2- Adrenergics Flashcards
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
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
What signalling is activated at alpha1 receptors?
Gq–> Ca2+ and PKC
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
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
What signalling is activated at alpha2 receptors?
Gi –> reduce cAMP-dep PK activity, open K channels
Which direct-acting adrenergic receptor agonists are non-selective for beta receptors (activate both beta1 and beta2)?
isoproterenol (Isuprel)
Which direct-acting adrenergic receptor agonists are selective for beta1 receptors?
dobutamine (Dobutrex)
Dopamine (Intropin)
Which direct-acting adrenergic receptor agonists are selective for beta2 receptors?
terbutaline (Brethine, Bricanyl) metaproterenol (Metprel, Alupent) albuterol (Proventil, Ventolin) salmeterol (Serevent) ritodrine (Yutopar)
What signalling pathway do beta receptors activate?
Gs ==> increase cAMP-dep PK activity
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
What are the three main characteristics of adrenergic agonists?
amine
alpha and beta carbons (alkyl chain)
catechol
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
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)
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)
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
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
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
Describe the effect of Epi on HR and BP.
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.
sel for beta1, beta2
beta2 - vasodilation –> decr BP
beta1 - incr HR (also baroreceptor reflex)
describe the effects of phenylephrine on HR and BP.
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?
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?
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?
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