Term
Selectivity
1) What is it
2) 2 components of it |
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Definition
1) Increasing probability of obtaining beneficial effects and minimizing the probability of negative effects
2) Dose- as dose increases, selectivity decreases. Time- how often, how it gets into body, how well it gets rid of drug |
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Term
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Definition
| Study of drug effects on the body. Dose-response relationships and drug interaction with receptors |
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Term
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Definition
| Study of the body's effects on the drug. How the drug travels through the body. Related concepts: time-action relationship, drug absorption, distribution, biotransformation and elimination |
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Term
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Definition
| Measure of the strength between the drug molecule and its binding site on the receptor. |
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Term
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Definition
| ability to cause the receptor the change to the active state |
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Term
| Give the relative efficacy and affinity of each type of drug: agonist, competitive antagonist, partial agonist |
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Definition
agonist: affinity; efficacy=1
comp antagonist: affinity; efficacy=0
partial agonist: affinity; efficacy is 0 |
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Term
| equilibrium dissociation constant KD |
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Definition
| the concentration of drug at which half the receptors are bound when the system has reached equilibrium |
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Term
| ED50. What does ED50 represent in quantal dose response curves |
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Definition
| the agonist concentration when E/Emax is 0.5 (half maximal effect). In a quantal curve, the dose at which half the population responds |
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Term
| Describe the concept of spare receptors |
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Definition
| Maximum response can be obtained with <100% receptor occupancy due to transduction amplification. |
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Term
| Effect of increasing affinity/potency and effect of increasing efficacy on the dose-response curve |
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Definition
| affinity/potency affect the position of the curve on the x-axis. More potent drugs are closer to the origin. Efficacy is reflected by the maximum effect produced; the ceiling of the curve. Higher efficacy drugs have a larger maximum |
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Term
| How does the addition of a competitive antagonist/non-competitive antagonist affect the dose-response curve |
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Definition
| Competitive agonist: behaves as a decrease in affinity/potency. Noncompetitive agonist: behaves as a decrease in efficacy. |
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Term
| Describe graded vs quantal dose-response curves. |
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Definition
| Graded: how much effect did this dose of drug cause in a patient. Quantal: Did this dose of drug have an effect in the patient; what is the probability this dose will produce the effect in someone? |
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Term
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Definition
| Median toxic dose and median lethal dose. Dose at which 50% of the population reports toxic/lethal effects |
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Term
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Definition
| TD50/ED50. LD50 can be used instead of TD50. |
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Term
| Describe the subunit structure of the insulin RTK. How does this differ from other RTK |
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Definition
| 2 a-chains containing hormone-binding sites. 2 beta chains that cross the membrane and contain TK domains. Most RTK have a single transmembrane alpha-helix divided into intracellular/extracellular domains |
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Term
| Describe the binding/activation of the insulin RTK. First molecule modified? |
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Definition
| 2 insulin molecules required to activate fully. Binding induces autophosphorylation stimulating tyrosine phosphorylation of the IRS-1 protein |
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Term
| 2 pathways mediated by IRS-1 |
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Definition
1. Growth pathway: IRS phosphorylates Shp --> Ras --> MAP kinase cascade --> transcripting factors that control growth promotion.
Glucose uptake pathway: IRS-1 phosphorylates P13K, initiating a phos cascade that eventually leads to GLUT 4 transporter placement in the plasma membrane |
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Term
| CML and how it relates to TRK processes. |
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Definition
| Bone marrow malignancy. 20% of all leukemias, always fatal. 90% have a philadelphia chromosome translocation that results in production of the aberrant fusion protein Bcr-Abl. This protein is dysregulated resulting in constitutive activation of the Growth Pathway mediated by IRS-1 phosphorylation leading to unregulated growth. |
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Term
| What molecule is erroneously produced during CML and what is its normal function |
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Definition
| Bcr-Abl is produced; Abl is normal and tightly regulated. Bcr-Abl is a piece of shit that results in activation of the Ras-MAP kinase pathway and unregulated growth |
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Term
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Definition
| Selectively binds and inactivates Bcr-Abl, mitigating CML |
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Term
| B-raf and the significance of its mutation |
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Definition
| B-raf is a Serine/Threonine Kinase that regulates the MAP Kinase pathway. 50% of melanoma patients have a mutation resulting in constitutive activity. |
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Term
| 3 Major Classes of G Protein Linked Receptors |
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Definition
| cAMP (Gs/Gi), Phospholipase C (Gp/Gq...DAG/IP3/Ca2+), Rhodopsin (Gt...cGMP) |
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Term
cAMP dependent Protein Kinase
1) Receptor structure
2) Effects of binding
3) How does reversal/moderation of response |
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Definition
1) The receptor is a tetramer with 2 cAMP binding chains and 2 catalytic chains.
