Книги фарма 2 / Bertram G. Katzung-Basic & Clinical Pharmacology(9th Edition)

Choice of a Beta-Adrenoceptor Antagonist Drug

Propranolol is the standard against which newer antagonists developed for systemic use have been compared. In many years of very wide use, it has been found to be a safe and effective drug for many indications. Since it is possible that some actions of a -receptor antagonist may relate to some other effect of the drug, these drugs should not be considered interchangeable for all applications. For example, only antagonists known to be effective in hyperthyroidism or in prophylactic therapy after myocardial infarction should be used for those indications. It is possible that the beneficial effects of one drug in these settings might not be shared by another drug in the same class. The possible advantages and disadvantages of receptor antagonists that are partial agonists have not been clearly defined in clinical settings, although current evidence suggests that they are probably less efficacious in secondary prevention after a myocardial infarction compared to pure antagonists.

Clinical Toxicity of the Beta-Receptor Antagonist Drugs

A variety of minor toxic effects have been reported for propranolol. Rash, fever, and other manifestations of drug allergy are rare. Central nervous system effects include sedation, sleep disturbances, and depression. Rarely, psychotic reactions may occur. Discontinuing the use of - blockers in any patient who develops a depression should be seriously considered if clinically feasible. It has been claimed that -receptor antagonist drugs with low lipid solubility are associated with a lower incidence of central nervous system adverse effects than compounds with higher lipid solubility (Table 10–2). Further studies designed to compare the central nervous system adverse effects of various drugs are required before specific recommendations can be made, though it seems reasonable to try the hydrophilic drugs nadolol or atenolol in a patient who experiences unpleasant central nervous system effects with other -blockers.

The major adverse effects of -receptor antagonist drugs relate to the predictable consequences of blockade. Beta2-receptor blockade associated with the use of nonselective agents commonly causes worsening of preexisting asthma and other forms of airway obstruction without having these consequences in normal individuals. Indeed, relatively trivial asthma may become severe after blockade. However, because of their life-saving possibilities in cardiovascular disease, strong consideration should be given to individualized therapeutic trials in some classes of patients, eg, those with chronic obstructive pulmonary disease who have appropriate indications for -blockers. While 1-selective drugs may have less effect on airways than nonselective antagonists, they must be used very cautiously, if at all, in patients with reactive airways. While 1-selective antagonists are generally well tolerated in patients with mild to moderate peripheral vascular disease, caution is required in patients with severe peripheral vascular disease or vasospastic disorders.

Beta-receptor blockade depresses myocardial contractility and excitability. In patients with abnormal myocardial function, cardiac output may be dependent on sympathetic drive. If this stimulus is removed by blockade, cardiac decompensation may ensue. Thus, caution must be exercised in using -receptor antagonists in patients with compensated heart failure even though long-term use of these drugs in these patients may prolong life. A life-threatening adverse cardiac effect of a antagonist may be overcome directly with isoproterenol or with glucagon (glucagon stimulates the heart via glucagon receptors, which are not blocked by antagonists), but neither of these methods is without hazard. A very small dose of a antagonist (eg, 10 mg of propranolol) may provoke severe cardiac failure in a susceptible individual. Beta-blockers may interact with the calcium antagonist verapamil; severe hypotension, bradycardia, heart failure, and cardiac conduction abnormalities have all been described. These adverse effects may even arise in

susceptible patients taking a topical (ophthalmic) -blocker and oral verapamil.

Some hazards are associated with abruptly discontinuing antagonist therapy after chronic use. Evidence suggests that patients with ischemic heart disease may be at increased risk if blockade is suddenly interrupted. The mechanism of this effect is uncertain but might involve up-regulation of the number of receptors. Until better evidence is available regarding the magnitude of the risk, prudence dictates the gradual tapering rather than abrupt cessation of dosage when these drugs are discontinued, especially drugs with short half-lives, such as propranolol and metoprolol.

