Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

Chapter 11. Drugs Used in Hypertension

Drugs Used in Hypertension: Introduction

Antihypertensive drugs are organized around a clinical indication—the need to treat a disease—rather than a receptor type. The drugs covered in this unit have a variety of mechanisms of action including diuresis, sympathoplegia, vasodilation, and antagonism of angiotensin, and many agents are available in most categories. A single renin inhibitor has recently been added to the drugs used in this condition.

Less than 20% of cases of hypertension are due to ("secondary" to) factors that can be clearly defined and corrected. This type of hypertension is associated with pheochromocytoma, coarctation of the aorta, renal vascular disease, adrenal cortical tumors, and a few other rare conditions. Most cases of hypertension are idiopathic, also called "primary" or "essential" hypertension. The strategies for treating idiopathic high blood pressure are based on the determinants of arterial pressure (see Figure 6-4). These strategies include reductions of blood volume, sympathetic tone, vascular smooth muscle tone, and angiotensin effects. Unfortunately, the baroreceptor reflex and the renin response in primary hypertension are reset to maintain the higher blood pressure. As a result, they respond to lower blood pressure with compensatory homeostatic responses, which may be significant (Table 11-1). As indicated in Figure 11-1, some compensatory responses can be counteracted with  blockers (for tachycardia) and diuretics or angiotensin antagonists (for salt and water retention).

TABLE 11-1 Compensatory responses to antihypertensive drugs and some of their adverse effects.

Class and Drug Compensatory Responses Adverse Effects Diuretics Hydrochlorothiazide Minimal Hypokalemia, slight to moderate hyperlipidemia, hyperuricemia, hyperglycemia, lassitude, weakness, impotence Furosemide Minimal Hypokalemia, hypovolemia, ototoxicity Sympathoplegics Clonidine Salt and water retention Dry mouth, severe rebound hypertension if drug is suddenly stopped Methyldopa Salt and water retention Sedation, positive Coombs, test, hemolytic anemia (rare) Ganglion blockers (obsolete) Salt and water retention Severe orthostatic hypotension, constipation, blurred vision, sexual dysfunction Reserpine (low dose) Minimal Diarrhea, nasal stuffiness, sedation, depression Alpha1-selective blockers

Salt and water retention, slight tachycardia Orthostatic hypotension (usually limited to first few doses) Beta blockers Minimal Sleep disturbances, sedation, impotence, cardiac disturbances, asthma Vasodilators Hydralazine Salt and water retention, tachycardia Reversible lupus-like syndrome (but lacking renal effects) Minoxidil Marked salt and water retention, marked tachycardia Hirsutism, pericardial effusion Nifedipine, other calcium channel blockers Minor salt and water retention Constipation, cardiac disturbances, flushing Nitroprusside Salt and water retention Cyanide, thiocyanate toxicity Angiotensin antagonists ACE inhibitors Minimal Cough, renal damage in the fetus and in preexisting renal disease Angiotensin receptor blockers Minimal Renal damage in the fetus and in preexisting renal disease

FIGURE 11-1

Compensatory responses (red boxes) to decreased blood pressure when treating hypertension. The initial treatment that causes the compensatory responses might be a vasodilator. Arrows with minus signs indicate drugs used (white boxes) to minimize the compensatory responses. ACE, angiotensin-converting enzyme.