2) Binding causes release of activated catalytic subunits. Catalytic Units phosphorylate various enzymes.
3) Dephosporylation of substrates/ degradation of cAMP by phosphodiesterase |
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Term
| Describe the effect of cAMP levels on glycogen synthase. What protein does cAMP activate? What is the result of this activation? |
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Definition
Increasing cAMP levels inactivate glycogen synthase
PKA is activated by cAMP, resulting in a phosphorylation cascade: PKA --> phosphorylase kinase --> glycogen phosphorylase --> glycogen to G1P and glycolysis |
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Term
| Gi- subunits, activity on adenylate cyclase |
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Definition
| Gi has B and g subunits like gs but also an ai subunit that binds and hydrolyzes GTP, and inactivates AC activity |
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Term
| Effect of epinephrine on B and a2? What organs are associated with each? |
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Definition
Fight or flight response
B- heart- vasodilation
A- peripheral organs- vasoconstriction |
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Term
| Describe the Gq protein of Ca2+/Phosphoinositide pathway |
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Definition
| Gq similar to Gs. aq subunit interacts with the receptor and activates effector enzymes. B/g dimer anchors Gq to the plasma membrane |
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Term
| Describe the process of activating Gq in the Ca2+/Phosphoinositide pathway. What 2nd messengers are produced? |
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Definition
| GTP bound Gq activates PLC. PLC cleaves PIP2 to yield DAG and IP3. |
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Term
| DAG/IP3 functions and solubilities |
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Definition
| Lipophilic DAG activates PKC leading to an intracellular phosphorylation cascade. IP3 moves to the cytoplasm to trigger Ca2+ release leading to Ca2+/calmodulin cascade |
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Term
| DAG/IP3 pharmaceutical mimics |
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Definition
Calcium ionophores- IP3
Phorbol esters- DAG |
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Term
| The results of the Ca2+/phosphoinositide signalling pathway: What are the effects of ACh binding on MLCK/NOS? |
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Definition
ACh binding--> increase in Ca2+--> PKC activation.
Activation of MLCK- phosphorylates myosin causing actin interaction and muscle contraction. Activation of NOS produces NO causing relaxation of smooth muscle and vasodilation |
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Term
| Effect/mechanism of NO on myosin light chains |
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Definition
| NO activates sGC- soluble guanylate cyclase, increasing cGMP, causing dephosphorylation of MLC causing relaxation and vasodilation. |
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Term
| Effect of nitrovasodilators and phosphodiesterases on the NO/cGMP pathway |
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Definition
| Nitrovasodilators- activate sGC. PDE block response by converting cGMP to inactive 5'-GMP |
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Term
| Location of PDE 5/3? What is the effect of viagra on each? |
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Definition
PDE 5- corpora cavernosa
PDE 3- heart
PDE 6- eye
PDE 5 has 4600x selectivity over PDE 3 and 10x selectivity over PDE6. Viagra side effect= blurred vision |
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Term
| Two step model of steroid receptor activation |
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Definition
1. Liganded receptor recruits CoA, which has histone acetyl transferase activity
2. Acetylation leads to unwinding of chromatin allowing binding of transcription factors (Pol II) |
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Term
| Name the 3 domains of the steroid/thyroid receptor family gene |
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Definition
1. Transcription activation domain- promotes DNApoly activity
2. DNA-binding domain- interacts with promoter on gene DNA
3. Ligand-binding domain- binds steroid hormones |
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Term
| Regarding the human genome- how many steroid/thyroid receptors are orphan receptors? How many nuclear receptors are contained? |
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Definition
| 30, including err1, err2, hap. Genome has 48 nuclear receptor genes. |
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Term
| Adopted orphan receptors. How are orphan receptors analyzed? |
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Definition
| bind dietary lipids. The implication is that they are involved in metabolism. Reverse endocrinology allows determination of function. |
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Term
| PPARg. What are they being used as a therapeutic target for? |
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Definition
