Appraisal and reappraisal of cardiac therapy Edited by Arthur C. DeGraff and Julian Frieden i
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Drugs in the management of hypertension. Part III Lot B. Page, M.D. Henry M. Yager, M.D. James J. Sidd, M.D. Newton and Boston, Mass.
Vasodilator drugs The vasodilator drugs act directly on vascular smooth muscle to produce vasodilatation and reduction in peripheral resistance. They include hydralazine, diazoxide, minoxidil, guancydine, and sodium nitroprusside. With the exception of sodium nitroprusside, these drugs have a selective effect on arterioles with little if any effect on venous capacitance vessels. This selective dilatation of arterioles results in an increase in venous return, which triggers a reflex increase in heart rate and stroke volume mediated through the sympathetic nervous system. As a result they share several common side effects due to increased cardiac action. These include palpitation, headache, and the capacity to precipitate angina pectoris in patients with coronary disease. In addition, drugs in this group share an ability to stimulate renin release and promote sodium retention. Increased cardiac output and sodium retention both act to reduce the hypotensive effects of vasodilatation. In most circumstances, drugs in this group should be use d together with propranolol and diuretics which counteract these effects, enhance the effectiveness of vasodilatation, and minimize side effects. Of the vasodilators, only hydralazine is available for oral use in the United States at present. Minoxidil and guancydine have given promising results in clinical trials. Diazoxide and sodium nitroprusside are available only for intravenous use, although diazoxide has been shown to be effective given orally, s:~
From the Departments of Medicine, Newton-Wellesley Hospital, and Tui~s University School of Medicine, Newton and Boston, Mass. Received for publication Mar. 10, 1976. Reprint requests to: Lot B. Page, M.D., 2000 Washington St., Newton Lower Falls, Mass. 02162.
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Oral vasodilators Hydralazine. Actions.
Hydralazine has been in use since the early 1950's. It acts directly on arteriolar smooth muscle producing vasodilatation and reduction in peripheral resistance. Splanchnic, coronary, cerebral, and renal blood flow increase, while blood flow in skeletal muscle and skin is unaffected,s4 Blood pressure is reduced in both the supine and standing posture. Hydralazine is rapidly absorbed from the gastrointestinal tract, reaching maximal effect in one hour, and the usual half-life is four hours25 However, this varies among individuals depending on the rate of inactivation of the drug by acetylation. "Slow acetylators" are more responsive to hydralazine and more likely to develop immunological side effects.8~ Hydralazine produces immediate stimulation of renin release, which through its effect on aldosterone is at least partly responsible for sodium retention. With long-term use of hydralazine alone, sodium retention suppresses the renin stimulation effect. Uses.
Although it has been available for many years, hydralazine has until recently had limited use because of its tendency to cause increased heart rate and cardiac output. When used in combination with a diuretic and propranolol, these effects are largely eliminated and a greater hypotensive effect is achieved. This combination has proved effective in managing patients who previously were poorly controlled on other drug regimens27 A dose-related hypotensive response can be demonstrated up to 800 mg. per day. 8~ However, long-term use at high dosage produces a high incidence of immunologic side effects, and t h e dose should generally be kept to 300 mg. per day or less.
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Drugs in the management of hypertension. III Side effects. Symptoms related to reflex increase in cardiac rate and output include palpitations, headache, and angina pectoris. Many patients develop positive antinuclear antibody reaction on prolonged use, 8~ and a syndrome similar to lupus erythematosus disseminatus occurs in 10 to 20 per cent of patients on doses greater than 400 mg. per day. This occurs with much lower frequency on doses less than 300 mg. per day. ~7 Other side effects include fever, skin eruptions, nausea, anorexia, and diarrhea. Many patients complain of flushing, ill-defined rushing sensations in the head, and mental fuzziness. Peripheral neuropathy and bone marrow depression have been reported. Minoxidil. Actions. Minoxidil is a potent vasodilating agent which is not yet available for general use. Like the other drugs in this group it acts directly on vascular smooth muscle, selectively dilating arteriolar resistance vessels, with little or no effect on venous capacitance vessels. This results in increased venous return and triggers a reflex increase in heart rate and cardiac output mediated by the sympathetic nervous system. This drug also promotes sodium retention by stimulating renin release, and probably also by a direct effect on the renal tubule28 Minoxidil is considerably more potent than either hydralazine or guancydine. When used alone, its effectiveness is gradually lost as a result of increased cardiac output and sodium retention. When used together with propranolol and a diuretic, these effects are counteracted and tachyphylaxis does not develop. Minoxidil is rapidly and completely absorbed from the gastrointestinal tract, with peak plasma levels in 1 hour, and a plasma halflife of 4 hours. ~9 The hypotensive effect does not correspond to the plasma concentration. This is due to accumulation of the drug in arterial smooth muscle where it exerts an effect which is prolonged for 12 hours or more. ~ After stopping the drug, blood pressure does not rise for several days, although over 90 per cent of the drug and its metabolites are excreted in 24 to 48 hours. ~ Minoxidil lowers blood pressure in both the supine and standing posture, and does not affect renal blood flow or glomerular filtration rate. Uses. Minoxidil appears to be an extremely promising
American Heart Journal
drug for clinical use. In clinical trials it has been shown to be remarkably effective in controlling blood pressure in patients with severe and refractory hypertension and renal failure, who have failed to respond to any of the drug regimens now available.9O. ~1 Furthermore, when used in combination with propranolol and diuretics it has produced no serious side effects in human subjects. The sodium retaining effect of minoxidil does not seem to be correlated with renin and aldosterone levels. In patients with renal failure, good blood pressure control has required meticulous adjustment of diuretic agents to control fluid retention and of propranolol to control reflex cardiac stimulation. Pettinger and Mitchell '' report a useful additive effect when several different types of diuretics were used together in patients on minoxidil. Doses of 2 to 40 rag. per day have been well tolerated in man. Patients formerly incapacitated by hypertension and renal failure have tolerated minoxidil, propranolol, and diuretic therapy with few drug side effects, unimpaired sexual function, and improvement in cardiac status. The long duration of action of minoxidil allows simple dosage schedules. Side effects. After prolonged use at high dose levels in dogs, a myocytic degenerative lesion of the right atrium frequently develops. Although this has not been reported in other species, this finding may account for the delay in releasing minoxidil for general use. In man, minoxidil has been free of serious side effects, and has not caused the lupuslike syndrome seen with hydralazine. In doses of 10 mg. per day and more, minoxidil regularly produces hirsutism which is most marked in the first few months and then tends to recede somewhat21 Characteristically, the temporal hair line grows toward the eyebrows, and there is increase in upper truncal hair in males and increased lanugo hair in females. ~ The mechanism is unknown, but similar hirsutism occurs in patients on oral diazoxide. ~5 No change in gonadal or adrenal function has been found. 8~ Minoxidil has been shown to stimulate hair growth when applied directly to the skin. 8~ Hirsutism is easily controlled with depilatory procedures. Guancydine. Actions. Although it is not yet available for general use, guancydine has been used in clinical trials since
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1968. Its mode of action is similar to the other vasodilating drugs. It acts directly on arteriolar smooth muscle causing vasodilatation and decreasing peripheral resistance. It has little if any effect on venous capacitance vessels. Thus it increases venous return, and like the other drugs in this group, it stimulates reflex increase in cardiac output and heart rate, stimulates renin release in some but not all patients/'~ and causes sodium retention. These side effects are counteracted when guancydine is used in combination with propranolol and a diuretic. '-~' '~ T a ke n orally, guancydine is well absorbed from the gastrointestinal tract, and produces a hypotensive effect which is maximal in 1-1/2 hours and lasts four to eight hours? ~ It is effective in both the supine and standing posture. In potency it is equal to or somewhat greater than hydralazine. '~' ,3 Uses. Guancydine shows promise as a vasodilator to be used in combination with diuretic and betaadrenergic blocking agents to offset the cardiac stimulation and sodium retention which all such drugs produce. It does not cause the immunologic side effects seen with hydralazine, nor the right atrial lesion reported in dogs on high doses of minoxidil. Its position in therapy is still uncertain. It should not be used alone, but shows promise as an alternative to hydralazine. Doses up to 1500 mg. per day have been tolerated in man. Higher doses usually produce intolerable side effects. Side effects. When used in combination with propranolol and a diuretic, palpitation, headache, chest discomfort; and edema do not occur. However, guancydine side effects include gynecomastia, galactorrhea, nausea, epigastric distress, mental Confusion, and hallucinations, most of which are dose-related. Intravenous vasodilators
