Vasodilators and Sympathoplegics DSA (from last session)

Question 1

vasodilators general mechanism of action

Answer 1

all vasodilators that are useful in hypertension relax smooth muscle of arterioles, thereby decreasing peripheral vascular resistance and thus arterial blood pressure; sodium nitroprusside and the nitrates also relax veins.
i) Intact sympathetic reflexes prevent orthostatic hypotension and sexual dysfunction in response to vasodilators used as monotherapy.

ii) Vasodilators work best when used in combination with other antihypertensive drugs that oppose the compensatory cardiovascular responses (e.g., a diuretic or β-blocker); but see cautionary note below regarding the potentially dangerous combination of non-DHP CCBs and β-blockers.

Question 2

Examples of vasodilators that release nitric oxide from drug or endothelium

Answer 2

Nitroprusside- for hypertensive emergencies
hydralazine- for long-term outpatient therapy of severe or resistant hypertension
nitrates- for hypertensive emergencies, angina

Question 3

Examples of vasodilators that work by reduction of calcium influx

Answer 3

verapamil, diltiazem, nifedipine, amlodipineused for long-term outpatient therapy of hypertension; hypertensive emergencies; angina

Question 4

Examples of vasodilators that work through hyperpolarization of smooth muscle membrane through opening of potassium channels

Answer 4

minoxidil- for long-term outpatient therapy of severe or resistant hypertension

diazoxide- for hypertensive emergencies

Question 5

Examples of vasodilators that work through activation of dopamine receptors

Answer 5

Fenoldopam- used for hypertensive emergencies”Fenoldopam? Fenoldopamine.”

Question 6

Subclasses and examples of calcium channel blockers (CCBs)

Answer 6

i) Dihydropyridines (DHPs)
(1) Prototypes: nifedipine and amlodipine.
(2) MOA: block L-type calcium channels in vasculature > cardiac channels.

ii) Non-Dihydropyridines (non-DHPs)
(1) Prototypes: verapamil and diltiazem.
(2) MOA: nonselective block of vascular and cardiac L-type calcium channels.”Vera’s Diadem for heart and vessels”

Question 7

MOA of Calcium Channel Blockers

Answer 7

: all CCBs block L-type calcium channels (voltage-gated), which are responsible for Ca2+ flux into smooth muscle cells, cardiac myocytes, and SA and AV nodal cells in the heart. i) 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.ii) CCBs bind more effectively to open channels and inactivated channels, and reduce the frequency of opening in response to depolarization.iii) Effects on smooth muscle: all CCBs cause vasodilation, which decreases peripheral resistance; arterioles are more sensitive than veins; orthostatic hypotension is not usually a problem; relaxation of arteriolar smooth muscle leads to decreased afterload and decreased O2 demand by the heart.iv) Effects on cardiac muscle include: reduced contractility throughout the heart and decreases in SA node pacemaker rate and AV node conduction velocity.(1) As noted above, non-DHPs exhibit more cardiac effects than DHPs.(2) 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.

Question 8

Pharmacokinetics of CCBs

Answer 8

all the CCBs are orally active, but have high first-pass metabolism; these drugs have a high degree of plasma protein binding, and are extensively metabolized; nifedipine, clevidipine, verapamil, and diltiazem are also used IV.i) Amlodipine has a long elimination t1/2 35-50 hours; relative to t1/2 of 2-12 hours for most other CCBs; extended release preparations are available for many of the CCBs.

Question 9

Therapeutic Use of CCBs

Answer 9

long-term outpatient therapy of hypertension; hypertensive emergencies; angina.

Question 10

CCBs ADRs

Answer 10

generally, these drugs are well tolerated.

i) Dihydropyridines: excessive hypotension, dizziness, headache, peripheral edema, flushing, tachycardia, rash, and gingival hyperplasia have been reported.
(1) 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.

ii) 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.
(1) Non-DHPs (verapamil > diltiazem) slow heart rate, can slow atrioventricular conduction, can cause heart block, and are contraindicated in patients also taking a β-blocker.
iii) Nifedipine does not decrease AV conduction and therefore can be used more safely than the non-DHPs in the presence of AV conduction abnormalities.iv) 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.