| Peroxisome Proliferator-Activated Receptor. Drugs pioglitazone and rosiglitazone target them and are used to treat type 2 diabetes |
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Term
| What are the effects of insulin on adipose and on muscle/liver? How is redistribution of fatty acids useful to treating diabetes? |
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Definition
| Insulin promotes glucose uptake as glycogen in the liver and muscle. It inhibits lipolysis in adipose, which reduces serum FFAs. Excess FFAs can build up in muscle/liver leading to desensitivity and hyperglycemia. FFAs are best distributed into adipose, which is achieved through PPARg activation |
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Term
| Location, method of activation and function of PPARa, PPARg, PPARd |
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Definition
PPARa- liver/muscle. Activated by fatty acids and fibrate drugs. Hypolipidemic actions- promote FFA uptake and B-oxidation. PPARg- expressed in muscle, liver, adipose and bone. Activated by FA, rachidonic acid derivative and TZD (anti diabetes drugs). PPARg have insulin sensitizing actions- they promote adipocyte differentiation, lipogenesis and storage. Promote glucose uptake in liver and muscle. More valuable drug target
PPARd- ubiquitous but low abundance. Little known; similar to PPARg |
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Term
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Definition
| Pioglitazone and rostiglitazone, anti-diabetic drugs that target PPARg and have insulin-sensitizing effects |
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Term
| LXR- expression locations, activation, effect |
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Definition
| Liver X Receptor- a cholesterol sensor expressed in liver, adipose, kidney, intestine and macrophages. Activated by cholesterol metabolites like oxysterols. Control homeostasis of cholesterol- transport, catabolism, excretion |
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Term
| FXR- expression locations, activation, effect |
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Definition
| Farnesoid X Receptor. Bile acid sensor. Expressed in liver and intestine, activated by bile acids and control efflux/excretion. |
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Term
| How do LXR/FXR affect each other |
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Definition
| Combined effect is to promote cholesterol excretion. LXR- promote cholesterol efflux into liver for metabolism or into the intestine for excretion. FXR- bile acid synth, efflux of bile into the pooper to be pooped out |
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Term
| Regarding drug transport through pores. What organs are pores most important in? What drugs are dependent on pores? What is the driving force for transport via pores? |
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Definition
| The nephron, but are the most important mechanism for entry of drugs into most tissues. Quaternary ammonium drugs. Water/hydrostatic pressure |
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Term
| Finish the statement: The rate of entry of the drug into most tissues is not limited by ________ but by ________ |
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Definition
| Lipid solubility, blood flow |
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Term
| What organs does active transport take place? 2 major classes? |
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Definition
| Proximal tubule, hepatocytes, GI tract; BBB, Choroid plexus, etc. 2 major classes are ABC and SLC |
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Term
| Name the families in the SLC superfamily. What type of reactions? |
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Definition
| Uniport/facilitated transport, and secondary (anti/sym-port). Families include the organic cation transporter (OCT), Multidrug and toxin extrusion (MATE), OCTN, and Organic Anion Transporters (OAT) |
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Term
| OCT Family of transporters- type of molecules? Type of transport? What direction across cell membrane? Where does energy come from? |
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Definition
| Transport of cations via facilitated transport/uniport. Electrochemical gradient is inwards, so OCTs mediate influx. Energy from NA/K ATPase |
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Term
| MATE/OCTN Family of transporters- type of molecules? Type of transport? What direction across cell membrane? Where does energy come from? |
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Definition
| Electroneutral drugs. Antiport with H+. Transport depends on pH gradient- this is an efflux pathway for cations. Na/H antiport simultaneously maintains the H+ gradient. NaK ATPase maintains the Na gradient. Na higher extracellularly. |
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Term
| OAT Family of transporters- type of molecules? Type of transport? What direction across cell membrane? How is the increased intracellular negative charge justified? Where does energy come from? What organ is important |
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Definition