Diazoxide. After clinical studies extending over more than 10 years, diazoxide has been released for intravenous use in hypertensive emergencies. Diazoxide exerts its action by a direct effect on smooth muscle of arteriolar resistance vessels Causing vasodilatation, and decreased peripheral resistance. It has little if any effect on venous capacitance vessels. Thus it increases venous return and stimulates a marked reflex increase in cardiac output and heart rate. It also promotes sodium
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retention both by stimulating the renin-angiotensin system and by a direct effect on the renal tubule2* Diazoxide also affects non-vascular smooth muscle, causing transient reduction in gastrointestinal motility '5 and relaxation of the uterus2 ~ It causes hyperglycemia partly by inhibiting release of insulin and partly by an extrapancreatic mechanismY ~ To be effective, diazoxide must be given by rapid bolus injection. This is attributed to binding of the drug by plasma albumin, which prevents it from reaching vascular receptor sites unless it is rapidly administered? ~ This explanation has been criticized on theoretical grounds ~" and it has also been shown t hat diazoxide produces a hypotensive effect when given by mouth, although it is not available for oral use in the United States. Following intravenous injection, blood pressure drops rapidly reaching a nadir in one to three minutes, then rising slightly over five to ten minutes to a plateau which is sustained for some hours before rising to pret reat m ent levels. Blood pressure characteristically drops to a satisfactory or "normal" level, and hypotensive reactions are uncommon. Duration of the hypotensive effect is variable, lasting from two to 24 hours. Blood levels of the drug are poorly correlated with the hypotensive actionY ~ T he drug is excreted unchanged in the urine over a 30 hour period.85, ,,,8 Uses. Intravenous use of diazoxide has proved effective for short term management of acute hypertensive emergencies, especially hypertensive encephalopathy. Its advantages are its rapid onset of action, the absence of a sedative effect, and the rarity of excessive hypotension. Since the drug reaches maximal effectiveness rapidly, close monitoring is required for only a short time after each dose. Since it causes marked reflex increase in cardiac action, it should not be used in dissecting aneurysm of the aorta, or in the presence of coronary insufficiency where sodium nitroprusside is preferable. Although diazoxide causes abrupt cessation of labor, it has been used successfully in eclampsia when used with oxytocin which overrides its relaxing effect on the uterus. Diazoxide is ineffective in pheochromocytoma?'' I ( s h o u l d be used together with intravenous furosemide to offset its sodium retaining effect: ~ Use of propranolol with diazoxide is hazardous. Although propranolol counteracts the
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Drugs in the management of hypertension. I I I
reflex s t i m u l a t i o n of cardiac action, use of the two drugs t o g e t h e r m a y result in severe h y p o t e n s i o n unless the dose of diazoxide is reduced. ~ I t h a s been claimed t h a t short t e r m use of i n t r a v e n o u s diazoxide alters the course of severe h y p e r t e n s i o n , m a k i n g p a t i e n t s m o r e responsive to s u b s e q u e n t use of o t h e r drugs? ~ O t h e r investigators h a v e n o t confirmed this finding. "~ Diazoxide is effective in m a n y patients. a l t h o u g h resistance occurs in some. requiring increase in dosage, or substitution by sodium nitroprusside. D u r i n g t r e a t m e n t with diazoxide, blood sugar should be m o n i t o r e d frequently a n d oral h y p o g l y c e m i c agents or insulin m a y be required for blood sugar control. Oral a n t i h y p e r t e n sive agents should be s u b s t i t u t e d for diazoxide as soon as the clinical s t a t u s of the p a t i e n t is stable. Side effects. Sodium r e t e n t i o n with diazoxide is readily c o u n t e r a c t e d with diuretics (preferably furosemide) given simultaneously. T a c h y c a r d i a occurs regularly a n d can precipitate angina pectoris. H y p e r g l y c e m i a is a f r e q u e n t occurrence, and h y p e r o s m o l a r n o n - k e t o t i c c o m a has been reported. P o s t u r a l h y p o t e n s i o n can occur with combined diazoxide and furosemide t h e r a p y , b u t is usually corrected by keeping the p a t i e n t in supine position. H y p o t e n s i v e reactions are likely to occur w h e n diazoxide is used in p a t i e n t s together w i t h propranolol. H y p o t e n s i o n also occurs occasionally in p a t i e n t s on multiple antih y p e r t e n s i v e drugs. Diazoxide can displace coumarin a n t i c o a g u l a n t s from binding proteins. amplifying the effect of the a n t i c o a g u l a n t ? ~ Mild reactions of flushing, and a b d o m i n a l discomfort occur frequently. Oral diazoxide causes h y p e r t r i chosis and e x t r a p y r a m i d a l s y m p t o m s 2 ~
Sodium nitroprusside. Actions. T h e effectiveness of i n t r a v e n o u s sodium nitroprusside for rapid blood pressure reduction h a s been known for m a n y years, b u t it has b e c o m e c o m m e r c i a l l y available only very recently. In its mode of action, sodium nitroprusside differs from all the other vasodilating drugs in t h a t it acts b o t h on the a r t e r i o l a r resistance vessel and also on the venous c a p a c i t a n c e vessels. This results in a drop in peripheral resistance w i t h o u t an increase in venous return. As a result, it does not regularly result in a reflex increase m cardiac o u t p u t and h e a r t rate. Its effect on cardiac
American Heart Journal
o u t p u t will v a r y depending on the prior s t a t e of the p a t i e n t s~' 1r and on posture. Tilting the p a t i e n t will produce pooling of blood in capacitance vessels and reduce cardiac o u t p u t ? ~ ~~ Sodium nitroprusside m u s t be given b y c o n s t a n t infusion, preferably with the aid of an infusion pump. I t is reliably effective in almost all patients, exerting its effects within seconds. I t s h y p o t e n s i v e action is dissipated within a few m i n u t e s after infusion is stopped. Conversion of nitroprusside to t h i o c y a n a t e occm's rapidly in vivo. T h i o c y a n a t e is relatively non-toxic at p l a s m a levels below 10 rag. per lO0 ml. ~ T h i o c y a nate is excreted in the urine, a n d m a y a c c u m u l a t e with time in p a t i e n t s with reduced renal function. Uses. Sodium nitroprusside is an e x t r e m e l y effective and useful drug for i n t r a v e n o u s t r e a t m e n t in all types of h y p e r t e n s i v e emergencies. Because of its unique effect on b o t h arterioles and venous s m o o t h muscle it does not s t i m u l a t e reflex increase in cardiac action. For this reason it is the drug of choice for t r e a t m e n t of h y p e r t e n s i o n associated with dissecting a n e u r y s m of the aorta. congestive h e a r t failure, and m y o c a r d i a l infarction. It has recently seen increasing use in reducing v e n t r i c u l a r afterload in p a t i e n t s with myocardial infarction. 1~'~ Sodium nitroprusside is ineffective if given by mouth. R a t e of i n t r a v e n o u s infusion m u s t be very carefully regulated, p r e f e r a b l y by an infusion pump. Blood pressure m u s t be m o n i t o r e d constantly, and an indwelling arterial c a n n u l a is usually necessary fbr this purpose. S e r u m levels of t h i o c y a n a t e can be by m e t h o d s easily performed in most clinical laboratories. 1~ Thioc y a n a t e should be m o n i t o r e d in p a t i e n t s receiving sodium nitroprusside for m o r e t h a n 24 or 48 hours and in those with renal insufficiency and should be k e p t below 10 mg. per 100 ml. T h e drug is lightsensitive. I t must be m a d e fi'esh every 24 hours and administered from a d a r k or foil-wrapped bottle. Oral a n t i h y p e r t e n s i v e agents should be s u b s t i t u t e d for sodium nitroprusside as rapidly as the clinical s t a t u s of the p a t i e n t allows it. Side effects. Toxicity of sodium nitroprusside is usually mild at t h e r a p e u t i c dose levels and a t blood levels below 10 rag. per 100 ml. However. nausea, dizziness. agitatibn, muscle spasms, chills, nasal stuffiness. confusion, and toxic psychosis can occur.
