Adverse Reactions of Enalapril

Adverse Reactions of Enalapril

Neutropenia, agranulocytosis, pancytopenia, thrombocytopenia, and aplastic anemia are infrequent but serious adverse effects associated with enalapril.Hemolytic anemia, including cases of hemolysis in patients with G-6-PD deficiency, has been reported; a causal relationship to enalapril cannot be excluded. Hematological reactions are more common in patients with impaired renal function or collagen vascular disease and in those receiving immunosuppressive therapy (see Contraindications). Complete blood counts should be done regularly during the first several months of therapy.

Renal function may decrease during enalapril treatment, but this effect is usually reversible if therapy is discontinued. Renal insufficiency (e.g. azotemia) may be related to hypovolemia, hyponatremia, or preexisting renal artery stenosis. In patients with renal artery stenosis, enalapril therapy must be held. In patients who are either hypovolemic or hyponatremic, correction of these abnormalities may correct the renal dysfunction. Although rare, serious renal effects include ischemic renal tubular necrosis and glomerulonephritis. Hypotension occurs in about 1—2% of patients receiving enalapril for hypertension, and in about 5—7% of patients receiving the drug for congestive heart failure. Hypotensive symptoms have required discontinuance of enalapril in 2% of patients receiving the drug for congestive heart failure. Hypotension is generally well tolerated but can cause such symptoms as orthostatic hypotension, dizziness, fatigue, headache, syncope, sinus tachycardia, and lightheadedness.
ACE inhibition can result in the accumulation of kinins in the respiratory tract, sometimes causing a persistent, nonproductive cough. However, accumulation of kinins does not adequately explain the mechanism of ACE inhibitor-induced cough. Kinins have a very short plasma half-life, therapeutic doses of ACE inhibitors are usually not high enough to cause accumulation of circulating bradykinin, and there is a female preponderance of cases. Rather, evidence is growing that ACE inhibitor-induced cough may be related to substance P stimulation of C-fiber receptors in the respiratory tract. This cough may occur more frequently in patients with chronic obstructive pulmonary disease and is often overlooked as a potential adverse effect of enalapril therapy. Dyspnea and bronchospasm also have been reported rarely during enalapril therapy.

Patients receiving drugs that can increase serum potassium, or patients with congestive heart failure or impaired renal function, may be at an increased risk for developing hyperkalemia during enalapril therapy (see Drug Interactions).

The frequency of maculopapular rash may be less with enalapril than with captopril, but rash does occur.
Angioedema, or angioneurotic edema, of the face, mucous membranes, tongue, lips, larynx, and glottis has occurred rarely during ACE inhibitor therapy but is reversible following discontinuance of the drug. Involvement of the upper respiratory tract can induce acute respiratory distress. The onset usually occurs within hours or at most 1 week after starting ACE inhibitor therapy. The mechanism is unknown but may involve drug-induced auto-antibodies, bradykinin accumulation, dysregulation of the complement system, or histamine.

Rare cases of eosinophilic pneumonitis have been reported with enalapril.

Hepatotoxicity has been reported rarely in patients receiving ACE inhibitors. Although not completely understood, hepatotoxicity has included cholestasis with jaundice, fulminant hepatic necrosis, and death. Patients who develop jaundice should discontinue enalapril therapy and receive appropriate treatment.

Due to the potential for teratogenesis, enalapril should not be used during the second or third trimesters of pregnancy. ACE inhibitors have been associated with fetal and neonatal abnormalities when administered to women during the 2nd or 3rd trimesters of pregnancy (see Precautions). Adverse fetal and neonatal effects have included hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure (e.g., renal tubular dysplasia), oligohydramnios, and death. Oligohydramnios is attributed to decreased fetal renal function and has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. The effects on fetal/neonatal morbidity and mortality do not appear to result from drug exposure limited to the first trimester (pregnancy category C).

Drug Interactions

Enalapril decreases aldosterone secretion, leading to small increases in serum potassium. Drugs that increase serum potassium, such as potassium-sparing diuretics, potassium salts, and heparin, should be given cautiously to patients receiving enalapril since the potassium-retaining actions of these drugs may be additive with those of enalapril.

