Medical Pharmacology Topics   

Preliminary Outline

Vasodilators   Nitrates          Nitroglycerine          Nitroprusside          Isosorbide Dinitrate   Calcium Blockers       Type I          Verapamil          Diltiazem       Type I          Nifedipine          Nimodipine   Arteriodilators          Minoxidil          Hydralazine   Adrenergic Blockers          Prazosin          Beta blockers   PDE Type 5 Inhibitors          Sildenafil

Vasodilator Drugs

Vasodilators are used to treat ischemic heart disease, heart failure, coronary artery insufficiency, peripheral vascular disease, hypertension and erectile disfunction. In ischemic heart disease, the terapeutic goal is to relieve chest pain. This is achieved pharmacologically by dilating coronary arteries, redistributing blood flow to the heart and reducing oxygen demand of the myocardium. In treating congestive heart failure or coronary artery insufficiency, vasodilator drugs increase output and blood flow while decreasing oxygen consumption of the myocardium. In peripheral vascular disease, vasodilators increase blood flo to the ischemic region. In erectyle dysfunction they induce vasodilation of the penile vasculature, increasing blood flow.

Drugs used as vasodilator include calcium blockers, nitroglycerine, nitrates, hydralazine, sodium nitroprusside, ACE inhibitors, minoxidil, prazosin and sidenafil. These drugs act in different ways to increase cytosolic nitrous oxide (NO) in endothelial cells. The NO diffusses to adjacent vascular smooth muscle, where it induces increases in cGMP, which in turn signals the muscle cell to relax.

Nitrates

Nitrates act by providing a substrate that can be converted to NO in the cell. Conversion of nitrate to NO requires reduced sulfhydryl gruops. A lack of sulfhidryl groups and subsequent decreased conversion of nitrates to NO may be the cause of tolerance to organic nitrates. Nitrates have a greater effect on veins than arteries (venodilators).

The most commonly used nitrates are nitroglycerine, nitroprusside and isosorbide dinitrate. Sublingua administration of these agents will have a more immediate effect of short duration (1 hr), while ointment preparations have a sligthly delayed but more sustained effect (> 3 hrs). Nitroglycerine is given sublingual or transdermal to prevent first-pass metabolism. Nitroglycerin is hemodynamically active, but not its metabolites.

Isosorbide dinitrite acts like nitroglycerine but with longer duration of action (t1/2 = 45 min and 2-5 hrs for active metabolites vs 3 min for nitroglycerine). The metabolites of isosorbide dinitrate are active, thus adding to its effective half-life. Sodium nitroprusside may lead to thiocyanate accumulation.

Important modulators of nitrate activity include sympathetic reflexes, the status of left ventricular function (normal vs. congestive heart failure or dilated ventricle), development of tolerance, and the amout of dose.

Calcium Blockers

Calcium Blockers can be classified according to their action in the myocardium and vasculature. Type I calcium blockers like verapamil and diltiazem have a "balanced" effect, i.e. they act both in the myocardium and the vasculature. Type II calcium blockers like nifedipine and nimodipine have predominant vascular effects. Nimodipine is the most specific for vascular effects, especially cerebral vasodilation. Nifedipine is more specific for peripheral and coronary vasodilation, and may increase heart rate through the baroreflex.

Most calcium blockers (excep nifedipine) have active metabolites, which prolong their effective half-time. The main side effects of calcium blockers are hypotension, headache (more with nifedipine), peripheral edema, and cardiovascular depression (more with verapamil).

Other Agents

Minoxidil is a potassium channel agonist that increases both venous and arterial relaxation by decreasing the excitability (by hyperpolarization) of vascular smooth muscle, thus inhibiting voltage-gated Ca channels and the cytoplasmic movilization of Canecessary for contraction. It is raely used to treat hypertension (usually for refractory cases). Most often used in the treatment of androgenic alopecia, it increases follicle size, thickens shafts and prolongs the hair cycle when used as a 2-5% topical solution. Adverse effects include contact dermatitis and hair growth in unwanted areas.

Hydralazine relaxes arteriolar smooth muscle by an unknown mechanism, probably by elevating PGI2 or NO concentrationss. Side effects include upset GI, hypotension and decreased renal function (this will increase renin/angiotensin/aldosterone activity thus hydralazine is used in combination with a diuretic. Hydralazine may also cause a lupus-like syndrome in slow acetylators.

Alpha-adrenergic blockers like prazosin prevent SNS-mediated vasoconstriction. Beta blockers are used to counter the increase in sympathetic stimulation induced by the decrease in arterial pressure that comes with systemic vasodilation. Left unchecked, the increase in sympathetic activity will lead to increased cardiac output, which would further deteriorate conditions usually treated by vasodilators.

Sidenafil inhibits phosphodiesterase type 5 (PDE-5), an enzyme specific to vascular smooth muscle, without affecting PDE-3, which affects cardiac contractility. Phosphodiesterases catalyze the degradation of cyclic nucleotides like cGMP. As a result, sidenafil potentiates the physiological response causing penile erection after sexual arousal, without increasing heart rate. Sidenafil may cause potentially fatal decreases in arterial blood pressue in patients taking nitrates for the treatment of angina. Other common side effects are flushing, dyspepsia, and ransient abnormal vision, probably due to inhibition of retinal phosphodiesterase.

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