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CV Module Pharm > Miscellaneous ANS drugs > Flashcards

Miscellaneous ANS drugs Flashcards

1
Q

What are the two classes of Miscellaneous Drugs used in the control/Rx of HTN?

A
  1. Agents acting at α2 sympathetic receptors in the CNS (α2-agonists)
  2. Agents acting at central (vasomotor) and peripheral sympathetic presynaptic nerve terminals (NE storage depletion)
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2
Q

What are the two locations that miscellaneous drugs act on to decrease CV activity and vascular tone?

A
  1. Vasomotor center (central)

2. Sympathetic Nerve terminals

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3
Q

What are the α2-agonists? (3+1)

A
  1. CLONIDINE
  2. Guanabenz
  3. Guanfacine
  4. METHLYDOPA
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4
Q

Where do the α2-agonists act?

A

They act at certain areas in the CNS to control CV function.

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5
Q

What is unique about Methlydopa?

A

It is a prodrug, that is converted to α-methyl-NE, which the active α2-agonist.

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6
Q

What is the catecholamine(NE)-storage-depleting drug used for CV purposes clinically?

A

Reserpine

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7
Q

What is the drug that inhibits catecholamine production? How does it work? What is it used for?

A

Metyrosine. It inhibits the tyrosine hydroxylase, the rate-limiting step of catecholamine synthesis. It is used for the Rx of pheochromocytoma (adrenal medulla), as it alleviates the HTN, headaches, nausea, sweating, and tachycardia due to the catecholamine excess produced by this type of tumor.

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8
Q

What are the factors involved in the complex system of BP regulation?

A

In the CV system, there is a complex relationship between centrally moderated SNS activity and BP regulation that involves many other factors, as SNS activity influences hemodynamic, volume, and neurohumoral circumstances, and the renin-angiotensin system.

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9
Q

What is the apparent frequency of CNS involvement in HTN? What does this mean therapeutically?

A

As many as 30% of patients with essential HTN have a primary neurogenic stimulus contributing to the condition.
CLONIDINE, which acts centrally to reduce SNS outflow can have a tremendous effect in this type of patient.

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10
Q

What mechanism do α2-R’s work thru once activated?

A

They are GPCR’s and when activated it induces G-protein (Gi) signaling.

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11
Q

What is an important aspect of α2-R activity under conditions of long-term α2-activation?

A

RECEPTOR DESENSITIZATION: w/ chronic stimulation, there can be a dysregulation in the signaling process, caused by an uncoupling of the activity from the cell surface and an endocytosis of the entire receptor complex, thereby rendering the signaling pathway inactive. (this is a common phenomenon w/ other pharmacologic receptor systems)

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12
Q

How does the activity of α2-R’s in a normal person compare w/ a person with chronic HF?

A

Under normal circumstances in which there was only occasional α2 stimulation, α2-R activity would be normal.
However, in a pt w/ chronic HF, there would would excessive catecholamine signaling on a constant basis, leading to a down-regulation of α2’s and its signaling mechanism. Therefore, there would be a consequent loss of drug activity for α2-agonists.

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13
Q

What is the mechanism of α2-R desensitization due to chronic stimulation? (not very important)

A

Activated α2-R’s interact w/ GPCR kinases (GRK’s). This enables GRKs to phosphorylate α2-R’s.
Spinophilin is able to block complex (α2+Gi) formation, allowing β-ARRESTINs to bind to P’d α2’s and initiate endocytosis.

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14
Q

What is the location and role of α2-R’s in an adrenergic synapse?

A

α2’s are autoreceptors located on the presynaptic terminal membrane, where activation by released NE causes an inhibition of further release of NE.

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15
Q

Where do α2-R’s serve as heteroreceptors? How does the activity of α2 autoreceptors compare to that of the heteroreceptors in the presence of α2-agonists?

A

These heteroreceptors are the expression of α2’s in cholinergic or non-adrenergic synapses.
The clinical activity produced by α2-agonists acting on α2 autoreceptors is relatively minor compared to the amount of activity produced by these drugs on α2 heteroreceptors.

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16
Q

What are the effects mediated by α2 agonists?

A
  1. On α2 autoreceptors
    a) Inhibition of NE release
    b) Bradycardia (minor component)
    c) Hypotension (minor)
  2. On α2 heteroreceptors
    a) SEDATION, aneasthetic-sparing, hypothermia, ANALGESIA
    b) Bradycardia (MAJOR component; involves vagal/PS activation)
    c) Hypotension (MAJOR; vagal/PS)
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17
Q

The action of α2- agonists on heteroreceptors is the primary cause of what effects produced by this class of agents?