The incidence of hypoglycemic episodes in diabetics that are exacerbated by -blocking agents is unknown. Nevertheless, it is inadvisable to use antagonists in insulin-dependent diabetic patients who are subject to frequent hypoglycemic reactions if alternative therapies are available. Beta1- selective antagonists offer some advantage in these patients, since the rate of recovery from hypoglycemia may be faster compared with diabetics receiving nonselective adrenoceptor antagonists. There is considerable potential benefit from these drugs in diabetics after a myocardial infarction, so the balance of risk versus benefit must be evaluated in individual patients.

Katzung PHARMACOLOGY, 9e > Section II. Autonomic Drugs > Chapter 10. Adrenoceptor Antagonist Drugs >

Preparations Available

Alpha Blockers

Doxazosin (generic, Cardura)

Oral: 1, 2, 4, 8 mg tablets

Phenoxybenzamine (Dibenzyline)

Oral: 10 mg capsules

Phentolamine (generic, Regitine)

Parenteral: 5 mg/vial for injection

Prazosin (generic, Minipress)

Oral: 1, 2, 5 mg capsules

Tamsulosin (Flomax)

Oral: 0.4 mg capsule

Terazosin (generic, Hytrin)

Oral: 1, 2, 5, 10 mg tablets, capsules

Tolazoline (Priscoline)

Parenteral: 25 mg/mL for injection

Beta Blockers

Acebutolol (generic, Sectral)

Oral: 200, 400 mg capsules

Atenolol (generic, Tenormin)

Oral: 25, 50, 100 mg tablets

Parenteral: 0.5 mg/mL for IV injection

Betaxolol

Oral: 10, 20 mg tablets (Kerlone)

Ophthalmic: 0.25%, 0.5% drops (generic, Betoptic)

Bisoprolol (Zebeta)

Oral: 5, 10 mg tablets

Carteolol

Oral: 2.5, 5 mg tablets (Cartrol)

Ophthalmic: 1% drops (generic, Ocupress)

Carvedilol (Coreg)

Oral: 3.125, 6.25, 12.5, 25 mg tablets

Esmolol (Brevibloc)

Parenteral: 10 mg/mL for IV injection; 250 mg/mL for IV infusion

Labetalol (generic, Normodyne, Trandate)

Oral: 100, 200, 300 mg tablets

Parenteral: 5 mg/mL for injection

Levobunolol (Betagan Liquifilm, others)

Ophthalmic: 0.25, 0.5% drops

Metipranolol (Optipranolol)

Ophthalmic: 0.3% drops

Metoprolol (generic, Lopressor, Toprol)

Oral: 50, 100 mg tablets

Oral sustained-release: 25, 50, 100, 200 mg tablets Parenteral: 1 mg/mL for injection

Nadolol (generic, Corgard)

Oral: 20, 40, 80, 120, 160 mg tablets

Penbutolol (Levatol)

Oral: 20 mg tablets

Pindolol (generic, Visken)

Oral: 5, 10 mg tablets

Propranolol (generic, Inderal)

Oral: 10, 20, 40, 60, 80, 90 mg tablets; 4, 8, 80 mg/mL solutions Oral sustained release: 60, 80, 120, 160 mg capsules Parenteral: 1 mg/mL for injection

Sotalol (generic, Betapace)

Oral: 80, 120, 160, 240 mg tablets

Timolol

Oral: 5, 10, 20 mg tablets (generic, Blocadren) Ophthalmic: 0.25, 0.5% drops, gel (generic, Timoptic) Synthesis Inhibitor

Metyrosine (Demser)

Oral: 250 mg capsules

Section III. Cardiovascular-Renal Drugs

Katzung PHARMACOLOGY, 9e > Section III. Cardiovascular-Renal Drugs > Chapter 11. Antihypertensive Agents >

Antihypertensive Agents: Introduction

Hypertension is the most common cardiovascular disease. Thus, the third National Health and Nutrition Examination Survey (NHANES III), conducted from 1992 to 1994, found that 27% of the USA adult population had hypertension. The prevalence varies with age, race, education, and many other variables. Sustained arterial hypertension damages blood vessels in kidney, heart, and brain and leads to an increased incidence of renal failure, coronary disease, cardiac failure, and stroke. Effective pharmacologic lowering of blood pressure has been shown to prevent damage to blood vessels and to substantially reduce morbidity and mortality rates. Many effective drugs are available. Knowledge of their antihypertensive mechanisms and sites of action allows accurate prediction of efficacy and toxicity. As a result, rational use of these agents, alone or in combination, can lower blood pressure with minimal risk of serious toxicity in most patients.

