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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

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Page 1: Adverse Reactions of Enalapril - Prince of Songkla …drug.pharmacy.psu.ac.th/wbfile/329310533.doc · Web viewThe effects have been attributed to nifedipine potentiation of the neuromuscular

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

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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

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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

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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-

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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

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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

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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.

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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.

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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.

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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.

FurosemideInteractions

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

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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.

Glucocorticoids with mineralcorticoid activity (e.g., cortisone, fludrocortisone, hydrocortisone) can cause hypokalemia. Amphotericin B, cisplatin, and other loop or thiazide diuretics can also cause hypokalemia and hypomagnesemia. Electrolyte loss can be severe and prolonged with amphotericin B or cisplatin. Concomitant administration of furosemide with any of these agents can lead to significant hypokalemia and/or hypomagnesemia. Clinicians should also note that combining loop diuretics with cisplatin produced permanent ototoxicity in guinea pigs. While it is possible to use furosemide with these agents safely, close monitoring of serum potassium and serum magnesium should occur along with regular assessments of hearing.

In a study of 6 healthy volunteers, concurrent administration of cholestyramine with oral furosemide reduced the bioavailability of furosemide by 95% and

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reduced the diuretic response by 77%. Concomitant administration with colestipol reduced furosemide bioavailability by 80% and the diuretic response by 58%. Although it was not evaluated in this study, staggering the times of administration (e.g., giving furosemide either 2 hours before or 6 hours after cholestyramine or colestipol) may alleviate this pharmacokinetic interaction.

The clinical effects of furosemide are exaggerated in patients with hypoalbuminemia who are receiving clofibrate. Since patients with nephrotic syndrome develop both edema and hyperlipidemia, it would not be unusual for these patients to be receiving both drugs simultaneously. Lower doses of furosemide may be necessary in these patients.

Lithium clearance may decrease in patients receiving furosemide, however, clinical data supporting this possibility are lacking. Nevertheless, careful monitoring of lithium serum concentrations is recommended when these drugs are administered together as concomitant administration could result in lithium toxicity.

Indomethacin has been shown to reduce the diuretic and antihypertensive effects of furosemide in both normal and hypertensive patients. Other NSAIDs may interact similarly. Sulindac may be less likely to interact with loop diuretics than other NSAIDs, however, this may be a function of its potency; many clinicians believe that sulindac is significantly less potent than indomethacin. NSAIDs inhibit renal prostaglandin synthesis, which can lead to fluid retention and increased peripheral vascular resistance. The risk of renal failure can be increased in patients receiving a NSAID and diuretic concurrently due to the decrease in renal blood flow caused by inhibition of renal prostaglandin synthesis.

Despite the widespread belief that furosemide enhances ototoxicity due to aminoglycosides, there is little evidence to support this. The risk of ototoxicity during combined therapy with an aminoglycoside and a loop diuretic is most likely for ethacrynic acid. Furosemide by itself, however, can be ototoxic, particularly if large, IV doses are

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administered too rapidly. Clinicians should remember that ototoxicity is difficult to assess, and many clinical studies do not evaluate this condition adequately. Although no clinical data are available, furosemide should be used cautiously with any of the following agents as they have been shown to be ototoxic: capreomycin, carboplatin, chloroquine, cisplatin, deferoxamine, erythromycin, hydroxychloroquine, NSAIDs, quinine, salicylates, vancomycin.

The use of other nephrotoxic agents with furosemide should be avoided or minimized since there is the possibility of additive nephrotoxicity, especially in the presence of preexisting renal impairment. Other nephrotoxic agents include: acyclovir, amphotericin B, aminoglycosides, cisplatin, cyclosporine, various cephalosporins, and vancomycin.

Concomitant administration of furosemide to patients receiving neuromuscular blockers has been reported to cause prolonged neuromuscular blockade, however, data is very limited.

Limited clinical data suggest that phenytoin, and perhaps other anticonvulsants, can interfere with the clinical response to furosemide. Phenytoin has been shown to decrease furosemide oral bioavailability by up to 50% without affecting its systemic clearance.