A
  1. Sedation
  2. Analgesia
  3. Bradycardia
  4. Hypotension
    3 and 4 involve vagal (PS) activation
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18
Q

What is the reason for the bradycardia and hypotension caused by α2-agonists?

A

The bradycardia and hypotension come primarily not from reduction of catecholamine (NE) sympathetic outflow, but from an activation of the vagal (Cholinergic, PS) system, which slows the heart.

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19
Q

What is the most important overall factor in the clinical effect produced by α2-agonists?

A

The overall clinical effect is clearly a combination of autorec and heterorec activity, but it is the activity of the heterorec’s that seems to be more important.

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20
Q

What is the mechanistis result of α2 autoreceptor activation?

A

They limit the release of NE from sympathetic nerves and the release of E from adrenal chromaffin cells at rest.

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21
Q

What causes desensitization of α2-autoreceptors? What is a clinical condition that causes this?

A

Desensitized due to chronic activation, such as during the enhanced sympathetic activity of chronic heart failure

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22
Q

What are the clinical effects of stimulation of α2-heteroreceptors in non-adrenergic neurons?

A
  1. Bradycardia and hypotension
    a. Vagal activation (cholinergic action)
  2. Analgesia
  3. Sedation
  4. Hypothermia
  5. Anesthetic-sparing effect
23
Q

If α2-R’s exist on the peripheral vasculature (vasoconstriction), how would an α2-agonist lead to a reduction in blood pressure?

A

Activation of vascular of vascular α2’s leads to vasoconstriction, but the vascular effects are normally obscured by Central inhibition of Sympathetic tone, thus decreasing BP.

24
Q

Based on this, how would α2-agonists that cannot penetrate the BBB affect BP?

A

α2-agonists that cannot penetrate the BBB do not effectively lower BP.

25
Q

What are the only situations where you would see vasoconstriction mediated by α2-agonists?

A

Observed only when α2-agonists are given locally, by rapid IV injection or in very high doses.

26
Q

What are the clinical effects of α2 agonists?

A
  1. Withdrawal of SNS tone producing parallel and balanced fall in PVR and systolic/diastolic BP
  2. there is NO reflex tachycardia, so HR may decrease
  3. CO and renal blood flow typically go unaffected
  4. Decreased plasma renin activity
  5. Regression of LV hypertrophy
  6. Dose-dependent salt and water retention
27
Q

How does α2-agonist affect PVR and BP?

A

Withdrawal of SNS tone produces parallel and balanced fall in PVR and systolic/diastolic BP. This effect persists in the long-term, and blocks exercise-induced increase in SNS activity.

28
Q

Why is there no reflex tachycardia w/ α2-agonists and what does this result in?

A

No reflex tach b/c of the increased vagal (PS) activity; so, HR may be reduced

29
Q

Why do α2-agonists decrease plasma renin activity?

A

b/c renin release is partly mediated by sympathetic β-adrenergic stimulation

30
Q

How does the dose-dependent salt and water retention due to α2-agonists change over time? What do you need to give w/ the α2-agonist to deal with this?

A

This effect diminishes the effectiveness???? of α2-agonists over time. This can be managed by co-prescribing a DIURETIC w/ the α2-agonist.

31
Q

How are α2-agonists primarily used clinically?

A

They are useful adjunctive agents, especially in blocking reflex tachycardia, a type of adverse reaction that is commonly seen with vasodilator drugs.

32
Q

Why do α2-agonists have utility in diabetics and asthmatics?

A

They do NOT produce meaningful adverse effects upon blood glucose levels or pulmonary/lung function, so they are particularly useful in the Rx of HTN in diabetics and asthmatics

33
Q

Which two α2-agonists are available by IV? (all others are oral only)

A
  1. Clonidine

2. Methyldopa

34
Q

Which α2-agonist is available as a transdermal patch? How does this affect drug levels?

A

Clonidine; this patch system takes a while (1-2 days) for drug levels to rise to a constant level, and it will also take time for the drug to dissipate/disappear once the patch is removed

35
Q

How do the half-lives of α2-agonists compare? Which has the shortest half-life? Which has the longest? How does half-life/serum drug level correlate with the duration of the central effect?