High-Yield Terms to Learn

Baroreceptor reflex Primary autonomic mechanism for blood pressure homeostasis; involves sensory input from carotid sinus and aorta to the vasomotor center and output via the parasympathetic and sympathetic motor nerves Catecholamine reuptake pump (norepinephrine transporter [NET]) Nerve terminal transporter responsible for recycling norepinephrine after release into the synapse Catecholamine vesicle pump Storage vesicle transporter that pumps amine from cytoplasm into vesicle End-organ damage Vascular damage in heart, kidney, retina, or brain Essential hypertensionHypertension of unknown etiology; also called primary hypertension False transmitterSubstance, for example, octopamine, stored in vesicles and released into synaptic cleft but lacking the effect of the true transmitter, for example, norepinephrine Orthostatic hypotension Hypotension on assuming upright posture; postural hypotension Postganglionic neuron blocker Drug that blocks transmission by an action in the terminals of the postganglionic nerves Rebound hypertension Elevated blood pressure (usually above pretreatment levels) resulting from loss of antihypertensive drug effect Reflex tachycardiaTachycardia resulting from lowering of blood pressure; mediated by the baroreceptor reflex Stepped care Progressive addition of drugs to a regimen, starting with one (usually a diuretic) and adding in stepwise fashion a sympatholytic, an ACE inhibitor, and (sometimes) a vasodilator Sympatholytic, sympathoplegic Drug that reduces effects of the sympathetic nervous system

Diuretics

Diuretics are covered in greater detail in Chapter 15 but are mentioned here because of their importance in hypertension. These drugs lower blood pressure by reduction of blood volume and probably also by a direct vascular effect that is not fully understood. The diuretics most important for treating hypertension are the thiazides (eg, hydrochlorothiazide) and the loop diuretics (eg, furosemide). Thiazides may be adequate in mild hypertension, but the loop agents are often used in moderate, severe, and malignant hypertension. Compensatory responses to blood pressure lowering by diuretics are minimal (Table 11-1). When thiazides are given, the maximum antihypertensive effect is often achieved with doses lower than those required for the maximum diuretic effect.

Skill Keeper 1: Development of New Antihypertensive Drugs

(See Chapter 5)

A new drug is under development for the treatment of hypertension. What types of data will the producer of this drug have to provide to carry out clinical trials? What data will be needed to market the drug?The Skill Keeper Answer appears at the end of the chapter.

Sympathoplegics

Sympathoplegic drugs interfere with sympathetic (SANS) control of cardiovascular function. The result is a reduction of one or more of the following: venous tone, heart rate, contractile force of the heart, cardiac output, and total peripheral resistance (see Figure 6-4). Compensatory responses and adverse effects are marked for some of these agents (Table 11-1). Sympathoplegics are subdivided by anatomic site of action (Figure 11-2).

FIGURE 11-2

Baroreceptor reflex arc and sites of action of sympathoplegic drugs. The letters (A-E) indicate potential sites of action of subgroups of sympathoplegics. No clinically useful drugs act at the baroreceptor (site A), but drugs are available for each of the other sites.

Baroreceptor-Sensitizing Agents

A few natural products, such as veratrum alkaloids, appear to increase sensitivity of baroreceptor sensory nerves and reduce SANS outflow while increasing vagal tone to the heart. These agents are toxic and no clinically available drugs act at this site.

Central Nervous System-Active Agents

Alpha2-selective agonists (eg, clonidine, methyldopa ) cause a decrease in sympathetic outflow by activation of 2 receptors in the CNS. These drugs readily enter the CNS when given orally. Methyldopa is a prodrug; it is converted to methylnorepinephrine in the brain. Clonidine and methyldopa both reduce blood pressure by reducing cardiac output, vascular resistance, or both. The major compensatory response is salt retention. Sudden discontinuation of clonidine causes rebound hypertension, which may be severe. This rebound increase in blood pressure can be controlled by reinstitution of clonidine therapy or administration of  blockers such as phentolamine. Methyldopa occasionally causes hematologic immunotoxicity, detected initially by test tube agglutination of red blood cells (positive Coombs' test) and in some patients progressing to hemolytic anemia. Both drugs may cause sedation—methyldopa more so at therapeutic dosage.

Ganglion-Blocking Drugs

Nicotinic blockers that act in the ganglia are very efficacious but because their adverse effects (Table 11-1) are severe, they are now considered obsolete. Hexamethonium and trimethaphan are extremely powerful blood pressure-lowering drugs. The major compensatory response is salt retention. Toxicities reflect parasympathetic blockade (blurred vision, constipation, urinary hesitancy, sexual dysfunction) and sympathetic blockade (sexual dysfunction, orthostatic hypotension).