Hypokalemia or hypomagnesemia may occur with administration of potassium-depleting drugs such as loop diuretics and thiazide diuretics, increasing the potential for dofetilide-induced torsade de pointes. Potassium levels should be within the normal range prior and during administration of dofetilide.

Escin, an active saponin in the horse chestnut seed, appears to have weak diuretic activity, but the exact mechanism is not clear. The effect appears to be dose-dependent and may be additive with traditional diuretics.

Ginseng may decrease the effectiveness of loop diuretics. One case report described a temporal relationship

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between the use of ginseng and resistance to furosemide therapy, resulting in edema, hypertension, and hospitalization on 2 separate occassions.

Other nutritional products were taken concurrently by the patient involved and were not specified in the report. A mechanism of action or causal relationship has not been definitively established.

Furosemide increased the metformin plasma and blood maximum concentrations by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. On the other hand, metformin decreased furosemide plasma and blood maximum concentrations by 31% and 12%, respectively, than when administered alone. Furosemide's terminal half-life was also decreased by 32% without any significant change in furosemide renal clearance.

Adverse reactionPolyuria during furosemide therapy can cause excessive fluid loss and dehydration. This results in hypovolemia and electrolyte imbalance. Large doses of furosemide and restricted sodium intake increases this possibility. Hypovolemia can lead to orthostatic hypotension and hemoconcentration, potentially more serious in chronic cardiac or geriatric patients. Close monitoring is necessary to check for hyponatremia, hypokalemia, hypocalcemia, hypochloremia, and hypomagnesemia. Symptoms of fluid or electrolyte imbalance are: lassitude, mental confusion, fatigue, dizziness, muscle cramps, headache, paresthesias, tachycardia, arrhythmia, thirst, anorexia, nausea, or vomiting. Hyperaldosteronism, secondary to cirrhosis or nephrosis, can predispose patients to developing potassium depletion when furosemide is administered. Hypokalemia and hypochloremia can cause metabolic alkalosis, particularly in patients with other conditions that cause potassium loss including vomiting, diarrhea, or excessive sweating. Volume loss can also cause azotemia (elevation of BUN), which may lead to an allergic interstitial nephritis attributable to furosemide.

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Furosemide occasionally can cause hyperuricemia. This condition may be associated with dehydration and should be avoided, especially in patients with renal insufficiency or gout.

Ototoxicity, manifested as tinnitus and reversible or permanent hearing loss has occurred during furosemide therapy and is usually associated with too rapid administration of large, parenteral doses. Ototoxicity increased proportionately as the rate of infusion of parenteral furosemide increased from 4 mg/min (no ototoxicity), to 5.6 mg/min (no ototoxicity), to 25 mg/min (9/15 patients developed reversible hearing loss), to 67 mg/min (10/10 patients developed tinnitus and deafness that persisted for 90 minutes). It has been recommended that parenteral furosemide not be administered more rapidly than 4 mg/min. Adverse otic effects occur more frequently in patients receiving other ototoxic agents (see Drug Interactions) or in those with severe renal impairment.

Furosemide can produce impaired glucose tolerance, glycosuria, and hyperglycemia. There have been occasional reports of precipitation of diabetes mellitus.

Diuretics, particularly thiazide and loop diuretics, have been shown to cause hypercholesterolemia, hypertriglyceridemia, as well as increased plasma concentrations of LDL. Some studies have suggested that these effects may decrease or cease with long-term therapy, and are not clinically important.

Adverse central nervous system effects associated with furosemide therapy include dizziness, lightheadedness, vertigo, headache, blurred vision, xanthopsia and paresthesias.

Adverse hematologic effects reported during furosemide therapy include anemia, hemolytic anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, thrombocytopenia, and agranulocytosis. Fever and weakness may result from blood dyscrasias.

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Dermatitis and/or photosensitivity can occur during furosemide therapy. Patients who are sensitive to sulfonamides may also have a hypersensitivity reaction to furosemide. Systemic lupus erythematosus may be exacerbated or activated. Other hypersensitivity reactions reported are systemic vasculitis and necrotizing angiitis.

