MEDICAL INTELLIGENCE CURRENT CONCEPTS IN THERAPY ANTIHYPERTENSIVE AGENTS. II. BENZOTHIADIAZINE COMPOUNDS, RMJWOLFIA ANII HYDRALAZINE~ EDWARD D. FREIS, M.D.? WASHINGTON, D. C. T HE apparent great variety of antihypertensive agents represents for the most part minor varia- tions on a few prototype compounds. The more ef- fective antihypertensive drugs can be included under the following groupings: saluretic agents; rauwolfia preparations; hydralazine; ganglion-blocking drugs; and sympathetic-blocking agents. SALURETIC AGENTS Chlorothiazide and the many varieties of related benzothiadiazine derivatives are used widely in the treatment of hypertension not only for their modest intrinsic antihypertensive effect but also for their ability to enhance the blood-pressure-reducing activity of other drugs. Benzothiadiazines act on the proximal and distal convoluted tubules to increase the excretion of sodium, chloride and potassium. When chlorothiazide is administered in a dose of 500 mg. twice daily to nonedematous hypertensive pa- tients a negative sodium balance lasting approximately forty-eight to seventy-two hours deve1ops.l The excess of excreted salt is derived primarily from a loss of isotonic total extracellular fluid, with a resulting re- duction in plasma vo1ume.2 After the initial diuresis unknown compensatory mechanisms prevent further depletion of body salt despite continued administra- tion of the drug. The moderate hypovolemia is associated with a de- crease in cardiac output. 3*4 After long continued ad- ministration of chlorothiazide the plasma and total extracellular volumes and cardiac output, but not the blood pressure, are at least partially restored.5-7 The mechanism of the maintained antihypertensive effect during this later period remains undeter- mined.2,6l7 The customary dose of chlorothiazide is 500 mg. twice daily. Some patients respond to a smaller dose, such as 250 mg. twice daily or 500 mg. once daily, which may be given before noon to cover the peak periods of dietary sodium ingestion. The larger dose is usually given initially, and after several weeks it can frequently be lowered without losing the anti- hypertensive effect. The other benzothiadiazine diu- retics differ from chlorothiazide only in potency and duration of action. For example, hydrochlorothiazide *From the Veterans Administration Hospital and the Department of Medicine, Georgetown University School of Medicine. +Senior medical investigator, Veterans Administration Hospital; asso- ciate professor of medicine, Georgetown University School of Medicine. has a similar duration of effect, but 50 mg. is as effective as 500 mg. of chlorothiazide. Chlorthalidone (Hygroton) has a longer duration of action so that 100 mg. given once daily is equivalent approximately to 500 mg. of chlorothiazide given twice daily. Aside from these differences in dosage the various drugs can be used interchangeably, and none seem to have significant advantages over the others in antihyper- tensive effectiveness or lesser toxicity. The toxic effects include dermatitis, bone-marrow depression and thrombocytopenic purpura. Hyper- uricemia is fairly common and can result in clinical gout. 8~D Hyperglycemia may occur, usually without acidosis. The most common disturbance is hypo- kalemia, usually with serum potassium levels between 3.0 and 3.5 milliequiv. per 1iter.l' When lower levels are observed additional factors producing potassium depletion such as heart failure, diarrhea and secondary aldosteronism like that seen in malignant hyperten- sion should be suspected. On the other hand, hypo- natremia or hypochloremia is relatively uncommon except when the benzothiadiazines are given to pa- tients in whom such electrolyte disturbance may occur from the basic process. RAUWOLFIA SERPENTINA Although a number of alkaloids have been extracted from Rauwolfia serpentina the most effective deriva- tive is reserpine. The search for other alkaloids that are antihypertensive without the side effects of reser- pine has resulted in the production of compounds with considerably weakened antihypertensive effects. In the laboratory animal reserpine reduces the catechol amine content of the tissues.llpl* The drug also affects the metabolism of the brain, as evidenced by changes in its content of nor-epinephrine and serotonin.ll'l' Reserpine by the parenteral route in doses of 2 to 4 mg. is used in the management of hypertensive emergencies,13,14 such as acute hypertensive encepha- lopathy and eclamptic toxemia of pregnancy.1s The sedative and antihypertensive effects develop gradu- ally an hour or two after the drug has been ad- ministered. Repeated doses are given as often as is necessary to maintain a reduced level of blood pres- sure. Reserpine can be supplemented when necessary with chlorothiazide, hydralazine by the parenteral route, veratrum and, in extremely resistant cases, blocking agents administered cautiously by titration. Reprinted from the Neo! England Journal of Medicine 266:4X7-GO9 (March 2), 1962 The principal hazard in the treatment of hyperten- sive "crises" is the precipitation of hypotensive col- lapse in patients with renal damage. The drastic change in renal hemodynamics produces oliguria and resulting nitrogen retention. Hemiparesis or other signs of critically reduced cerebral blood flow may appear during severe hypotension. Fortunately, the latter usually recede with prompt treatment of the collapse. Reserpine and hydralazine are less apt than veratrum and particularly the blocking agents to pro- duce sudden severe hypotension. The blocking agents are more potent, however, and are often resorted to when milder measures fail. In chronic hypertension reserpine is given by mouth, usually in an initial dose of 0.5 mg. twice daily for two weeks, followed by a lower maintenance dose of 0.25 mg. once daily or lessI The antihypertensive effectiveness is quite variable from one patient