Postganglionic Sympathetic Nerve Terminal Blockers

Drugs that deplete the adrenergic nerve terminal of its norepinephrine stores (eg, reserpine ) or that deplete and block release of the stores (eg, guanethidine) can lower blood pressure. The major compensatory response is salt and water retention. In high dosages, both reserpine and guanethidine are very efficacious but produce severe adverse effects. Reserpine is still occasionally used in low doses as an adjunct to other agents. Guanethidine has been withdrawn from the US market. Reserpine readily enters the CNS; guanethidine does not. Both have long durations of action (days to weeks). The most serious toxicity of reserpine is behavioral depression, which may require discontinuation of the drug. The major toxicities of guanethidine are orthostatic hypotension and sexual dysfunction. Guanethidine requires the norepinephrine reuptake pump (uptake 1, NET; see Figure 6-2) to reach its intracellular site of action. Therefore, drugs that inhibit this pump (eg, cocaine, tricyclic antidepressants) interfered with the action of guanethidine.

Monoamine oxidase (MAO) inhibitors were once used in hypertension because they cause the formation of a false transmitter (octopamine) in sympathetic postganglionic neuron terminals and lower blood pressure. This octopamine is stored, along with increased amounts of norepinephrine, in the transmitter vesicles. SANS nerve impulses then release a mixture of octopamine (which has very low efficacy) and norepinephrine, resulting in a smaller than normal increase in vascular resistance. Large doses of indirect-acting sympathomimetics, on the other hand (eg, the tyramine in a meal of fermented foods), may cause release of very large amounts of stored norepinephrine (along with the octopamine) and result in a hypertensive crisis. (Recall that tyramine normally has very low bioavailability because of metabolism by MAO. In the presence of MAO inhibitors, it has much higher bioavailability.) Because of this risk and the availability of better drugs, MAO inhibitors are no longer used in hypertension. However, they are still occasionally used for treatment of severe depressive disorder (Chapter 30).

Adrenoceptor Blockers

Alpha1-selective agents (eg, prazosin, doxazosin, terazosin ) are moderately effective antihypertensive drugs. Alpha blockers reduce vascular resistance and venous return. The nonselective  blockers (phentolamine, phenoxybenzamine) are of no value in chronic hypertension because of excessive compensatory responses, especially tachycardia. Alpha1-selective adrenoceptor blockers are relatively free of the severe adverse effects of the nonselective  blockers and postganglionic nerve terminal sympathoplegic agents. They do, however, cause orthostatic hypotension, especially with the first few doses. On the other hand, they relax smooth muscle in the prostate, which is useful in benign prostatic hyperplasia.

Beta blockers are used very heavily in the treatment of hypertension. Propranolol is the prototype, and atenolol, metoprolol, and carvedilol are among the most popular. They initially reduce cardiac output, but after a few days their action may include a decrease in vascular resistance as a contributing effect. The latter effect may result from reduced angiotensin levels ( blockers reduce renin release from the kidney). Nebivolol is a newer  blocker with some direct vasodilator action. Beta-blocker therapy is associated with slightly elevated glucose, low-density lipoprotein and triglyceride concentrations, and diminished high-density lipoprotein levels in the blood; other potential adverse effects are listed in Table 11-1. As noted in Chapter 10, 1-selective blockers with fewer CNS effects may have some advantages over the nonselective and more lipid-soluble agents.

Vasodilators

Drugs that dilate blood vessels by acting directly on smooth muscle cells through nonautonomic mechanisms are useful in treating some hypertensive patients. Vasodilators act by four major mechanisms: release of nitric oxide, opening of potassium channels (which leads to hyperpolarization), blockade of calcium channels, and activation of D1 dopamine receptors (Table 11-2). Compensatory responses are marked for some vasodilators (especially hydralazine and minoxidil) and include both salt retention and tachycardia (Table 11-1).