Severe abdominal pain with nausea/vomiting may indicate pancreatitis which has been attributed to furosemide therapy. Other adverse gastrointestinal effects of furosemide include anorexia, constipation, and diarrhea. Furosemide may rarely cause jaundice due to cholestasis.

HCTZAdverse Reactions

Patients receiving hydrochlorothiazide should be monitored closely for signs of electrolyte imbalance including hyponatremia, hypokalemia, hypomagnesemia, and hypochloremia. Patients should be aware of the symptoms of these disturbances (e.g., lassitude, mental confusion, fatigue, faintness, dizziness, muscle cramps, tachycardia, headache, paresthesia, thirst, anorexia, nausea, or vomiting), and report these signs immediately. Thiazides also can decrease urinary calcium excretion, resulting in hypercalcemia.

Hypokalemia is one of the most common adverse effects associated with thiazide diuretic therapy and can lead to cardiac arrhythmias. This effect is especially important to consider in patients receiving cardiac glycoside therapy because potassium depletion increases the risk of cardiac toxicity. Hyperaldosteronism, secondary to cirrhosis or nephrosis, can predispose patients to hypokalemia when hydrochlorothiazide is administered. Low dietary-potassium intake, potassium-wasting states, or administration of potassium-wasting drugs also can predispose patients to hydrochlorothiazide-induced hypokalemia. Patients receiving hydrochlorothiazide

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therapy may require supplemental potassium to prevent hypokalemia or metabolic alkalosis.

Adverse GI effects associated with thiazide therapy include anorexia, gastric irritation, nausea/vomiting, cramps, diarrhea, constipation, sialadenitis, and pancreatitis.

Hypochloremic alkalosis can occur with hypokalemia during hydrochlorothiazide therapy, and it is particularly likely to occur in patients with other losses of potassium and/or chloride such as through severe vomiting, diarrhea, excessive sweating, GI drainage, paracentesis, or potassium-losing renal diseases.

Patients receiving hydrochlorothiazide can develop a dilutional hyponatremia, but it usually is asymptomatic and moderate. Withdrawal of the drug, fluid restriction, and potassium or magnesium supplementation typically will return the serum sodium concentration to normal, but severe hyponatremia can occur. Geriatric patients are especially susceptible to developing hyponatremia, so care should be taken when diuretics are administered to these patients.

Hydrochlorothiazide reportedly has caused azotemia and interstitial nephritis, resulting in reversible renal failure. These effects have occurred mainly in patients with preexisting renal disease.

Hydrochlorothiazide can produce glycosuria and hyperglycemia in diabetic patients, possibly due to potassium depletion. Blood and/or urine glucose levels should be assessed more carefully in diabetic patients receiving hydrochlorothiazide.

Thiazide diuretics are well known to cause hyperuricemia. The Framingham Study showed that acute gout occurred in only 20% of patients with hyperuricemia. Thiazide diuretics appear to interfere with proximal tubule secretion of uric acid since thiazides are also organic acids and they compete with uric acid for binding at this site. Since thiazides reduce the clearance of uric acid, patients

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with gout or hyperuricemia may have exacerbations of their disease.

Hypercholesterolemia and/or hypertriglyceridemia have been associated with thiazide diuretic therapy. Although elevations in total cholesterol concentrations of 8% can negate the protection against coronary heart disease provided by a 5 mmHg reduction in blood pressure, data from long-term studies suggest diuretic-induced cholesterol changes are not clinically significant and do not contribute to coronary heart disease risk. After approximately one year of treatment, total serum cholesterol concentrations will subside to baseline or lower, suggesting diuretic-induced cholesterol changes are not a significant coronary heart disease risk factor.

Orthostatic hypotension and hypotension can occur during hydrochlorothiazide therapy and can be exacerbated by alcohol, narcotics, or antihypertensive drugs.

Interactions

Hydrochlorothiazide can have additive effects when administered with other antihypertensive drugs or diuretics. In some patients, these effects may be desirable, but orthostatic hypotension is possible. Dosages must be adjusted accordingly. In addition, amiloride hydrochloride, spironolactone, and triamterene can reduce the risk of developing hypokalemia because of their potassium-sparing effects; these agents have been used as therapeutic alternatives to potassium supplements.