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and are generally dose-related. T he drug can regularly produce.profound hypotension if the rate of infusion is increased. At toxic levels. tremors and sudden respiratory arrest can occur.
Beta-adrenergic blocking agents Actions. Th e beta-adrenergic blocking agents, of which propranolol is still the only member currently available in the United States, have been used clinically since 1964 as antihypertensive agents. The earliest reports on the antihypertensive action of beta-adrenergic blockade suggested t h a t the reduction in blood pressure was due to a primary reduction in cardiac output resulting from the negative inotropic and chronotropic action of these drugs.l~ There is evidence both in man and in animals that sympathetic stimulation promotes release of renin in the kidney and that propranolol inhibits renin release. 1~''~'11~ Buhler and associates ~ reported t hat propranolol was more likely to produce a fall in blood pressure in patients with high plasma renin activity than in patients with normal or low plasma renin activity. Other investigators have not confirmed Buhler's work. ~u Another important mechanism of action of propranolol in the t r e a t m e n t of hypertension is its ability to prevent reflex stimulation of the heart rate and cardiac out put resulting from the primary action of vasodilating agents such as hydralazine. When used alone, the effectiveness of vasodilating agents is limited by a reflex increase in sympathetic discharge triggered by peripheral vasodilatation. Propranolol blocks these effects and facilitates the vasodilating effect of these agents. A combination of propranolol in a dose of 80 to 160 rag. per day and hydralazine in a dose of 100 to 400 mg. per day resulted in satisfactory blood pressure control in a group of patients not previously controlled with other drug programs2 ~ Another mechanism of action of propranolol may be a direct effect on the central nervous system Ibrain stem) resulting in a decrease in the sympathetic tone2 ~'-' This action probably only occurs with doses of propranolol exceeding 160 mg. per day. Uses.
Patients with hypertension who also clinically exhibit a hyperdynamic circulatory state are ideal candidates for beta blockade therapy. Such 256
patients have a disturbing cardiac awareness manifested by an unpleasant rapid and forceful cardiac action. ''3 Gorlin 11~ has reported hemodynamic studies on these patients and described them as having a hyperkinetic heart syndrome. Propranolol therapy for hypertension in this group seems to work well. "~ In all patients with hypertension, propranolol may produce a smooth lowering of systolic and diastolic blood pressure without postural hypotension. A number of trials demonstrate that when the drug is used in a sufficient dose. the antihypertensive effect is substantial and comparable to t hat produced by methyldopa and guanethidine." ..... ~Other workers report t hat the drug produces only a modest and at times inconsequential reduction in blood pressure. "~. 11~ At present, propranolol shows greatest promise as an agent to use in combination with the vasodilators. T he cardiac effects of the two drugs oppose each other, vasodilators increasing and propranolol decreasing both heart rate and cardiac output. T he modifying effect of propranolol thus allows the full vasodilatory effect of these drugs to be exerted. Balanced against each other, the side effects of each drug tend to be cancelled by the action of the other drug. The use of propranolol together with guanethidine demands caution since both drugs depress myocardial contractility and heart rare. Data concerning the effects of using propranolol together with other antihypertensive agents are scant y. The effective dose of propranolol varies widely among patients. The initial a m o u n t should be approximately 40 to 60 mg. per day in divided doses, and should not be increased more often than once every two to three days to avoid cumulative pharmacologic effects. The dose can be increased until a desired effect is achieved unless heart rate slows to less than 50 per minute. Doses up to 1.000 mg. per day have been used in the treatment of hypertension. Other betaadrenerglc blocking drugs that may be more cardioselective in action are currently being studied. 1~0 In using propranolol in combination with hydralazine, it is best to start both drugs simultaneously beginning with 50 to 75 mg. per day of hydralazine and 40 to 60 mg. per day of propranolol in divided doses. Dosage may then be increased gradually until satisfactory blood pressure control is achieved. It is preferable to keep August, 1976, Vol. 92, No. 2
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doses of each drug below 300 rag. per day, although larger doses have been used. One of the oral diuretic agents is usually also used with this combination. It has been reported ~ that the patients with high plasma renin levels respond better to propranolol than those with low or normal plasma renin. Side effects. Propranolol is relatively free of side effects if certain precautions are observed. Because the beta blocking drugs diminish myocardial contractility, they should not ordinarily be used in patients with cardiomegaly or a history of congestive heart failure. Propranolol t r e a t m e n t should not in general be initiated in patients with bradycardia. The dose should be reduced if the sinus rate falls to less than 50 per minute during treatment. Because beta-adrenergic blockade may potentiate atrioventricular block, the drug should not be used in patients with atrioventricular conduction defects. Propranolol may produce or aggravate bronchospasm in patients with a history of asthma or chronic obstructive lung disease. Other side effects are minimal and consist of occasional nausea, diarrhea, cramps, and fatigue. The fatigue in occasional patients may be quite disabling and necessitate reduction in dose or discontinuing the drug.
Ganglionic blocking agents Actions. The ganglionic blocking drugs reduce blood pressure by interfering with neurotransmission in the sympathetic ganglions. These drugs compete with acetylcholine for cholinoceptive sites in the ganglion and thereby prevent postsynaptic depolarization. 1~' The interference with transmission in sympathetic ganglions produced by these drugs results in a decreased sympathetic tone. causing a decrease in peripheral vascular resistance and a fall in blood pressure. T he ganglionic blockers reduce cardiac output by decreasing venous return to the heart rather than by any direct action on the myocardium. Peripheral pooling of blood as a consequence of venous dilatation accounts for the decrease in venous return. ~. 1~ Changes in the heart rate are not predictable and depend upon the degree of impairment of vagal tone due to parasympathetic ganglionic blockade. Almost invariably renal blood flow and glomerular filtration rate are reduced by these drugs.'~ American Heart Journal
Uses. The only commonly used ganglionic blocking drug at present is trimethaphan camsylate (Arfonad) which is used intravenously for the purpose of emergency reduction in blood pressure. Trimethaphan has all the pharmacologic effects of the longer acting oral drugs but has a very brief duration of action. Tolerance to trimethaphan develops rapidly and many patients become refractory to its effects in 48 to 72 hours. A significant hypotensive effect is evident within minutes after starting an intravenous infusion of trimethaphan. This drug is particularly useful in immediately lowering blood pressure in patients with acute dissection of the aorta, because it reduces cardiac output together with blood pressure. Intravenous nitroprusside (not a ganglionic blocker J is also ideal in this situation whereas diazoxide is contraindicated in the t r e a t m e n t of dissection of the aorta, because it elicits reflex increase in cardiac output. T ri m et haphan also may be used for the emergency lowering of blood pressure in patients with hypertensive encephalopathy and malignant hypertension although diazoxide and nitroprusside are equally satisfactory agents for these disorders. Other h y p o t e n s i v e agents should be started on the first day of treatment with trimethaphan in order t hat blood pressure will be adequately controlled when patients become refractory to the drug. Slanting of the bed in the "head up" position augments the hypotensive effect of trimethaphan as the drug effect is primarily an orthostatic one. Side effects. There are numerous side effects of the ganglionic blocking agents resulting from their widespread actions on the autonomic nervous system. Parasympathetic blockade produces many disturbing symptoms including drying of the mucous membranes and paralysis of accommodation. Generalized ganglionic blockade usually results in constipation, paralytic ileus, urinary retention, and impotence in males. Postural hypotension is a common problem due to the peripheral pooling of blood. T he side effects are dose related and respond to reduction in dosage or omission of the drug.
