Adrenergic Agonists Flashcards
In general terms, what are the steps to synthesis of NE and epi?
from tyrosine to DOPA, then dopamine, norepinephrine, epinephrine
What is the rate limiting step for adrenergic amine synthesis
tyrosine hydroxylase (the first step)
How are adrenergic amines stored?
in granules with ATP-protein complexes
IN order for NE to be released, a preganglionic sympathetic nerves releases ___ onto ___ receptors on the postganglionic nerve.
ACh onto nicotinic nerves
How do the indirectly-acting sympathomimetics work?
they reverse the direction of the axoplasmic catecholamine transporter, so you don’t get NE taken back up into the cell and it stays in the synapse
What are three indirectly-acting sympathomimetics?
tyramine, amphetamine, ephedrine
What are two drugs that inhibit the axoplasmic pump to potentiate sympathetic responses?
cocaine and imipramine
What drug inhibits the granular pump and what does this lead to?
Reserpine inhibits the granular pump so NE can’t get put in vesicles. This means it’s out in the cytosol with the degradation enzymes so you get a depetion of catecholamines
What drugs induce catecholamine release from the vesicles via displacement? WHat does this do to NE stores?
Guanethidine and Guanadrel
this depletes NE stores because the NE is out in the cytosol and gets degraded by MAO
How does the ody terminate adrenergic amine signals?
either reuptake or degradation with COMT and MAO
What is the example of MAOI we should know from this lecture?
pargyline
What are the adrenergic receptors and where are they located?
alpha 1 smooth muscle
alpha 2 prejunctional nerve terminal, platelets, gut, medulla oblongata
beta 1 heart, JG aparatus
beta 2 lungs and smooth muscle
Order epi, NE and isoproterenol for alpha1 receptors
epinephrine > norepinephrine»_space; isoproterenol
Order epi, NE and isoproterenol for alpha 2
epinephrine > norepinephrine»_space; isoproterenol
Order epi, NE and isoproterenol for beta 1
isoproterenol > epinephrine = norepinephrine
Order epi, NE and isoproterenol for beta 2
isoproterenol > epinephrine»_space; norepinephrine
What does activation of alpha 1 receptors do? How?
smooth muscle contraction = vasoconstriction
activates phospholipase C with a Gq dependent process to increase intracellular calcium
What does activation of alpha 2 receptors do? How?
inhibits neural NE release to dull the general sympathetic response
decreases cAMP or activates an Na/H antiporter in a Gi dependent process
WHat does activation of beta 1 receptors do?How?
increases HR and contractility, stimulates renin release
increases cAMP via Gs
What does activation of beta 2 receptors do? How?
relaxation of smooth muscle and metabolic glycogenolytic effects (bronchodilation too)
increases cAMP via Gs
What is the one beta 1 agonist?
dobutamine
What is dobutamine used for? Contraindicated in?
used for congestive heart failure or acute MI with heart failure
contraindicated in a fib
What does dobutamine do to blood pressure?
Directly causes an increase in blood pressure
What is the alpha 1 agonist we learned?
phenylephrine
What does phenylephrine do to BP?
increases BP by causeing vasoconstrction and increase in TPR
What are some examples of beta 2 selective agonists? What are they used for?
used for either asthma or to delay labor:
metaproterenol, terbutaline, albuterol, ritodrine, salmeterol
What do the beta 2 agonists do for BP?
They decrease BP by their vasodilatory effects
What are the effects of isoproterenol?
vasodilation with activation of beta 2
tachycardia with activation of beta 1 (conflicting response!)
What is the overall effect on blood pressure by isoproterenol?
Although it causes tachycardia with increased SV, the effect on radius is more important, so overall it causes a decrease in blood pressure
What can you use to block the effects of isorpoterenol>
beta blockers (nonspecific) like propranolol
WHat are the effects of norepinephrine?
vasocosntriction via alpha 1
increased HR and contractility via beta 1
reflex reduction in HR mediated by vagus nerve
What does NE do to blood pressure then?
increases blood pressure - used to treat hypotension as a pressor
If you block the alpha 1 receptors with terazosin, what does NE do to blood pressure?
you still get a slight increase in BP because of the increased HR and contractility thorugh beta 1
What are the effects of epinephrine?
vasoconstriction via alpha` at high doses
vasodilation at lower doses via beta 2
increase HR and contractility via beta 1, but reflexes can suppress heart rate
What does epinephrine do to blood pressure?
at the doses we generally use (high), it increases BP
If you give terazosin before epinrphine, what does it do to blood pressure?
decreases it now! If the alpha 1 receptors are blocked, beta 2 activity will occur and you get vasodilation with decrease in BP. This is “epinephrine reversal”
If drug X causes an increase in BP, but no response after terazosin, what is the drug?
an alpha1 agonist like phenylephrine
If drug x causes a decrease in BP, but no response after propranolol, what was drug x?
a beta 2 agonist like isoproterenol
note, also has beta 1 effect, but radius wins out to cause decreased BP
If drug X causes an increase in BP, but only a slighter increase in BP after terazosin, what is drug X?
Norepinephrine
still causes icnreased HR and contractility after terazosin, but doesn’t stimulate beta 2=
If drug X causes an increase in BP, but then a decrease in BP after terazosin, what was drug X?
epinephrine - this is epinephrine reversal - after terazosin, epinephrine activates beta 2, leading to vasodilation and decreased BP
What do amphetamines do in this system?
they cause release of catecholamines from nerves by reversing the catecholamine axoplasmic uptake pump
are thus noncatecholamine sympathomimetics
How does ephedrine work?
same as amphetamine - reverses axopaslmic transporter to mimic sympathetic stimulation