Hypertension & Regulation of Blood Pressure

Diagnosis

The diagnosis of hypertension is based on repeated, reproducible measurements of elevated blood pressure. The diagnosis serves primarily as a prediction of consequences for the patient; it seldom includes a statement about the cause of hypertension.

Epidemiologic studies indicate that the risks of damage to kidney, heart, and brain are directly related to the extent of blood pressure elevation. Even mild hypertension (blood pressure 140/90 mm Hg) in young or middle-aged adults increases the risk of eventual end organ damage. The risks—and therefore the urgency of instituting therapy—increase in proportion to the magnitude of blood pressure elevation. The risk of end organ damage at any level of blood pressure or age is greater in black people and relatively less in premenopausal women than in men. Other positive risk factors include smoking, hyperlipidemia, diabetes, manifestations of end organ damage at the time of diagnosis, and a family history of cardiovascular disease.

It should be noted that the diagnosis of hypertension depends on measurement of blood pressure and not on symptoms reported by the patient. In fact, hypertension is usually asymptomatic until overt end organ damage is imminent or has already occurred.

Etiology of Hypertension

A specific cause of hypertension can be established in only 10–15% of patients. It is important to consider specific causes in each case, however, because some of them are amenable to definitive surgical treatment: renal artery constriction, coarctation of the aorta, pheochromocytoma, Cushing's disease, and primary aldosteronism.

Patients in whom no specific cause of hypertension can be found are said to have essential hypertension.*

* The adjective originally was intended to convey the now abandoned idea that blood pressure elevation was essential for adequate perfusion of diseased tissues.

In most cases, elevated blood pressure is associated with an overall increase in resistance to flow of blood through arterioles, while cardiac output is usually normal. Meticulous investigation of autonomic nervous system function, baroreceptor reflexes, the renin-angiotensin-aldosterone system, and the kidney has failed to identify a primary abnormality as the cause of increased peripheral vascular resistance in essential hypertension.

Elevated blood pressure is usually caused by a combination of several abnormalities (multifactorial). Epidemiologic evidence points to genetic inheritance, psychological stress, and environmental and dietary factors (increased salt and decreased potassium or calcium intake) as perhaps contributing to the development of hypertension. Increase in blood pressure with aging does not occur in populations with low daily sodium intake. Patients with labile hypertension appear more likely than normal controls to have blood pressure elevations after salt loading.

The heritability of essential hypertension is estimated to be about 30%. Mutations in several genes have been linked to various rare causes of hypertension. Functional variations of the genes for angiotensinogen, angiotensin-converting enzyme (ACE), and the 2 adrenoceptor appear to contribute to some cases of essential hypertension.

Normal Regulation of Blood Pressure

According to the hydraulic equation, arterial blood pressure (BP) is directly proportionate to the product of the blood flow (cardiac output, CO) and the resistance to passage of blood through precapillary arterioles (peripheral vascular resistance, PVR):

Physiologically, in both normal and hypertensive individuals, blood pressure is maintained by moment-to-moment regulation of cardiac output and peripheral vascular resistance, exerted at three anatomic sites (Figure 11–1): arterioles, postcapillary venules (capacitance vessels), and heart. A fourth anatomic control site, the kidney, contributes to maintenance of blood pressure by regulating the volume of intravascular fluid. Baroreflexes, mediated by autonomic nerves, act in combination with humoral mechanisms, including the renin-angiotensin-aldosterone system, to coordinate function at these four control sites and to maintain normal blood pressure. Finally, local release of hormones from vascular endothelium may also be involved in the regulation of vascular resistance. For example, nitric oxide (see Chapter 19: Nitric Oxide, Donors, & Inhibitors) dilates and endothelin-1 (see Chapter 17: Vasoactive Peptides) constricts blood vessels.