TABLE 11-2 Mechanisms of action of vasodilators.

Mechanism of Smooth Muscle Relaxation Examples Release of nitric oxide from drug or endothelium Nitroprusside, hydralazine Hyperpolarization of vascular smooth muscle through opening of potassium channels Minoxidil sulfate, diazoxide Reduction of calcium influx nifedipine Verapamil, diltiazem, via L-type channels Activation of dopamine D1 receptors

Fenoldopam

Hydralazine and Minoxidil

These older vasodilators have more effect on arterioles than on veins. They are orally active and suitable for chronic therapy. Hydralazine apparently acts through the release of nitric oxide from endothelial cells. However, it is rarely used at high dosage because of its toxicity; therefore, its efficacy is limited. Its toxicities include compensatory responses (tachycardia, salt and water retention; Table 11-1) and drug-induced lupus erythematosus, which is reversible upon stopping the drug. However, hydralazine-induced lupus is uncommon at dosages below 200 mg/d.

Minoxidil is extremely efficacious, and systemic administration is therefore reserved for severe hypertension. Minoxidil is a prodrug; its metabolite, minoxidil sulfate, is a potassium channel opener that hyperpolarizes and relaxes vascular smooth muscle. The toxicity of minoxidil consists of excessive hypotension, severe compensatory responses (Table 11-1, Figure 11-1), hirsutism, and pericardial abnormalities. Because it can cause hirsutism, minoxidil is also available as a topical agent for the treatment of baldness.

Calcium Channel-Blocking Agents

Calcium channel blockers (eg, nifedipine, verapamil, diltiazem ) are effective vasodilators; because they are orally active, these drugs are suitable for chronic use in hypertension of any severity. Verapamil and diltiazem also reduce cardiac output in most patients. Nifedipine is the prototype dihydropyridine calcium channel blocker, and many dihydropyridine analogs are available (eg, amlodipine, felodipine, isradipine ). Because they produce fewer compensatory responses, the calcium channel blockers are much more commonly used than hydralazine or minoxidil. Their mechanism of action and toxicities are discussed in greater detail in Chapter 12.

Nitroprusside, Diazoxide, and Fenoldopam

These parenteral vasodilators are used in hypertensive emergencies. Nitroprusside is a light-sensitive, short-acting agent (duration of action is a few minutes) that must be infused continuously. The drug's mechanism of action involves the release of nitric oxide (from the drug molecule itself), which stimulates guanylyl cyclase and increases cyclic guanine monophosphate (cGMP) concentration in smooth muscle. The toxicity of nitroprusside includes excessive hypotension, tachycardia, and, if infusion is continued over several days, accumulation of cyanide or thiocyanate in the blood.

Diazoxide is a thiazide derivative but lacks diuretic properties. It is given as intravenous boluses or as an infusion and has a duration of action of several hours. Diazoxide opens potassium channels, thus hyperpolarizing and relaxing smooth muscle cells. This drug also reduces insulin release and can be used to treat hypoglycemia caused by insulin-producing tumors. The toxicity of diazoxide includes hypotension, hyperglycemia, and salt and water retention.

Dopamine D1 receptor activation by fenoldopam causes prompt, marked arteriolar vasodilation. This drug is given by intravenous infusion. It has a short duration of action (10 min) and is used for hypertensive emergencies.