Selection of antihypertensive drugs For virtually all patients with hypertension, treatment with a diuretic agent should be a first choice. Diuretic therapy alone is adequate to control blood pressure in m any patients with mild 257
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t o m o d e r a t e h y p e r t e n s i o n , a n d is g e n e r a l l y s m o o t h in i t s effect a n d r e l a t i v e l y free o f s e r i o u s side effects. I f d i u r e t i c t h e r a p y fails t o c o n t r o l blood pressure, additional drugs may be added, but diuretic therapy should be continued, since an additive hypotensive effect is t h e r e b y achieved. Furthermore, the antiadrenergic and vasodilator drugs promote sodium retention, and t h i s is c o u n t e r a c t e d b y t h e d i u r e t i c . It has been suggested that propranolol alone m a y b e t h e d r u g of c h o i c e in p a t i e n t s w i t h h i g h r e n i n '~ a n d t h a t v i g o r o u s d i u r e t i c t h e r a p y is e s p e c i a l l y e f f e c t i v e in p a t i e n t s w i t h l o w r e n i n h y p e r t e n s i o n . '':~ A m o r e b a l a n c e d view is p r e s e n t e d b y Koch-Weser.:' Drug therapy with several agents simultan e o u s l y is n e c e s s a r y in m o s t p a t i e n t s w i t h m o r e than mild blood pressure elevation. Many patients respond well to combinations of a diuretic and an antiadrenergic medication, preferably methyldopa. Others, including many patients with accelerated or malignant hypertension, r e s p o n d b e t t e r to c o m b i n a t i o n s of a d i u r e t i c , propranolol, and hydralazine. For patients with severe h y p e r t e n s i o n w h o do n o t r e s p o n d s a t i s f a c torily to either regimen, substitution of hydralazine b y m i n o x i d i l or g u a n c y d i n e m a y offer h o p e of more satisfactory control when these agents are r e l e a s e d for g e n e r a l use. M e a n w h i l e , c o m b i n a t i o n s of a l l a v a i l a b l e t y p e s of a n t i h y p e r t e n s i v e a g e n t s a r e o c c a s i o n a l l y r e q u i r e d in t h o s e p a t i e n t s with the most severe and resistant forms of h y p e r t e n s i o n . T h e r o l e o f c l o n i d i n e in t h e r a p y is s t i l l n o t clear. A t p r e s e n t i t s e e m s m o s t u s e f u l as a n a l t e r n a t i v e to m e t h y l d o p a in p a t i e n t s w h o tolerate this drug poorly. S i n c e t r e a t m e n t of h y p e r t e n s i o n is p r i m a r i l y designed to reduce the risk of cardiovascular disease, d r u g t h e r a p y s h o u l d be s u p p l e m e n t e d b y a t t e n t i o n to o t h e r , c o e x i s t e n t c a r d i o v a s c u l a r r i s k f a c t o r s s u c h as o b e s i t y , h y p e r l i p i d e m i a , c i g a r e t t e smoking, and physical conditioning. REFERENCES
79. Becker-Christensen, F., Burg, H. O., and Ditzel, J.: Treatment of severe hypertension with Catapres (St 155), Acta Med. Scand. 190:21, 1971, 80. Putzeys, M. R., and Hoobler, W. W.: Comparison of clonidine and methyldopa on blood pressure and side effects in hypertensive patients, AM. HEART J. 83:464, 1972. 81. Mroczek, W. J., Leibel, B. A., and Finnerty, F. A.: Comparison of clonidine and methyldopa in hypertensive patients receiving a diuretic, Am. J. Cardiol. 29:712, 1972.
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82. Hunyor, S. N., Hansson, L., Harrison, T. S., and Hoobler, S, W.: Effects of clonidine withdrawal: Possible mechanisms and suggestions for management, Br. Med. J. 2:209, 1973. 83. Pohl, J. E. F., and Thurston, H.: Use of diazoxide in hypertension with renal failure, Br. Med. J. 4:142, 1971. 84. Ablad, B.: A study of the mechanism of the hemodynamic effects of hydralazine in man, Acta Pharmacol. Toxicol. 20:(Suppl. 1):1-53, 1963. 85. Koch-Weser, J.: Vasodilator drugs in the treatment of hypertension, Arch. Intern. Med. 133:1017, 1974. 86. Perry, H. M., Jr., Tan, M., Carmody, S., and Sakamoto, A.: Relationship of acetyl transferase activities to antinuclear antibodies and toxic symptoms in hypertensive patients treated with hydralazine, J. Lab. Clin. Med. 76:114, 1970. 87. Zacest, R., Gilmore, E., and Koch-Weser, J.: Treatment of essential hypertension with combined vasodilation and beta adrenergic blockade, N. Engl. J. Med. 286:617, 1972. 88. Chidsey, C. A., Gottlieb, T. B., Pluss, R. G., Orcutt, J. C., and Well, J. V.: The use of vasodilator and beta adrenergic blockade in hypertension, in Hypertension: mechanisms and management, edited by G. Onesti, K. E. Kim, and J. H. Moyer, New York, 1973, Grune & Stratton, Inc., pp. 357-367. 89. Chidsey, C. A., and Gottlieb, T. B.: The pharmacologic basis of antihypertensive therapy: The role of vasodilator drugs, Progr. Cardiovasc. Dis. 1 7:99, 1974. 90. Gottlieb, T. B., Katz, F. H., and Chidsey, C. A.: Combined therapy with vasodilator drugs and beta adrenergic blockade in hypertension-A comparative study of minoxidil and hydralazine, Circulation 45:571, 1972. 91. Pettinger, W. A., and Mitchell, H. C.: Minoxidil-An alternative to nephrectomy in refractory hypertension, N. Engl. J. Med. 167:171, 1973. 92. Hammer, J., Ulryeh, M., and Freis, E. D.: Hemodynamic and therapeutic effects of guancydine in hypertension, Clin. Pharmacol. Ther. 12:78, 1972. 93. Gupta, N., and Goldberg, L. I.: Guancydine, a new vasodilator: Comparison with hydralazine in a regimen including propranolol and quinethazone, in Hypertension: Mechanism and management, edited by G. Onesti, K. Kim, and J. Moyer, New York, 1973, Grune & Stratton, Inc., pp. 351-356. 94. Johnson, B. F.: Diazoxide and renal function in man, Clin. Pharmacol. Ther. 12:815, 1971. 95. Beamer, V. L., and McDonald, R. H.: Failure of repeated diazoxide injections to modify the course of severe hypertension, AM. HEART J. 79:742, 1970. 96. Landesman, R.; Coutinho, E. M., Wilson, K. H., and Lopez, A. C. V.: The relaxant effect of diazoxide on nongravid human myometrium in vivo, Am. J. Obstet. Gynecol. 102:1080, 1968. 97. Fajans, S. S., Floyd, J. C., Jr., Thiffault, C. A., Knoff, R. F., Harrison, T. S., and Conn, J. W.: Further studies on diazoxide suppression of insulin release from abnormal and normal islet tissue in man, Ann. N. Y. Acad. Sci. 150:261, 1968. 98. Sellers, E. M., and Koch-Weser, J.: Protein binding and vascular activity of diazoxide, N. Engl. J. Med. 281:1141, 1969. 99. Miller, W. E., Gifford, R. W., Humphrey, D. C., and Vidt, D. G.: Management of severe hypertension with intravenous injections of diazoxide, Am. J. Cardiol. 24:870, 1969. 100. Finnerty, F. A., Jr., Kakaviatos, N., and Davidov, M.:
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101.
