Diazoxide — an effective vasodilator in accelerated hypertension

Appraisal Edited

by Arthur

and

reappraisal

C. DeGraff

and Julian

Diazoxide - an effective accelerated hypertension Marvin White

Reprint Plains, *Assistant Medicine; N. Y.

therapy

Frieden

vasodilator

in

Moser, M.D.*

Plains,

h? Y.

Ample proof exists that the immediate treatment of accelerated hypertension has been lifesaving and is more than just an academic exercise. Numerous studies, including our own data, have demonstrated that adequate blood pressure lowering in patients with “malignant hypertension” will frequently result in a reversal of a rapidly progressive downhill c~urse.‘~~This is true even in patients with evidence of renal insufficiency prior to treatment. In these cases, a temporary decrease in renal function usually occurs as blood pressure is lowered. Renal plasma flow and glomerular filtration rate will usually return to pre-treatment levels, however, with stabilization of blood pressure and patients may live for many years if adequate blood pressure control is maintained. The syndrome of accelerated hypertension has become less common in recent years, presumably because more patients are treated for elevated blood pressure at an earlier stage of the disease. In past years, many different medications have been used in the treatment of malignant hypertension in an attempt to reverse both the pathologic process of necrotizing arteriolitis and the clinical syndrome of encephalopathy with or without congestive heart failure, markedly elevated blood pressure, and widespread vascular hemorrhages. In the 1940’s tetraethylammonium chloride (TEAC), a ganglion blocking agent, and the veratrum derivatives, drugs which interfere with baroreceptor and cardiac reflexes, were used for emergency treatment. Received

of cardiac

for publication

Jan.

requeets to: Marvin N. Y. 10605. Profemx of Clinical Chief of Cerdiology,

15, 1974. Moser,

M.D.,

33 Davis

Ave.,

White

Medicine, Albert En&in College of White Plains Hospital, White Plaine,

June, 1974, Vol. 87, No. 6, pp. 791-795

The duration of action of TEAC was extremely short and careful titration of the dosage was necessary. The drug was not universally effective. The veratrum drugs were potent but had a narrow range of safety and produced good results in only a limited number of cases. Blood pressure lowering was frequently followed by collapse, nausea, vomiting, and other serious reactions. In the 1950’s, Hexamethonium, another ganglion blocker, was used both intravenously and intramuscularly with some success, but responses were erratic and reactions frequent. Many patients did, however, experience a remission of the “accelerated” phase of hypertension with this medication. Intravenous or intramuscular hydralasine (Apresolinel also proved to be effective in some cases of accelerated hypertension and is still being used for therapy, especially in patients with acute glomerulonephritis or preeclampsia. In recent years, the treatments of choice have included (Table I): (1) Intravenous trimethaphan (Arfonadl, a short acting potent ganglion blocking agent, which must be monitored carefully. Blood~pressure rises rapidly after the infusion is stopped. (2) Intramuscular reserpine in dosages of 0.25 to as high as 5.0 mg. every 4 to 6 hours. This drug is effective in many cases. (31 Intravenous pentolinium (Ansolysen), a longer acting ganglion blocking agent, and less frequently (4) Oral mecamylamine (Inversine). Parenteral guanethidine (Ismelinl or alpha-methyl-dopa (Aldometl have also been used with some success but have limited usefulness because of delay in response and a lower rate of effectiveness. Intravenous furosemide (Lasixl, or the use of oral thiazide diuretics, have proved of great value when used in conjunction with any of these drugs.

American Heart Journal

791

Moser

Table I. Effective

DW

drugs in “accelerated Mode of action

hypertension”

Dosage

Disadvantages

Comments

Reserpine

Catechol depletion “Central effect”

0.25-5.0 mg.1.M. g 4-6 hrs

Delay in B.P. response (l-2 hours). Excessive drowsiness. Effect not always predictable

Effective in many cases. Should not be used for longer than 24-48 hrs.

Trimethaphan (Arfonadl

Ganglion blocker

I.V. dosage titrated by B.P. response (1000 mgJL.1

Hypotension. Short duration of action - constant monitoring necessary. Excessive B.P. fall. Dosage variable

Effective in many cases. Prolonged use impractical

Pentolinium (Ansolysen)

Ganglion blocker

I.M. or IV. Excessive B.P. fall. (1.0 mg. -20 mg.) Dosage variable must be titrated

Longer duration of action (4-12 hours), An advantage over shorter acting dlWgS.