Angiotensin Antagonists and a Renin Inhibitor

The two primary groups of angiotensin antagonists are the angiotensin-converting enzyme (ACE) inhibitors and the angiotensin II receptor blockers (ARBs). ACE inhibitors (eg, captopril ), which inhibit the enzyme variously known as angiotensin-converting enzyme, kininase II, and peptidyl dipeptidase, cause a reduction in blood levels of angiotensin II and aldosterone and an increase in endogenous vasodilators of the kinin family (bradykinin; Figure 11-3). ACE inhibitors have a low incidence of serious adverse effects when given in normal dosage (except in pregnancy) and produce minimal compensatory responses (Table 11-1). The ACE inhibitors are useful in heart failure and diabetes as well as in hypertension. The toxicities of ACE inhibitors include cough (up to 30% of patients), renal damage in occasional patients with preexisting renal vascular disease (although they protect the diabetic kidney), and renal damage in the fetus. These drugs are absolutely contraindicated in pregnancy. The second group of angiotensin antagonists, the receptor blockers, are represented by the orally active agents losartan and several analogs, which competitively inhibit angiotensin II at its AT1 receptor site. Losartan, valsartan, irbesartan, candesartan, and other ARBs appear to be as effective in lowering blood pressure as the ACE inhibitors and have the advantage of a lower incidence of cough. However, they do cause fetal renal toxicity like that of the ACE inhibitors and are thus contraindicated in pregnancy.

FIGURE 11-3

Actions of aliskiren, angiotensin-converting enzyme inhibitors, and AT1 receptor blockers. Renin converts angiotensinogen to angiotensin I. Block by aliskiren blocks the sequence at its start. ACE is responsible for activating angiotensin I to angiotensin II and for inactivating bradykinin, a vasodilator normally present in very low concentrations. Block of this enzyme thus decreases the concentration of a vasoconstrictor and increases the concentration of a vasodilator. The AT1 receptor antagonists lack the effect on bradykinin levels, which may explain the lower incidence of cough observed with these agents.

The newest drug in the antihypertensive group is aliskiren , an inhibitor of renin's action on its substrate, angiotensinogen. It thus reduces the formation of angiotensin I and, in consequence, angiotensin II. Toxicities include headache and diarrhea. It does not appear to cause cough, but it is not yet known whether it has the other toxicities of the angiotensin antagonists. It does not show reproductive toxicity in animals but is considered to be contraindicated in pregnancy because of the toxicity of ACE inhibitors and ARBs.

Angiotensin antagonists and renin inhibitors reduce aldosterone levels (angiotensin II is a major stimulant of aldosterone release) and cause potassium retention. Potassium accumulation may be marked, especially if the patient has renal impairment, is consuming a high-potassium diet, or is taking other drugs that tend to conserve potassium, such as potassium-sparing diuretics. Under these circumstances, potassium concentrations may reach toxic levels.

Clinical Uses of Antihypertensive Drugs

Stepped Care (Polypharmacy)

Therapy of hypertension is complex because the disease is symptomless until far advanced and because the drugs can be expensive and sometimes cause major compensatory responses and significant toxicities. However, overall toxicity can be reduced and compensatory responses minimized by the use of multiple drugs at lower dosages. This approach is usually used in patients with severe hypertension. Typically, drugs are added to a patient's regimen in stepwise fashion; each additional agent is chosen from a different subgroup until adequate blood pressure control has been achieved. The usual steps include (1) lifestyle measures such as salt restriction and weight reduction, (2) diuretics (a thiazide), (3) sympathoplegics (a  blocker), (4) ACE inhibitors, and (5) vasodilators. The vasodilator chosen first is usually a calcium channel blocker. The ability of drugs in steps 2 and 3 to control the compensatory responses induced by the others should be noted (eg, propranolol reduces the tachycardia induced by hydralazine). Thus, rational polypharmacy minimizes toxicities while producing additive or supra-additive therapeutic effects.

Monotherapy

It has been found in large clinical studies that many patients do well on a single drug (eg, an ACE inhibitor, calcium channel blocker, or combined  and  blocker). This approach to the treatment of mild and moderate hypertension has become more popular than stepped care because of its simplicity, better patient compliance, and—with modern drugs—a relatively low incidence of toxicity.

Age and Ethnicity

Older patients of most races respond better to diuretics and  blockers than to ACE inhibitors. African Americans of all ages respond better to diuretics and calcium channel blockers, less well to ACE inhibitors. There is considerable interindividual variability in metabolism of  blockers.