| Influx of anions. OAT2 is for Nucleotides. OAT1/3 are for low MW anions, drugs, PGE2, urate. Influx of anions is not favored- so coupling with efflux of alpha-ketoglutarate results in net efflux of negative charge. akg is replenished via symport with Na+ via NaDC3. Energy comes from NaK ATPase. OAT is important in the liver |
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Term
| How is energy acquired by ABC transporters? What is their function? What transporters are in the ABC transporter family? What type of transport is performed by each? |
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Definition
| ATP is directly hydrolyzed. They pump drugs out of cells. P-glycoprotein transports large neutral or positive hydrophobic drugs (drugs that enter via passive diffusion). Multidrug resistance protein2 (MRP2) transports amphiphilic organic anions, esp glucuronide, glutathione and SO4. Breast Cancer Resistance Protein transports neutral/negative charged drugs, SO4 conjugates. |
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Term
| What is the significance of active transport in the brain, choroid plexus, nephron and liver/GI? |
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Definition
Brain/choroid- protect tissue
Nephron- excretion
Liver/GI- absorption/elimination; biotransformation, transport into bile/blood |
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Term
| What type of drugs are absorbed in the stomach |
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Definition
| Weak acids. Insignificant |
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Term
| Metabolism of drugs first pass through GI system? Significance of the hepatic portal vein? |
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Definition
| P-glycoprotein transports back into lumen; metabolism in gut. All drugs absorbed from the GI tract pass through the hepatic portal vein before entering systemic circulation |
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Term
| What is bioavailability? How does this relate to the first pass effect? When is 0 bioavailability useful |
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Definition
| Bioavailability is the fraction of unchanged drug that reaches the systemic circulation (metabolism in liver/GI tract/excretion in shit). Drugs with a high 'first pass' effect have very low bioavailability. 0 bioavailability is useful if metabolites are active. |
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Term
| Describe a mechanism to increase the bioavailability of a normally low BA drug |
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Definition
| Drug interaction- add a drug that occupies metabolizing enzymes that process the original drug |
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Term
| What % of drug enters systemic circulation via sublingual/rectal administration |
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Definition
Sublingual- 100
Rectal- 50 |
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Term
| Pros/Cons of IV drug administration |
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Definition
Pro: Rapid, best control
Con: Concentration rises rapidly; need to inject slowly. Vein damage from repeat dosing. Drug must be aqueous. Non reversible |
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Term
| Pros/Cons of IM drug administration. How are drugs absorbed into the bloodstream? |
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Definition
| Absorption through capillary pores/lymphatic system. Pro: Fairly rapid absorption, can provide slow sustained absorption of poorly water soluble drugs in oil. Con: pain/hematoma, can't use with anticoag therapy |
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Term
| Pros/Cons of SC drug administration |
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Definition
| Absorption through capillary pores/lymphatic system. Pro: rapid, sustained effect/solid pellet insertion. Con: certain drugs irritate the tissue. |
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Term
| What types of drug are supplied topically? |
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Definition
| Local effect/minimize exposure. Some are applied in patches for slow, systemic supply. Drugs applied topically need to be potent and have a very favorable PC |
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Term
| Describe the structure of the BBB that makes it so difficult to penetrate pharmaceutically. How do drugs pass the BBB? |
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Definition
| Capillaries have tight junctions instead of pores, and are surrounded by glial cells. They also contain drug transporters (p-gp) that extrude drugs. Drugs reach the CNS via passive diffusion across 4 lipid bilayers. A very favorable PC is required. Inflammation increases capillary permeability. Certain areas of the brain (chemoreceptor trigger zone/hypothalamus) lack the BBB |
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Term
| Location and structure of the Blood-CSF barrier? How do drugs penetrate the Blood-CSF barrier? What is the relative area of the blood-CSF barrier? |
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Definition