102. 103. 104.
105. 106. 107. 108.
109. 110.
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The long term effect of repeated acute reductions of arterial pressure with diazoxide in patients with severe hypertension, Ann. N. Y. Acad. Sci. 150:461, 1968. Sellers, E. M., and Koch*Weser, J.: Displacement of warfarin from h u m a n albumin by diazoxide and ethacrynic, mefanamic and nalidixic acids, Clin. Pharmacol. Ther. 1 1:524, 1970. Thurston, H., and Pohl, J. E. F.: Development of extrapyramidal symptoms in hypertensive patients treated with diazoxide, Br. Med. J. 3:474, 1973. Palmer, F. R., and Lasseter, K. C.: Drug therapy: Sodium nitroprusside, N. Engl. J. Med. 292:294, 1975. Franciosa, J. A., Giulha, N. H., and Limas, C. J.: Improved left ventricular function during nitroprusside infusion in acute myocardial infarction, Lancet 1:650, 1972. Tuzel, I., Limjuice, R., and Kahn, D.: Sodium nitroprusside in hypertensive emergencies, Curr. Ther. Res. 17:95, 1975. Barker, M. H.: The blood cyanates in the t r e a t m e n t of hypertension, J.A.M.A. 106:762~ 1936. Frohlich, E. D., Tarazi, R. C., Dustan, H. P., and Page, I. H.: The paradox of beta-adrenergic blockade in hypertension, Circulation 37:417, 1968. Wilson, D. F., Watson; O. F., Piel, J. S., Langley, R. B., and Turner, A. S.: Some hemodynamic effects of trasicor (Ciba 39089/Ba), N. Zealand J.M. 68:145, 1968. Winer, N., Chokshi, D. S, Yoon, M. S., and Freedman, A. D.: Adrenergic receptor mediation of renin secretion, J. Clin. Endocrinol. Metab. 29:1168, 1969. Michelakis, A. M., and McAllister, R. G.: The effect of chronic adrenergic receptor blockade on plasma renin activity in man, J. Clin. Endocrinol. Metab. 34:386, 1972. Tarazi, R. C.: Long-term hemodynamic effects of betaadrenergic blockade in hypertension, in Hypertension: Mechanisms and management, edited by G. Onesti, K. Kim, and J. Moyer, New York, 1973, Grune & Stratton, Inc., p. 347.
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112. Stern, S., Hoffman, M., and Braun, K.: Cardiovascular responses to carotid and vertebral artery infusions of propranolol, Cardiovasc. Res. 5:425, 1971. 113. Frohlich, E. D., Dustan, H. P., and Page, I. H.: Hyperdynamic beta-adrenergic circulatory state, Arch. Intern. Med. 1 1 7:614, 1966. 114. Gorlin, R.: The hyperkinetic heart syndrome, J.A.M.A. 182:823, 1962. 115. Frohlich, E. D.: The use of beta-adrenergic blockade in hypertension, in Hypertension: Mechanisms and management, edited by G. Onesti, K. Kim, and J. Moyer, New York, 1973, Grune & Stratton, Inc., pp. 335-336. 116. Prichard, B. N. C.: Propranolol as an antihypertensive agent, AM. HEART J. 79:128, 1970. 117. Prichard, B. N. C., and Gillam, P. M. S.: Propranolol in hypertension, Am. J. Cardiol. 18:387, 1966. 118. Waal, H. J.: Hypotensive action of propranolol, Clin. Pharmacol. Ther. 7:588, 1966. 119. Humphreys, G. S., and Delvin, D. G.: Ineffectiveness of propranolol in hypertensive Jamaicans, Br. Med. J. 2:601, 1968. 120. Wilson, A. G., Brooke, O. G., Lloyd, H. J., and Robinson, B. F.: Mechanism of action of fl-adrenergic receptor blocking agents in angina pectoris: Comparison of action of propranolol with dexpropranolol and practolol, Br. Med. J. 4:399, 1969. 121. Volle, R. L., and Koelle, G. B.: Ganglionic stimulating and blocking agents, in The pharmacological basis of therapeutics, fourth edition, edited by L. S. Goodman, and A. Gilman, New York, 1970, Macmillan Publishing Company, Inc., pp. 585-600. 122. Ford, R. V., Moyer, J. H., and Spurr, C. L.: Hexamethonium in the chronic t r e a t m e n t of h y p e r t e n s i o n - I t s effects on renal hemodynamics and on the excretion of water and electrolytes, J. Clin. Invest. 32:1133, 1953. 123. Dustan, H. P., Tarazi, R. C., and Bravo, E. L.: Physiological characteristics of hypertension, Am. J. Med. 52:610, 1972.
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Drugs in the management of hypertension. Part III Lot B. Page, M.D. Henry M. Yager, M.D. James J. Sidd, M.D. Newton and Boston, Mass.
Vasodilator drugs The vasodilator drugs act directly on vascular smooth muscle to produce vasodilatation and reduction in peripheral resistance. They include hydralazine, diazoxide, minoxidil, guancydine, and sodium nitroprusside. With the exception of sodium nitroprusside, these drugs have a selective effect on arterioles with little if any effect on venous capacitance vessels. This selective dilatation of arterioles results in an increase in venous return, which triggers a reflex increase in heart rate and stroke volume mediated through the sympathetic nervous system. As a result they share several common side effects due to increased cardiac action. These include palpitation, headache, and the capacity to precipitate angina pectoris in patients with coronary disease. In addition, drugs in this group share an ability to stimulate renin release and promote sodium retention. Increased cardiac output and sodium retention both act to reduce the hypotensive effects of vasodilatation. In most circumstances, drugs in this group should be use d together with propranolol and diuretics which counteract these effects, enhance the effectiveness of vasodilatation, and minimize side effects. Of the vasodilators, only hydralazine is available for oral use in the United States at present. Minoxidil and guancydine have given promising results in clinical trials. Diazoxide and sodium nitroprusside are available only for intravenous use, although diazoxide has been shown to be effective given orally, s:~
From the Departments of Medicine, Newton-Wellesley Hospital, and Tui~s University School of Medicine, Newton and Boston, Mass. Received for publication Mar. 10, 1976. Reprint requests to: Lot B. Page, M.D., 2000 Washington St., Newton Lower Falls, Mass. 02162.
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Oral vasodilators Hydralazine. Actions.
Hydralazine has been in use since the early 1950's. It acts directly on arteriolar smooth muscle producing vasodilatation and reduction in peripheral resistance. Splanchnic, coronary, cerebral, and renal blood flow increase, while blood flow in skeletal muscle and skin is unaffected,s4 Blood pressure is reduced in both the supine and standing posture. Hydralazine is rapidly absorbed from the gastrointestinal tract, reaching maximal effect in one hour, and the usual half-life is four hours25 However, this varies among individuals depending on the rate of inactivation of the drug by acetylation. "Slow acetylators" are more responsive to hydralazine and more likely to develop immunological side effects.8~ Hydralazine produces immediate stimulation of renin release, which through its effect on aldosterone is at least partly responsible for sodium retention. With long-term use of hydralazine alone, sodium retention suppresses the renin stimulation effect. Uses.
Although it has been available for many years, hydralazine has until recently had limited use because of its tendency to cause increased heart rate and cardiac output. When used in combination with a diuretic and propranolol, these effects are largely eliminated and a greater hypotensive effect is achieved. This combination has proved effective in managing patients who previously were poorly controlled on other drug regimens27 A dose-related hypotensive response can be demonstrated up to 800 mg. per day. 8~ However, long-term use at high dosage produces a high incidence of immunologic side effects, and t h e dose should generally be kept to 300 mg. per day or less.
