Antihypertensive Drugs

Many antihypertensive drugs and almost all mind-altering drugs affect sympathetic neuronal storage, uptake, metabolism, or release of neurotransmitters. For instance, the antihypertensive drug reserpine depletes the granules of norepinephrine, epinephrine, and dopamine in both the brainstem and periphery. Depletion of transmitters in sympathetic nerve endings renders drugs such as ephedrine and metaraminol ineffective because these drugs act primarily by releasing catecholamines ( Fig. 27-21 ). Guanethidine and guanadrel deplete granular norepinephrine and affect only the peripheral sympathetic system. In amounts used clinically, reserpine decreases MAC by 20% to 30%, whereas guanethidine has no effect on anesthetic requirements. ^[287] In addition to causing a lack of response to indirect-acting vasopressors, reserpine can cause denervation supersensitivity and hyperresponsiveness (with

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Another group of antihypertensive drugs consists of "false neurotransmitters." False neurotransmitters replace norepinephrine in the granules at the nerve ending. α-Methyldopa (Aldomet) becomes α-methyldopamine, which is further metabolized to α-methyl norepinephrine ( Fig. 27-22 ). In some nerve endings and for some receptors, α-methyldopamine or α-methylnorepinephrine is more potent than dopamine or norepinephrine as dopaminergic or α-adrenergic receptor stimulants. However, at most nerve endings, the false neurotransmitters are less potent stimulants; this lower degree of stimulation is one means by which their antihypertensive action is produced. Alternatively, α-methyldopa may act by stimulating the brainstem sympathetic nervous system. When this system antagonizes the peripheral sympathetic nervous system, the activity of the latter decreases and BP is reduced. Through its central effect, α-methyldopa decreases anesthetic requirements 20% to 40%.^[287]

In addition to altering the response to exogenously administered vasopressors, these neurotransmitter-depleting drugs can also produce side effects: psychic depression, nightmares, drowsiness, nasal stuffiness, diarrhea, bradycardia, and orthostatic hypotension with impotence (reserpine).^{[938] [939]} Guanethidine and guanadrel can cause orthostatic hypotension, bradycardia, asthma, diarrhea, and inhibition of ejaculation. α-Methyldopa is associated with drowsiness, orthostatic hypotension, bradycardia, diarrhea, acute or chronic hepatitis, cirrhosis, and autoimmune hemolytic anemia (i.e., a positive Coombs test result).^[938] Because of these side effects, ACE inhibitors (captopril, enalapril, lisinopril, enalaprilat, and

Figure 27-22 In the granules of the nerve terminal, α-methyldopa (Aldomet) is converted enzymatically to α-methyldopamine by the same enzyme that converts dopa to dopamine. α-Methyldopamine is converted to α-methylnorepinephrine by the same enzyme that converts dopamine to norepinephrine.

Catecholamine or sympathetic receptor blocking drugs affect the three major types of catecholamine receptors: α-adrenergic, β-adrenergic, and dopaminergic. The existence of subdivisions (e.g., β₁ and β₂ ) suggested the possibility that some drugs would be found to affect only one set of receptors. For example, terbutaline is used more frequently than isoproterenol because terbutaline is said to exert a preferential effect on β₂ -receptors (i.e., dilation of bronchial smooth muscle), thereby avoiding the cardiac stimulation produced by drugs that stimulate β₁ -receptors. In fact, the selectivity is dose related. At a certain dose, a direct β₂ -receptor stimulating drug will affect only those receptors but, at a higher dose, will stimulate both β₁ - and β₂ -receptors. The effect of a given dose varies with each patient. A certain dose may stimulate β₁ - and β₂ -receptors in one patient but neither receptor in another patient. More and more selective blocking drugs are being developed in hope of widening the margin between β₁ - and β₂ - and α-adrenergic effects. Ultimately, however, even more selectivity is desired. It would be advantageous to be able to decrease the heart rate without changing myocardial contractility or to increase contractility without changing the heart rate. Such is the goal of much drug research and the development of dobutamine. However, to date, all such selectivity appears to be dose related, even for dobutamine.^[941]

Metoprolol (Lopressor) and atenolol (Tenormin) (both β₁ -adrenergic receptor blocking drugs) and propranolol, betaxolol, timolol, esmolol, pindolol, oxprenolol, acebutolol, carteolol, penbutolol, and nadolol are widely available β-adrenergic receptor blocking drugs used for chronic therapy in the United States. Because nadolol has poor lipid solubility, it has a long elimination half-life (17 to 24 hours) and does not cross the blood-brain barrier readily. Although selective β-adrenergic receptor blocking drugs should be more appropriate in patients with increased airway resistance or diabetes, this advantage is apparent only when low doses are used. The use of β-adrenergic receptor blocking drugs has become widespread because these drugs treat everything from angina and hypertension to priapism and stage fright. These drugs appear to decrease morbidity and mortality in patients who have initially survived MI^{[236] [942] [943]} and to increase perioperative survival (see the earlier section on cardiovascular disease and Chapter 25 ).^{[226] [310] [318]}

