2- Adrenergics Flashcards by Maggie Kl

Describe the major steps in catecholamine synthesis and metabolism.

-import tyrosine –hydroxylase–>
dopa –decarboylase–>
dopamine –> import into vessicle –> –methyltransferase–> NE

NE released into synapse. Take back up and recycled or broken down by MAO.

NE ==>
–MAO–> aldehyde reductase –> COMT adds methyl to catechol –> alcohol dehydrogenase, aldehydedehydrogenase
==> vanilyllmandelic acid = VMA

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Where are alpha1, alpha2, and beta1 and beta2 receptors?

alpha1=vascular smooth muscle, arteries, salivary glands, skin, sweat stress, radial iris

alpha2=CV control center of brain, gastric secretions

beta1=heart, kidneys

beta2=lungs, arteries in skeletal muscle, uterus (preg), ciliary epithelium

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What signalling is activated at alpha1 receptors?

Gq–> Ca2+ and PKC

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Which direct-acting adrenergic receptor agonists act on alpha1 receptors?

What can these agents be used for?

phenylephrine (Neosynephrine)
methoxamine (Vasoxyl)
Oxymetazoline (Visine)

vasoconstriction: incr BP, decongestants

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Which direct-acting adrenergic receptor agnists acton alpha2 receptors?

What can these agents be used for?

clonidine (Catapres)
methyldopa (Aldomet)
Guanabenz (Wytensin)
Guanfacine (Tenex)
Tizanidine (Zanaflex)

these affec the CV control center of brain…turn off symp NS

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What signalling is activated at alpha2 receptors?

Gi –> reduce cAMP-dep PK activity, open K channels

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Which direct-acting adrenergic receptor agonists are non-selective for beta receptors (activate both beta1 and beta2)?

isoproterenol (Isuprel)

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Which direct-acting adrenergic receptor agonists are selective for beta1 receptors?

dobutamine (Dobutrex)

Dopamine (Intropin)

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Which direct-acting adrenergic receptor agonists are selective for beta2 receptors?

terbutaline (Brethine, Bricanyl)
metaproterenol (Metprel, Alupent)
albuterol (Proventil, Ventolin)
salmeterol (Serevent)
ritodrine (Yutopar)

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What signalling pathway do beta receptors activate?

Gs ==> increase cAMP-dep PK activity

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Who does NE interact with the G-protein active site to produce a response?

catechol h-bonds with serines

the positive amine is stabilized by anionic aspartate

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What are the three main characteristics of adrenergic agonists?

amine
alpha and beta carbons (alkyl chain)
catechol

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Describe how alterations to the amine of an adrenergic receptor agonist affect its activity/selectivity.

increase in size of alkyl substituents increases beta-receptor activity ; beta2 receptor selective drugs tend to have larger amine head groups. –> also MAO resistance

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How do alpha substitutions on the alkyl chain of an adrenergic receptor agonist affect its activity/selectivity?

block oxidation by MAO
increase lipophilicity (incr CNS act)
reduce direct agonist activity at both alpha and beta adrenergic receptors
alter receptor selectivity: alpha2>alpha1, beta2>beta1
introduces chiral center (s-preferred)

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How do beta substitutions on the alkyl chain of an adrenergic receptor agonist affect its activity/selectivity?

a. direct agonists possess beta-hydroxyl group
b. enhances uptake and storage in vesicles
c. introduces chiral center (R-preferred)

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How do alterations of the aromatic rings of an adrenergic receptor agonist affect its activity/selectivity?

a. 3 and 4 positions most important
b. reduced susceptibility to COMT (incr oral BA)
c. removal of OH incr lipophilicity
d. replace catechol (3,4) w resorcinol (2, 4) to incr beta2 R selecivity

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What are the two S/A relationships that allow us to drive beta2 selectivity?

bulky head group on amine
replace catechol w resorcinol

this is favorable for design f bronchodilators w/o activity on heart

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Describe the effect of NE on HR and BP.

sel for a1 and B1

alpha1 - vasoconstrict –> INCR BP

beta1 –> expect incr HR but baroreceptors –> decr HR

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Describe the effect of Epi on HR and BP.

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sel for a1, B1, B2

a1 - vasoconstrict –> incr BP
beta2 –> musculoskeletal vasodilation –> decr BP –> NO NET CHANGE IN BP

beta1 –> incr HR

Describe the effects of isoproterenol on HR and BP.

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sel for beta1, beta2

beta2 - vasodilation –> decr BP
beta1 - incr HR (also baroreceptor reflex)

describe the effects of phenylephrine on HR and BP.

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sel for a1

a1 – vasoconstrict –> incr BP
baroreceptors decr HR

can be used acutely as a vasopressor and for some arrythmias.

Describe NE as a direct-acting adrenergic receptor agonist.

What are its use and clinical considerations?

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alpha and beta1 agonist
substrate for MAO and COMT
PE admin

use: pressor

Nabisulfite used in prep to prevent ox

Describe Epi as a direct-acting adrenergic receptor agonist.

What are its use and clinical considerations?