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Drugs in the management of hypertension. III Side effects. Symptoms related to reflex increase in cardiac rate and output include palpitations, headache, and angina pectoris. Many patients develop positive antinuclear antibody reaction on prolonged use, 8~ and a syndrome similar to lupus erythematosus disseminatus occurs in 10 to 20 per cent of patients on doses greater than 400 mg. per day. This occurs with much lower frequency on doses less than 300 mg. per day. ~7 Other side effects include fever, skin eruptions, nausea, anorexia, and diarrhea. Many patients complain of flushing, ill-defined rushing sensations in the head, and mental fuzziness. Peripheral neuropathy and bone marrow depression have been reported. Minoxidil. Actions. Minoxidil is a potent vasodilating agent which is not yet available for general use. Like the other drugs in this group it acts directly on vascular smooth muscle, selectively dilating arteriolar resistance vessels, with little or no effect on venous capacitance vessels. This results in increased venous return and triggers a reflex increase in heart rate and cardiac output mediated by the sympathetic nervous system. This drug also promotes sodium retention by stimulating renin release, and probably also by a direct effect on the renal tubule28 Minoxidil is considerably more potent than either hydralazine or guancydine. When used alone, its effectiveness is gradually lost as a result of increased cardiac output and sodium retention. When used together with propranolol and a diuretic, these effects are counteracted and tachyphylaxis does not develop. Minoxidil is rapidly and completely absorbed from the gastrointestinal tract, with peak plasma levels in 1 hour, and a plasma halflife of 4 hours. ~9 The hypotensive effect does not correspond to the plasma concentration. This is due to accumulation of the drug in arterial smooth muscle where it exerts an effect which is prolonged for 12 hours or more. ~ After stopping the drug, blood pressure does not rise for several days, although over 90 per cent of the drug and its metabolites are excreted in 24 to 48 hours. ~ Minoxidil lowers blood pressure in both the supine and standing posture, and does not affect renal blood flow or glomerular filtration rate. Uses. Minoxidil appears to be an extremely promising
American Heart Journal
drug for clinical use. In clinical trials it has been shown to be remarkably effective in controlling blood pressure in patients with severe and refractory hypertension and renal failure, who have failed to respond to any of the drug regimens now available.9O. ~1 Furthermore, when used in combination with propranolol and diuretics it has produced no serious side effects in human subjects. The sodium retaining effect of minoxidil does not seem to be correlated with renin and aldosterone levels. In patients with renal failure, good blood pressure control has required meticulous adjustment of diuretic agents to control fluid retention and of propranolol to control reflex cardiac stimulation. Pettinger and Mitchell '' report a useful additive effect when several different types of diuretics were used together in patients on minoxidil. Doses of 2 to 40 rag. per day have been well tolerated in man. Patients formerly incapacitated by hypertension and renal failure have tolerated minoxidil, propranolol, and diuretic therapy with few drug side effects, unimpaired sexual function, and improvement in cardiac status. The long duration of action of minoxidil allows simple dosage schedules. Side effects. After prolonged use at high dose levels in dogs, a myocytic degenerative lesion of the right atrium frequently develops. Although this has not been reported in other species, this finding may account for the delay in releasing minoxidil for general use. In man, minoxidil has been free of serious side effects, and has not caused the lupuslike syndrome seen with hydralazine. In doses of 10 mg. per day and more, minoxidil regularly produces hirsutism which is most marked in the first few months and then tends to recede somewhat21 Characteristically, the temporal hair line grows toward the eyebrows, and there is increase in upper truncal hair in males and increased lanugo hair in females. ~ The mechanism is unknown, but similar hirsutism occurs in patients on oral diazoxide. ~5 No change in gonadal or adrenal function has been found. 8~ Minoxidil has been shown to stimulate hair growth when applied directly to the skin. 8~ Hirsutism is easily controlled with depilatory procedures. Guancydine. Actions. Although it is not yet available for general use, guancydine has been used in clinical trials since
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1968. Its mode of action is similar to the other vasodilating drugs. It acts directly on arteriolar smooth muscle causing vasodilatation and decreasing peripheral resistance. It has little if any effect on venous capacitance vessels. Thus it increases venous return, and like the other drugs in this group, it stimulates reflex increase in cardiac output and heart rate, stimulates renin release in some but not all patients/'~ and causes sodium retention. These side effects are counteracted when guancydine is used in combination with propranolol and a diuretic. '-~' '~ T a ke n orally, guancydine is well absorbed from the gastrointestinal tract, and produces a hypotensive effect which is maximal in 1-1/2 hours and lasts four to eight hours? ~ It is effective in both the supine and standing posture. In potency it is equal to or somewhat greater than hydralazine. '~' ,3 Uses. Guancydine shows promise as a vasodilator to be used in combination with diuretic and betaadrenergic blocking agents to offset the cardiac stimulation and sodium retention which all such drugs produce. It does not cause the immunologic side effects seen with hydralazine, nor the right atrial lesion reported in dogs on high doses of minoxidil. Its position in therapy is still uncertain. It should not be used alone, but shows promise as an alternative to hydralazine. Doses up to 1500 mg. per day have been tolerated in man. Higher doses usually produce intolerable side effects. Side effects. When used in combination with propranolol and a diuretic, palpitation, headache, chest discomfort; and edema do not occur. However, guancydine side effects include gynecomastia, galactorrhea, nausea, epigastric distress, mental Confusion, and hallucinations, most of which are dose-related. Intravenous vasodilators
Diazoxide. After clinical studies extending over more than 10 years, diazoxide has been released for intravenous use in hypertensive emergencies. Diazoxide exerts its action by a direct effect on smooth muscle of arteriolar resistance vessels Causing vasodilatation, and decreased peripheral resistance. It has little if any effect on venous capacitance vessels. Thus it increases venous return and stimulates a marked reflex increase in cardiac output and heart rate. It also promotes sodium
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retention both by stimulating the renin-angiotensin system and by a direct effect on the renal tubule2* Diazoxide also affects non-vascular smooth muscle, causing transient reduction in gastrointestinal motility '5 and relaxation of the uterus2 ~ It causes hyperglycemia partly by inhibiting release of insulin and partly by an extrapancreatic mechanismY ~ To be effective, diazoxide must be given by rapid bolus injection. This is attributed to binding of the drug by plasma albumin, which prevents it from reaching vascular receptor sites unless it is rapidly administered? ~ This explanation has been criticized on theoretical grounds ~" and it has also been shown t hat diazoxide produces a hypotensive effect when given by mouth, although it is not available for oral use in the United States. Following intravenous injection, blood pressure drops rapidly reaching a nadir in one to three minutes, then rising slightly over five to ten minutes to a plateau which is sustained for some hours before rising to pret reat m ent levels. Blood pressure characteristically drops to a satisfactory or "normal" level, and hypotensive reactions are uncommon. Duration of the hypotensive effect is variable, lasting from two to 24 hours. Blood levels of the drug are poorly correlated with the hypotensive actionY ~ T he drug is excreted unchanged in the urine over a 30 hour period.85, ,,,8 Uses. Intravenous use of diazoxide has proved effective for short term management of acute hypertensive emergencies, especially hypertensive encephalopathy. Its advantages are its rapid onset of action, the absence of a sedative effect, and the rarity of excessive hypotension. Since the drug reaches maximal effectiveness rapidly, close monitoring is required for only a short time after each dose. Since it causes marked reflex increase in cardiac action, it should not be used in dissecting aneurysm of the aorta, or in the presence of coronary insufficiency where sodium nitroprusside is preferable. Although diazoxide causes abrupt cessation of labor, it has been used successfully in eclampsia when used with oxytocin which overrides its relaxing effect on the uterus. Diazoxide is ineffective in pheochromocytoma?'' I ( s h o u l d be used together with intravenous furosemide to offset its sodium retaining effect: ~ Use of propranolol with diazoxide is hazardous. Although propranolol counteracts the
