
|
|
Term
| What are the 2 possible causes of hemorrhage in fibrinolytic drugs? |
|
Definition
1) lysis of fibrin in physiological thromi at sites of vascular injury
2) systemic lytic state that results from systemic formation of plasmin => fibrinogenolysis & destruction of other coagulation factors (esp. V & VIII) |
|
|
Term
| What is the antidote to fibrinolysic drug toxicity to inhibit fibrinolysis? |
|
Definition
|
|
Term
| What are the 7 contraindications of thrombolytic therapy? |
|
Definition
1) surgery within 10 days
2) serious GI bleed within 3 mo
3) Hx of HTN
4) Active bleeding/hemorrhagic disorder
5) Previous cerebrovascular accident or active intracranial process
6) Aortic dissection
7) Acute pericaditis |
|
|
Term
| What are the 5 antiplatelet drugs? |
|
Definition
1) aspirin
2) dipyridamole
3) clopidogrel
4) ticlopidine
5) glycoprotein IIb/IIIa inhibitors |
|
|
Term
|
Definition
| block platelet aggregation & vasoconstriction |
|
|
Term
|
Definition
| inhibit synthesis of TXA2 (thromboxane A2) via acetylation of serine residue near active site of COX-1 |
|
|
Term
Function
COX-1 (cyclooxygenase) |
|
Definition
| produce cycliv endoperoxide precursor of TXA2 |
|
|
Term
|
Definition
1) vasodilator
2) inhibits embolization from prosthetic heart vavles, strokes, transient ischemic attack |
|
|
Term
|
Definition
| inhibit platelet activation |
|
|
Term
MOA
clopidogrel & ticlopidone |
|
Definition
| platelet ADP receptor antagonist |
|
|
Term
| What are the 3 glycoprotein IIb/IIIa inhibitors? |
|
Definition
1) Abciximab
2) Eptifibatide
3) Tirofiban |
|
|
Term
MOA
glycoprotein IIb/IIIa inhibitors |
|
Definition
| block binding of glycoprotein IIb/IIIa platelet-surface integrin to fibrinogen => inhibition of platelet aggregation |
|
|
Term
|
Definition
| Fab portion of Ab to Glycoprotein IIb/IIIa platelet-surface integrin |
|
|
Term
|
Definition
| cyclic peptide inhibitor of fibrinogen binding site on Glycoprotein IIb/IIIa platelet-surface integrin |
|
|
Term
|
Definition
| nonpeptide, small-molecule inhibitor of Glycoprotein IIb/IIIa platelet-surface integrin |
|
|
Term
| When is aspirin used clinically? |
|
Definition
1) immediately after one MI to reduce risk of second or death of cardiac tissue
2) long-term prevention of MI, strokes, & blood clot formation in high risk ppl |
|
|
Term
| When is dipyridamole used clinically? |
|
Definition
| in combination of warfarin for post-op primary prophylaxis of thromboemboli in patients with prosthetic heart valves |
|
|
Term
| When is ticlopidine used clinically? |
|
Definition
| reduce risk of thrombotic stroke in patients who have experienced stroke precursors or have had a thrombotic stroke |
|
|
Term
| When is clopidogrel used clinically? |
|
Definition
1)with aspirin after angioplasty (1 yr)
2)to reduce risk of stroke & MI in patients with recent MI or stroke, established peripheral aterial disease, or acute coronary syndrome |
|
|
Term
|
Definition
|
|
Term
| What 2 drugs when combined with aspirin can increase the risk of upper GI bleeds? |
|
Definition
|
|
Term
|
Definition
Common: N/V/D
most serious: leukopenia |
|
|
Term
| What antiplatelet drug has the most favorable toxicity profile? |
|
Definition
|
|
Term
| Why does clopidogrel have the most favorable toxicity profile than any other antiplatelet drugs? |
|
Definition
| less frequent thrombocytopenia & leukopenia |
|
|
Term
| When is abciximab used clinically? |
|
Definition
in conjunction with:
1)percutaneous angioplasty for coronary thrombosis
2)aspirin & heparin to prevent resenosis, recurrent MI & death |
|
|
Term
| What is eptifibatide used for clinically? |
|
Definition
1)acute coronary syndrome
2)angioplastic coronary interventions => reduced MI & death |
|
|
Term
| What is tirofiban used for clinically? |
|
Definition
in conjunction with heparin for:
1) non-Q wave MI
2) unstable angina |
|
|
Term
SE
abciximab & eptifibatatide |
|
Definition
|
|
Term
| What can reverse the aggregation defect induced by abciximab or eptifibatide? |
|
Definition
|
|
Term
|
Definition
| bleeding on local sites of clinical inervention & systemically |
|
|
Term
| How do you reverse the effects of tirofiban? |
|
Definition
| tranfusions (to terminate bleeding & improve bleeding-related anemia) |
|
|
