New Drugs in Hypertension

New drugs in hypertension

*Ontarjo Heart Foundation senior research fellow Reprint requests to: Dr. MG. Myers, Division of cardiology, Sunnybrook Medical Centre, 2075 Bayview Ave., Toronto, Ont. M4N 3M5 of the baroreceptor mechanism and is excreted almost entirely unchanged and patient compliance may be ad- thus inhibit central sympathetic outflow by the kidney; hence changes in renal versely affected. when stimulated, producing a decrease function may alter dose requirements.'0 Sudden withdrawal of clonidine may in arteriolar smooth muscle tone and Clonidine is effective in both mild produce a rebound hypertensive crisis blood pressure. This central sympatho- and severe hypertension (Table II)." 24 to 48 hours after ingestion of the inhibitory effect of methyldopa appears Postural or exertional hypotension oc- last tablet.13 The exact frequency of to be the major mechanism of its hypo- curs infrequently and the drug may be this reaction is unknown but it does tensive action. given to patients engaged in moderately appear to occur more often with higher Ganglionic blocking agents such as heavy physical work without fear of doses and longer duration of therapy. trimethaphan and pentolinium reduce syncope. Clonidine is also useful in men It is postulated that sudden cessation arterial pressure by blocking transmis- in that it rarely interferes with sexual of clonidine therapy removes abruptly sion at the proximal sympathetic gan- function as do the adrenergic-neuron- the inhibition of central sympathetic glia. Guanethidine exerts a similar by- blocking agents. The drug's rapid onset outflow. The resultant increase in sym- potensive effect by interfering with of action renders it helpful in situations pathetic activity produces a pheo- transmission at the terminal adrenergic where control of blood pressure is ur- chromocytoma-like syndrome, with neuron. Other drugs such as hydrala- gent - for example, in accelerated hy- tachycardia, severe hypertension, trem- zine, diazoxide and nitroprusside act pertension with neurologic complica- or, anxiety and diaphoresis. These directly on the effector organ, relaxing tions. Clonidine may also prevent mi- effects can be reversed rapidly by re- the arteriolar smooth muscle. graine attacks in certain individuals." instituting clonidine therapy (with an As with all antihypertensive agents intravenous preparation if available*) or Actions of specific drugs clonidine has several features that limit by blocking the peripheral effects of Clonidine its clinical use. It produces anticholin- excessive adrenergic activity with intra- ergic effects, such as dry mouth and venous administration of pentolamine The imidazoline derivative cloni- decreased tearing, and sedates about and propranolol. The physician should dine hydrochloride (Catapres) decreases one half of treated patients." These warn the patient about the dangers of blood pressure by inhibiting central side effects probably occur more fre- stopping clonidine abruptly and unre- sympathetic activity (Fig. 1).'' Studies quently with clonidine than with com- in animals and humans have demon- parably effective doses of methyldopa, 6Licen.d in Canada for investigational use only. strated that the drug facilitates the baroreceptor reflex by rendering it more sensitive to increases in systemic Table I-Clinical pharmacology of four antihypertensive drugs blood pressure and thus permitting sympathetic outflow to diminish and, Drug hence, arteriolar smooth muscle to re- lax and blood pressure to decrease. Feature Clonidine Propranolol Bethanidine Debrisoquine At the cellular level clonidine appears Tablet size (mg) 0.1, 0.2 10, 40, 80 10, 25 10, 20 to reduce vasomotor activity by two closely related mechanisms. Experi- Daily dose (mg) 0.3 - 2.4 80 - 1000 20 - 200 mental data suggest that Timeof onsetof action (h) 1- 2 24- 72 2-3 the drug facil- Time of maximum effect (h) 2 - 4 4 - 6 itates transmission in noradrenergic Duration of action (h) 8- 12 + 12 + 8-12 + neurons directly involved in the baro- Plasma half-life (h) 12.7 3 - 6 7 - 11 receptor reflex.1'2'4'5 There is also evid- ence that clonidine stimulates other neurons with a-adrenergic receptors that inhibit sympathetic activity. Table Il-Clinical advantages and disadvantages of the four drugs Clonidine may also lower blood pressure by decreasing renin secretion from Drug the kidney.6 This effect is thought to be mediated by the central