Hydrochlorothiazide-induced electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypercalcemia) can predispose patients to digoxin toxicity, resulting in possibly fatal arrhythmias. Electrolyte balance should be corrected prior to initiating digoxin therapy. Hypokalemia also potentiates neuromuscular blockade with nondepolarizing neuromuscular blockers.

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The risk of developing severe hypokalemia can be increased when other hypokalemia-causing agents (e.g., corticosteroids, corticotropin, amphotericin B, other diuretics) are coadministered with hydrochlorothiazide. Monitoring serum potassium levels and cardiac function is advised, and potassium supplementation may be required.

Concomitant administration of hydrochlorothiazide to patients receiving nondepolarizing neuromuscular blockers can cause prolonged neuromuscular blockade due to hydrochlorothiazide-induced hypokalemia. Serum potassium concentrations should be determined and corrected (if necessary) prior to initiation of neuromuscular blockade therapy.Thiazide diuretics reduce lithium renal clearance and can increase lithium serum concentrations. In some cases, thiazide diuretics can be used to counteract lithium-induced polyuria. Lithium dosage should be reevaluated and serum lithium concentrations monitored when a thiazide is added.

Thiazide diuretics can decrease insulin sensitivity thereby leading to glucose intolerance and hyperglycemia. Diuretic-induced hypokalemia may also lead to hyperglycemia. Because of this, a potential pharmacodynamic interaction exists between thiazide diuretics and all antidiabetic agents. This interference can lead to a loss of diabetic control, so diabetic patients should be monitored closely. Enhanced hyperglycemia is also possible during concurrent use of diazoxide and thiazide diuretics.

Hydrochlorothiazide-induced hypovolemia could cause an increased concentration of procoagulant factors in the blood, which could decrease the effects of concomitantly administered anticoagulants and require dosage adjustments of these agents; these effects, however, have not been reported to date.

Hydrochlorothiazide can reduce the renal clearance of amantadine, with subsequent increased serum concentrations and possible toxicity. This interaction has been reported with a combination product of

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hydrochlorothiazide and triamterene. Since it is unclear which component was responsible for the interaction, caution should be exercised when administering either drug concurrently with amantadine.

NSAIDs can decrease the diuretic, natriuretic, and antihypertensive actions of diuretics through inhibition of renal prostaglandin synthesis. Concomitant administration of NSAIDs with diuretics also can increase the risk for renal failure secondary to decreased renal blood flow. Patients should be monitored for changes in the effectiveness of their diuretic therapy and for signs and symptoms of renal impairment.

Cholestyramine, an anion-exchange resin, may bind to acidic drugs, such as the thiazide diuretics in the GI tract, and decrease their absorption and therapeutic effectiveness. It is recommended that thiazides be administered at least 4 hours before cholestyramine. Although to a lesser extent than cholestyramine, colestipol also has been shown to inhibit the GI absorption and therapeutic response of thiazide diuretics. Administering the diuretic dose at least 2 hours before colestipol has been suggested.

Thiazide diuretics may increase the photosensitization effects griseofulvin, phenothiazines, sulfonamides, sulfonylureas, tetracyclines, vitamin A analogs, and photosensitizing agents used in photodynamic therapy.

The occurrence of hypersensitivity reactions may be increased in patients with renal impairment who receive allopurinol and thiazide diuretics in combination. It does not appear that the concomitant use of thiazide diuretics and allopurinol leads to increased allopurinol toxicity.

Hypokalemia or hypomagnesemia may occur with administration of potassium-depleting drugs such as loop diuretics and thiazide diuretics, increasing the potential for dofetilide-induced torsade de pointes. Potassium levels should be within the normal range prior and during administration of dofetilide. In a population pharmacokinetic analysis of plasma dofetilide

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concentrations, the mean dofetilide clearance of dofetilide was 16% lower in patients on thiazide diuretics.

Thiazide diuretics have been associated with cholestatic jaundice. Caution should be used when thiazides are administered to jaundiced infants due to the risk of hyperbilirubinemia.