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potent a, B1, B2 ag
substrate for MAO and COMT
PE admin
Nabisulife antiox

Uses: anaphylaxis, glaucoma, in comb w local anesthetics

Describe phenylephrine as a direct-acting adrenergic receptor agonist.
What are its use and clinical considerations?

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potent a1 ag
substrate for MAO
admin PE, po, local

uses: mydriasis w/o cycloplegia
glaucoma
nasal decongestant

Describe the S/A of 2-aralkylimidazolines.

substituted aromatic ringe + metylene or aminoe + five-membered dibasic ring --> very basic these compounds exist in ionized form at physiologic pH

Describe 2-aralkylimidazolines as a direct-acting adrenergic receptor agonist. List them. What are its use and clinical considerations?

naphazoline (Privine) tetrahydrozolnie (Visine) oxymetazoline (Afrin, Visine) partial agonists at alpha Rs - admin local/top to promote vasoconstriction use: nasal and ophtalmic decongestants tachyphylaxis/desensitization

Describe clonidine as a direct-acting adrenergic receptor agonist. Describe S/A. What are its use and clinical considerations?

sel alpha2 R ag --> act CV center in nucleus of solitary tract --> reduce sympathetic tone (phenyliminio)imidazoline basicity of guanidine is decr'd d/t dichlorophenyl rings --> can cross BBB admin: po, PE, TD Uses: HTN, opiate withdrawl

What are the effects of alpha2 mediated reduction in sympathetic tone?

decr B1, a1 act decr HR/contractility decr renin decr vasoconstriction ==> decr BP

Describe open-ring imidazolides as a direct-acting adrenergic receptor agonist. List them. Describe S/A. What are its use and clinical considerations?

bridge to guanidine decr pKa so non-ionized at physio pH guanabenz (Wytensin)--short half life ~2 guanfacine (Tenex, Intuiv) admin po Uses: HTN, ADHD (guanfacine)

What are the uses of apraclonidine (Iopidine) and tizanidine (Zanaflex)?

glauma muscle spasticity

What are the adverse effects of alpha2-adrenergic R ag?

sedation Na and water retention (RAAS act) dry mouth withdrawl syndrme (rebound HTN, tachycardia)--> taper to dc

Describe isoproterenol as a direct acting adrenergic receptor agonist. What are its uses and clinical considerations?

non-sel beta r ag metab by phase II and COMT (not MAO) effects: bronchodil and incr CO admin: po, PE, inhaled uses: asthma, COPD, cardiostimulant

Describe resorcinol derivatives as a direct acting adrenergic receptor agonists. List them What are their uses and clinical considerations?

metaproterenol (Alupent, Metaprel) terbutaline (Brianyl, Brethine) sel B2 R ag --> bronchodil (card effect at high doses) no metab by MAO or COMT; longer doa than isoproterenol Uses: asthma, COPD terbutaline as tocolytic

What is the fxn of a tocolytic?

prevent premature labor

Describe meta hydroxylmethyl derivatives as a direct acting adrenergic receptor agonists. List them What are their uses and clinical considerations?

albuterol levalbuterol salmeterol sel beta2 R ag --> bronchodil (card at high dose) no metab by MAO or COMT, longer doa than isoproterenol use: asthma, COPD

Which are the long-acting beta-receptor agonists? | Describe moa and use.

salmeterol formoterol sel B2 not met'd by MAO or COMT DPI or MDI uses: asthma, COPD (not acute asthma Sx)

Describe the moa of dobutamine as a direct-acting adrenergic receptor agonist. Describe it's uses.

``` dopamine-deriv racemic mix (+)-B1 ag; a1 antag (-)-a1 ag NET: incr inotropic effect w little chronotropic effect ``` metab by COMT admin PE USe: acute HF, shock

What is the moa of indirect-acting sympathomimetics? List them.

promote release of NE via reverse action of plasma membrane transporter. ``` amphetamine pseduoephedrine ephedrine phenylpropanolamine tyramine ```

What are the clinical uses of indirect-acting sympathomimetics?

amphetamines: ADHD, narcolepsy, anorexiant others: nasal decongestants

Compare and contrast the activity of (-)-Ephedrine and (+)- Pseduoephredrine

ephredrine has R config at beta-OH and S at alpha carbon for direct ag activity at adrenergic R pseudoephredrine is S,S. S configuration of beta-OH reduces agonist activity-major mechanism is via reversal of the transporter

What is the chemical difference between pseudoephedrine and meth?

beta hydroxyl (S-config) converted to H after rxn with Li and NH4+ more hydrophobic--get CNS activation

How are cocaine and antidepressants indirect-acting sympathomimetics? i.e. moa

block reuptake transporters on presynaptic neuron, incr amt of NT in synapse

How do MAO inhibitors act as indirect sympathomimetics?

decrease amt of NE that is broken down, incr amt of NE available to be secreted into synapse

Coadministration of MAOI with other indirect-acting sympathomimetics can lead to what complication?

hypertensive crisis

What are examples of MAOIs?

phenelzine | selegiline

2- Adrenergics Flashcards

(45 cards)