Malignant Hypertension

Malignant hypertension is an accelerated form of severe hypertension associated with rising blood pressure and rapidly progressing damage to vessels and end organs. This condition may be signaled by deterioration of renal function, encephalopathy, and retinal hemorrhages or by angina, stroke, or myocardial infarction. Management of malignant hypertension must be carried out on an emergency basis in the hospital. Powerful vasodilators (nitroprusside, fenoldopam, or diazoxide) are combined with diuretics (furosemide) and  blockers to lower blood pressure to the 140-160/90-110 mm Hg range promptly (within a few hours). Further reduction is then pursued more slowly.

Skill Keeper 2: Compensatory Responses to Antihypertensive Drugs

(See Chapter 6)

If hydralazine in moderate dosage is administered for several weeks, compensatory cardiac and renal responses will be observed. Specify the exact mechanisms and structures involved in these responses. The Skill Keeper Answer appears at the end of the chapter.

Skill Keeper 1 Answer: Development of New Antihypertensive Drugs

(See Chapter 5)

The FDA requires a broad range of animal data, provided by the developer in an investigational new drug (IND) application, before clinical trials can be started. These data must show that the drug has the expected effects on blood pressure in animals and has low and well-defined toxicity in at least two species. A new drug application (NDA) must be submitted and approved before marketing can begin. This application usually requires data on pharmacokinetics in volunteers (phase 1), efficacy and safety in a small group of closely observed patients (phase 2), and efficacy and safety in a much larger group of patients under conditions of actual use (phase 3).

Skill Keeper 2 Answer: Compensatory Responses to Antihypertensive Drugs

(See Chapter 6)

The compensatory responses to hydralazine are tachycardia and salt and water retention. These responses are generated by the baroreceptor and renin-angiotensin-aldosterone mechanisms summarized in Figure 6-4. The motor limb of the sympathetic response consists of outflow from the vasomotor center to the heart and vessels, as shown in Figure 11-2.You should be able to reproduce these diagrams from memory.

Checklist

When you complete this chapter, you should be able to:

List the 4 major groups of antihypertensive drugs, and give examples of drugs in each group. (Renin inhibitors are not considered an independent major group; can you name the drug that acts by this mechanism?)

 Describe the compensatory responses, if any, to each of the 4 major types of antihypertensive drugs.

 List the major sites of action of sympathoplegic drugs in clinical use, and give examples of drugs that act at each site.

 List the 4 mechanisms of action of vasodilator drugs.

 List the major antihypertensive vasodilator drugs and describe their effects.

 Describe the differences between the 2 types of angiotensin antagonists.

 List the major toxicities of the prototype antihypertensive agents.

Drug Summary Table: Drugs Used in Hypertension

Subclass Mechanism of Action Clinical Applications Pharmacokinetics Toxicities, Interactions Diuretics (see also Chapter 15) Hydrochlorothiazide, chlorthalidone Block Na/Cl transporter in distal convoluted tubule Hypertension, mild edema Oral Duration: 8-12 h Hypokalemia, hyperglycemia, hyperuricemia, hyperlipidemia Furosemide Block Na/K/2Cl transporter in thick ascending limb Hypertension, heart failure, edema, hypercalcemia Oral, parenteral Duration: 2-3 h Hypokalemia, hypovolemia, ototoxicity Sympathoplegics Centrally acting Clonidine Agonist at 2 receptors; in CNS this results in decreased SANS outflow