Hydralaxine (Apresolinel

Vasodilator

15-30 mg. I.M. or IV.

Effect unpredictable. Excessive tachycardia

Low rate of response. Most effective in acute nephritis and severe toxemia of pregnancy

Nitroprusside

Vasodilator

I.V. Dosage Variable. Titrate by B.P. response (100 mg./L.)

Short duration of action. Constant monitoring necessary. Unstable solutipn

Not generally available

Diasoxide (Hyperstatl

Vasodilator

300500 mg. I.V. (as a bolus)

Transient hyperglycemia. Nausea

Rapid effect l-5 min. -high rate of response (over 75 percent). Standard dose. Relatively long duration of effect 2-12 hours

The above drugs produce a fall in blood pressure in many cases and their use frequently results in an excellent long-range response. However, many have side effects; for example: excessive sedation and even coma following increasing doses of reserpine, and excessive blood pressure fall from intravenous ganglion-blocking agents such as pentolinium, lack of response in many patients after intravenous hydralazine, or the inconvenience of constant monitoring and possible danger from the administration of intravenous trimethaphan. These problems have led to a continuing search for a more reliable effective treatment of accelerated hypertension. Intravenous sodium nitroprusside is an effective vasodilator and has been used successfully by several investigators3 This drug must be prepared just prior to use and is unstable in solution. It is not available in most institutions but, when a stable preparation is released for use, nitroprusside may become one of the preferred treat-

792

ments of accelerated hypertension. Unfortunately, the blood pressure lowering effects of the drug are of short duration and constant monitoring of a continuous intravenous infusion is required. The recent introduction of diaxoxide (Hyperstat) for intravenous use in accelerated hypertension represents a major breakthrough in treatment. Diazoride is a non-diuretic agent related to the benzothiadiazines. Unlike chlorothiazide, which it resembles structurally, d&oxide administration results in sodium and water retention, yet blood pressure is significantly reduced N

Cl N H,NOcS

0so2 NH

Chlorothiazide

Cl

Diaxoxide

June, 1974, Vol. 87, No. 6

D&oxide-an

Pharmacologic actions of diazoxide

Animal data have demonstrated that the blood pressure lowering effects of diazoxide probably result from a direct action on the smooth muscle tissues of the arterioles. Unlike the ganglion blocking drugs, such as pentolinium, diazoxide has little, if any, effect upon the tone of venous smooth muscle. Venous pooling with a subsequent decrease in venous return and cardiac output do not, therefore, occur. The exact mode of action on arteriolar smooth muscle has not been determined. Several possibilities have been suggested. 1. The possibility that diazoxide produced a reduction of arteriolar tone by a direct stimulating effect on beta adrenergic receptors was investigated by injecting the drug into animals before and after the administration of propranolol, a beta adrenergic blocking agent. These studies demonstrated that, while the heart rate and cardiac output increases normally seen after diazoxide were blocked by the propranolol injection, blood pressure fell significantly. Presumably, therefore, diazoxide reduces blood pressure by a mechanism other than stimulation of beta adrenergic receptors in the peripheral vessels.6 2. The possibility that diazoxide has some primary influence on nerve pathways or humoral factors in producing its hypotensive effect has largely been ruled out by animal studies which have demonstrated that the blood pressure lowering effect of diazoxide is not blocked by previous administration of atropine, phentolamine, ganglion blockers such as hexamethonium, antihistamines, reserpine, or surgical transection of the spinal cord.5 3. There are some data to suggest that the effect of d&oxide on peripheral arteriolar tone is involved in some way with the interaction of the drug with calcium at the receptor site, but an exact mechanism has not been defined. Approximately 90 per cent of diazoxide is rapidly bound to plasma protein in humans following an intravenous injection. Because of this, the dosage must be given rapidly in a bolus to obtain the desired hypotensive effect. Mroczek and co-workers6 have clearly demonstrated that when diazoxide is administered over a 10 to 15 second period of time rather than as a drip infusion or a slow injection, a higher level or concentration of free (unbound) drug is available

American

Heart Journal

effective vasodilator

to be delivered to the arteriolar blood vessels and greater vasodilatation results. This is especially true in accelerated hypertension where the initial degree of vasoconstriction is significantly greater than in less severe cases. Renal and cardiac actions