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reflex s t i m u l a t i o n of cardiac action, use of the two drugs t o g e t h e r m a y result in severe h y p o t e n s i o n unless the dose of diazoxide is reduced. ~ I t h a s been claimed t h a t short t e r m use of i n t r a v e n o u s diazoxide alters the course of severe h y p e r t e n s i o n , m a k i n g p a t i e n t s m o r e responsive to s u b s e q u e n t use of o t h e r drugs? ~ O t h e r investigators h a v e n o t confirmed this finding. "~ Diazoxide is effective in m a n y patients. a l t h o u g h resistance occurs in some. requiring increase in dosage, or substitution by sodium nitroprusside. D u r i n g t r e a t m e n t with diazoxide, blood sugar should be m o n i t o r e d frequently a n d oral h y p o g l y c e m i c agents or insulin m a y be required for blood sugar control. Oral a n t i h y p e r t e n sive agents should be s u b s t i t u t e d for diazoxide as soon as the clinical s t a t u s of the p a t i e n t is stable. Side effects. Sodium r e t e n t i o n with diazoxide is readily c o u n t e r a c t e d with diuretics (preferably furosemide) given simultaneously. T a c h y c a r d i a occurs regularly a n d can precipitate angina pectoris. H y p e r g l y c e m i a is a f r e q u e n t occurrence, and h y p e r o s m o l a r n o n - k e t o t i c c o m a has been reported. P o s t u r a l h y p o t e n s i o n can occur with combined diazoxide and furosemide t h e r a p y , b u t is usually corrected by keeping the p a t i e n t in supine position. H y p o t e n s i v e reactions are likely to occur w h e n diazoxide is used in p a t i e n t s together w i t h propranolol. H y p o t e n s i o n also occurs occasionally in p a t i e n t s on multiple antih y p e r t e n s i v e drugs. Diazoxide can displace coumarin a n t i c o a g u l a n t s from binding proteins. amplifying the effect of the a n t i c o a g u l a n t ? ~ Mild reactions of flushing, and a b d o m i n a l discomfort occur frequently. Oral diazoxide causes h y p e r t r i chosis and e x t r a p y r a m i d a l s y m p t o m s 2 ~
Sodium nitroprusside. Actions. T h e effectiveness of i n t r a v e n o u s sodium nitroprusside for rapid blood pressure reduction h a s been known for m a n y years, b u t it has b e c o m e c o m m e r c i a l l y available only very recently. In its mode of action, sodium nitroprusside differs from all the other vasodilating drugs in t h a t it acts b o t h on the a r t e r i o l a r resistance vessel and also on the venous c a p a c i t a n c e vessels. This results in a drop in peripheral resistance w i t h o u t an increase in venous return. As a result, it does not regularly result in a reflex increase m cardiac o u t p u t and h e a r t rate. Its effect on cardiac
American Heart Journal
o u t p u t will v a r y depending on the prior s t a t e of the p a t i e n t s~' 1r and on posture. Tilting the p a t i e n t will produce pooling of blood in capacitance vessels and reduce cardiac o u t p u t ? ~ ~~ Sodium nitroprusside m u s t be given b y c o n s t a n t infusion, preferably with the aid of an infusion pump. I t is reliably effective in almost all patients, exerting its effects within seconds. I t s h y p o t e n s i v e action is dissipated within a few m i n u t e s after infusion is stopped. Conversion of nitroprusside to t h i o c y a n a t e occm's rapidly in vivo. T h i o c y a n a t e is relatively non-toxic at p l a s m a levels below 10 rag. per lO0 ml. ~ T h i o c y a nate is excreted in the urine, a n d m a y a c c u m u l a t e with time in p a t i e n t s with reduced renal function. Uses. Sodium nitroprusside is an e x t r e m e l y effective and useful drug for i n t r a v e n o u s t r e a t m e n t in all types of h y p e r t e n s i v e emergencies. Because of its unique effect on b o t h arterioles and venous s m o o t h muscle it does not s t i m u l a t e reflex increase in cardiac action. For this reason it is the drug of choice for t r e a t m e n t of h y p e r t e n s i o n associated with dissecting a n e u r y s m of the aorta. congestive h e a r t failure, and m y o c a r d i a l infarction. It has recently seen increasing use in reducing v e n t r i c u l a r afterload in p a t i e n t s with myocardial infarction. 1~'~ Sodium nitroprusside is ineffective if given by mouth. R a t e of i n t r a v e n o u s infusion m u s t be very carefully regulated, p r e f e r a b l y by an infusion pump. Blood pressure m u s t be m o n i t o r e d constantly, and an indwelling arterial c a n n u l a is usually necessary fbr this purpose. S e r u m levels of t h i o c y a n a t e can be by m e t h o d s easily performed in most clinical laboratories. 1~ Thioc y a n a t e should be m o n i t o r e d in p a t i e n t s receiving sodium nitroprusside for m o r e t h a n 24 or 48 hours and in those with renal insufficiency and should be k e p t below 10 mg. per 100 ml. T h e drug is lightsensitive. I t must be m a d e fi'esh every 24 hours and administered from a d a r k or foil-wrapped bottle. Oral a n t i h y p e r t e n s i v e agents should be s u b s t i t u t e d for sodium nitroprusside as rapidly as the clinical s t a t u s of the p a t i e n t allows it. Side effects. Toxicity of sodium nitroprusside is usually mild at t h e r a p e u t i c dose levels and a t blood levels below 10 rag. per 100 ml. However. nausea, dizziness. agitatibn, muscle spasms, chills, nasal stuffiness. confusion, and toxic psychosis can occur.
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and are generally dose-related. T he drug can regularly produce.profound hypotension if the rate of infusion is increased. At toxic levels. tremors and sudden respiratory arrest can occur.
Beta-adrenergic blocking agents Actions. Th e beta-adrenergic blocking agents, of which propranolol is still the only member currently available in the United States, have been used clinically since 1964 as antihypertensive agents. The earliest reports on the antihypertensive action of beta-adrenergic blockade suggested t h a t the reduction in blood pressure was due to a primary reduction in cardiac output resulting from the negative inotropic and chronotropic action of these drugs.l~ There is evidence both in man and in animals that sympathetic stimulation promotes release of renin in the kidney and that propranolol inhibits renin release. 1~''~'11~ Buhler and associates ~ reported t hat propranolol was more likely to produce a fall in blood pressure in patients with high plasma renin activity than in patients with normal or low plasma renin activity. Other investigators have not confirmed Buhler's work. ~u Another important mechanism of action of propranolol in the t r e a t m e n t of hypertension is its ability to prevent reflex stimulation of the heart rate and cardiac out put resulting from the primary action of vasodilating agents such as hydralazine. When used alone, the effectiveness of vasodilating agents is limited by a reflex increase in sympathetic discharge triggered by peripheral vasodilatation. Propranolol blocks these effects and facilitates the vasodilating effect of these agents. A combination of propranolol in a dose of 80 to 160 rag. per day and hydralazine in a dose of 100 to 400 mg. per day resulted in satisfactory blood pressure control in a group of patients not previously controlled with other drug programs2 ~ Another mechanism of action of propranolol may be a direct effect on the central nervous system Ibrain stem) resulting in a decrease in the sympathetic tone2 ~'-' This action probably only occurs with doses of propranolol exceeding 160 mg. per day. Uses.