Propranolol is the current standard for β-adrenergic receptor blocking drugs. Smulyan and colleagues^[944] studied

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α-Adrenergic receptor blocking drugs include phentolamine, prazosin, terazosin, doxazosin, phenoxybenzamine, the phenothiazines, and the butyrophenones (e.g., droperidol). Dopaminergic receptor antagonists include the antischizophrenic drugs (phenothiazines and butyrophenones) and metoclopramide. The receptor blocking drugs inhibit the action of sympathomimetic drugs at the receptor in a dose-related fashion. Thus, propranolol lowers BP by blocking the tendency of norepinephrine and epinephrine to increase the rate and force of contractions of the heart (and perhaps their tendency to increase the secretion of renin as well). To overcome this blockade, one need only provide more β-receptor stimulating drug. Thus, high doses of vasopressors may be needed to increase BP in a patient given large doses of propranolol.

When administration of β-adrenergic receptor blocking drugs is terminated, sympathetic stimulation often increases, as though the body had responded to the presence of these drugs by increasing sympathetic neuron activity. Thus, propranolol and nadolol (to name just two) withdrawal can be accompanied by a hyper-β-adrenergic condition that increases myocardial oxygen demands. Administering propranolol or metoprolol can cause bradycardia, CHF, fatigue, dizziness, depression, psychoses, bronchospasm, and Peyronie's disease.^{[938] [939]} Side effects of dopaminergic receptor blocking drugs are discussed later in this chapter. Prazosin (Minipress), terazosin, and oxazocin are α₁ -adrenergic receptor blocking drugs used to treat hypertension, ischemic cardiomyopathy, receding hairlines, and benign prostatic hypertrophy because they dilate both veins and arteries and reduce sphincter tone. These drugs are associated with vertigo, palpitations, depression, dizziness, weakness, and anticholinergic effects.

Brainstem sympathomimetic drugs stimulate α-adrenergic receptors in the brainstem. Clonidine (Catapres), a drug with a half-life of 12 to 24 hours, guanabenz, and guanfacine (Tenex) are α₂ -adrenergic receptor stimulants. Presumably, α₂ -adrenergic agonists, including clonidine, guanabenz, and guanfacine, chronically lower BP through the central brainstem adrenergic stimulation referred to previously. They may also be used chronically to treat opiate, cocaine, food, and tobacco withdrawal. Occasionally, withdrawal from clonidine can precipitate a sudden hypertensive crisis, analogous to that occurring on withdrawal from propranolol, and cause a hyper-β-adrenergic condition. The degree of hypertensive crisis after clonidine withdrawal is now being debated. (Although intravenous clonidine is not yet available in the United States, a skin patch of clonidine has been approved and is being used preoperatively to ablate sympathomimetic responses perioperatively.) Tricyclic antidepressant drugs and presumably phenothiazines and the butyrophenones interfere with the action of clonidine. Although administration of a butyrophenone (e.g., droperidol) to a patient taking clonidine, guanabenz, or guanfacine chronically could theoretically precipitate a hypertensive crisis, none has been reported. Clonidine administration can be accompanied by drowsiness, dry mouth, orthostatic hypotension, bradycardia, and impotence. Acute clonidine or dexmedetomidine administration decreases anesthetic requirements by 40% to 60%; chronic administration decreases requirements by 10% to 20%.^{[227] [228] [306] [948]} Because of the relative safety of these drugs and their ability to decrease anesthetic requirements, block narcotic-induced muscle rigidity, and provide pain relief, their popularity preoperatively is increasing.^{[227] [228] [306] [948] [949] [950] [951] [952] [953] [954]}

Three other classes of antihypertensive drugs affect the sympathetic nervous system indirectly: diuretics, arteriolar dilators, and slow (calcium) channel blocking agents. Thiazide diuretic drugs are associated with hypochloremic alkalosis, hypokalemia, hyperglycemia, hyperuricemia, and hypercalcemia. The potassium-sparing diuretic drug spironolactone is associated with hyperkalemia, hyponatremia, gynecomastia, and impotence. All diuretic drugs can cause dehydration. The thiazide diuretics and furosemide appear to prolong neuromuscular blockade.^[955] The arteriolar dilator hydralazine can cause a lupus-like condition (usually with renal involvement), nasal congestion, headache, dizziness, CHF, angina, and GI disturbances. Such a syndrome is nonexistent with the other direct vasodilator on the U.S. market, minoxidil.

