Antihypertensive Drugs

Published on 08/02/2015 by admin

Filed under Basic Science

Last modified 08/02/2015

Print this page

This article have been viewed 1799 times

Chapter 20 Antihypertensive Drugs

MAJOR DRUG CLASSES

Diuretics

Renin-angiotensin inhibitors

Adrenergic receptor antagonists

Centrally acting sympatholytics

(α₂ receptor agonists)

Ca⁺⁺ channel blockers

Direct vasodilators

Abbreviations
ACE	Angiotensin-converting enzyme
ARB	Angiotensin receptor blocker
AV	Atrioventricular
CNS	Central nervous system
CO	Cardiac output
Epi	Epinephrine
NE	Norepinephrine
TPR	Total peripheral resistance

Therapeutic Overview

Hypertension is the most prominent risk factor contributing to the prevalence of cardiovascular disease. For every 20 mm Hg increase in systolic blood pressure or 10 mm Hg increase in diastolic blood pressure, the risk of death from ischemic heart disease and stroke doubles. The incidence of hypertension, particularly elevated systolic blood pressure, increases with age, and approximately half of all people aged 60 to 69 years old and three quarters of those more than 70 years old have elevated blood pressure. The importance of hypertension as a public health problem will increase as the population ages, and preventing hypertension will be a major public health challenge for this century.

Although these statistics are daunting, prevention of hypertension and the associated reduction in cardiovascular disease has been remarkably successful over the last 30 years, and age-adjusted death rates from stroke and coronary heart disease have declined approximately 50% since 1972. However, it is also estimated that in the United States, approximately 30% of hypertensive adults are unaware of their condition, more than 40% are not being treated, and more than 60% of patients who are receiving treatment are not being adequately controlled.

Hypertension is defined as an elevation of arterial blood pressure above an arbitrarily defined normal value. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) classifies hypertension based on both systolic and diastolic blood pressures. Most candidates for antihypertensive drug therapy have a systolic blood pressure above 140 mm Hg, a diastolic pressure above 90 mm Hg, or both. The presence of other risk factors (e.g., smoking, hyperlipidemia, target-organ damage) is also an important determinant in the decision to treat patients with drugs.

A small number (<10%) of people have hypertension traceable to specific causes, such as renal disease or endocrine tumors. However, most patients are simply at the

upper end of the normal distribution of blood pressure values for their population group. This most common form of hypertension, with no readily identifiable cause, is called essential hypertension. It is usually first diagnosed in middle-aged people but can also be found in children and young adults. Because of its prevalence, it is the disease most often treated with antihypertensive drugs.

Unless its onset is rapid and severe, hypertension does not produce noticeable symptoms. The purpose of treating hypertension is to prevent or reduce the severity of diseases, such as atherosclerosis, coronary artery disease, aortic aneurysm, congestive heart failure, stroke, diabetes, and renal and retinal disease. In this regard many clinical trials have shown that antihypertensive drug therapy reduces the morbidity and mortality associated with these disorders.

Therapy of hypertension involves both pharmacological and nonpharmacological interventions. The therapeutic goal is to reduce blood pressure to below 140/90 mm Hg. This can often be accomplished by targeting a reduction in systolic blood pressure to below 140 mm Hg, which is usually accompanied by a reduction in diastolic pressure below 90 mm Hg. For initial treatment, monotherapy with a single drug is advisable. If necessary, drug dose should be gradually increased toward the upper range of its therapeutic effectiveness or until side effects become limiting. Although monotherapy increases patient compliance, nearly two thirds of patients will require more than one drug to control their blood pressure. If two or more drugs are used, each should be selected to target distinct physiological mechanisms.

Adoption of healthy lifestyles may lower blood pressure as much as some drugs. It may also prevent the onset or progression of hypertension. Patients differ in their sensitivity to these techniques. For example, maintenance of normal body weight and increased physical activity lowers blood pressure in most sedentary and overweight hypertensive individuals, whereas Na⁺ restriction lowers

Therapeutic Overview
Hypertension is defined as:
Systolic pressure >140 mm Hg and/or diastolic pressure >90 mm Hg
Hypertension is a major risk factor for:
Atherosclerosis
Coronary artery disease
Congestive heart failure
Diabetes
Insulin resistance
Stroke
Renal disease
Retinal disease
Hypertension therapy
Nonpharmacological
Weight reduction, dietary (reduce salt and saturated fat, increase fruits and vegetables, use low-fat dairy products), exercise, smoking cessation, decrease excessive (>30 mL/day) alcohol intake
Pharmacological
Diuretics, renin-angiotensin inhibitors, sympatholytics, Ca⁺⁺ channel blockers, direct vasodilators

blood pressure mainly in hypertensive people categorized as “salt-sensitive.” The major advantage of nonpharmacological therapies is relative safety, as compared with drug therapy. Their principal limitation is the lack of compliance by most people. For most hypertensive patients control of hypertension requires drug treatment to achieve an adequate, sustained blood pressure reduction. Nevertheless, lifestyle modification plays a valuable and important role in management.

