Adrenergic Agonist Flashcards
What is the difference between the effects mediated by low dose epinephrine vs. high dose epinephrine? Thus, the effects of epinephrine are said to be concentration-dependent.
At low doses, vasodilation and a decrease in BP will predominate due to increased stimulation of b2 (and b1) receptors compared to a1 stimulation. Recall, b2 receptors use Gs mechanism. Activation of Gs increases cAMP. cAMP inhibits MLCK in vascular smooth muscle, thus causing relaxation/vasodilation.
However, at high epinephrine doses, the net effect will be vasoconstriction, with an increase in BP, due to greater stimulation of a1 and b1 receptors, with less stimulation of b2 receptors. A1 and B1 receptors are largely found on the heart, juxtaglomerular cells and smooth muscle. B1 operates on the heart, and an increase in cAMP in the heart will lead to contraction (the cardiac muscle’s MLCK is not inhibited by cAMP like it is in smooth muscle). A1 receptors use the Gq protein, thus, increasing Ca-calmodulin, which enhances contraction, via an increase in IP3/DAG.
Explain how activation of the Gs protein in cardiac cells and skeletal (striated) muscle differs in effect from activation on smooth muscle cells.
Striated cells: increased cAMP leads to an increase in calcium. Calcium-calmodulin protein works to enhance contraction via the MLCK (phosphorylates myosin and causes contraction).
Smooth muscle: cAMP works to inhibit the MLCK (myosin-light chain kinase), and inhibition of MLCK will cause relaxtion to occur.
A2 receptors, which use the Gi mechanism, therefore will cause contraction when stimulated. Decreased [cAMP] will lead to diminished inhibition of MLCK. Thus, contraction will ensue.
For receptors utilizing the Gq protein for GPCR (i.e. A1), explain how the phospholipase C and Rho-kinase pathways can cause contraction of smooth muscle cells when activated.
Phospholipase C pathway: Phospholipase C produces IP3 and DAG. DAG works to enhance cell contraction. IP3 binds to IP3/Ca receptors on the SR, allowing for the release of Calcium. The calcium-calmodulin protein and then activate MLCK, enhancing contraction.
Rho-kinase pathway:Inhibits myosin-light chain phosphatase, thereby enhancing contraction.
MLCK phosphorylates mysoin, causing contraction.
GPCRs using Gq proteins can enduce contraction when activated via the phospholipase C and Rho-kinase pathways. What are common agonists of this receptor?
Norepinephrine, Epinephrine, Endothelin-I, Angiotensin II, argininie, vasopressin, and acetylcholine
Explain the cGMP signal transduction. Why does NO and cGMP initiate vasodilation. Note their effecgs on potassium channels (increase conductance), inhibition of IP3 (less Calcium entry)
Note the type, location, and actions when stimulated of adrenergic and dopaminergic receptors:
Explain why epinephrine at lower doses has a greater affinity for beta 2 receptors causing vasodilation while at higher doses, the affinity for a1 and b1 receptors is greater than that of b2 receptors.
Explain why there is a net increase in BP even though there exists activity at the b2 (causes vasodilation/bronchodilation.
Explain why epinephrine at lower doses has a greater affinity for beta 2 (and b1) receptors causing vasodilation while at higher doses, the affinity for a1 and b1 receptors is greater than that of b2 receptors.
Explain why there is a net increase in BP even though there exists activity at the b2 (causes vasodilation/bronchodilation.
A few uses for epinephrine includes relief for anaphylactic shock and its treatment of bronchospasms (such as asthma). Epinephrine is also useful for mydriasis and to treat open-angle glaucoma by increasing the outflow of aqueous humor. Explain the mechanism behind using Epi for anaphylactic shock:
Epinephrine activates b2 receptors, which inhibits the release of histamine from mast cells.
T or F: Norepinephrine activtes b2 receptors?
FALSE; equal effects on b1 receptors similar to that of epinephrine.
Dopamine has been shown to exhibit mixed-receptor acitivating properties. Describe how dopamine is dose-dependent in terms of its actions on D1 and D2 receptors as well as on a1 receptors.
Dopamine has equal affinity for D1 and D2 (autoreceptor) receptors. However, at higher doses, Dopamine can activate a1 receptors, causing vasoconstriction to occur.
Differentiate between the types of shocks where epinephrine or norepinephrine will be used.
Epinephrine- useful for anaphylactic shock, because NE binds to b2 receptors, inhibiting the release of histamine from mast cells.
Norepinephrine- useful for cardiogenic and nephrogenic shock. NE binds to a1 and b1 (not to b2) receptors to increase HR, vasoconstricition, SV, and conduction velocity.
Isoproternol is a synthetic analog of catecholamines and is an agonist at all beta receptors. Isoproterenol is found to cause a drop in diastolic pressure, but an increase in cardiac output. How does this occur?
The drop in diastolic pressure is due to a decrease in peripheral resistance, due to activation of b2 receptors. However, cardiac output is increased due to activation of b1 receptors, which cause an increase in dromotropic, chronotropic, and ionotropic effects.
Regarding increases in bronchodilation, rank the three catecholamines (ISP, NE, Epi) regarding their effect on bronchodilation:
ISP > Epi > NE
Recall… this is the same setup for activation of beta receptors, which ultimately causes vasodilation of the smooth muscles found in the lungs, causing bronchodilation.
B receptors= ISP > Epi > NE
Dopamine is useful in cardiogenic shock and hypotension because it makes the heart work more efficiently by increasing stroke volume and contractility, while minimizing increases in heart rate. Describe the effect of dopamine at low and high concentrations.
Also, not what other conditions dopamine can be useful for.
High doses: affects a1 and b1 receptors = vasoconstriction, increased contractility/HR/conduction velocity.
Low doses: affects D1 receptors, causing vasodilation of renal blood vessels, which increases blood flow to the kidneys.
Dobutamine is a beta1 agonist that has some functions on b2 receptors at higher doses. Explain how dobutamine can be used for cardiogenic shock and to improve myocardial function in congestive heart failure.
Dobutamine does not act on Dopamine receptors.
low doses- b1 receptors - vasoconstriction
high doses- b2 receptors- vasodilation
Explain how phenyleprine can be used as a nasal decongestant.
Phenyleprine causes vasoconstriction of nasal blood vessels, which reduces mucosal edema.
Phenyleprine is a selective alpha 1 agonist.
Identidy a few locations where alpha 1 receptors can be found.
Describe the pathogenesis of pre-eclampsia. Note the drugs that can be given in this type of crisis:
Drugs: selective alpha 2 agonist = reduced levels of NE = less vasoconstriction
Methyldopa
Clonidine
What are the effects of amphetamines on the CNS