The slow-channel calcium ion antagonists ("calcium channel blocking drugs") inhibit the transmembrane influx of calcium ions into cardiac and vascular smooth muscle. Such inhibition reduces the heart rate (negative chronotropy); depresses contractility (negative inotropy); decreases conduction velocity (negative dromotropy); and dilates coronary, cerebral, and systemic arterioles^[956] ( Fig. 27-23 ). Verapamil, diltiazem, and nifedipine all produce such effects, but to varying degrees and apparently by similar, but different mechanisms.^{[956] [957]} These mechanisms relate to the three different classes of calcium channel antagonists that they represent: the phenylalkylamines, the benzothiazepines, and the dihydropyridines, respectively.^{[956] [957]} Nifedipine is the most potent of the three as a smooth muscle dilator, whereas verapamil and diltiazem have negative dromotropic and inotropic effects and vasodilating properties. Diltiazem has weak vasodilating properties when compared with nifedipine and has less AV conduction effect than verapamil does. Thus, verapamil and diltiazem can increase the PR interval and produce AV block. In fact, reflex activation of the sympathetic nervous system may be necessary during the

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Figure 27-23 Schematic drawing of a smooth muscle cell showing calcium flux and possible sites of interference by halothane and nifedipine. The concentration of calcium (Ca²⁺ ) in the cytoplasm increases (red arrows) because of entry through the plasma membrane (PM) and release from surface vesicles (SV) or the sacroplasmic reticulum (SR). When the concentration of cytoplasmic Ca²⁺ is sufficiently high, adenosine triphosphate (ATP) is activated. Splitting of ATP by adenosine triphosphatase (ATPase) into phosphatidylinositol (Pi) and adenosine diphosphate (ADP) provides the interaction and contraction of actin filaments and myosin particles constituting muscle fibers. The concentration of cytoplasmic Ca²⁺ decreases (white arrows) with the return of Ca²⁺ to cellular stores and the extracellular transport of Ca²⁺ . Both halothane and nifedipine probably (1) inhibit the entry of Ca²⁺ and (2) may also interfere with cytoplasmic Ca²⁺ flux by reducing the release of Ca²⁺ by the SR, by (3) reducing storage and reuptake, or by (4) blocking ATPase or the contractile mechanism (or both). (Redrawn from Tosone SR, Reves JG, Kissin I, et al: Hemodynamic responses to nifedipine in dogs anesthetized with halothane. Anesth Analg 62:903, 1983.)

The use of calcium channel blocking drugs has several important implications for anesthetic management.^{[956] [958] [959] [960] [961] [962] [963] [964] [965] [966] [967] [968]} First, the effects of inhaled and narcotic anesthetics and nifedipine in decreasing systemic vascular resistance, BP, and contractility may be additive.^{[956] [959] [960] [961] [962]} Similarly, verapamil and anesthetics (inhaled anesthetics, nitrous oxide, and narcotics) increase AV conduction times and additively decrease BP, systemic vascular resistance, and contractility.^{[960] [961] [962] [965] [968]} Second, verapamil and presumably the other calcium channel blocking drugs have been found to decrease anesthetic requirements by 25%.^[958] These drugs can produce neuromuscular blockade, potentiate both depolarizing and nondepolarizing neuromuscular blocking drugs, and in at least one type of myopathy (Duchenne's muscular dystrophy), even precipitate respiratory failure.^{[963] [964] [966]} Finally, because slow-channel activation of calcium is necessary to cause spasms of cerebral and coronary vessels, bronchoconstriction, and normal platelet aggregation, these drugs may have a role in treating ischemia of the nervous system, bronchoconstriction, and unwanted clotting disorders perioperatively.^[963] All three drugs are highly protein bound and may displace or be displaced by other drugs that are also highly protein bound (e.g., lidocaine, bupivacaine, diazepam, disopyramide, and propranolol). Adverse consequences can be minimized by titrating the inhaled or narcotic drug to the hemodynamic and anesthetic effects. By monitoring for side effects, the anesthetist can prevent side effects from becoming serious (S. Slogoff and coworkers, personal communication). Hemodynamic, but not electrophysiologic changes can usually be reversed by administering calcium.^[967] Reversal of the electrophysiologic effects may occur if "industrial" doses of β-adrenergic agonists are given.