Adverse CNS effects associated with thiazide therapy include dizziness, headache, paresthesias, vertigo, and xanthopsia.

While their incidence is rare, agranulocytosis, aplastic anemia, pancytopenia, hemolysis with anemia, leukopenia, and thrombocytopenia have been reported with thiazide diuretic therapy.

Other adverse effects reported with hydrochlorothiazide include blurred vision, muscle spasm, impotence, and weakness.

Due to the diuretic action of hydrochlorothiazide, polyuria can be troublesome for some patients during therapy.

Adverse dermatologic reactions to hydrochlorothiazide and other thiazide diuretics are uncommon but may occur. These reactions include purpura, photosensitivity, rash, alopecia, urticaria, erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis (TEN), and polyarteritis nodosa.

PropranololAdverse Reactions

The adverse effects of propranolol are generally mild and temporary; they usually occur at the onset of therapy and diminish over time.Most adverse reactions of propranolol are manifestations of its therapeutic effect. Sinus bradycardia and hypotension are rarely serious and can be reversed with IV

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atropine if necessary. AV block, secondary to depressed conduction at the AV node, may necessitate sympathomimetic and/or pressor therapy or use of a temporary pacemaker.

Congestive heart failure is more likely to occur in patients with preexisting left ventricular dysfunction and usually will respond to discontinuation of propranolol therapy.

Adverse CNS effects of beta-blockers include dizziness, fatigue, and depression and are more common with lipophilic agents such as propranolol. Other CNS-related side effects include nightmares and hallucinations, which may occur more frequently in elderly patients.

Diarrhea and nausea/vomiting are propranolol's most common GI adverse effects.

Patients with preexisting bronchospastic disease are at high risk for exacerbation of asthma, dyspnea, or bronchospasm.

Propranolol can prolong or enhance hypoglycemia by interfering with glycogenolysis; this effect may be less pronounced with beta1-selective beta-blockers than with nonselective agents. Propranolol can also mask signs of hypoglycemia, especially tachycardia, palpitations, and tremors; in contrast, diaphoresis and the hypertensive response to hypoglycemia are not suppressed with beta-blockade. Beta-blockers can occasionally cause hyperglycemia. This is thought to be due to blockade of beta2-receptors on pancreatic islet cells, which would inhibit insulin secretion.

Rare but severe hematologic side effects, such as agranulocytosis, have been reported with propranolol therapy.

beta-blockers have been shown to cause hypertriglyceridemia and decrease plasma HDLs during therapy. The clinical implications of these effects, in light of other cardivascular advantages of beta-blockers, is

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unknown.Myalgias and musculoskeletal pain can occur with propranolol therapy.Propranolol has been associated with increases in hepatic enzymes.Sexual dysfunction, impotence, and libido decrease are less frequent adverse effects of beta-blocker therapy than is generally perceived.Dermatologic reactions with beta-blockers are usually mild and transient. Some of these reactions include pruritus, skin hyperpigmentation, reversible alopecia, xerosis, and exfoliative dermatitis.

Interactions

While additive effects are possible if a beta-blocker is administered with any other antiarrhythmic agent, particular attention should be given to using beta-blockers in combination with cardiac glycosides, diltiazem, verapamil, or other antiarrhythmics that significantly depress AV nodal conduction. When used with beta-blockers, these agents can cause complete AV block. In addition, diltiazem and verapamil decrease propranolol clearance. Amiodarone also appears to decrease the clearance of beta-blockers eliminated by hepatic metabolism (e.g., metoprolol, propranolol) and severe cardiovascular reactions have occurred when propranolol was administered to patients receiving amiodarone. Propafenone has been shown to increase the plasma concentrations and prolong the elimination half-life of propranolol. Additive negative inotropic effects are possible if beta-blockers are used with diltiazem, disopyramide, quinidine, or verapamil. Quinidine may also inhibit the clearance of propranolol. Propranolol and flecainide each appear to inhibit the clearance of the other and both drugs also possess negative inotropic activity. Propranolol has been shown to decrease lidocaine clearance and symptoms of lidocaine toxicity have been seen as a result of this interaction.