sympatho- Bethanidine and lytic action of the drug. Activation of Clinical aspect Clonidine Propranolol debrisoquine sympathetic fibres supplying the kidney Advantages stimulates renin release and this re- Treats coexisting Migraine Migraine, angina sponse may be blocked by clonidine. conditions pectoris (Methyldopa may exert a similar action Useful combined since it also reduces central sympathetic with other agents - Yes Yes, with propranolol activity and plasma renin activity.1'7) Others - - Diarrhea less frequent The role of renin in the antihyperten- and half-life shorter sive action of clonidine in man has not than with guanethi- been fully elucidated. dine In normotensive persons clonidine Disadvantages exerts a pronounced hypotensive action Causes postural or Infrequently Rarely Frequently within 1 to 2 hours after oral ingestion exertional of a 0.3-mg dose (Table I)Y The peak hypotension effect occurs between 2 and 4 hours Prevents ejaculation Rarely Rarely Frequently and the depressor response lasts 8 to Others Dry mouth, sedation May provoke left 12 hours. Studies in hypertensive pa- Rebound hypertensive ventricular failure - tients suggest that the pharmacologic crisis with sudden Contraindicated with withdrawal airway obstruction effect persists for at least 12 hours and Risk of hypoglycemia that administration of doses twice daily in insulin-dependent achieves satisfactory control of blood diabetics pressure in most individuals.9 Clonidine 174 CMA JOURNAL/JANUARY 22, 1977/VOL. 116 liable patients should not receive the olol alone or combined with a diuretic. be compensated for by an increase in drug. However, in more severe hypertension sympathetic activity. a combination of agents may be neces- Because the clinical pharmacology of Propranolol sary to achieve normotension; propran- bethanidine and debrisoquine is quite olol with hydralazine, bethanidine or similar (Table I) the two compounds Propranolol hydrochloride (Inderal) debrisoquine and a diuretic may be will be treated as one in this discussion. is a nonselective blocker of p-adrener- particularly useful. The onset of the hypotensive action gic receptors, antagonizing both those Propranolol is the treatment of after administration of an oral dose of in the heart Q3.-receptors) and those in choice for patients with hypertension these two drugs is about 2 to 3 hours'0 the lungs and peripheral vasculature and angina pectoris who do not have and the maximum depressor effect oc- (/.s-receptors).'4 left ventricular failure. Beta-blockade curs in 4 to 6 hours. The exact duration In spite of extensive clinical and ex- alleviates angina by reducing both sys- of action of these compounds is un- perimental studies the exact mechanism temic arterial pressure and myocardial known but administration twice or of propranolol's antihypertensive action oxygen consumption. Since propranolol thrice daily appears to provide satis- has yet to be defined. The drug sup- may provoke heart failure in susceptible factory control of blood pressure. This presses plasma renin activity'5 but a individuals it should be given more observation is compatible with the significant correlation between this ef- cautiously to these patients. Signs of known plasma half-life of bethanidine, fect and its hypotensive action has not left ventricular failure usually appear 7 to 11 hours. Bethanidine and debriso- been found in all studies.'6-'8 Recent with relatively low doses (40 to 80 mg quine are useful in treating moderate or reports suggest that propranolol may daily) and serious problems can be severe hypertension (Table II). They decrease blood pressure by reducing avoided if such patients are followed represent an important improvement sympathetic activity in the central nerv- more closely during the initial treat- over guanethidine in that their onset ous system (CNS).'9-23 The drug may ment period. of action is more rapid30 and they are therefore exert a dual peripheral and Propranolol is generally contraindi- less likely to produce diarrhea.3' In central action, reducing blood pressure cated in hypertensive patients with hospital the dose of bethanidine or directly by decreasing sympathetic ac- asthma since it may increase airway debrisoquine can be increased at in- tivity, plasma renin activity and cardiac obstruction by blocking /3-adrenergic tervals of 2 or 3 days until the most output via peripheral blockade of /3- receptors in the bronchi. Since pro- effective