Hypertension Oral and transdermal Oral duration: 2-3 days; 1 week transdermal Sedation, danger of severe rebound hypertension if suddenly stopped Methyldopa Prodrug converted to methylnorepinephrine in CNS, with result like clonidine Hypertension Oral Duration: 12-24 h Sedation, induces hemolytic antibodies Ganglion blockers Hexamethonium Obsolete prototype nicotinic acetylcholine (ACh) receptor blocker in ganglia; blocks all ANS transmission None Oral, parenteral Severe orthostatic hypotension, constipation, blurred vision, sexual dysfunction Trimethaphan: IV, rarely used short-acting ganglion blocker for hypertensive emergencies, controlled hypotension Mecamylamine: Oral ganglion blocker, several hours' duration, experimental use in smoking cessation Postganglionic neuron blockersReserpine Blocks vesicular pump (VMAT) in adrenergic neurons Occasionally used in hypertension, Huntington's disease Oral Duration: 5 days Sedation; severe psychiatric depression (high doses) Guanethidine: Blocks reuptake of norepinephrine (NET) and depletes stores; oral, long duration; severe orthostatic hypotension (withdrawn in the United States) Alpha blockers Prazosin Selective 1 blocker; reduces peripheral vascular resistance; prostatic smooth muscle tone

Mild hypertension, benign prostatic hyperplasia Oral Duration: 6-8 h First dose orthostatic hypotension Doxazosin, terazosin: Similar to prazosin but longer duration of action Beta blockers Propranolol Prototype nonselective blocker; reduces cardiac output; possible secondary reduction in renin release Hypertension; many other applications (see Chapter 10) Oral, parenteral Duration: 6-8 h (extended release forms available) Bronchospasm in asthmatics; excessive cardiac depression, sexual dysfunction, sedation, sleep disturbances Atenolol, metoprolol: Like propranolol but 1-selective; fewer adverse effects Labetalol, carvedilol: Combined  and  blockade; oral and parenteral Vasodilators, oral Calcium channel blockers Verapamil, diltiazem Prototype L-type calcium channel blockers; combine moderate vascular effect with strong cardiac effect Hypertension, angina, arrhythmias Oral, parenteral Durations: 6-8 h Excessive cardiac depression; constipation Nifedipine, other dihydropyridines: Oral and parenteral; greater vasodilator than cardiodepressant effects Older oral vasodilators Hydralazine Probably causes release of nitric acid (NO) by endothelial cells causes arteriolar dilation Hypertension (also used in; heart failure in combination with isosorbide dinitrate) Oral Duration: 6-8 h Tachycardia, salt and water retention, lupus-like syndrome Minoxidil Prodrug, sulfate metabolite opens K+ channels, causes arteriolar smooth muscle hyperpolarization and vasodilation

Severe hypertension; male-pattern baldness Oral, topical Duration: 6-8 h Marked tachycardia, salt and water retention; hirsutism Vasodilators, parenteral Nitroprusside Releases NO from drug molecule Hypertensive emergencies; cardiac decompensation Parenteral only Duration: minutes; requires constant infusion Excessive hypotension; prolonged infusion may cause thiocyanate and cyanide toxicity Diazoxide K+ channel opener in smooth muscle, secretory cells

Hypertensive emergencies; hypoglycemia due to insulin-secreting tumors Parenteral for hypertension, oral for insulinoma Hyperglycemia; edema, excessive hypotension Fenoldopam D1 agonist; causes arteriolar dilation

Hypertensive emergencies Parenteral only, very short duration Excessive hypotension Renin antagonist Aliskiren Renin inhibitor; reduces angiotensin I synthesis Hypertension Oral Duration: 12 h Angioedema, renal impairment Angiotensin antagonists ACE inhibitors Captopril ACE inhibitor; reduces angiotensin II synthesis Hypertension, diabetic renal disease, heart failure Oral Half-life: 2.2 h but large doses provide duration of 12 h Hyperkalemia; teratogen; cough Benazepril, enalapril, lisinopril, others: Like captopril but longer half-lives Angiotensin II receptor blockers (ARBs) Losartan Blocks AT1 receptors

Hypertension Oral Duration: 6-8 h Hyperkalemia; teratogen Candesartan, irbesartan, others: Like losartan

ACE, angiotensin-converting enzyme; ANS, autonomic nervous system; CNS central nervous system; SANS, sympathetic autonomic nervous system.



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