If a beta-blocker is to be substituted for clonidine,

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clonidine should be gradually tapered and the beta-blocker should be gradually increased over several days to avoid the possibility of rebound hypertension; administration of beta-blockers during withdrawal of clonidine can precipitate severe increases in blood pressure as a result of unopposed alpha stimulation. It is possible to administer clonidine and beta-blockers concurrently without sequelae, although hypotensive effects can be additive.The hypotensive effects of beta-blockers are additive with other antihypertensive agents. This interaction is often used advantageously in treating hypertension, however, lower doses of one or more agents may be necessary. Blood glucose and serum triglyceride concentrations appear to increase significantly when beta-blockers are used with thiazide diuretics. Orthostatic hypotension may be more likely if beta-blockers are coadministered with dihydropyridine calcium-channel blockers such as nifedipine; nifedipine and propranolol may each increase the bioavailability of the other. In general, beta-blockers can be administered safely with most other antihypertensives although it may be wise to avoid using beta-blockers with agents that cause catecholamine depletion such as guanethidine, reserpine, or other rauwolfia alkaloids. beta-blockers can interfere with reflex tachycardia, worsening orthostatic hypotension.

The effects of beta-blockers may be reduced due to the cardiac stimulation produced by liothyronine.

beta-blockers exert complex actions on the body's ability to regulate blood glucose. beta-blockers can prolong hypoglycemia by interfering with glycogenolysis (secondary to blocking the compensatory actions of epinephrine) or can promote hyperglycemia (by inhibiting insulin secretion and decreasing tissue sensitivity to insulin). Since insulin secretion is mediated via beta2-receptors, beta-blockers, particularly nonselective agents, can directly antagonize the major beneficial effect of sulfonylureas. The ability to decrease tissue sensitivity to insulin interferes with one of the therapeutic effects of metformin. Also, beta-blockers can blunt the tachycardic

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response and exaggerate the hypertensive response to hypoglycemia. Thus, while no pharmacokinetic interaction has been observed between beta-blockers and antidiabetic agents, beta-blockers may interact pharmacodynamically. Selective beta-blockers, such as acebutolol, atenolol, metoprolol, or penbutolol, antagonize beta2-receptors less than nonselective agents and, as a result, may cause fewer problems with blood glucose regulation, although all beta-blockers can still mask the tachycardic response to hypoglycemia.

Concurrent use of beta-blocking agents with sympathomimetics or adrenergic agonists can result in antagonism of the desired therapeutic effect(s) of either agent (e.g., beta1- and/or beta2-agonism or antagonism) and/or may lead to excessive alpha pharmacodynamic effects. Concomitant use of epinephrine and beta-blockers can lead to excessive alpha tone which may cause a hypertensive response. In addition, local anesthetics that contain epinephrine or other vasoconstrictor should be used cautiously in patients receiving beta-blockers. Beta-blockade may intensify the localized vasoconstriction from these local anesthetics.

In a small, crossover study, coadministration of 2 g ascorbic acid, vitamin C substantially reduced propranolol AUC and also diminished the bradycardic action of propranolol. Since there were decreased amounts of propranolol metabolites recovered in the urine after pretreatment with ascorbic acid, it was postulated that ascorbic acid reduces the oral bioavailability of propranolol. Until more data are available, clinicians should advise patients against taking large doses of ascorbic acid with doses of propranolol. Taking ascorbic acid at least 1 hour prior to doses of oral propranolol may alleviate this problem, however, further study is necessary to confirm this.

Athough beta-blocking agents are used to treat or reduce the signs and symptoms of cocaine intoxication and the subsequent cardiovascular manifestions of cocaine withdrawal, care must be exercised that excessive alpha-

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agonism - either secondary to cocaine or due to endogenous catecholamines - does not result.

General anesthetics can potentiate the antihypertensive effects of beta-blockers and can produce prolonged hypotension. Patients receiving beta-blockers before or during surgery involving general anesthetics that possess negative inotropic effects (e.g., ether or cyclopropane) should be monitored closely for signs of heart failure. Severe, protracted hypotension and difficulty in restarting the heart have been reported after surgery on patients receiving beta-blockers.