Question 11

CCB Drug-drug interactions

Answer 11

i) Verapamil may increase digoxin blood levels through a pharmacokinetic interaction.
ii) DHPs: additive with other vasodilators.
iii) Non-DHPs: additive with other cardiac depressants and hypotensive drugs.

Question 12

Diazoxide MOA

Answer 12

opens potassium channels in smooth muscle.

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

Question 13

Diazoxide PK

Answer 13

relatively long-acting (4-12 hours after injection); exhibits high protein binding; metabolism is not well understood.
(1) Typically administered as 3-4 injections, 5-15 minutes apart as needed; sometimes administered by IV infusion.

Question 14

Diazoxide therapeutic Use

Answer 14

hypertensive emergencies (diminishing use)

Question 15

Diazoxide ADRs

Answer 15

excessive hypotension resulting in stroke and myocardial infarction.

(1) 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.
(2) Hyperglycemia, particularly in patients with renal insufficiency.
(3) 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.

Question 16

Diazoxide Counterindications

Answer 16

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

Question 17

Minoxidil MOA

Answer 17

active metabolite (minoxidil sulfate) opens potassium channels in smooth muscle.

(1) Increased potassium permeability hyperpolarizes the smooth muscle membrane, reducing the probability of contraction.
(2) Dilation of arterioles, but not veins; more efficacious than hydralazine.

Question 18

Minoxidil therapeutic use

Answer 18

(1) Long-term outpatient therapy of severe hypertension.

(2) Topical formulations (e.g., Rogaine) are used to stimulate hair growth.`

Question 19

Minoxidil ADRs

Answer 19

common – headache, sweating, hypertrichosis (abnormal hair growth).
(1) 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.

Question 20

Fenoldopam: MOA, PK, Therapeutic use, ADRs, CIs

Answer 20

a) MOA: agonist at dopamine D1 receptors; peripheral arteriolar dilator; natriuretic.
b) PK: administered by continuous IV infusion due to rapid metabolism and short t1/2 10 minutes.
c) Therapeutic Use: hypertensive emergencies, peri- and postoperative hypertension.
d) ADRs: tachycardia, headache, and flushing.e) CIs: should be avoided in patients with glaucoma due to increases in intraocular pressure.

Question 21

Hydralazine MOA and PK

Answer 21

i) MOA: stimulates release of nitric oxide from endothelium resulting in increased cGMP levels.
(1) Dilation of arterioles, but not veins; reflex tachycardia.
ii) PK: well absorbed, but high first-pass effect results in low bioavailability.
(1) Metabolism occurs in part via acetylation; so bioavailability is variable among individuals, dependent on rate of acetylation.

Question 22

Hydralazine: therapeutic use

Answer 22

(1) Long-term outpatient therapy of hypertension.
(2) Combination with nitrates is effective in heart failure and should be considered in patients, especially African-Americans, with both hypertension and heart failure.
(3) First-line therapy for hypertension in pregnancy, with methyldopa.
(4) Parenteral formulation is useful in hypertensive emergencies.

Question 23

Hydralazine: ADRs

Answer 23

common – headache, nausea, anorexia, palpitations, sweating, and flushing.

(1) In patients with ischemic heart disease, reflex tachycardia and sympathetic stimulation may provoke angina or ischemic arrhythmias.
(2) Rare – peripheral neuropathy, drug fever.

Question 24

Sodium Nitroprusside

Answer 24

i) MOA: drug metabolism releases nitric oxide resulting in increased cGMP levels.
(1) Powerful dilation of arterial and venous vessels, reduces peripheral vascular resistance and venous return.
(2) In the absence of heart failure, blood pressure decreases and cardiac output does not change (or decreases slightly).
(3) When cardiac output is already low due to heart failure, cardiac output often increases due to afterload reduction.