dose is achieved. The shorter adrenergic receptors, and indirectly by pranolol affects the activity of brain duration of action of these compounds suppressing sympathetic outflow from stem neurons it is not surprising that allows a more rapid reversal of adverse the brain. its use in man is associated with CNS effects. Following oral ingestion propranolol side effects; sedation, mental fatigue Postural and exertional hypotension undergoes extensive extraction by the and nightmares have been reported but may occur in patients receiving any of liver and only a small proportion of these symptoms are usually less severe the adrenergic-neuron-blocking agents the parent compound reaches the sys- than those produced by methyldopa or and reduction in dosage may be neces- temic circulation.2' There is consider- clonidine, and withdrawal of propran- sary to eliminate excessive decreases in able interindividual variation in the rate olol is rarely necessary. blood pressure. Persons engaging in of hepatic extraction, so that a 10- to Propranolol interferes with glyco- heavy physical work should probably 20-fold variation in plasma propranolol genolysis and may mask the effects of not receive these drugs unless satisfac- values can be seen after ingestion of hypoglycemia. The drug is therefore tory control of blood pressure cannot identical oral doses.25 Since the anti- not recommended for patients with in- be obtained with any other therapy. hypertensive effect of the drug may be sulin-dependent diabetes and hyper- Bethanidine, debrisoquine and guan- related to the plasma concentration'6 tension. ethidine are generally not popular with the extent of hepatic clearance may be men since they often prevent ejacula- an important determinant of individual Bethanidine and debrisoquine tion. It is advisable to discuss the dose requirements. Indeed, the effective possibility of this side effect with the oral dose required to block appreciably Bethanidine sulfate (Esbaloid) and patient early in therapy. /3-adrenergic receptors may vary from debrisoquine sulfate (Declinax) are sim- The concentration of bethanidine 80 to 1000 mg or more.2"2' ilar to guanethidine in that they are and debrisoquine in the postganglionic The time of onset of propranolol's concentrated in postganglionic sympa- neuron32 is inhibit. by tricyclic anti- antihypertensive action appears to de- thetic neurons by uptake via an active depressants;3' therefore concomitant pend on the initial dose. In some transport system. All three compounds administration of these two classes of studies, doses of 160 mg daily reduced reduce blood pressure by interfering drugs is contraindicated. blood pressure substantially within sev- with neuronal transmission (Fig. 1). eral days.'5"8 Although this dosage may However, guanethidine also depletes Principles of antihypertensive therapy not be suitable for initiation of therapy the nerve terminals of noradrenalin by in all patients, it does appear reasonable interfering with reuptake of noradren- As more information on the patho- to start most individuals with 40 mg alin into the neuron. In contrast, beth- genesis of "essential" hypertension ac- twice or thrice daily. anidine and debrisoquine inhibit the cumulates there is an increasing tend- Propranolol is effective in treating enzyme monoamine oxidase,2"2' which ency to select drugs on the basis of most hypertensive patients when used metabolizes noradrenalin; thus they possible pathogenetic factors such as alone or with other drugs (Table II).2' leave neuronal noradrenalin concentra- blood volume, plasma renin activity It is especially well tolerated by pa- tions relatively unchanged. and plasma catecholamine or aldo- tients who are young, male or physi- Interference with transmission at the sterone concentrations. Although some cally active since it rarely produces postganglionic sympathetic neuron ex- patients appear to have "renin-depend- postural hypotension and has little or plains the occurrence of postural hypo- ent" or "volume-dependent" hyperten- no effect on sexual function. It often tension in patients treated with these sion, the response to specific drug ther- prevents migraine;27 the mechanism of agents. Since the efferent limb of the apy has not been well documented in this effect is not well understood. baroreceptor reflex arc is no longer clinical studies. Until further data are Mild or moderate hypertension may intact, the sudden decrease