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Renal II Exam 2 > 8-4 Vasodilators & Sympathoplegics DSA > Flashcards

8-4 Vasodilators & Sympathoplegics DSA Flashcards

1
Q

What are the 2 major categories of Ca++ channel blockers? What are the major drugs in each category?

A

Dihyrdropyridines

inc: amplodipine and nifedipine

Non-dihydropyridines

inc: diltiazem and verapamil

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2
Q

What is the general mechanism of action and effect of vasodilators?

A

All vasodilators that are useful in hypertension relax smooth muscle of arterioles

decreasing peripheral vascular resistance

decreases arterial blood pressure

sodium nitroprusside and the nitrates also relax veins

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3
Q

Vasodilators could potentially have some major side effects. What endogenous system helps to counteract these?

A

Intact sympathetic reflexes prevent orthostatic hypotension and sexual dysfunction in response to vasodilators used as monotherapy

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4
Q

What is the MOA for dihydropyridines (DHPs)?

A

Prototypes: Nifedipine, Amlodipine

MOA: Blocks L-type calcium channels in vasculature > cardiac channels

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5
Q

What is the mechanism of action for non-dihydropyridines?

A

Non-Dihydropyridines

Prototypes: Verapamil, Diltiazem
MOA: Nonselective block of vascular and cardiac L-type calcium channels

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6
Q

What channel do all CCBs work on? How do they differ from DHPs and non-DHPs?

A

All CCBs block L-type calcium channels (voltage-gated), which are responsible for Ca++ flux into smooth muscle cells, cardiac myocytes, and SA and AV nodal cells in the heart

All CCBs bind to L-type calcium channels, but DHPs and non-DHPs bind to different sites on the channel proteins; this leads to differences in effects on vascular versus cardiac tissue responses and different kinetics of action at the receptor

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7
Q

What channel conformation do CCBs bind best?

A

CCBs bind more effectively to open channels and inactivated channels, and reduce the frequency of opening in response to depolarization

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8
Q

What is the effect of CCBs on smooth mm?

A

All CCBs cause vasodilation and decrease peripheral resistance

arterioles are more sensitive than veins;

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9
Q

Do CCBs cause orthostatic hypotension?

A

orthostatic hypotension is not usually a problem;

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10
Q

What is the effect of CCBs on cardiac mm?

A

Effects on cardiac muscle include reduced contractility throughout the heart and decreases in SA node pacemaker rate and AV node conduction velocity

non-DHPs exhibit more cardiac effects than DHPs

DHPs do have effects on cardiac muscle, but they block channels in smooth muscle at much lower concentrations; thus, cardiac effects are negligible at effective therapeutic concentrations

relaxation of arteriolar smooth muscle leads to decreased afterload and decreased O2 demand by the heart

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11
Q

What are some adverse effects/contraindications for dihydropyridine CCBs?

A

Dihydropyridines: excessive hypotension, dizziness, headache, peripheral edema, flushing, tachycardia, rash, and gingival hyperplasia have been reported

Some studies reported increased risk of MI, stroke, or death in patients receiving short-acting nifedipine for HTN; therefore short-acting DHPs should not be used for management of chronic HTN; Slow-release and long-acting DHPs are preferred to minimize reflex cardiac effects

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12
Q

What are some adverse effects from non-DHPs?

A

Non-Dihydropyridines:

Dizziness,

headache,

peripheral edema,

constipation (especially verapamil),

AV block, bradycardia, heart failure,

lupus-like rash with diltiazem,

pulmonary edema, coughing, and wheezing are possible

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13
Q

What is an important contraindication with non-DHPs? What causes this?

A

contraindicated in patients also taking a beta-blocker

Non-DHPs (verapamil > diltiazem) slow heart rate, can slow atrioventricular conduction, can cause heart block

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14
Q

If you have a patient with an AV conduction abnormality that really needs a CCB, what could you use?

A

Nifedipine does not decrease AV conduction and therefore can be used more safely than the non-DHPs in the presence of AV conduction abnormalities

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15
Q

Are CCBs indicated for use in heart failure?

A

Initial studies suggested that CCBs (especially cardiac-selective non-DHPs) could cause further worsening of heart failure as a result of their negative ionotropic effect; later studies demonstrated neutral effects of the vasoselective CCBs amlodipine and felodipine on mortality; as a result, the CCBs are not indicated for use in HF, but amlodipine of felodipine can be used if necessary for another indication, such as angina or hypertension

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16
Q

What are some drug-drug interactions with CCBs?

A

Verapamil may increase digoxin blood levels through a pharmacokinetic interaction

DHPs: Additive with other vasodilators
Non-DHPs: Additive with other cardiac depressants and hypotensive drugs

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17
Q

What is the effect and MOA of K+ channel openers?