The antihypertensive effects of enalapril can be additive with other antihypertensive agents or diuretics if given concomitantly. This additive effect can be desirable, but dosages must be adjusted accordingly. Hyponatremia or hypovolemia predispose patients to developing reversible renal insufficiency when enalapril and diuretic therapy are given concomitantly.

NSAIDs have been shown to reduce the antihypertensive activity of ACE inhibitors. In some patients with compromised renal function who are being treated with NSAIDs, the coadministration of ACE inhibitors (e.g., enalapril and lisinopril) may result in a further deterioration of renal function. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking an ACE inhibitor.

Enalapril can decrease the renal elimination of lithium, which can lead to lithium toxicity. A few cases of lithium toxicity have been reported in patients receiving concomitant enalapril and lithium and were reversible upon discontinuation of both drugs. Plasma lithium concentrations should be monitored frequently during concomitant enalapril therapy.

Three clinic patients were observed as having systemic reactions to intravenous sodium ferric gluconate complex during concomittant use of the angiotensin converting enzyme inhibitor, enalapril. Reactions included diffuse erythema, high fever, nausea, vomiting, hypotension, abdominal cramps, and diarrhea. Fifteen clinic patients who received sodium ferric gluconate complex without enalapril over the same time period did not have similar reactions. R & D Laboratories is expected to submit the Final Study Report by January 2001 to the FDA regarding evaluation of the possibility of increased risk of allergic/anaphylactic reactions in patients receiving angiotensin converting enzyme inhibitors and sodium ferric gluconate complex.

The use of ACE inhibitors in hypertensive patients receiving azathioprine has been reported to induce anemia and severe leukopenia.This combination should be avoided where possible. When concurrent azathioprine and ACE inhibitor therapy is necessary, the patient should be monitored cautiously for potential myelosuppression.

Aspirin, ASA may reduce the vasodilatory efficacy of ACE inhibitors by inhibiting the synthesis of vasodilatory prostaglandins. This interaction has been documented primarily in heart failure patients. However, the established benefits of using aspirin in combination with an ACE inhibitor in patients with ischemic heart disease and left ventricular dysfunction generally outweigh this concern. Patients receiving concurrent salicylates and ACE inhibitor therapy should be monitored for antihypertensive or vasodilatory efficacy; the dose of the ACE inhibitor can be adjusted if indicated based on clinical evaluation.

Several cases of acute renal failure have been associated with the addition of enalapril to cyclosporine therapy in renal transplant patients. In response to cyclosporine-induced renal afferent vasoconstriction and glomerular hypoperfusion, angiotensin II is required to maintain an adequate glomerular filtration rate. Inhibition of angiotensin-converting enzyme (ACE) could reduce renal function acutely. Closely monitor renal function in patients receiving cyclosporine concurrently with ACE inhibitors.

Captopril, enalapril, and possibly other ACE inhibitors, can enhance the activity of oral antidiabetic agents. Hypoglycemia has occurred when captopril was added to either glyburide or biguanide (e.g., metformin) therapy. Caution should be observed when enalapril or possibly other ACE-inhibitors are added to the antidiabetic regimen.

Nifedipine

Adverse Reactions

The most common cardiovascular adverse effect attributed to nifedipine therapy is peripheral edema. This reaction reflects the potent vasodilatory effect of this drug because it occurs more frequently with nifedipine than with other calcium-channel blockers. Although peripheral edema may indicate a worsening of congestive heart failure, it more commonly is due to vasodilation. Other common side effects, primarily related to vasodilation, include flushing, weakness, headache (more common with the XL preparation), syncope, hypotension, palpitations, dizziness, and lightheadedness.

Although calcium-channel blockers are effective drugs for treating angina, worsening of angina has occurred in as many as 10% of patients receiving nifedipine for angina pectoris. This reaction may be a result of excessive hypotension, coronary steal, or reflex sinus tachycardia. Myocardial infarction has also been associated with nifedipine therapy. Patients with angina should be observed for worsening symptoms when nifedipine therapy is begun, particularly if beta-blocker therapy is being withdrawn. Serious adverse effects have been reported with the use of immediate-release nifedipine, primarily due to the unpredictable rate and degree of blood pressure lowering. Profound hypotension, myocardial infarction, and death have been reported when immediate-release nifedipine is used to lower blood pressure acutely, especially when used in elderly patients. Due to the risks associated with the immediate-release nifedipine capsules, this dosage formulation should not be used in patients with chronic hypertension, acute hypertensive crisis, acute myocardial infarction, or in the setting of acute coronary syndrome.