in systemic available it is preferable to select anti- be controlled satisfactorily by propran- pressure produced by gravity cannot hypertensive therapy on the basis of CMA JOURNAL/JANUARY 22, 1977/VOL. 116 175 4. HAELJSLER 0: Further similarities between the age, sex, occupation, severity of hyper- of the two-drug combinations given to action of clonidine and a central activation patients whose mild hypertension is of the depressor baroreceptor reflux. Naunyn tension and coexisting diseases, so that Schmiedebergs Arch Pharmacol 285: 1, 1974 drug efficacy and patient compliance resistant to single-drug therapy (Table 5. SLEIGHT P, KORNER P1, OLIvER JL, et al: Effects of clonidine on baroreflex arc in can be maximized. III) may be used, but if a satisfactory conscious rabbits and man. Br Heart / 37: In general the doses of all antihyper- response is not obtained there may be 560, 1975 6. REID IA, MACDONALD DM, PACHNIS B, et al: tensive agents (except diuretics and no complementary agent available to Studies concerning the mechanism of renin suppression by clonidine. / Pharmacol Ex1.' hydralazine) should be titrated against improve control of blood pressure. Suc- Ther 192: 713, 1975 both the decrease in blood pressure cess may more often be achieved if the 7. WEIDMANN P. HIRsCH D, MAXWELL MH. et al: Plasma renin and blood pressure during and dose-limiting factors such as in- individual with severe hypertension is treatment with methyldopa. Am J Cardiol 34: 671, 1974 tolerable side effects, cost, or number first given a diuretic and propranolol, 8. DOLLERY CT, DAVIES DS, DRAFFAN GH, et of tablets. The cost! efficacy ratio of unless the latter is contraindicated. al: Clinical pharmacology and pharmacokinetics of clonidine. Clin Pharmacol Ther the newer compounds is comparable to Once a reasonable degree of .e3-adren- 19: 11, 1976 9. JAIN AK, RYAN JR, V.um..s R, et al: A that of methyldopa, hydralazine and ergic blockade (for example, heart rate comparative study of the effectiveness of spironolactone and may be lower than while resting, 50 to 60 beats/mm, and various dose regimens of clonidine. Ibid, p 109 that of other cardiovascular drugs such after exercise, 70 to 80 beats/mm) has 10. REHBINDER D: The metabolism of clonidine, as quinidine preparations. been achieved a third drug (hydrala- in Catapres in Hypertension, CONOLLY ME (ed), London, Butterworths, 1970, p 227 zine, bethanidine or debrisoquine) may 11. CONOLLY ME, BRIANT RH, GEORGE CF. Mild hypertension et al: A crossover comparison of clonidine be added. These drug combinations will and methyldopa in hypertension. Eur J Clin effectively control blood pressure Pharmacol 4: 222, 1972 Single-drug therapy may produce a in 12. SHAFAR J, TALLETr ER, KNOWLSON PA: satisfactory hypotensive response in most patients with administration only Evaluation of clonidine in the prophylaxis of migraine. Lancet 1: 403, 1972 patients with relatively mild, uncom- twice or thrice daily and a minimum 13. HUNYOR SN, HANSSON L, HARRISON TS, et number of tablets will be required al: Effects of clonidine withdrawal: possible plicated hypertension (diastolic pressure (for mechanisms and suggestions for management. under 110 mm Hg). Initial treatment example, hydrochlorothiazide, 50 mg; Br Med .! 2: 209, 1973 14. DOLLERY CT, PATERSON JW, CONOLLY ME: for these individuals could be selected propranolol, 480 mg; and hydralazine, Clinical pharmacology of beta-receptor-block- 100 mg: total, nine tablets). ing drugs. Clin Pharmacol Ther 10: 765, 1969 from a thiazide diuretic, propranolol 15. BuHLER FR, LARAGH JH, BAJtR L, et al: or methyldopa (Table III). The drugs In especially resistant conditions it Propranolol inhibition of renin secretion. N Engi J Med 287: 1209, 1972 can be administered once (thiazides) or may be necessary to add methyldopa 16. LEONSi-rI G, MAYER G, MORGANTI A, et al: or clonidine to the above combinations. Hypotensive and renin suppressing activities twice daily and the number of tablets of propranolol in hypertenssve patients. Clin can be reduced if proper sizes are pre- In rare instances a patient may re- Sci Mo! Med 48: 491, 1975 17. BRAVO EL, TARAZI RC, DUSTAN HP, et al: scribed (Table I). Traditionally diuretic spond strikingly to either methyldopa Dissociation between renin and arterial pres- or clonidine plus a diuretic. sure responses to beta-adrenergic blockade therapy has been the most popular, but in human essential hypertension. Clrc Res 