The disorders for which hypertension represents a major risk factor and the treatments for hypertension are presented in the Therapeutic Overview Box.

Mechanisms of Action

Blood Pressure Regulation

Systemic blood pressure is regulated redundantly by several physiological control systems to ensure optimal tissue perfusion throughout the body. When blood pressure decreases by any means, including antihypertensive drug therapy, one or more of these regulatory mechanisms are activated to compensate for decreases in arterial blood pressure (Fig. 20-1).

FIGURE 20–1 Physiological compensatory mechanisms that counteract a decrease in blood pressure.

The Sympathetic Nervous System

A decrease in blood pressure activates the baroreceptor reflex (Chapter 19), producing increased sympathetic activity, leading to:

• Increased force and rate of cardiac contraction and enhanced cardiac filling, which combine to elevate cardiac output (CO).

• Constriction of most blood vessels, increasing total peripheral resistance (TPR) and venous return of blood to the heart.

• Release of renin from the kidney.

• Renal retention of salt and H₂O, mediated by sympathetic nerves innervating renal blood vessels and tubules.

Renin-Angiotensin-Aldosterone System

A decrease in arterial pressure produces a decrease in renal perfusion pressure and baroreflex-mediated sympathetic activation of renal β₁ adrenergic receptors, inducing the release of renin from the juxtaglomerular cells of the kidney into the blood. Renin cleaves the decapeptide angiotensin I from a circulating glycoprotein, angiotensinogen, which is synthesized mainly in liver. Angiotensin I is converted to the octapeptide angiotensin II by angiotensin–converting enzyme (ACE) present in endothelial cell membranes, especially in the lung. Angiotensin II constricts blood vessels, enhances sympathetic nervous system activity, and causes renal Na⁺ and H₂O retention by direct intrarenal actions and by stimulating the adrenal cortex to release aldosterone (see Fig. 20-1).

Role of Vasopressin

A decrease in arterial pressure causes a baroreflex-mediated release of vasopressin (antidiuretic hormone) from the neurohypophysis of the pituitary gland, which acts on the renal collecting duct to enhance H₂O retention by the kidney.

Fluid Retention by the Kidney

A decrease in arterial pressure causes the kidney to excrete less Na⁺ and H₂O. This results, in part, from the direct intrarenal hydraulic effect of reduced renal perfusion pressure and, in part, from the mechanisms discussed. The resultant expansion of extracellular fluid and plasma volume tends to increase CO and arterial pressure, which can reduce the blood pressure-lowering action of many antihypertensive drugs.

The most effective and best-tolerated antihypertensive drug regimens impair the operation of one or more of these physiological mechanisms. In addition, drug therapy for hypertension must usually be continued for the lifetime of the patient.

Diuretics

Diuretics cause Na⁺ excretion and reduce fluid volume by inhibiting electrolyte transport in the renal tubules. The diuretics can be classified into three broad categories related to their sites and mechanisms of action (see Chapter 21). Thiazide diuretics inhibit the Na⁺/Cl⁻ cotransporter principally in the distal convoluted tubules and produce a relatively sustained diuresis, natriuresis, and kaliuresis. These diuretics are most effective in patients with adequate renal function.

Loop diuretics inhibit electrolyte transport in the ascending limb of the loop of Henle. They are useful in patients with compromised renal function and in those resistant to the actions of thiazides. Loop diuretics produce a pronounced, although shorter, diuresis than do the thiazides. Both thiazide and loop diuretics can cause K⁺ depletion. With chronic administration, this effect is more pronounced with the longer-acting thiazides.

K⁺-sparing diuretics inhibit Na⁺ reabsorption in the collecting duct. Thiazide and loop diuretic-induced hypokalemia can often be alleviated by including one of the K⁺-sparing diuretics in the drug regimen. The K⁺-sparing diuretics, although producing relatively less diuresis and natriuresis than the thiazide or loop diuretics, can counteract their hypokalemic properties.