| The choroid plexus is in the lateral, 3rd and 4th ventricles. The cells of the choroid plexus are connected by tight junctions- the BCSFB. Drugs pass through the Blood-CSF barrier by passive diffusion across the epithelia. The area is 1/1000 of the BBB. Has drug metabolizing enzymes and active transporters. |
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Term
| Describe the structure of the placental barrier. What types of drugs cross? What |
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Definition
| No pores; but only large/multiple charge drugs do NOT cross. Lipophilic drugs enter circulation readily via simple passive diffusion. The fetal blood is more acidic- basic drugs may accumulate here preferentially. P glycoprotein present. |
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Term
| 2 other organs with no pores |
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Definition
| Synovial membrane, testes/prostate |
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Term
| How do plasma binding proteins affect multi drug interactions |
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Definition
| Addition of a second drug causes a transient increase in the first drug because of displacement on plasma binding proteins. Transient because the drug is excreted more quickly. |
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Term
| Diseases that lead to decrease in levels of plasma proteins (2). How do these diseases affect drug concentration? |
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Definition
| 1. Severe liver disease- albumin synthesized in the liver. 2. Renal disease- proteinuria. Increase in free drug concentration due to less bound drug |
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Term
| Diseases that lead to increase in plasma binding proteins? Effect on drug concentration? |
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Definition
| Cancer/arthritis/Crohn's, MI- diseases that induce acute phase response |
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Term
| Renal filtration- what molecules are filtered? What molecules are reabsorbed? What is the filtration fraction? How does drug concentration change/dissociate from binding proteins upon filtration? |
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Definition
| All molecules <50kD in weight are filtered. Useful molecules are reabsorbed. 1% of filtered volume ends up in the bladder. Filtration fraction= amount of drug filtered dependent on renal blood flow (normally 20%, lower in old/young/renal disease). Concentration of drug in unfiltered fraction doesn't change since water is also filtered- no dissociation from albumin. |
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Term
| Active Tubular Secretion- Describe the flow of charged drugs from the capillaries to the lumen of the convoluted tubule. How does this process affect protein binding proteins in the blood? |
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Definition
| Movement through pores from blood into interstitium. Active transport from interstitium into tubule cells. Exchange systems into lumen of tubule. As free concentration of drug in the interstitium falls, free drug in capillary diffuses lowering capillary conc --> drug dissociates from proteins. |
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Term
| Cation Secretion of the kidney tubule cells. Describe the transporters in the basolateral and apical membrane. |
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Definition
| Basolateral: OCT2/3 import drugs with net increase in positive charge moving intracellularly. This is driven by the membrane potential produced by the Na/K pump. Apical membrane: MATE1/MATE2-K SLC transporters mediate efflux by electroneutral cation/H+ exchange (H+ flows into cell, cation into lumen). Apical membrane: MDR/P-glycoprotein pumps cation into lumen by hydrolyzing ATP. H+/Na+ pump removes H+ pumped into the lumen by MATE and provides substrate for the NaK ATPase. |
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Term
| Anion Secretion of the kidney tubule cells. Describe the transporters in the basolateral and apical membrane. |
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Definition
| Basolateral domain: Uniport not feasible, need antiport with aKG (OAT1/OAT3). Net flux of negative charge is out of the cell, which is favorable. NaDC3 transports aKG back into the cell via symport with 2Na+. Na+ conc is justified by the efflux action of NaK ATPase. Apical domain: MRP2/MRP4 (ABC transporters) transport anions into the lumen via hydrolyzation of ATP |
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Term
| Regarding the nephron: describe the factors that promote formation of a gradient for drug reabsorption. |
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Definition
| Salt/water are actively reabsorbed during passage through the nephron. Drugs in the urine become concentrated and diluted in the plasma. This generates a gradient for reabsorption |
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Term
| What types of drugs are reabsorbed by the nephron? What does the rate of reabsorption depend on? What other factors affect amount of drug reabsorbed? |
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Definition
| Neutral drugs; or weak acid/weak base with a favorable partition coefficient. Rate depends on partition coefficient, pK and pH. Amount reabsorbed decreases when volume/flow increase. |