Although diazoxide has little direct effect upon the heart, cardiac stimulation results from a reflex response to arteriolar dilatation and the subsequent decrease in peripheral vascular resistance. Increases in cardiac index from 50 to as high as 75 per cent and increases in heart rate of from 20 to 30 per cent have occurred within 5 to 30 minutes after a standard rapid injection of 300 mg. of diazoxide intravenously in man.‘,* These changes usually occur simultaneously with a marked reduction of blood pressure, an increase in pulse pressure, and a decrease in systemic vascular resistance and left ventricular end diastolic pressure. In many cases, an acute blood pressure drop will occur in from 2 to 5 minutes after injection. The mechanism of diazoxide’s antidiuretic and antinaturetic actions have not been clearly defined. In some animal studies, little effect on glomerular filtration rate has been demonstrated. In humans, some investigators have noted an initial decrease in both renal blood flow and glomerular filtration rate; renal function parameters return to normal in many instances within 1 to 2 hours. Other investigators have noted a persistent decrease in renal blood flow which they attribute to a secondary effect of lowered blood pressure. Antinaturetic effect probably results from enhanced proximal tubular reabsorption of sodium and a decreased delivery of salt and water to the distal portion of the nephron. This may represent an attempt on the part of the kidney to conserve sodium and water as a result of blood pressure lowering and peripheral vasodilatation. Effect on blood sugar. Intravenous diazoxide causes transient hyperglycemia and the chronic oral administration of the drug may result in more sustained rises in blood sugar. Studies have indicated that the drug reacts both at pancreatic and extrapancreatic levels. Diazoxide inhibits insulin secretion; however, in de-pancreatized dogs, the already high blood sugar levels increase further following an injection of the drug sug-

793

Moser

gesting an extra-pancreatic effect. The hyperglycemic effect of d&oxide is eliminated in adenalectomized and pancreatectomized animals. Diazoxide causes a direct increase in catecholamine levels which decrease insulin release. This action may explain at least a portion of the effect on blood sugar. Glucose levels in animals have generally returned to normal within 24 hours after the drug is stopped and studies have failed to demonstrate significant long-term effects on blood chemistries, or electrolyte values. Method

of use in accelerated

hypertension.

Diazoxide is supplied in 20 C.C. ampules containing 300 mg. of the drug. Because the solution is alkaline, it is important to avoid extravasation of the fluid when a rapid intravenous injection is given. If some fluid does leak into the tissues, severe burning sensation and pain may occur and persist for 2 to 3 hours. The injection of the bolus in 10 to 15 seconds results in a prompt blood pressure fall in a high percentage of cases9 A maximal blood pressure response usually occurs within 5 to 10 minutes. We have noted a rapid return in blood pressure in some patients within a 15 to 30 minute period of time (usually not to pretreatment levels); in other cases a rise in pressure is noted within 1 to 2 hours and the drug may have to be given again. In most instances, however, blood pressure lowering persists for from 6 to 18 hours. As noted above, a slower injection will frequently be ineffective. Diazoxide may be administered every four to six hours in an effort to “titrate” the blood pressure to levels where symptoms and signs of accelerated hypertension will begin to clear. X0/90 - 160 - 170 mm./Hg 100 Blood pressure reduction occurs in the recumbent position and only a slight additional postural fall in blood pressure is noted following the injection of d&oxide. This is in marked contrast to results obtained with the ganglion blockers (pentolinium or trimethaphan). Side effects

Symptoms suggestive of a decrease in coronary or cerebral blood flow may occur but are uncommon, despite the rapid fall in blood pressure and the often critical condition of the patient. Some instances of non-specific electrocardiographic changes have been reported following in794