Less common but potentially serious adverse effects include dyspnea, wheezing (especially if underlying respiratory disease or pulmonary edema exists), asthenia, paresthesia (often associated locally with sublingual administration), immune-complex glomerulonephritis, vertigo, priapism, and visual disturbances.

Photosensitivity has been observed during nifedipine therapy, but appears to be rare. Exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported rarely.

Gynecomastia has been reported in < 1% of patients receiving nifedipine. However, a causal relationship has not been established

Drug Interactions

Digoxin serum concentrations may be increased by up to 45% by concomitant administration of nifedipine. This is believed to be due to decreased renal and nonrenal clearance of digoxin by nifedipine. Despite some reports showing no effect on digoxin, plasma levels of digoxin should be monitored carefully when nifedipine is administered.

Concomitant use of calcium-channel blockers and alpha-blockers or other antihypertensive agents can cause additive effects on hypotension and, possibly, orthostatic hypotension.

In general, concomitant therapy of nifedipine with beta-blockers is well tolerated and can even be beneficial in some cases (i.e., inhibition of nifedipine-induced reflex tachycardia by beta-blockade). Negative inotropic and/or chronotropic effects can be additive when these drugs are used in combination. Finally, angina has been reported when beta-adrenergic blocking agents are withdrawn abruptly and nifedipine therapy is initiated. A gradual downward titration of the beta-adrenergic blocking agent dosage during initiation of nifedipine therapy may minimize or eliminate this potential interaction.

Cimetidine and, to a lesser degree, ranitidine have been shown to increase the oral bioavailability of other dihydropyridines. These drugs potentially affect the disposition of nifedipine due to their inhibitory effects on cytochrome P-450 and, subsequently, first-pass metabolism of nifedipine, which increases nifedipine bioavailability and serum concentrations. Lower doses of nifedipine may be considered during concomitant therapy with either of these H2-antagonists.

Concomitant use of nifedipine and fentanyl, especially in combination with beta- adrenergic blocking agents during surgical procedures, has resulted in severe hypotension. It is recommended that nifedipine be withheld for at least 36 hours, if possible, prior to the use of high-dose fentanyl.

Quinidine concentrations decrease by 20—40% when nifedipine is added and rise after nifedipine is withdrawn. This appears to be an idiosyncratic reaction, although quinidine doses may need to be adjusted when nifedipine is added or withdrawn. Careful monitoring of serum quinidine concentrations is prudent following the addition or discontinuation of nifedipine.

Ethanol can increase the bioavailability of nifedipine, presumably due to P-450 inhibition.

Rifampin is a potent hepatic enzyme inducer and has been shown to exert a dramatic effect on the oral bioavailability of some calcium channel blockers. Both nifedipine pharmacokinetics (e.g., decreased nifedipine AUC) and pharmacodynamics (e.g., loss of antianginal and antihypertensive effect) were affected when rifampin was added. Patients should be monitored for loss of antihypertensive effect if rifampin is added to nifedipine therapy. Other hepatic enzyme inducers such as rifabutin, carbamazepine, phenytoin (or fosphenytoin), phenobarbital (or primidone) may also affect nifedipine in a manner similar to rifampin. Nifedipine does not affect the pharmacokinetics of carbamazepine.

The exogenous administration of calcium salts can attenuate the pharmacodynamic response to calcium-channel antagonists.

The concomitant use of nifedipine with disopyramide or flecainide is not recommended because of additive negative inotropic properties.

Estrogens can cause excess fluid retention that can increase peripheral edema as well as blood pressure. Patients receiving nifedipine should be monitored for either of these adverse effects if estrogens are added.

Tacrolimus is metabolized by CYP3A4 isoenzyme. CYP3A4 is the major isoenzyme that metabolizes nifedipine. When coadministered with nifedipine, tacrolimus whole blood trough concentrations are increased. In a retrospective study of liver transplant patients with hypertension, nifedipine decreased the daily and cumulative dosage requirements of tacrolimus by 26%, 29%, and 38% at 3, 6, and 12 months, respectively, compared with the dosage for patients who did not receive nifedipine. It is recommended that tacrolimus blood concentrations be closely monitored when nifedipine and tacrolimus are administered concomitantly.