A

Diazoxide

MOA: Opens potassium channels in smooth muscle

Increased potassium permeability hyperpolarizes the smooth muscle membrane, reducing the probability of contraction
Arteriolar dilator resulting in reduced systemic vascular resistance and mean arterial pressure

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18
Q

What are some major adverse effects associated with K+ channel openers?

A

Excessive hypotension resulting in stroke and myocardial infarction

Hypotensive effects are greater in patients with renal failure (due to reduced protein binding) and in patients pretreated with β-blockers to prevent reflex tachycardia; smaller doses should be administered to these patients

Also: hyperglycemia…because reasons.

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19
Q

What are some important contraindications with K+ channel blockers?

A

Should be avoided in patients with ischemic heart disease due to propensity for angina, ischemia, and cardiac failure

In contrast to the structurally related thiazide diuretics, diazoxide causes sodium and water retention; this is rarely a problem due to the typical short duration of use

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20
Q

What is the clinical use of K+ channel openers?

A

Clinical Uses: Hypertensive emergencies (diminishing use)

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21
Q

What is the MOA for minoxidil? What kind of drug is it?

A

K+ channel opener

MOA: Active metabolite (minoxidil sulfate) opens potassium channels in smooth muscle

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22
Q

What are the effects of minoxidil?

A

Increased potassium permeability hyperpolarizes the smooth muscle membrane, reducing the probability of contraction

Dilation of arterioles, but not veins; more efficacious than hydralazine

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23
Q

What are some adverse effects/contraindications associated with minoxidil? What should minoxidil be used with?

A

Common: headache, sweating, hypertrichosis (abnormal hair growth)

Even more than with hydralazine, use is associated with reflex sympathetic stimulation and sodium and fluid retention resulting in tachycardia, palpitations, angina, and edema; minoxidil must be used in combination with a β-blocker and loop diuretic in order to avoid these effects

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24
Q

What are the clinical uses of minoxidil?

A 
Long-term outpatient therapy of severe hypertension
Topical formulations (e.g., Rogaine) are used to stimulate hair growth
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25
Q

What is the MOA for fenoldopam?

A

Agonist at dopamine D1 receptors

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26
Q

What are the effects of fenoldopam? How is it administered?

A

Peripheral arteriolar dilator; natriuretic

Administered by continuous IV infusion due to rapid metabolism and short half-life (10 min)

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27
Q

What are some adverse effects associated with fenoldopam? What is a contraindication with this drug?

A

Tachycardia, headache, and flushing

Should be avoided in patients with glaucoma due to increases in intraocular pressure - apparently there’s a dopamine receptor in the eye that will increase IOP when stimulated

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28
Q

What is the clinical use for fenoldopam?

A

Hypertensive emergencies, peri- and postoperative hypertension

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29
Q

What is the MOA for hydralazine?

A

NITRIC OXIDE MODULATOR

MOA: Stimulates release of nitric oxide from endothelium resulting in increased cGMP levels

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30
Q

What is the effect of hydralazine?

A

dilation of arterioles, but not veins; reflex tachycardia

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31
Q

What are some common adverse effects with hydralazine?

A

Common: headache, nausea, anorexia, palpitations, sweating, and flushing

Rare: peripheral neuropathy, drug fever

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32
Q

What group of patients is hydralazine contraindicated for?

A

In patients with:

ischemic heart disease

reflex tachycardia

and sympathetic stimulation

may provoke angina or ischemic arrhythmias

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33
Q

What are the many clinical uses of hydralazine?

A

Long-term outpatient therapy of hypertension

Combination with nitrates is effective in heart failure and should be considered in patients, especially African-Americans, with both hypertension and heart failure

First-line therapy for hypertension in pregnancy, with methyldopa

Parenteral formulation is useful in hypertensive emergencies

34
Q

What is the MOA for Na nitroprusside?

A

NO modulator

MOA: Drug metabolism releases nitric oxide resulting in increased cGMP levels

35
Q

What is the effect of Na nitroprusside?

A

Powerful dilation of arterial and venous vessels, reduces peripheral vascular resistance and venous return

In the absence of heart failure, blood pressure decreases and cardiac output does not change (or decreases slightly)

When cardiac output is already low due to heart failure, cardiac output often increases due to afterload reduction

36
Q

What are some adverse effects associated with Na nitroprusside?

A

Excessive hypotension

Cyanide and thiocyanate are released during metabolism; this is typically not problematic because nitroprusside is used only briefly; cyanide poisoning (metabolic acidosis, arrhythmias, excessive hypotension, and death) can occur if infusions are administered for several days

37
Q

What are the clinical uses of Na nitroprusside?