Glucagon has positive inotropic properties and may be a useful alternative for treating beta-blocker-induced heart failure unresponsive to beta-agonists. Further, beta-blockade can blunt the hyperglycemic response to glucagon by interfering with glucagon-induced catecholamine release. Clinicians should be aware of these opposing pharmacologic actions of glucagon and beta-blockers.

Simultaneous use of antimuscarinic anticholinergic agents, such as atropine or some tricyclic antidepressants, with beta-blockers can antagonize beta-blocker-induced bradycardia.

Propranolol can potentiate the effects of neuromuscular blockers, such as tubocurarine, possibly by interfering with the ionic permeability of the postjunctional membrane.

Simultaneous use of beta-blockers with some ergot alkaloids such as ergotamine or ergonovine can cause severe peripheral vasoconstriction with pain and cyanosis. The combination of beta-blockade with the alpha-agonism of ergot alkaloids can lead to excessive alpha effects.

Cimetidine interferes with the hepatic metabolism of propranolol, causing reduced clearance and increased serum concentrations of propranolol. Fluvoxamine can also inhibit hepatic cytochrome P-450 isoenzymes and has been shown to interfere with propranolol clearance

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however clinical symptoms of excessive beta-blocker effects were not seen.

Several interactions can occur between levodopa and beta-blockers. Levodopa is metabolized to dopamine. beta-blockers can antagonize the beta-adrenergic actions (e.g., positive inotropic action; tremor; hypotensive action) of levodopa but may potentiate the dopaminergic actions of levodopa on growth hormone release.

NSAIDs can reduce the hypotensive effects of beta-blockers however the mechanism of this interaction is not well defined. Therapy with NSAIDs for not more than several days would not be expected to produce substantial changes in blood pressure.

Propranolol has been shown to inhibit the metabolism of some phenothiazines, like chlorpromazine, mesoridazine, and thioridazine. Thioridazine and other phenothiazines may also inhibit the metabolism of propranolol. The manufacturers of mesoridazine and thioridazine consider propranolol to be contraindicated for use with these phenothiazines. Other phenothiazines may also interact with propranolol, but interactions are less well documented; additive hypotension or other effects are possible.

Limited data suggest that bradycardia is worsened when MAOIs are administered to patients receiving beta-blockers. Although the sinus bradycardia observed was not severe, until more data are available, clinicians should use MAOIs cautiously in patients receiving beta-blockers.

Propranolol can inhibit the hepatic metabolism and subsequent clearance of theophylline. In addition, because of the potential for beta-blockers to induce bronchospasm in predisposed individuals, it would be illogical for patients to be receiving theophylline and beta-blockers simultaneously.

Rifampin, a potent inducer of hepatic enzymes, has been shown to alter the pharmacokinetics of propranolol.

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Although the clinical significance of this pharmacokinetic interaction is uncertain, patients should be monitored for loss of propranolol effects if rifampin is added. Barbiturates may also accelerate the hepatic metabolism of propranolol.

Propranolol has been shown to increase warfarin AUC, and concurrent increases in INR values have been reported. Patients should be monitored for changes in anticoagulation parameters during concurrent therapy with propranolol and warfarin.

In vitro studies have demonstrated the positive inotropic effects of ginger, Zingiber officinale. It is theoretically possible that ginger could affect the action of antiarrhythmics, however, no clinical data are available.

Cevimeline may alter cardiac conduction and/or heart rate. Conduction disturbances are possible with concurrent use of beta-blockers and cevimeline.

Concurrent use of mefloquine and beta-blockers can result in ECG abnormalities or cardiac arrest.

There are no studies that have adequately evaluated the use of feverfew, Tanacetum parthenium in combination with common medications used for migraine prophylaxis (e.g., methysergide or propranolol). Due to some similarities in the pharmacology of feverfew and propranolol, there seems to be a theoretical basis to avoid concurrent use.

Quinidine is a known inhibitor of cytochrome P450 2D6. Quinidine may impair the hepatic clearance of timolol, metoprolol, and possibly propranol and other metabolized beta-blockers. These interaction may be more pronounced in extensive metabolizers. Patients should be monitored for excess beta-blockade.