travenous administration of diazoxide.l’ If an “overshoot” or marked hypotension does occur, it can be counteracted by the Trendelenburg position or by the administration of sympathomimetic drugs. Repeated injections of diazoxide may cause increasing sodium retention, decreased urinary output, and congestive heart failure. A decreasing effect on blood pressure with successive doses may also occur. For this reason, the simultaneous administration of a potent diuretic agent such as furosemide is indicated in most caseslo Forty to 120 mg. should be given immediately and repeated every 8 to 12 hours as necessary to maintain an adequate urinary output (1.5 to 2 liters daily). In patients who are nauseated or comatose, intravenous administration is necessary. In others, furosemide or a thiazide diuretic may be given by mouth. Our experience has indicated that in patients with poor renal function large doses of furosemide may be necessary (120 to 160 mg. every 4 to 6 hours for 1 to 2 days). Repeated injections of diazoxide increase the risk of hyperglycemia. Finnertye suggests concomitant treatment with oral antidiabetic drugs when possible in patients with known glucose intolerance. In diabetics receiving more than 1 to 2 injections of diazoxide, additional insulin will usually be effective in reducing blood sugar levels. Hyperglycemia following one injection of diazoxide is usually transient and persists for only 12 to 18 hours. It is important to wean the patient away from parenteral therapy as soon as possible. This usually can be done within 1 to 2 days or after 2 to 3 doses of diazoxide and a potent diuretic agent. Blood pressures can usually be brought under control and symptoms of encephalopathy reversed, unless the patient has severe azotemia. The use of oral thiazides and one or more of the other antihypertensive drugs (Rauwolfia, hydralazine, methyldopa, propranolol, or guanethidine) should be instituted as soon as oral therapy is tolerated. Diazoxide is ineffective in treating blood pressure elevations secondary to pheochromocytoma. Acute reactions. Following the injection of diazoxide, flushing, some abdominal discomfort, nausea, sensations of warmth, and occasional throbbing headache and sweating may occur. These reactions usually are of short duration. June, 1974, Vol. 87, No. 6

Diazoxide-an

Summary

1. &220&e is a potent arteriolar vasodilator which, when administered rapidly (within 10 to 15 seconds) by the intravenous route, lowers recumbent blood pressure significantly without producing postural hypotension in a large percentage of patients with accelerated hypertension. Antihypertensive effect occurs within 1 to 5 minutes and persists for from 1 to as long as 18 hours. Cardiac output is increased. 2. The ease of administration (a single bolus), relatively long duration of action, lack of significant acute side effects, and a high rate of response, even among patients with renal insufficiency, make diazoxide a preferred drug for the emergency management of accelerated hypertension. 3. Repeated injections may result in diminished effectiveness, sodium retention, and hyperglycemia. The concurrent administration of furosemide is frequently necessary, therefore, to produce a continuing antihypertensive effect. 4. Patients should be placed on oral antihypertensive therapy with other drugs as soon as the clinical condition is stable.

Americau Heart Journal

effective uasodilator

REFERENCES

1. Perry, H. M., Schroeder, H. A., Catanxaro, F. J., MooreJones, D., and Camel, G. H.: Studies on the control of hypertension VIII, Circulation 33:968,1966. 2. Moser, M., and Goldman, A. G.: Hypertensive vascular disease, Philadelphia, Pa., 1967, J. B. Lippincott Co., p. 277-297.

Schlant, Ft. C., Tsgaris, T. S., and Robertson, R. L.: Studies on the acute cardiovascular effects on intravenous sodium nitroprusside, Am. J. Cardiol. 951, 1962. 4. Thirlwell, M. P., and Esoter, T. T.: The effect of diasoxide on the veins, h. HEART J. 83:612,1972. 6. Rubin, A. A., Roth, F. E, Taylor, Ft. M., and Rosenkilde, H.: Pharmacology of d&oxide, an antihypertensive, nondiuretic benxothiadiasine, J. Pharmacol. Exp. Ther. 3.

136:344,

1962.

Mrocxek, W. J., Leibel, B. A., Davidov, M., and Finnerty, F.: The importance of the rapid administration of diaxoxide in accelerated hypertension, N. Engl. J. Med. 285:603, 1971. 7. Wilson, W. R., and Okun, R.: The acute hemodynamic effects of diaxoxide in man, Circulation 28:89, 1963. 8. Finnerty, F., Kakaviatos, N., Tuckman, J., and Magill, J.: Clinical evaluation of d&oxide, Circulation 28:203, 1963. 9. Miller, W. E., Gifford, R. W., Humphrey, D. C., and Vidt, D. G.: Management of severe hypertension with intravenous injections of diasoxide, Am. J. Cardiol. 6.

24t870.1969.

10.

Finnerty, F. A.: Hypertensive encephalopathy, AM. HEART J. 76X%9,1968. 11. Moser, M.: Treatment of hypertensive encephalopathy, AM. HOT J, 77:704,1969.

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