A

Clinical Uses: Hypertensive emergencies; acute decompensated heart failure

38
Q

What is the prototype organic nitrate? What are some other drugs in the same class?

A

Prototype: Nitroglycerin

Other agents: isosorbide dinitrate, isosorbide mononitrate

39
Q

What is the MOA of organic nitrates? What are the effects?

A

MOA: Release of nitric oxide via enzymatic metabolism

Relaxes most types of smooth muscle (veins > arteries); virtually no direct effect on cardiac or skeletal muscle

Increases venous capacitance; decrease ventricular preload; pulmonary vascular pressures and heart size are reduced

In the absence of heart failure, cardiac output is reduced

Decreases platelet aggregation

40
Q

What are some important pharmacokinetics associated with organic nitrates?

A

route of administration - sublingual, no first pass

Therapeutic plasma levels in 15-30 min

tolerance can occur, go 8 hours between doses to avoid

41
Q

What are some adverse effects associated with organic nitrates?

A

Common: orthostatic hypotension, syncope, throbbing headache

42
Q

What are the mechanics of tolerance associated with organic nitrates?

A

Mechanisms of tolerance are incompletely understood, but may include:

Diminished release of NO due to reduced bioactivation
Reduced availability of sulfhydryl donors
Increased generation of oxygen free radicals
Diminished availability of calcitonin gene-related peptide (CGRP)
Compensatory responses contributing to the development of tolerance: tachycardia, increased cardiac contractility, retention of salt and water

43
Q

What are some drug-drug interactions associated with organic nitrates?

A

Drug-drug Interactions: Synergistic hypotension with phosphodiesterase type 5 inhibitors (sildenafil, tadalafil, vardenafil)

44
Q

What are some clinical uses for organic nitrates?

A

Clinical Uses: Hypertensive emergencies, angina, heart failure

45
Q

What do sympathoplegic agents do? What limits their effect?

A

Alters SNS function

Can cause compensatory effects outside of adrenergic nerves - ie efficacy limited by Na+ retention and expansion of blood volume

46
Q

Combining what with a sympathoplegic agent will make them more effective?

A

use with diuretic

47
Q

What are the major categories of beta adrenoceptor agonists? What are the major drugs?

A

Non-selective

non-ISA

propranolol

carvedilol

ISA

labetalol

Beta-1 selective

Non-ISA

Metoprolol

Atenolol

ISA

Acebutolol

Nebivolol

48
Q

What are beta blockers useful for?

A

HTN

Preventing the reflex tachycardia that often results from treatment with direct vasodilators in severe hypertension

Reduce mortality after MI

some reduce mortality in patients with heart failure

49
Q

What is the prototype beta blocker?

A

propranolol

50
Q

How do non-selective beta blockers work?

A

Non-selective agents primarily decrease blood pressure by decreasing cardiac output

51
Q

How do selective beta blockers work?

A

Other β-blockers may decrease cardiac output and/or decrease peripheral vascular resistance

  • depending on cardioselectivity and partial agonist activities

Some agents exhibit vasodilating activity mediated by a variety of molecular mechanisms

52
Q

Do beta blockers cause hypotension?

A

These agents do not usually cause hypotension in healthy, normotensive patients

53
Q

What happens to the kidneys with beta blocker administration?

A

Blockade of β1 receptors in the kidney inhibits renin release (see notes on ACE inhibitors and ARBs)

54
Q

How do some beta blockers cause a local anesthetic action?

A

Several β-blockers exhibit local anesthetic action due to blockade of sodium channels and resultant membrane stabilization

these effects are usually not apparent at plasma concentrations achieved after systemic administration

55
Q

How are most beta blockers administered?

A

Except esmolol, all are available as oral preparations; carvedilol, metoprolol, and propranolol are available as extended-release tablets; atenolol, esmolol, labetalol, metoprolol, and propranolol are available as parenteral preparations

A wide range of half-lives contributes to differences in dosing schemes

56
Q

What are some important contraindications with beta blockers?

A

Asthma/COPD

DM

57
Q

Why are beta blockers contraindicated in someone with COPD?

A

Blockade of β2 receptors in bronchial smooth muscle may lead to an increase in airway resistance

no currently available β1-selective agents are specific enough to completely avoid β2 blockade

these agents should be avoided in asthmatics;

patients with COPD may tolerate these drugs and the benefits may outweigh the risks, especially in the case of concurrent ischemic heart disease

58
Q

Why is DM a contraindication with beta blockers?

A

glycogenolysis is partially inhibited after β2 blockade

may mask signs of hypoglycemia and delays recovery from insulin-induced hypoglycemia

use with caution in insulin-dependent diabetics (benefits may outweigh risks in diabetics after MI)

59
Q

What are some common side effects with beta blockers?

