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? |
|
Definition
|
|
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 |
|
|
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) |
|
|
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 |
|
|
Term
|
Definition
|
|
Term
| What channels open following adrenergic memebrane depolarization? |
|
Definition
| Ca2+ => extracellular Ca2+ to enter neurons |
|
|
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) |
|
|