Renin-Angiotensin Inhibitors

As discussed, renin catalyzes the cleavage of angiotensinogen to angiotensin I. In 2007, the first direct-acting renin inhibitor was approved for the treatment of hypertension by the U.S. Food and Drug Administration. This agent, aliskiren, binds renin in the plasma with high affinity to prevent the first and rate-limiting step of the renin-angiotensin-aldosterone system, leading to reduced levels of both angiotensin I and II.

The active component of the renin-angiotensin system, angiotensin II, is generated by enzymatic conversion of the decapeptide angiotensin I to angiotensin II, a reaction catalyzed by ACE (or kininase II), which is widely distributed in the body, with highest activity in the endothelium of the pulmonary vasculature. ACE inhibitors such as captopril, enalapril, and lisinopril reversibly inhibit this enzyme and reduce blood pressure by inhibiting angiotensin II formation.

The angiotensin receptor blockers (ARBs) such as losartan and valsartan reversibly bind the AT₁ subtype of angiotensin II receptors in blood vessels and other tissues to reduce the physiological effects of angiotensin II. The ARBs have antihypertensive actions similar to those of the ACE inhibitors.

Drugs Affecting the Sympathetic Nervous System

Adrenergic Receptor Antagonists

There is wide diversity in the pharmacological profile of adrenergic β receptor antagonists (see Chapter 11). Some of these compounds, such as propranolol and pindolol, are nonselective and antagonize both β₁ and β₂ receptors, whereas others, like atenolol, are selective for the β₁ receptor subtype. In addition, some β receptor blockers such as pindolol have modest intrinsic sympathomimetic activity, while others including labetalol and carvedilol are competitive antagonists at α₁, β₁, and β₂ adrenergic receptors. Despite these differences, all β receptor blockers used for the treatment of hypertension share the common characteristic of competitively antagonizing the effects of norepinephrine (NE) and epinephrine (Epi) on β₁ adrenergic receptors in the heart and renin-secreting cells of the kidney. Furthermore, clinically useful α₁ adrenergic receptor antagonists lower blood pressure by blocking α₁ receptors on vascular smooth muscle.

Centrally Acting Sympatholytics

Sympatholytics with actions in the central nervous system (CNS) decrease blood pressure by reducing the firing rate of sympathetic nerves, principally by activation of α₂ adrenergic receptors. Drugs in this class include α-methyldopa, clonidine, guanfacine, and guanabenz.

The antihypertensive effects of the prodrug α-methyldopa are attributed to its conversion in the brain by l-aromatic amino acid decarboxylase and dopamine-β-hydroxylase to α-methyl-NE, which is a preferential agonist at α₂ adrenergic receptors (see Chapter 11, Fig. 11-12). Clonidine, guanfacine, and guanabenz, which readily enter the brain after systemic administration, are selective agonists at central α₂ receptors (see Chapter 11). In addition, because these drugs are taken orally for the treatment of hypertension, activation of presynaptic α₂ adrenergic receptors on peripheral sympathetic nerve terminals may inhibit the release of NE and potentially contribute to their antihypertensive action.

The central site(s) where α₂ receptor agonists act to lower blood pressure have not been completely identified and characterized but may include the nucleus of the solitary tract and the C1 neurons of the rostral ventrolateral medulla (see Chapter 19).

Peripheral Sympatholytics

Sympatholytics with a peripheral action lower blood pressure by interfering with the synthesis, storage, and release of NE from sympathetic nerve terminals. α-Methylparatyrosine (metyrosine) inhibits the enzyme tyrosine hydroxylase, which is rate-limiting for the synthesis of catecholamines. Guanethidine and guanadrel are charged molecules that serve as substrates for the NE transporter and the vesicular amine transporter and are thus taken up into peripheral noradrenergic nerve terminals and concentrated in synaptic vesicles. These drugs displace NE from synaptic vesicles into the nerve terminal cytoplasm, where it is degraded by monoamine oxidase. Thus the amount of vesicular NE that can be released by depolarization is reduced. When used chronically, these drugs lead to a long-term depletion of NE from synaptic vesicles in peripheral sympathetic nerves.

