Marie-France Beauchesne, Pharm.D. Candidate
Rubina Sunderji, Pharm.D., Karen Shalansky, Pharm.D.
Reviewed by Dr. A. Fung, Cardiology
This article appeared in Vancouver Hospital Drug & Therapeutics Newsletter 1998;5(2):6-8
The term hypertensive crisis is defined as an elevation of the blood pressure to a degree which is potentially life-threatening and that requires immediate management in order to prevent end-organ damage.1 This condition has been classified as hypertensive emergencies and hypertensive urgencies. The delineation between these two situations is not based on the extent to which the blood pressure is increased, but by the presence or absence of target organ damage.2 In hypertensive emergencies, the elevation of blood pressure is accompanied by an acute or ongoing end-organ damage (eg. renal failure, encephalopathy), whereas in hypertensive urgencies, the increase in blood pressure (usually a diastolic blood pressure greater than 110 mmHg) is not associated with any evidence of acute end-organ damage.1
Management of Hypertensive Urgencies
While hypertensive emergencies generally require parenteral therapy, the management of hypertensive urgencies is usually satisfactory with oral medication.3 The goal in the treatment of hypertensive urgencies is to gradually reduce the blood pressure over several hours.1 Precipitous reductions in blood pressure or reductions to normotensive levels are not desirable since it can cause end-organ hypoperfusion and damage.2 In the recent past, the most popular agent for the treatment of hypertensive urgencies was short-acting nifedipine, given either sublingually or orally.2 Several severe side effects, however, have been reported with its use.4
Adverse effects from short-acting nifedipine
In a review of serious adverse reactions associated with short-acting nifedipine, 16 published case reports have been described.4-13 Of these, 12 patients were treated with 10 mg, 2 patients with 30 mg and 2 patients with 20 mg of short-acting nifedipine (per os or sublingual). The age of the patients ranged from 33 to 72 years old. In most cases (12 patients), nifedipine was given to treat high blood pressure. It was also used for the management of unstable angina in two patients, for pulmonary hypertension in one patient, and for pregnancy-induced hypertension in one patient. The adverse drug reactions were hemiparesis in three patients,loss of consciousness in one patient, one case of fetal distress, and cardiac events in 11 patients (ECG changes (4), syncope and complete heart block (1), myocardial infarction (5), hypotension and sinus arrest (1). Overall, 14 patients recovered and two died. Both deaths were reported in patients who were given nifedipine for unstable angina.
In a study designed to evaluate the benefit of nifedipine alone and in combination with metoprolol in patients with unstable angina, monotherapy with short-acting nifedipine was associated with an increased risk of nonfatal MI or recurrent angina within the first 48 hours of therapy.14 This trial was terminated prematurely due to a higher risk of myocardial infarction in patients assigned to nifedipine alone. Another trial evaluating the effect of nifedipine on mortality in patients with acute myocardial infarction was also terminated early because of an excess number of deaths in the nifedipine group.15 Therefore, short-acting nifedipine should be avoided especially in patients with coronary artery disease.
The 1997 sixth report of the Joint National Committee in detection, evaluation and treatment of high blood pressure does not recommend the use of sublingual nifedipine for the management of hypertensive crisis due to the serious adverse events that have been reported with its use.16 The use of short-acting nifedipine is no longer considered appropriate because it can cause a rapid unpredictable fall in blood pressure and may precipitate ischemic events.16,17
What are some alternatives to nifedipine ?
Oral agents with a relatively fast onset of action can be used for the management of hypertensive urgencies16 (Table 2). These include captopril (angiotensin-converting enzyme (ACE) inhibitor), labetalol (alpha- and beta-adrenergic blocker), atenolol (beta-adrenergic blocker) and clonidine (central alpha-2 agonists). A lower starting dose of these agents should be admin- istered in the elderly, volume-depleted patients, patients on concomitant antihypertensive therapy, and patients with preexisting cerebrovascular or cardiovascular diseases.2
Table 2. Oral agents for hypertensive urgencies 1-3, 20,21
|Drug||Captopril (Capoten)||Labetalol (Trandate)||Atenolol (Tenormin)||Clonidine (Catapres)|
|Dose||6.25-25mg q30min prn po or sl1||200-400mg q3-4h prn po||100mg q12-24h prn po||0.1-0.2mg q1h prn po (max .0.8mg)|
|Peak Effect (hours)||1||3-4||12-16||2-4|
|Side Effects||Hypotension, acute renal failure||Orthostasis, broncho-spasm, bradycardia||Broncho-spasm, bradycardia||Sedation, dry mouth, dizziness, drowsiness|
|Comments||Caution if volume depleted or renal failure; avoid in RAS2||Longer time to peak effect; avoid in asthma, heart failure or block||gradual and prolonged reduction in BP; avoid as per labetalol||Avoid in patients with altered mental status|
1No studies have demonstrated the superiority of sublingual captopril over oral administration18
Captopril can be effectively used as an alternative to nifedipine19,20 and has been suggested as a first-line agent for the treatment of hypertensive urgencies.19 Caution is advised in patients who are volume-depleted as hypotensive episodes may be precipitated1. In addition, a sudden severe deterioration of renal function may occur in patients with renal artery stenosis.1 Labetalol reduces blood pressure in hypertensive crisis without producing a reflex tachycardia or a change in cardiac output, which can be beneficial in patients with coronary artery disease.1,3 This agent should be avoided in patients with heart failure, bradycardia, second- or third-degree heart block and bronchospastic airway disease.18 Since labetalol has a longer onset of action, it is necessary to wait 3 to 4 hours before repeating a second dose in order to avoid excessive hypotension.18 Similar to labetalol, atenolol has been used for hypertensive urgencies but has a slower onset of action and more prolonged duration.21,22 Repeat atenolol doses should not be administered for 12-18 hours. Oral loading with clonidine provides a gradual and predictable reduction in blood pressure in hypertensive urgencies.19, 23 This agent is not recommended in patients with altered mental status because it may produce drowsiness.1
For those patients who are unable to take oral medications, parenteral therapy may be used to initially manage hypertensive urgencies (Table 3).