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Term
| What factors contribute to drug precipitation in the tubule? |
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Definition
| Volume of water decreases dramatically as urine flows through a tubule. Low water soluble drugs may precipitate out |
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Term
| Describe the properties of inulin that lead to its simple excretion process |
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Definition
| It is small, uncharged (no active secretion), has a PC of 0 (not reabsorbed) and does not bind plasma proteins (Filtration fraction = fraction filtered = 20%). Amount in urine dependent only on GFR. |
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Term
| Describe the properties of penicillin G that affect its excretion process |
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Definition
| Small enough to be filtered, weak acid so active secretion is very efficient (90%), 60% bound to plasma proteins and 40% free (20% filtration fraction x 0.4 = 8%) and its partition coefficient is 0 so it is not reabsorbed. Half life is very short- 30 minutes. Its not reabsorbed so its excretion is not pH dependent. |
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Term
| Describe the properties of probenicid that affect its excretion process |
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Definition
| Small MW, 10% free so filtration fraction is 20% x 0.1 = 2%. Anion is actively secreted which competes with other anions (penicillin). PC very favorable so it is reabsorbed almost completely in distal tubule. Blocks secretion by competition and has a long half life (5-8 hours) |
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Term
| What weight of drugs are filtered by the kidney? What type of particles are actively transported? What type of particles are reabsorbed? How does excretion change with age/disease |
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Definition
| < 50kD MW. Net +/- charge are substrates for active transport in proximal tubule. Weak acids/bases will undergo reabsorption in the distal nephron in a pH-dependent manner. GFR decreases with age/renal disease so dose is lowered. Plasma drug conc increase, t1/2 increases, toxicity increases. |
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Term
| Phases of biotransformation and what each phase accomplishes. Most important site? |
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Definition
Phase I: Oxidation/hydrolysis/reduction to make drugs more water soluble. Phase II: Conjugation. Increases solubility, provide negative charge, attach to hydrophilic substance, lower PC, inactivate drug.
Results in less binding to albumin, more filtering, producing a substrate for anion pumps so more is secreted, less reabsorption in the kidney, more efficient elimination.
Most important site is the liver. |
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Term
| Cytochrome P450- location? effect? required coenzymes? 3 P's? Most active families in the liver? |
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Definition
| Located in SER. Oxidizes liphophilic substrates using a heme iron-O2 complex while reducing water to H2O- 'mixed function.' Requires electrons from NADPH-P450 reductase. P450s are Pink in the presence of CO abs Peak at 450 nm. Most active families are CYP2D6 and CYP3A4. |
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Term
| 4 Major types of P450 Oxidation? These are all phase 1 reactions. |
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Definition
| 1. Hydroxylation of aliphatic/aromatic carbons. 2. Deamination/N-dealkylation. Produces an amine/ammonia and a keto compound. 3. O-dealkylation. Oxidation of the carbon attached to O in an ether produces an alcohol and keto compound. 4. N-oxidation/S-oxidation. Direct addition of an oxygen. |
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Term
| 3 Phase 1 hydrolysis reactions. Where are the enzymes located? Which can activate a drug? |
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Definition
| 1. Epoxidide Hydrolase (Epoxides produced by CYP)- turns epoxide to a diol. Enzyme in the microsome. 2. Esterase. Hydrolyze esters into acid + alcohol. Found in the ER/cytosol. Can activate a drug. 3. Amidase- hydrolyze amides to an amine and an acid |
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Term
| 2 drugs activated by conjugation? |
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Definition
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Term
| Name the 5 conjugation reactions |
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Definition
| 1. Glucuronidation, Sulfation, Glutathione conjugation, N-acetylation, Methylation |
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Term
| Glucuronidation. What enzymes? Where are these enzymes found? How does glucuronidation facilitate excretion? |
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Definition
| UDP-glucuronosyltransferases in the ER esp liver/GI tract. Glucuronidation increases water solubility and provides a negative charge. This results in less albumin binding and more glomerular filtration. The product becomes an anion pump substrate and cannot undergo reabsorption. |