A

These drugs vary in their half-lives.
Methyldopa having the shortest, and Guanfacine having the longest.
There is a poor correlation b/t serum drug levels and the duration of the central effect of these drugs.

36
Q

How does methyldopa differ from the other α2-agonists?

A

It is a pro-drug that has to be metabolized to the active compound α-methyl-NE.

37
Q

What two factors can cause the need to adjust the administration of methyldopa, but do not affect the other α-agonists?

A
  1. Dose adjustment if the patient has renal failure
  2. It is chelated by concurrent iron supplements. If the patient needs both, separate the timing interval of the two by 2hrs to reduce the chelation.
38
Q

What are the most common adverse effects of α2-agonists?

A
  1. Somnolence/drowsiness

2. Dry Mouth

39
Q

What is the #1 adverse effect/complaint of patients on α2-agonists? What steps should be taken to minimize/avoid this?

A

Drowsiness/Somnolence.

  1. Give the drug just before bed.
  2. Avoid other CNS depressants (1st-generation antihistamines, alcohol, sedatives/hypnotics)
40
Q

Why do α2-agonists cause dry mouth? What is this associated w/ an increased risk of?

A

Due to α2-mediated decrease in salivary flow.

Increased likelihood of caries, periodontal disease, and oral infection/candidiasis

41
Q

What are the less common side effects of α2-agonists?

A
  1. GI problems: Abdominal pain, Constipation
  2. Hypotension and Sinus Bradycardia
  3. Decreased Libido and Impotence
42
Q

Why is methyldopa relatively contraindicated in the Rx of pheochromocytoma?

A

Methyldopa interferes w/ catecholamine quantitation, and in pt’s w/ pheochromocytoma, you would like to be able to quantitate catecholamine levels in the circulation.

43
Q

In treating HTN in pregnant women, which of these miscellaneous drugs are preferred? Which should you not use?

A 
Preferred:
1. METHYLDOPA
2. Guanfacine
DONT USE:
1. Clonidine
2. Guanabenz
3. Reserpine
44
Q

Which α2-agonist has a long history of safe use in the Rx of HTN during pregnancy?

A

Methyldopa

45
Q

What two antihypertensive drugs are strongly contraindicated in the Rx of HTN during pregnancy?

A

ACEi’s and ARBs

46
Q

What is the result of reserpine use at the level of the adrenergic synapse?

A

depletion of catecholamine storage in the presynaptic terminal

47
Q

What is reserpine? How does it work? Effect?

A

Reserpine is a long-lasting drug that binds very tightly to adrenergic storage vesicles in central and peripheral adrenergic neurons, where it inhibits VMAT2 (vesicular catecholamine transporter). This results in lost capacity to concentrate and store NE and dopamine, so when the presynaptic terminal depolarizes, there is insufficient quantal release of nt into the synaptic cleft.

48
Q

Is reserpine long-lasting or short-lasting? Why?

A

It produces a long duration of effect, given that recovery from its action requires the synthesis of new storage vesicles. So, it may take days to weeks for full neuronal activity to be recovered.

49
Q

Are the antihypertensive effects of reserpine related to central or peripheral actions?

A

the antihypertensive effects are related to its actions in both of these areas

50
Q

How is reserpine action terminated?

A

It is completely metabolized to inactive products

51
Q

What the general type of the most signigicant toxicities caused by reserpine? Why?

A

Its most significant toxicities are CNS toxicities, as it depletes catecholamine levels in the CNS

52
Q

What are the CNS toxicities caused by Reserpine? What type of patients is it contraindicated in for CNS-related reasons?

A

A. Sedation and inability to concentrate or perform complex tasks
b. (KNOW THIS ONE) Occasionally, psychotic depression and suicide.
It is contraindicated in patients with a history of MAJOR DEPRESSION, esp those who have SUICIDAL IDEATION

53
Q

With regards to peripheral tissue actions, what are other contraindications of Reserpine?

A
  1. Contraindicated in PUD and Ulcerative Colitis as it can exacerbate these conditions
  2. Avoid in pregnancy b/c it’s teratogenic
  3. Avoid breastfeeding b/c it can cause neonatal problems
54
Q

Although, these miscellaneous drugs are not commonly used in the Rx of HTN due to the presence of newer and better drugs, why are they being reconsidered for use?

A

They are extremely cheap and still have benefits in the control of HTN for those who cannot afford the more expensice BB’s, diuretics, and ACEi’s/ARB’s.

CV Module Pharm (13 decks)

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