In conclusion, the use of short-acting sublingual or oral nifedipine is no longer recommended for the treatment of hypertensive urgencies, as it may precipitate serious adverse reactions. Other alternatives have been shown to be efficacious and safer for the management of hypertensive crisis.
Table 3. Formulary Parenteral Alternatives for the Management of Hypertensive Urgencies
|Drug||Labetalol (Trandate)||Propranolol (Inderal)||Hydralazine (Apresoline)||Methyldopa (Aldomet)|
|Dose||20-80mg IV q10 min prn||1-3mg IV q4-6h prn||10-20mg IV q4-6h prn||250-500mg IV q6h prn|
|Peak Effect||5-15 mins||15 mins||10-80 mins||3-6 hours|
|Comments||Avoid if asthma, heart failure, heart block or bradycardia||As per Labetalol||May cause reflex tachycardia, avoid if CAD2||Avoid in patients with altered mental status|
1Check Parenteral Drug Therapy Manual (PDTM) for administration guidelines and restrictions
1. Hirschl MM. Guidelines for the drug treatment of hypertensive crises. Drugs 1995;50:991-1000.
2. Gifford RW. Management of hypertensive crises. Jama 1991;266:829-835.
3. Abdelwahab W et al. Management of hypertensive urgencies and emergencies. J Clin Pharmacol 1995; 35:747-62.
4. Grossman E , Messerli FH, Rodzicki T et al. Should a moratorium be placed on sublingual nifedipine capsules given for hypertensive emergencies and pseudoemergencies? JAMA 1996;276:1328-31.
5. Nobile-Orazio E, Sterzi R. Cerebral ischemia after nifedipine treatment. BMJ 1981; 283:948.
6. Schwartz M, Naschitz JE. Oral nifedipine in the treatment of hypertensive urgency: cerebrovascular accident following a single dose. Arch Intern Med 1990;150:686-7.
7. Wachter RM. Symptomatic hypotension induced by nifedipine in the acute treatment of severe hypertension. Arch Intern Med 1987;147:556-8.
8. Zangerle KF, Wolford R. Syncope and conduction disturbances following sublingual nifedipine for hypertension. Ann Emerg Med 1985;14:1005-6.
9. Leavitt AD, Zweifler AJ, Meriden T et al. Nifedipine, hypotension, and myocardial injury. Ann Intern Med 1988;108:305-6.
10. OMailia JJ, sander GE, GIles TD. Nifedipine-associated myocardial ischemia or infarction in the treatment of hypertensive urgencies. Ann Intern Med 1987;107:185-6.
11. Shettigar UR, Loungani R. Adverse effects of sublingual nifedipine in acute myocardial infarction.Crit Care Med 1989;17:196-7.
12. Aromatorio GJ, Uretsky BF, Reddy PS. Hypotension and sinus arrest with nifedipine in pulmonary hypertension. Chest 1985;87:265-7.
13. Impey L. Severe hypotension and fetal distress following sublingual administration of nifedipine to a patient with severe pregnancy induced hypertension at 33 weeks. Br J Obstet Gynaecol 1993;100:959-61.
14. Lubsen J, Tijssen JGP. Efficacy of nifedipine and metoprolol in the early treatment of unstable angina in the coronary care unit: findings from the holland interuniversity nifedipine/metoprolol trial (HINT). Am J Cardiol 1987;60:18A-25A.
15. Goldbourt U, Behar S, Reicher-Reiss H et al. Early administration of nifedipine in suspected acute myocardial infarction. Arch Intern Med 1993;153:345-353.
16. Joint National Committee on prevention, detection, evaluation and treatment of high blood pressure. The sixth report of the joint national committee on prevention, detection, and treatment of high blood pressure. Arch Intern Med 1997;157:2413-2446.
17. Messerli F. Safety of calcium antagonists: dissecting the evidence. Am J Cardiol 1996; 78 (suppl 9A):19-23.
18. Gales MA. Oral antihypertensives for hypertensive urgencies. Ann Pharmacother 1994;28:352-8.
19. McKindley DS, Boucher BA. Advances in pharmacotherapy: Treatment of hypertensive crisis. J Clin Pharm Ther 1994;19:163-80.
20. Varon J, Fromm RE. Hypertensive crises.The need for urgent management.Postgrad med 1996;99:189-203.
21. Isles CG et al. Slow release nifedipine and atenolol as initial treatment in blacks with malignant hypertension. Br J clin Pharmac 1986;21:377-83.
22. Bannan LT, Beevers DG. Emergency treatment of high blood pressure with oral atenolol. Br Med J 1981;282:1757-8.
23. Houston MC. The comparative effects of clonidine hydrochloride and nifedipine in the treatment of hypertensive crises. Am Heart J 1988;115 (1041):152-9.