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Term
| 2 families of UDP-glucuronosyltransferases? What is each used for? |
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Definition
| UGT-1: bilirubin conjugation. 9 genes. UGT-2: 10 genes; for endogenous substrates like steroids |
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Term
| Gilbert's Syndrome? Crigler-Najjar Syndrome |
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Definition
| Both are UGT-1 mutations associated with jaundice. Gilbert's syndrome causes an increase in plasma bilirubin and increases risk of drug interaction. Caused by promoter mutation. C-N: no active UGT1A1. No bilirubin conjugation and early death |
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Term
| Sulfotransferase enzymes- function? Substrate? What types of drugs do they affect? Role in xenobiotic processing? |
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Definition
| Sulfotransferase enzymes add SO4 from 3-phosphadenosine-5'phosphosulfate (PAPS). Primarily add to Ar-OH but also R-OH/R-NH2. Functions on endogenous substrates (sterols) but also on xenobiotics in the liver and intestine |
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Term
| Glutathione conjugation. Describe the glutathione molecule. What types of substrates does it act on? |
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Definition
| The glutathione molecule has a reactive thiol attached to a g-carboxyl group. Reacts with oxidative substances which yields a glutathione GSSG dimer |
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Term
| Glutathione reductase, Glutathione-S-transferases |
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Definition
| Glutathione reductase uses NADPH to reduce oxidized glutathione (GSSG). GST is the enzyme that mediates conjugation |
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Term
| Regarding n-acetylation. What group is transfered? Effect on the substrate? What enzyme catalyzes this? Slow/fast acetylaters? |
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Definition
| An acetyl group is transfered from acetyl-CoA to an aromatic amine/hydrazine group. Polarity is decreased, weird. NAT1 family is ubiquitous, NAT2 is in liver/GI. Slow/fast acetylaters refer to the bioavailability of acetyl CoA. Slow acetylaters can have SLE. |
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Term
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Definition
| N-oxidation yields toxic NAPQI. GST conjugation produces a nontoxic metabolite. Glutamate and glycine are removed from the glutathione and the remaining cysteine is N-acetylated. N-acetylcysteine is supplied to prevent toxicities. |
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Term
| What two conjugation reactions decrease polarity? |
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Definition
| N-acetylation, methylation |
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Term
| Methylation: what group is transfered? What enzymes? |
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Definition
| Methyl group from SAM to O/N/S atoms. Many methyltransferases exist for various substrates. |
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Term
| Azathioprine. How is it activated? What is it activated to? |
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Definition
| Pro drug metabilized by TPMT, a methylating enzyme. It becomes 6-mercapto-purine which is incorporated into DNA and stops replication. Used for immune suppression/chemo. |
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Term
| How do drugs reach the liver from the GI tract/body? Two fates of drugs after being processed by hepatocytes? |
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Definition
| GI--> HPV body--> HA. The drugs can go to systemic circulation and be excreted by the kidney or can go into bile caniculus/gallbladder to be released into SI with bile. |
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Term
| Describe the influx of drugs in the hepatocyte and the efflux to the blood and bile |
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Definition
| Influx: OCT/OAT transporters driven by Na/K ATPase. Efflux into bile by ABC transporters in the canicular membrane- P-gp, MRP, BRCP driven by ATP hydrolysis. Efflux into blood by MRP in sinusoidal membrane driven by ATP hydrolysis. |
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Term
| Following biliary excretion, what are (3) possible pathways a drug can follow |
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Definition
| 1. Poor PC drugs remain in GI and are shat out. 2. Good PC reabsorbed and pass back to liver via blood. 3. Enterohepatic cycling: Glucuronic acid conjugated drugs have a very unfavorable PC but can be cleaved. The released drug can pass through to the liver if it has a good PC. |
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Term
| Consequences of enterohepatic cycling? |
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Definition
| Half life prolonged and eventual excretion by kidney. Agents that block enterohepatic cycling by preventing reabsorption can dramatically decrease half life- antibiotics that kill bacteria; non-absorbable polymers |
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