Patients with hypertension who also clinically exhibit a hyperdynamic circulatory state are ideal candidates for beta blockade therapy. Such 256
patients have a disturbing cardiac awareness manifested by an unpleasant rapid and forceful cardiac action. ''3 Gorlin 11~ has reported hemodynamic studies on these patients and described them as having a hyperkinetic heart syndrome. Propranolol therapy for hypertension in this group seems to work well. "~ In all patients with hypertension, propranolol may produce a smooth lowering of systolic and diastolic blood pressure without postural hypotension. A number of trials demonstrate that when the drug is used in a sufficient dose. the antihypertensive effect is substantial and comparable to t hat produced by methyldopa and guanethidine." ..... ~Other workers report t hat the drug produces only a modest and at times inconsequential reduction in blood pressure. "~. 11~ At present, propranolol shows greatest promise as an agent to use in combination with the vasodilators. T he cardiac effects of the two drugs oppose each other, vasodilators increasing and propranolol decreasing both heart rate and cardiac output. T he modifying effect of propranolol thus allows the full vasodilatory effect of these drugs to be exerted. Balanced against each other, the side effects of each drug tend to be cancelled by the action of the other drug. The use of propranolol together with guanethidine demands caution since both drugs depress myocardial contractility and heart rare. Data concerning the effects of using propranolol together with other antihypertensive agents are scant y. The effective dose of propranolol varies widely among patients. The initial a m o u n t should be approximately 40 to 60 mg. per day in divided doses, and should not be increased more often than once every two to three days to avoid cumulative pharmacologic effects. The dose can be increased until a desired effect is achieved unless heart rate slows to less than 50 per minute. Doses up to 1.000 mg. per day have been used in the treatment of hypertension. Other betaadrenerglc blocking drugs that may be more cardioselective in action are currently being studied. 1~0 In using propranolol in combination with hydralazine, it is best to start both drugs simultaneously beginning with 50 to 75 mg. per day of hydralazine and 40 to 60 mg. per day of propranolol in divided doses. Dosage may then be increased gradually until satisfactory blood pressure control is achieved. It is preferable to keep August, 1976, Vol. 92, No. 2
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doses of each drug below 300 rag. per day, although larger doses have been used. One of the oral diuretic agents is usually also used with this combination. It has been reported ~ that the patients with high plasma renin levels respond better to propranolol than those with low or normal plasma renin. Side effects. Propranolol is relatively free of side effects if certain precautions are observed. Because the beta blocking drugs diminish myocardial contractility, they should not ordinarily be used in patients with cardiomegaly or a history of congestive heart failure. Propranolol t r e a t m e n t should not in general be initiated in patients with bradycardia. The dose should be reduced if the sinus rate falls to less than 50 per minute during treatment. Because beta-adrenergic blockade may potentiate atrioventricular block, the drug should not be used in patients with atrioventricular conduction defects. Propranolol may produce or aggravate bronchospasm in patients with a history of asthma or chronic obstructive lung disease. Other side effects are minimal and consist of occasional nausea, diarrhea, cramps, and fatigue. The fatigue in occasional patients may be quite disabling and necessitate reduction in dose or discontinuing the drug.
Ganglionic blocking agents Actions. The ganglionic blocking drugs reduce blood pressure by interfering with neurotransmission in the sympathetic ganglions. These drugs compete with acetylcholine for cholinoceptive sites in the ganglion and thereby prevent postsynaptic depolarization. 1~' The interference with transmission in sympathetic ganglions produced by these drugs results in a decreased sympathetic tone. causing a decrease in peripheral vascular resistance and a fall in blood pressure. T he ganglionic blockers reduce cardiac output by decreasing venous return to the heart rather than by any direct action on the myocardium. Peripheral pooling of blood as a consequence of venous dilatation accounts for the decrease in venous return. ~. 1~ Changes in the heart rate are not predictable and depend upon the degree of impairment of vagal tone due to parasympathetic ganglionic blockade. Almost invariably renal blood flow and glomerular filtration rate are reduced by these drugs.'~ American Heart Journal
Uses. The only commonly used ganglionic blocking drug at present is trimethaphan camsylate (Arfonad) which is used intravenously for the purpose of emergency reduction in blood pressure. Trimethaphan has all the pharmacologic effects of the longer acting oral drugs but has a very brief duration of action. Tolerance to trimethaphan develops rapidly and many patients become refractory to its effects in 48 to 72 hours. A significant hypotensive effect is evident within minutes after starting an intravenous infusion of trimethaphan. This drug is particularly useful in immediately lowering blood pressure in patients with acute dissection of the aorta, because it reduces cardiac output together with blood pressure. Intravenous nitroprusside (not a ganglionic blocker J is also ideal in this situation whereas diazoxide is contraindicated in the t r e a t m e n t of dissection of the aorta, because it elicits reflex increase in cardiac output. T ri m et haphan also may be used for the emergency lowering of blood pressure in patients with hypertensive encephalopathy and malignant hypertension although diazoxide and nitroprusside are equally satisfactory agents for these disorders. Other h y p o t e n s i v e agents should be started on the first day of treatment with trimethaphan in order t hat blood pressure will be adequately controlled when patients become refractory to the drug. Slanting of the bed in the "head up" position augments the hypotensive effect of trimethaphan as the drug effect is primarily an orthostatic one. Side effects. There are numerous side effects of the ganglionic blocking agents resulting from their widespread actions on the autonomic nervous system. Parasympathetic blockade produces many disturbing symptoms including drying of the mucous membranes and paralysis of accommodation. Generalized ganglionic blockade usually results in constipation, paralytic ileus, urinary retention, and impotence in males. Postural hypotension is a common problem due to the peripheral pooling of blood. T he side effects are dose related and respond to reduction in dosage or omission of the drug.
Selection of antihypertensive drugs For virtually all patients with hypertension, treatment with a diuretic agent should be a first choice. Diuretic therapy alone is adequate to control blood pressure in m any patients with mild 257
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t o m o d e r a t e h y p e r t e n s i o n , a n d is g e n e r a l l y s m o o t h in i t s effect a n d r e l a t i v e l y free o f s e r i o u s side effects. I f d i u r e t i c t h e r a p y fails t o c o n t r o l blood pressure, additional drugs may be added, but diuretic therapy should be continued, since an additive hypotensive effect is t h e r e b y achieved. Furthermore, the antiadrenergic and vasodilator drugs promote sodium retention, and t h i s is c o u n t e r a c t e d b y t h e d i u r e t i c . It has been suggested that propranolol alone m a y b e t h e d r u g of c h o i c e in p a t i e n t s w i t h h i g h r e n i n '~ a n d t h a t v i g o r o u s d i u r e t i c t h e r a p y is e s p e c i a l l y e f f e c t i v e in p a t i e n t s w i t h l o w r e n i n h y p e r t e n s i o n . '':~ A m o r e b a l a n c e d view is p r e s e n t e d b y Koch-Weser.:' Drug therapy with several agents simultan e o u s l y is n e c e s s a r y in m o s t p a t i e n t s w i t h m o r e than mild blood pressure elevation. Many patients respond well to combinations of a diuretic and an antiadrenergic medication, preferably methyldopa. Others, including many patients with accelerated or malignant hypertension, r e s p o n d b e t t e r to c o m b i n a t i o n s of a d i u r e t i c , propranolol, and hydralazine. For patients with severe h y p e r t e n s i o n w h o do n o t r e s p o n d s a t i s f a c torily to either regimen, substitution of hydralazine b y m i n o x i d i l or g u a n c y d i n e m a y offer h o p e of more satisfactory control when these agents are r e l e a s e d for g e n e r a l use. M e a n w h i l e , c o m b i n a t i o n s of a l l a v a i l a b l e t y p e s of a n t i h y p e r t e n s i v e a g e n t s a r e o c c a s i o n a l l y r e q u i r e d in t h o s e p a t i e n t s with the most severe and resistant forms of h y p e r t e n s i o n . T h e r o l e o f c l o n i d i n e in t h e r a p y is s t i l l n o t clear. A t p r e s e n t i t s e e m s m o s t u s e f u l as a n a l t e r n a t i v e to m e t h y l d o p a in p a t i e n t s w h o tolerate this drug poorly. S i n c e t r e a t m e n t of h y p e r t e n s i o n is p r i m a r i l y designed to reduce the risk of cardiovascular disease, d r u g t h e r a p y s h o u l d be s u p p l e m e n t e d b y a t t e n t i o n to o t h e r , c o e x i s t e n t c a r d i o v a s c u l a r r i s k f a c t o r s s u c h as o b e s i t y , h y p e r l i p i d e m i a , c i g a r e t t e smoking, and physical conditioning. REFERENCES
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