Miscellaneous Drugs

Question 1

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

Answer 1

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

Question 2

What does binding to B adrenoceptors cause?

Answer 2

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.

Question 3

What does binding to a2 adrenoceptors cause?

Answer 3

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.

Question 4

Are there alpha-2 receptors in vasculature?

Answer 4

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

Question 5

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

Answer 5

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

Question 6

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

Answer 6

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

Question 7

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

Answer 7

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

Question 8

When would a a2 agonist be indicated?

Answer 8

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.

Question 9

What are the a2 agonists?

Answer 9

• clonidine
• guanfacine
• methyldopa (prodrug)

Question 10

What drugs causes NE storage depletion?

Answer 10

• reserpine

- metyrosine

Question 11

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.

Answer 11

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.

Question 12

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

Answer 12

T.

Question 13

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

Answer 13

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.

Question 14

What can alpha-2 agonist stimulate in the CNS?

Answer 14

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.

Question 15

What are the main effects of a2 agonists?

Answer 15

• 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

Question 16

Do a2 agonists affect CO?

Answer 16

Nope, and renal blood flow also typically goes unaffected

Question 17

What are a2 agonists commonly used with?

Answer 17

• thiazide diuretics
• chlorthalidone
• furosemide

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

Question 18

What can adding a diuretic to an a2 agonist do?

Answer 18

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

Question 19

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

Answer 19

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

Question 20

What are some indications for a2 agonists?

Answer 20

useful adjunctive to block reflex tachycardia

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

Question 21

How is Methyldopa given? Guanfacine?

Clonidine?

Answer 21

IV; PO; transdermal patch

Question 22

Are any a2 agonists prodrugs?

Answer 22

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

Question 23

Which a2 agonists require dose adjustment in renal failure?

Answer 23

just Methyldopa

note that is is also chelated by concurrent iron supplements

Question 24

What are the major adverse effects of a2 agonists?

Answer 24

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

Question 25

Is Methyldopa safe to use in pregnancy?

Answer 25

Yes- often first line

Question 26

What is preeclampsia?

Answer 26

hypertension of pregnancy

Question 27

What are some drugs used to treat preeclampsia?

Answer 27

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

Question 28

What is the MOA of nifedipine?

Answer 28

ca2+ channel blocker

Question 29

What does Reserpine do?

Answer 29

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

Question 30

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

Answer 30

they leak into the cytoplasm and are metabolized

Question 31

How long does recovery from reserpine take?

Answer 31

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

Question 32

Side effects of reserpine?

Answer 32

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

Question 33

When is reserpine contraindicated?

Answer 33

• Those with severe depression

- PUD or ulcerative colitis

Question 34

What does metyrosine do?

Answer 34

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.

Question 35

What is metyrosine used to treat?

Answer 35

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