Question 25

Sodium Nitroprusside: PK

Answer 25

ii) PK: rapid metabolism results in rapid onset and short duration of effect.
(1) Should be administered by IV infusion with continuous monitoring of arterial blood pressure.

Question 26

Sodium Nitroprusside: Therapeutic use

Answer 26

hypertensive emergencies; acute decompensated heart failure

Question 27

Sodium nitroprusside: ADRs

Answer 27

excessive hypotension

(1) 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.

Question 28

Organic Nitrates: examples and MOA

Answer 28

i) Prototype: nitroglycerin.
ii) Other agents: isosorbide dinitrate, isosorbide mononitrate.

iii) MOA: release of nitric oxide via enzymatic metabolism.
(1) 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.
(2) In the absence of heart failure, cardiac output is reduced.

(3) Decreases platelet aggregation.

Question 29

Organic nitrates: PK

Answer 29

iv) PK: high first-pass effect results in low bioavailability; sublingual route of administration is typically used to avoid first-pass.
(1) Therapeutic blood levels are reached within minutes and last 15-30 minutes.
(2) When longer duration of action needed: oral, transdermal, and buccal preparations available.
(3) Tolerance may occur following continuous exposure, especially with nitroglycerin; a nitrate-free period of at least 8 hours between doses is required to prevent tolerance.

Question 30

Organic nitrates: therapeutic use

Answer 30

hypertensive emergencies, angina, heart failure

Question 31

Organic nitrates: ADRs

Answer 31

common – orthostatic hypotension, syncope, throbbing headache.

(1) Mechanisms of tolerance are incompletely understood, but may include:
(a) Diminished release of NO due to reduced bioactivation
(b) Reduced availability of sulfhydryl donors
(c) Increased generation of oxygen free radicals
(d) Diminished availability of calcitonin gene-related peptide (CGRP)
(e) Compensatory responses contributing to the development of tolerance: tachycardia, increased cardiac contractility, retention of salt and water

Question 32

Organic nitrates: CIs

Answer 32

glaucoma was previously thought to be a contraindication, but it has been shown that nitrates can be used safely in the presence of intraocular pressure.(1) Contraindicated if intracranial pressure is elevated.(2) Transdermal patches should be removed before the use of external defibrillators.

Question 33

Organic nitrates: DDIs

Answer 33

synergistic hypotension with phosphodiesterase type 5 inhibitors (sildenafil, tadalafil, vardenafil)

Question 34

Sympatholytic agents

Answer 34

a) Sympathoplegic agents alter sympathetic nervous system function.
b) Can elicit compensatory effects through mechanisms independent of adrenergic nerves (e.g., efficacy may be limited by sodium retention and expansion of blood volume).
c) Most effective when used concomitantly with a diuretic.

Question 35

non-selective beta blockers that are non-ISA (not intrinsic sympathomimetic activity)

Answer 35

Propanolol, carvedilol

Question 36

non-selective beta blockers with ISA

Answer 36

labetalol

Question 37

B1 selective beta blockers, non-ISA

Answer 37

metoprolol, atenolol

Question 38

Beta blockers general uses

Answer 38

a) Especially useful in preventing the reflex tachycardia that often results from treatment with direct vasodilators in severe hypertension.
b) Reduce mortality after MI; some reduce mortality in patients with heart failure.
c) Prototype: propranolol.

Question 39

Beta blocker MOA

Answer 39

non-selective β-blocker, other agents exhibit various selectivity profiles (see table above).

i) Non-selective agents primarily decrease blood pressure by decreasing cardiac output.
ii) Other β-blockers may decrease cardiac output and/or decrease peripheral vascular resistance depending on cardioselectivity and partial agonist activities.
iii) Some agents exhibit vasodilating activity mediated by a variety of molecular mechanisms.
iv) These agents do not usually cause hypotension in healthy, normotensive patients.
v) Blockade of β1 receptors in kidney inhibits renin release (see notes on ACE inhibitors and ARBs).
vi) 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.