Nifedipine is metabolized by CYP3A4. Dalfopristin; quinupristin may decrease the metabolism of nifedipine by inhibiting CYP3A4.

Nifedipine is metabolized by CYP3A4. Pioglitazone is partially metabolized by the CYP3A4 and may induce the enzyme. The bioavailability of drugs metabolized by CYP3A4 may be reduced when administered with pioglitazone. Coadministration of pioglitazone with nifedipine has not been studied.

Concomitant administration of vincristine and nifedipine resulted in a 4-fold prolongation in the elimination half-life of vincristine. Increased cytotoxicity due to vincristine could be expected.

Clinicians should be aware that food interactions with some calcium channel blockers are possible. Grapefruit juice contains an unknown compound that can inhibit cytochrome P-450 isozymes in the gut wall. Limited data indicate that grapefruit juice can increase the serum concentrations and AUC of amlodipine, felodipine, nifedipine, nimodipine, and verapamil. No significant effect on diltiazem was seen. Despite increased serum concentrations, clinical sequelae did not always occur.

Preclinical data suggest that calcium-channel blockers could decrease the efficacy of porfimer or verteporfin photodynamic therapy.

When administered with nifedipine, highly protein-bound medications, such as warfarin, phenytoin, NSAIDs, salicylates, sulfinpyrazone, or amiodarone, have the potential to increase free or unbound concentrations of nifedipine due to displacement from protein-binding sites. Nifedipine also can displace any of these agents, although these reactions have not occurred in clinical practice.

In contrast to diltiazem and verapamil, nifedipine, isradipine, and nitrendipine have been shown to have minimal effects on cyclosporine blood levels. Cyclosporine may increase nifedipine blood levels when given concomitantly. In addition, concurrent use of cyclosporine and nifedipine has been associated with frequent gingival hyperplasia.

A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that co-administration of nifedipine increased plasma metformin Cmax and AUC by 20% and 9%, respectively, and increased the amount of metformin excreted in the urine. Metformin half-life was unaffected. Nifedipine appears to enhance the absorption of metformin

Clinically significant drug interactions including neuromucsular blockade and hypotension have occured when IV magnesium salts were given concurrently with nifedipine during the treatment of hypertension or premature labor during pregnancy. The women affected presented with either pronounced muscle weakness and/or hypotension. In a few cases, fetal harm was noted as a result of the hypotensive episodes. The effects have been attributed to nifedipine potentiation of the neuromuscular blocking effects of magnesium. It is recommended that nifedipine not be given concurrently with magnesium therapy for pre-eclampsia, hypertension, or tocolytic treatment during pregnancy.

Furosemide

Interactions

Furosemide-induced electrolyte disturbances such as hypokalemia and/or hypomagnesemia can predispose patients to digitalis toxicity, possibly resulting in fatal arrhythmias. Electrolyte imbalances should be corrected prior to initiating cardiac glycoside therapy. In the absence of electrolyte imbalances, furosemide and cardiac glycosides can be used together safely.

Concomitant use of metolazone with a loop diuretic can cause severe electrolyte loss. Metolazone should only be used in combination with furosemide in patients who are refractory to loop diuretics alone. Close monitoring of serum electrolytes and cardiac function is advised. In patients with creatinine clearances > 30 ml/min, the combination of a loop diuretic with a thiazide diuretic may also lead to profound fluid and electrolyte loss. Thus, furosemide should be used very cautiously in combination with either metolazone or thiazide diuretics. Conversely, amiloride, spironolactone, and triamterene can counteract furosemide-induced hypokalemia. These agents have been used as therapeutic alternatives to potassium supplements in patients receiving loop diuretics. In addition, amiloride and triamterene may counteract the magnesium wasting actions of furosemide.

Additive hypotension is possible if furosemide used in combination with any other antihypertensive agents including drugs such as nitroglycerin. Hyponatremia or hypovolemia predisposes patients to acute hypotensive episodes following initiation of ACE inhibitor therapy. While ACE inhibitors and loop diuretics are routinely administered together in the treatment of heart failure, if an ACE inhibitor is to be administered to a patient receiving furosemide, initial doses should be conservative.

Ethanol, since it also possesses diuretic properties, should be taken in small quantities in patients receiving loop diuretics. The diuretic properties may be additive, leading to dehydration in some patients.