A

Most common side effects are bradycardia and fatigue; sexual dysfunction and depression sometimes occur

Chronic use has been associated with unfavorable plasma lipid profiles (increased VLDL and reduced HDL)

60
Q

Should beta blockers ever be stopped abruptly?

A

No!

Sudden withdrawl may cause rebound hypertension, angina, and possibly MI; mechanism may involve upregulation of receptor synthesis

61
Q

What is an important drug-drug interaction with beta blockers?

A

Can cause heart block, especially if combined with the CCBs verapamil or diltiazem, which also slow conduction

62
Q

What are the clinical uses of beta blockers?

A

HTN

HF

Ischemic Heart Disease

Cardiac Arrythmias

Glaucoma

63
Q

What beta blockers are commonly used for HTN?

A

Hypertension: Metoprolol and atenolol are the most widely used; not commonly used for initial monotherapy in the absence of a specific indication

64
Q

How are beta blockers helpful with HF?

A

Heart Failure: administration may worsen acute congestive heart failure; even in stable, compensated heart failure,

cardiac decompensation may occur if cardiac output is dependent on sympathetic drive;

but careful long-term use with gradual dose increases may prolong life; specifically, carvedilol, bisoprolol, and metoprolol reduce mortality; mechanisms unknown

65
Q

How are beta blockers helpful with ischemic heart disease?

A

Ischemic Heart Disease:

beta-blockers reduce the frequency of angina episodes and improve exercise tolerance in many patients

timolol, metoprolol, and propranolol prolong survival after MI

66
Q

How are beta blockers helpful with glaucoma?

A

Glaucoma: topical drops of timolol, betaxolol, carteolol, and others reduce intraocular pressure

(agents with local anesthetic action are not used topically on the eye)

67
Q

What conditions is beta 1 selectivity advantageous in treating?

A

β1-selectivity may be advantageous in treating patients with comorbid asthma, diabetes, or peripheral vascular disease

68
Q

What conditions is beta 2 selectivity advantageous in treating?

A

Agents with partial β2-agonist activity may be advantageous in patients with bradyarrhythmias or peripheral vascular disease

69
Q

What is the prototype alpha blocker? What is its MOA?

A

Prazosin

reversible antagonist at alpha 1 receptor

70
Q

What are the physiological changes associated with prazosin?

A

Prevent vasoconstriction of both arteries and veins; blood pressure is reduced by lowering peripheral vascular resistance

Relaxes smooth muscle in the prostate

Retention of salt and water occur when used without a diuretic

Associated with either no change or improvement (increased HDL) in plasma lipid profiles; mechanism of this effect is unknown

71
Q

What are the adverse effects associated with prazosin?

A

Generally well tolerated

Orthostatic hypotension, dizziness (especially “first-dose” syncope), palpitations, headache, lassitude

Less incidence of reflex tachycardia than non-selective alpha adrenergic blockers because α2 receptor inhibition of NE release from nerve endings is unaffected

72
Q

What are the drug-drug interactions to keep in mind with alpha-1 blockers?

A

Most effective when used in combination with other agents

(e.g., a β-blocker and a diuretic)

73
Q

What are the clinical uses for alpha 1 blockers?

A

Used in men with HTN and BPH

74
Q

What are the prototype drugs for centrally acting agents?

A

clonidine, methyldopa

75
Q

What is the MOA for alpha 2 agonists?

A

General MOA: reduce sympathetic outflow from vasomotor centers in the brainstem but allow these centers to retain or even increase their sensitivity to baroreceptor control

Agonists at central α2 receptors
Slight variations in hemodynamic effects of clonidine and methyldopa suggest that these two drugs may act at different populations of central neurons

76
Q

What are the clinical uses for alpha 2 agonists?

A

With the exception of clonidine, these agents are rarely used today

methyldopa is used for hypertension during pregnancy

77
Q

What are the pharmacodynamics of clonidine?

A

lowers blood pressure

  • by reducing cardiac output (decreased heart rate and relaxation of capacitance vessels)

reducing peripheral vascular resistance

78
Q

What are the adverse effects associated with clonidine?

A

Adverse Effects: sedation, dry mouth, depression, sexual dysfunction

Transdermal preparation is associated with less sedation than oral, but may cause skin reaction

Abrupt withdrawal can lead to life-threatening hypertensive crisis

79
Q

What are the pharmacodynamics associated with methyldopa?

A

lowers blood pressure by reducing peripheral vascular resistance; variable reduction in heart rate and cardiac output

80
Q

What are some adverse effects with methyldopa?

A

sedation

dry mouth

lack of concentration

sexual dysfunction

Renal II Exam 2 (8 decks)

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