Question 40

Beta blocker PK

Answer 40

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.

i) A wide range of t1/2’s contribute to differences in dosing schemes.
ii) Most exhibit low-to-moderate lipid solubility; exceptions are propranolol and penbutolol, which are quite lipophilic and readily cross the blood-brain barrier.

Question 41

Beta blocker therapeutic use

Answer 41

i) Hypertension: metoprolol and atenolol are the most widely used; not commonly used for initial monotherapy in the absence of a specific indication.
ii) 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.
iii) Ischemic heart disease: β-blockers reduce the frequency of angina episodes and improve exercise tolerance in many patients; timolol, metoprolol, and propranolol prolong survival after MI.
iv) Cardiac arrhythmias: β-blockers are often effective in the treatment of supraventricular and ventricular arrhythmias.v) Glaucoma: topical drops of timolol, betaxolol, carteolol, and others reduce intraocular pressure (agents with local anesthetic action are not used topically on the eye).
vi) β1-selectivity may be advantageous in treating patients with comorbid asthma, diabetes, or peripheral vascular disease.
vii) Agents with partial β2-agonist activity may be advantageous in patients with bradyarrhythmias or peripheral vascular disease.

Question 42

Beta blocker ADRs

Answer 42

most common – bradycardia and fatigue; sexual dysfunction and depression sometimes occur.

i) Chronic use has been associated with unfavorable plasma lipid profiles (increased VLDL and reduced HDL).
ii) Sudden withdrawal may cause rebound hypertension, angina, and possibly MI; mechanism may involve upregulation of receptor synthesis.

Question 43

Beta blocker CIs

Answer 43

i) Asthma/COPD: 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 benefits may outweigh risks, especially in concurrent ischemic heart disease.ii) Diabetes: 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).

Question 44

Beta blocker DDIs

Answer 44

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

Question 45

Alpha 1 blockers: prototype and MOA

Answer 45

a) Prototype: prazosin.
b) MOA: reversible antagonists at α1-receptors.
i) Prevent vasoconstriction of both arteries and veins; blood pressure is reduced by lowering peripheral vascular resistance.
ii) Relaxes smooth muscle in the prostate.
iii) Retention of salt and water occur when used without a diuretic.
iv) Associated with either no change or improvement (increased HDL) in plasma lipid profiles; mechanism of this effect is unknown.

Question 46

Alpha blocker therapeutic use, ADRs and DDIs

Answer 46

primarily used in men with concurrent hypertension and benign prostatic hyperplasia.

d) ADRs: 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.
e) DDIs: most effective when used in combination with other agents (e.g., a β-blocker and a diuretic).

Question 47

Centrally acting alpha 2 agonists: prototypes and general MOA

Answer 47

a) Prototypes: clonidine and methyldopa.
b) 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.
i) Agonists at central α2-receptors.
ii) Slight variations in hemodynamic effects of clonidine and methyldopa suggest that these two drugs may act at different populations of central neurons.

Question 48

Centrally acting alpha 2 agonists: therapeuic use

Answer 48

c) Therapeutic Use: with the exception of clonidine, these agents are rarely used today; methyldopa is used for hypertension during pregnancy (see below).

Question 49

Clonidine MOA and ADRS

Answer 49

i) MOA: lowers blood pressure by reducing cardiac output (decreased heart rate and relaxation of capacitance vessels) and reducing peripheral vascular resistance.
ii) ADRs: sedation, dry mouth, depression, sexual dysfunction.
(1) Transdermal preparation is associated with less sedation than oral, but may cause skin reaction.
(2) Abrupt withdrawal can lead to life-threatening hypertensive crisis.

Question 50

Methyldopa MOA, PK and ADRs

Answer 50

i) MOA: lowers blood pressure by reducing peripheral vascular resistance; variable reduction in heart rate and cardiac output.
ii) PK: methyldopa is an analog of L-dopa; it is converted to α-methylnorepinephrine by an enzymatic pathway that directly parallels synthesis of norepinephrine from L-dopa.iii) ADRs: sedation, dry mouth, lack of concentration, sexual dysfunction.