36 the development of glucose intolerance (suppl 1): 241, 1975 Conclusion 18. HANISON L, ZWEIFLER AJ, JULIus 5, et al: in a substantial number of patients. Propranolol therapy in essential hypertension. Observations on predictability of therapeuti- suggests that other agents may be better If antihypertensive therapy is se- response. mt J Clin Pharmacol 10: 79, 1974 for younger individuals. lected on an individual basis, with all 19. REID JL, LEWIS PJ, MYERS MG, et al: Car- diovascular effects of intracerebroventricular If single-drug therapy does not drug-related factors considered, it d-, 1- and dl-propranolol in the conscious blood rabbit. J Pharmacol Exp Ther 188: 394, 1974 achieve satisfactory control of should be possible to control the blood 20. MYERS MG, LEWIS PJ, REID JL, et El: pressure a combination of two com- pressure of virtually every patient with- Brain concentration of propranolol in relation to hypotensive effect in the rabbit with pounds may be necessary (Table III) or out producing intolerable side effects. observations on brain propranolol levels in clonidine may be given alone or with man. 3 Pharmacol Exp Ther 192: 327, 1975 I thank Dr. John lazzetta, department of 21. DAY MD, ROACH AG: Cardiovascular effects a diuretic. The choice of therapy for of beta-adrenoceptor blocking agents after pharmacy, Sunnybrook Medical Centre, intracerebroventricular administration in con- each individual should be selected on for his assistance in the preparation of this cious normotensive cats. Clin Exp Pharmacol the basis of possible beneficial and ad- Physiol 1: 333, 1974 manuscript. 22. LEWIS PJ, HAEUSLER G: Reduction in sym- verse effects such as those outlined in pathetic nervous activity as a mechanism for the hypotensive effect of propranolol. Nature Table II. References 246: 440, 1975 23. KLEVANS LR, KovAcs JL, KELLY R: Central Severe or complicated hypertension 1. VAN ZWIETEN PA: The central action of effect of beta-adrenergic blocking agents on antihypertensive drugs, mediated via central arterial blood pressure. / Pharmacol Exp alpha-receptors. J Pharm Pharmacol 25: 89, Ther 196: 389, 1976 Patients with severe hypertension 1973 24. SHAND DG: Pharmacokinetic properties of 2. HAEUSLER G: Cardiovascular regulation by the beta-adrenergic receptor blocking drugs. (diastolic pressure above 110 to 120 central adrenergic mechanisms and its altera- Drugs 7: 39, 1974 mm Hg) and those with renal, cardio- tion by hypotensive drugs. Circ Res 36 (suppi 25. Idem: Individualization of propranolol ther- 1): 223, 1975 apy. Med Clin North Am 58: 1063, 1974 vascular or neurologic complications 3. CHALMERS JP: Brain amines and models of 26. ZACHARIAS FJ, COWaN KJ, PRESST J, et al: experimental hypertension. Circ Res 36: 469, Propranolol in hypertension: a study of long- often require combination therapy. One 1975 term therapy. Am Heart 3 83: 755, 1972 27. WEBER RB, REINMUTH OM: The treatment of migraine with propranolol. Neurology 22: 336, 1972 Table Ill-Treatment regimen for mild or severe hypertension 28. PETrINGER WA, KORN A, SPIEGEL H, et al: Debrisoquine, a selective inhibitor of intra- neuronal monoamine oxidase in man. Gun Pharmacol Ther 10: 667, 1969 Therapy (mg/d) 29. MALMFORS T, AEstAMs WB: The effects of Status of debrisoquine and bretylium on adrenergic nerves as revealed by fluorescence histo- hypertension Initial If condition resistant chemistry. / Pharmacol Exp Ther 174: 99. 1970 Mild Thiazide diuretic or propranolol Thiazide + propranolol (80-1000) 30. SHEa D, GIBALDI M, THRONE M, et al: (80-480) or thiazide + methyldopa Pharmacokinetics of bethanidine in hyper- or methyldopa (500-1500) (500-3000) tensive patients. Gun Pharmacol Ther 17: or thiazide + clonidine 363, 1975 31. PRICHARD BNC, JOHNSTON AW, HnL ID, (0.3-2.4) et al: Bethanidine, guanethidine, and methyl- or clonidine (0.3-2.4) dopa in treatment of hypertension: a within- patient comparison. Br Med / 1: 135, 1968 Severe or complicated Thiazide + propranolol + hy- Add methyldopa or clonidine 32. LAvERTY R: The mechanisms of action of dralazine some antihypertensive drugs. Br Med Bull 29: 152, 1973 or thiazide + propranolol + 33. Ivssssoa LL: Catecholamine uptake processes. bethanidine Ibid, p 130 or thiazide + propranolol + 34. LEWIS P3, KOHNER EM, PETRIE A, Ct al: debrisoquine Deterioration of glucose tolerance in hypertensive patients on prolonged diuretic treatment. Lancet 1: 564, 1976 176 CMA JOURNAL/JANUARY 22, 1977/VOL. 116