Figure 11–1.

Anatomic sites of blood pressure control.

Blood pressure in a hypertensive patient is controlled by the same mechanisms that are operative in normotensive subjects. Regulation of blood pressure in hypertensive patients differs from healthy patients in that the baroreceptors and the renal blood volume-pressure control systems appear to be "set" at a higher level of blood pressure. All antihypertensive drugs act by interfering with these normal mechanisms, which are reviewed below.

Postural Baroreflex

Baroreflexes are responsible for rapid, moment-to-moment adjustments in blood pressure, such as in transition from a reclining to an upright posture (Figure 11–2). Central sympathetic neurons arising from the vasomotor area of the medulla are tonically active. Carotid baroreceptors are stimulated by the stretch of the vessel walls brought about by the internal pressure (blood pressure). Baroreceptor activation inhibits central sympathetic discharge. Conversely, reduction in stretch results in a reduction in baroreceptor activity. Thus, in the case of a transition to upright posture, baroreceptors sense the reduction in arterial pressure that results from pooling of blood in the veins below the level of the heart as reduced wall stretch, and sympathetic discharge is disinhibited. The reflex increase in sympathetic outflow acts through nerve endings to increase peripheral vascular resistance (constriction of arterioles) and cardiac output (direct stimulation of the heart and constriction of capacitance vessels, which increases venous return to the heart), thereby restoring normal blood pressure. The same baroreflex acts in response to any event that lowers arterial pressure, including a primary reduction in peripheral vascular resistance (eg, caused by a vasodilating agent) or a reduction in intravascular volume (eg, due to hemorrhage or to loss of salt and water via the kidney).

Figure 11–2.

Baroreceptor reflex arc.

Renal Response to Decreased Blood Pressure

By controlling blood volume, the kidney is primarily responsible for long-term blood pressure control. A reduction in renal perfusion pressure causes intrarenal redistribution of blood flow and increased reabsorption of salt and water. In addition, decreased pressure in renal arterioles as well as sympathetic neural activity (via -adrenoceptors) stimulates production of renin, which increases production of angiotensin II (see Figure 11–1 and Chapter 17: Vasoactive Peptides). Angiotensin II causes (1) direct constriction of resistance vessels and (2) stimulation of aldosterone synthesis in the adrenal cortex, which increases renal sodium absorption and intravascular blood volume. Vasopressin released from the posterior pituitary gland also plays a role in maintenance of blood pressure through its ability to regulate water reabsorption by the kidney (see Chapter 17: Vasoactive Peptides).

Katzung PHARMACOLOGY, 9e > Section III. Cardiovascular-Renal Drugs > Chapter 11. Antihypertensive Agents >

Basic Pharmacology of Antihypertensive Agents

All antihypertensive agents act at one or more of the four anatomic control sites depicted in Figure 11–1 and produce their effects by interfering with normal mechanisms of blood pressure regulation. A useful classification of these agents categorizes them according to the principal regulatory site or mechanism on which they act (Figure 11–3). Because of their common mechanisms of action, drugs within each category tend to produce a similar spectrum of toxicities. The categories include the following:

(1) Diuretics, which lower blood pressure by depleting the body of sodium and reducing blood

volume and perhaps by other mechanisms.

(2)Sympathoplegic agents, which lower blood pressure by reducing peripheral vascular resistance, inhibiting cardiac function, and increasing venous pooling in capacitance vessels. (The latter two effects reduce cardiac output.) These agents are further subdivided according to their putative sites of action in the sympathetic reflex arc (see below).

(3)Direct vasodilators, which reduce pressure by relaxing vascular smooth muscle, thus dilating resistance vessels and—to varying degrees—increasing capacitance as well.

(4)Agents that block production or action of angiotensin and thereby reduce peripheral vascular resistance and (potentially) blood volume.

Figure 11–3.

Sites of action of the major classes of antihypertensive drugs.

The fact that these drug groups act by different mechanisms permits the combination of drugs from two or more groups with increased efficacy and, in some cases, decreased toxicity. (See Monotherapy versus Polypharmacy in Hypertension.)