to another, but on the average it is only moderate, pro- ducing a reduction of about 5 to 10 mm. of mercury in the basal diastolic blood pressure.l? As a con- sequence rauwolfia or reserpine is frequently used as adjunctive therapy with other antihypertensive agents. The most common side effect, nasal congestion, to- gether with increased appetite and frequency of bowel movements may represent unopposed parasympathetic activity resulting from the depletion of catechol amines. Nightmares can be sufficiently disturbing to demand reduction in dosage or discontinuation of the drug. Obsessive, compulsive and aggressive traits often give way to a more philosophical attitude toward job demands, time schedules and the like (the so-called tranquilizing effect) .I8 In some patients the emotional reaction is a distasteful lethargy necessitating further reduction in dosage. A more serious psychic reaction, distinctly different from the lethargic effect, is the appearance of a true depression at any time during the course of treatment.l" This reaction is indistin- guishable from the depressed phase of manic-de- pressive pyschosis or of involutional melancholia. The disorder may pass unrecognized since the patient often rationalizes his depressed feelings on the basis of innate deficiencies or environmental factors or may convert them into symptoms mimicking organic dis- ease. The reaction is especially dangerous because it may lead to suicide before the depression is recog- nized. For this reason it seems mandatory to warn patients at the time that treatment is begun of the infrequent but definite depressive tendency of the drug, and to indicate the importance of discontinuing the medication if a severely depressive mood change develops. HYDRALAZINE Hydralazine (Apresoline) exhibits the unique he- modynamic properties of increasing cardiac stroke volume and rate, decreasing total peripheral resistance and redistributing blood flow to favor the renal, splanchnic and coronary circulations.20-2' AS a result of the markedly decreased peripheral resistance and increased stroke volume the reduction in diastolic pressure is greater than that of the systolic. Hydralazine has been used parenterally in doses of 10 to 15 mg. in an attempt to lower blood pressure in hypertensive emergencies. It is almost always given in addition to parenterally administered reserpine when the latter fails by itself to achieve an adequate con- trol. In chronic hypertension the drug is administered orally. The initial doses may precipitate acute side effects of headache, palpitation and dyspnea on exertion that tend to diminish as treatment pro- gressesZ3 These side effects can often be circumvented if two precautions are observed: small, widely spaced beginning doses (25 mg. once daily or 10 mg. twice daily) with gradual elevation to the effective level (25 to 50 mg. two or three times daily) over a period of several weeks; and concomitant treatment with a saluretic agent or rauwolfia or both. Thus, hydralazine is best tolerated when used as an adjunct in rather small dosage. Doses are sometimes raised above 200 mg. per day for short periods to obtain an antihypertensive effect, after which the dose is reduced to below this level for maintenance. High doses should not be continued for more than several weeks. The severe toxic reactions, which are more com- mon with continued administration of the larger doses, resemble disseminated lupus erythematosus, with arthritis, dermatitis and lupus cells in the blood.24p25 Occasionally, after the drug is withdrawn arthralgias and increased sedimentation rate in the blood may persist although the usual result is a complete re- versal of the toxic process. GENERAL CONSIDERATIONS The three drugs discussed above can be considered antihypertensive agents of moderate effectiveness as compared to the more potent blocking agents to be discussed later. Their principal advantages are as fol- lows: acute hypotensive reactions, particularly ortho- static hypotension, are not produced in the dosage customarily employed; and the effective dose levels are fairly standard from one patient to another so that less manipulation is required. Because of individual variations in reactivity of different patients one may respond with a significant fall of blood pressure to a saluretic agent, and another to rauwolfia, whereas a third would require a com- bination of several agents. The majority of hyper- tensive patients fall into the last group. For these reasons each case should be considered an individual therapeutic experiment. A common routine is to begin with chlorothiazide alone, the other drugs being added one at a time as the occasion demands. This permits observation of the response to each agent for both therapeutic effect and side reactions so that the most effective and best tolerated drug or combination for the particular patient will be made evident. Controlled trials have demonstrated that the anti- hypertensive effects of these agents are essentiall! additive.*6 Despite great individual variation the average response of a group of patients to a combina- tion of these agents approximates the sum of the average response to each drug individually. The advantage of greater antihypertensive effectiveness of such combinations, however, is offset by the increased exposure to toxic effects and, incidentally, the in- creased expense to the patient. Frequently, after months of intensive treatment the level of blood pres- sure becomes modified so that adequate control can 1 be maintained on a reduced dose schedule. REFERENCES 1. 2. 3. 4. 5. Freis, E. D., Wanko, A.,, Wilson, I. M., and Parrish, A. E. Chlorothiazide in hypertenswe and normotensive patientx. Ann. Neu York Acod. SC. 71:450-455, 1958. Freis, E. D. Mechanism of antihypertensive effects of diuretics: possible role of salt in hypertension. Clin. 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