Reserpine is a plant alkaloid that was the first drug to be used widely for the treatment of mild to moderate hypertension. Reserpine is lipophilic and binds almost irreversibly to the vesicular amine transporter in both peripheral and CNS catecholaminergic and serotonergic nerves. This action prevents accumulation of monoamines into protective synaptic vesicles, and catecholamine and indoleamine neurotransmitters are degraded by intraneuronal monoamine oxidase, resulting in long-term depletion of NE from peripheral sympathetic nerves, accompanied by some reduction in monoaminergic neurotransmitters in the brain.

Calcium Channel Blockers

The primary action of these drugs is to inhibit the inward movement of Ca⁺⁺ through L-type voltage-dependent Ca⁺⁺ channels. Based on their electrophysiological and pharmacological properties, the voltage-dependent Ca⁺⁺ channels can be divided into different types. The best characterized are the L-type (long-lasting, large channels), T-type (transient, tiny channels), and N-type (present in neuronal tissue and distinct from the other two in terms of kinetics or inhibitor sensitivity). Only the L-type Ca⁺⁺ channels, which are enriched in cardiac and vascular muscle, are affected by Ca⁺⁺ channel blockers, which accounts for the generally low toxicity of these drugs.

The primary modulator of these channels is membrane potential. Under resting conditions the membrane potential is -30 to -100 mV, depending on cell type, and channels are closed. Free intracellular Ca⁺⁺ (0.1 µM) is more than 10,000 times lower than extracellular Ca⁺⁺ (1 to 1.5 mM), a gradient that provides an enormous driving force for Ca⁺⁺ to enter the cell. This gradient is maintained by a membrane largely impermeable to Ca⁺⁺ that contains active-transport systems that pump Ca⁺⁺ out of the cell. When the membrane depolarizes, the channels open, and Ca⁺⁺ enters the cell. This is followed by relatively slow inactivation of the channels in which they are impermeable to Ca⁺⁺. They must transition from the inactivated state to the resting conformation before they can open again.

Ca⁺⁺ channel-blocking drugs bind with high affinity only when the channel is in the inactivated state. Because the channel can transition to the inactivated state only after opening, and channel opening depends on membrane depolarization, drug binding is said to be “use-dependent.” In addition to use dependence, binding of Ca⁺⁺ channel blockers is also frequency-dependent. In part, because these drugs are lipid soluble, they dissociate relatively rapidly from their binding sites on the channel. If the time between sequential membrane depolarizations is relatively long, most drugs will dissociate from the channel between depolarizations, resulting in little inhibition of Ca⁺⁺ flux. However, if the frequency is rapid, the channels will cycle more frequently, drug will bind to or remain bound to the channel, and blockade of the channel will persist. Therefore inhibition of Ca⁺⁺ channels will be directly proportional to depolarization rate, that is, it will be frequency-dependent. Verapamil exhibits much more frequency dependence than nifedipine. The frequency dependence of diltiazem is intermediate.

Voltage-dependent Ca⁺⁺ channels play important roles in the excitation-contraction-relaxation cycle (see Chapter 22 and Chapter 24). Under resting conditions, when intracellular Ca⁺⁺ is low, regulatory proteins prevent actin and myosin filaments from interacting with each other, and muscle is relaxed. When intracellular Ca⁺⁺ concentrations increase by influx or release from internal stores, Ca⁺⁺ occupies binding sites on Ca⁺⁺-binding regulatory proteins, such as troponin C (in cardiac and skeletal muscle) and calmodulin (in vascular smooth muscle). These proteins then interact with other proteins and enzymes (e.g., troponin I in cardiac and skeletal muscle and myosin light-chain kinase in smooth muscle), facilitating cross-bridge formation between actin and myosin, which underlies contraction. When Ca⁺⁺ channels inactivate, Ca⁺⁺ is pumped out of the cell, activation of contractile proteins is reversed, actin dissociates from myosin, and the muscle relaxes.

Direct Vasodilators

The direct-acting vasodilators are among the most powerful drugs used to lower blood pressure and include hydralazine, minoxidil, diazoxide, nitroprusside, and fenoldopam. As indicated in Chapter 24, several purported mechanisms have been proposed to mediate the ability of hydralazine to dilate arterioles, whereas minoxidil and pinacidil bind to ATP-sensitive K⁺ channels, causing them to open. This allows K⁺ to partially equilibrate along its concentration gradient, which shifts the membrane potential toward the K⁺

Buy Membership for Basic Science Category to continue reading. Learn more here