Vasodilators and Sympathoplegics DSA Flashcards
vasodilators general mechanism of action
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.
Examples of vasodilators that release nitric oxide from drug or endothelium
Nitroprusside- for hypertensive emergencies
hydralazine- for long-term outpatient therapy of severe or resistant hypertension
nitrates- for hypertensive emergencies, angina
Examples of vasodilators that work by reduction of calcium influx
verapamil, diltiazem, nifedipine, amlodipine
used for long-term outpatient therapy of hypertension; hypertensive emergencies; angina
Examples of vasodilators that work through hyperpolarization of smooth muscle membrane through opening of potassium channels
minoxidil- for long-term outpatient therapy of severe or resistant hypertension
diazoxide- for hypertensive emergencies
Examples of vasodilators that work through activation of dopamine receptors
Fenoldopam- used for hypertensive emergencies
“Fenoldopam? Fenoldopamine.”
Subclasses and examples of calcium channel blockers (CCBs)
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”
MOA of Calcium Channel Blockers
: 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.
Pharmacokinetics of CCBs
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.
Therapeutic Use of CCBs
long-term outpatient therapy of hypertension; hypertensive emergencies; angina.
CCBs ADRs
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.
CCB Drug-drug interactions
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.
Diazoxide MOA
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.
Diazoxide PK
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.
Diazoxide therapeutic Use
hypertensive emergencies (diminishing use)
Diazoxide ADRs
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.
Diazoxide Counterindications
should be avoided in patients with ischemic heart disease due to propensity for angina, ischemia, and cardiac failure.
Minoxidil MOA
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.
Minoxidil therapeutic use
(1) Long-term outpatient therapy of severe hypertension.
(2) Topical formulations (e.g., Rogaine) are used to stimulate hair growth.
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Minoxidil ADRs
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.
Fenoldopam: MOA, PK, Therapeutic use, ADRs, CIs
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.