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Compare the effects of alpha-2 receptors in comparison with that of
the beta-receptor.

Whereas the former is an inhibitory action mediated by Gi, the latter is stimulatory, mediated through Gs.


What does binding to B adrenoceptors cause?

stimulates adenylyl cyclase by activating the stimulatory G
protein, Gs, which leads to the dissociation of its alpha subunit charged with GTP. This activated αs subunit directly activates adenylyl cyclase, resulting in an increased rate
of synthesis of cAMP.


What does binding to a2 adrenoceptors cause?

Alpha2-adrenoceptor ligands inhibit adenylyl cyclase by causing dissociation of the inhibitory G protein, Gi, into its subunits; i.e., an activated αi
subunit charged with GTP and a β-γ unit. The mechanism by which these subunits inhibit adenylyl cyclase is uncertain. cAMP binds to the regulatory subunit (R) of cAMP-dependent protein kinase, leading to the liberation of active catalytic subunits
(C) that phosphorylate specific protein substrates and modify their activity. These catalytic units also phosphorylate the cAMP response element binding protein (CREB), which modifies gene expression.


Are there alpha-2 receptors in vasculature?

Yes, (although alpa1 dominate) acting via the Gi proteins.


T or F. vasculature alpha-2 receptors have little contribution to the pharmacology of alpha-2 agonists.

T, because
the central hypotensive actions of the drugs prevail over peripheral vasoconstrictive


When is the vasoconstriction mediated by alpha-2 agonists seen?

when the agonists are given locally, by rapid IV injection or in very high oral doses


What are the main effects of a2 agonists (clonidine) when given orally?

central effects dominate leading to inhibition of sympathetic tone and reduced blood pressure (thus, can be used to treat HTN)


When would a a2 agonist be indicated?

In patients with pure autonomic failure, characterized by neural degeneration
of postganglionic noradrenergic fibers, alpha-2 agonist, like clonidine, may increase BP because the central sympatholytic effects of clonidine become
irrelevant, whereas the peripheral vasoconstriction remains intact.


What are the a2 agonists?

-methyldopa (prodrug)


What drugs causes NE storage depletion?



Increased sympathetic nervous system activity plays a significant role in HTN and therefore drugs that control sympathetic tone, or outflow, represent a reasoned approach to pharmacologic control of this disease.

Increased sympathetic nervous system activity plays a significant role in HTN and therefore drugs that control sympathetic tone, or outflow, represent a reasoned approach to pharmacologic control of this disease.


T or F. the central effects of alpha-2 receptor activity prevail over any
peripheral actions on vascular smooth muscle.



What does activation of pre-synaptic alpha-2 receptors cause?

reduces the release of NE from the presynaptic terminal, and thereby reduce the stimulation of the heart and contraction of the vasculature that would normally ensue.


What can alpha-2 agonist stimulate in the CNS?

For example, dexmedetomidine a relatively selective,
centrally acting, alpha2-adrenoceptor agonist produces sympatholytic, sedative, and
analgesic properties without significant ventilatory effects. It is used to produce and
maintain sedation.


What are the main effects of a2 agonists?

-withdrawal of SNS tone producing parallel and balanced fall in PVR and systolic/diastolic BP

- NO reflex tachycardia; HR may reduce

-decreased plasma renin activity

-regression of left ventricular hypertrophy


Do a2 agonists affect CO?

Nope, and renal blood flow also typically goes unaffected


What are a2 agonists commonly used with?

-thiazide diuretics

thereby producing a greater reduction in BP than is obtained with either drug alone


What can adding a diuretic to an a2 agonist do?

The use of a diuretic may aid in overcoming tolerance to the alpha-2 agonist and
permit reduction in dose.


T or F. Long term use of a2 agonists leads to tolerance

T. This decrease in
receptor density could occur through an increase in receptor degradation, a decrease in receptor synthesis, or simply receptor internalization


What are some indications for a2 agonists?

useful adjunctive to block reflex tachycardia

no effect on BG or lung function so useful in diabetics and asthmatics


How is Methyldopa given? Guanfacine?

IV; PO; transdermal patch


Are any a2 agonists prodrugs?

Yes, methyldopa is metabolized to a-methylnorepinephrine. The others are active as the parent compound


Which a2 agonists require dose adjustment in renal failure?

just Methyldopa

note that is is also chelated by concurrent iron supplements


What are the major adverse effects of a2 agonists?

-dry mouth
-abdominal pain, constipation
-hypotension, sinus bradycardia
-decreased libido, impotence


Is Methyldopa safe to use in pregnancy?

Yes- often first line


What is preeclampsia?

hypertension of pregnancy


What are some drugs used to treat preeclampsia?

-methyldopa (a2 agonist)
-labetalol (a/B blocker)
-metoprolol (b-blocker)
-nifedipine (long acting only)


What is the MOA of nifedipine?

ca2+ channel blocker


What does Reserpine do?

binds tightly (long-lasting) to adrenergic neurons and inhibits the vesicular catecholamine transporter, VMAT2 causing a lost capacity to concentrate and store NE and dopamine


What happens to the catecholamines that cant be concentrated after giving reserpine?

they leak into the cytoplasm and are metabolized


How long does recovery from reserpine take?

requires synthesis of new storage vesicle which can take days to weeks


Side effects of reserpine?

-CNS toxicities (sedation and inability to concentrate)
-suicidal thoughts
-teratogenic (avoid breastfeeding too)


When is reserpine contraindicated?

- Those with severe depression
- PUD or ulcerative colitis


What does metyrosine do?

works by reducing the availability of E and NE in the presynaptic vesicles by blocking the activity of the rate-limiting step in the
sequential synthesis of catecholamines from the common precursor, tyrosine.


What is metyrosine used to treat?

Metyrosine [Demser] is not used to treat hypertension but rather the consequences
of pheochromocytoma, the rare tumor of the adrenal medulla that causes release of
large quantities of NE and to a lesser extent E.

Until the definitive treatment of surgical excision can be accomplished, drug like metyrosine can be used to modulate the sympathetic excess that leads to severe hypertension