Antihypertensive Drug Interactions.docx

Antihypertensive drug interactions Kelompok 8 (Azimah, selvi, axl) 1. ACE inhibitors + Albumin Solution Interaction : Acute hypotension has been seen in patients taking enalapril when rapidly infused with a stable plasma protein solution (SPPS). Mechanism : Not fully established, but it is believed that SPPS contains low levels of pre-kallikrein activator which stimulates the production of bradykinin and other kinases which can cause vasodilatation and hypotension. Normally they are destroyed by kininase II (ACE), but with the ACE inhibited by the enalapril, their inactivation appear to be delayed so that their hypotensive effects are exaggerated and prolonged. 2. ACE inhibitors + Allopurinol Interaction : Three cases of serious Stevens-Johnson syndrome (one fatal) and two cases of hypersensitivity have been attributed to the concurrent use of captopril and allopurinol. Neutropenia and serious infection has also occurred. Anaphylaxis and myocardial infarction occurred in one man on enalapril when given allopurinol. Mechanism : Not understood. It is uncertain whether these are interactions, because allopurinol alone can cause severe hypersensitivity reactions, particularly in the presence of renal failure and the use of diuretics. Captopril can also induce a hypersensitivity reaction. 3. ACE inhibitors + Antacids Interaction : Antacids have been found to reduce the absorption of captopril and fosinopril by about one-third, but this is unlikely to be clinically important. Antacids did not affect the pharmacokinetics of ramiprilat. Clinical evidence, mechanism, importance and management : An antacid containing aluminium hydroxide, magnesium carbonate and magnesium hydroxide reduced the AUC of 50 mg captopril in 10 healthy subjects by about 40%. However, this did not alter the extent of the reduction in blood pressure. Another study found that Mylanta (aluminium and magnesium hydroxides) similarly reduced the bioavailability of fosinopril 20 mg by about onethird. The mechanism of this interaction is uncertain, but is unlikely to be due to elevated gastric pH since cimetidine did not have a similar effect. Note that greater decreases in captopril bioavailability (caused by food) were found not to be clinically relevant (see ‘Antihypertensives + Food’), therefore, it is unlikely these changes will be clinically important. However, the makers of fosinopril suggest separating administration of fosinopril and antacids by at least 2 h. It is briefly noted in a

review that antacid administration did not affect the pharmacokinetics of ramiprilat, the active metabolite of ramipril. 4. ACE inhibitors + Aspirin and NSAIDs Interaction : The antihypertensive effects of captopril, enalapril, lisinopril and possibly cilazapril and perindopril can be reduced by indometacin. Low-dose aspirin (<300 mg daily) appears to have little effect on the antihypertensive efficacy of captopril and enalapril, but high-dose aspirin may reduce it in about 50% of patients. Ibuprofen reduced the antihypertensive efficacy of captopril. Lornoxicam caused a small rise in diastolic pressure in those on enalapril. Celecoxib had a minor effect on the efficacy of lisinopril in a single study. However, a case report describes an increase in blood pressure with rofecoxib and lisinopril. Sulindac had little or no effect on blood pressure in those on captopril or enalapril. It is unclear whether aspirin attenuates the benefits of ACE inhibitors in coronary artery disease and heart failure. The likelihood of an interaction may depend on disease state. The combination of NSAID and ACE inhibitor may increase the risk of renal impairment. Rarely, hyperkalaemia has been associated with the combination. Mechanism : 

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Effects on blood pressure : Some, but not all the evidence suggests that prostaglandins may be involved in the hypotensive action of ACE inhibitors, and that NSAIDs, by inhibiting prostaglandin synthesis, may antagonise the effect of ACE inhibitors. This effect may be dependent on sodium status and on plasma renin, therefore, it does not occur in all patients. It may also depend on the NSAID, with indometacin being frequently implicated, and aspirin and sulindac less so. Effects in coronary artery disease and heart failure : Uncertain. The beneficial effects of ACE inhibitors in heart failure and ischaemic heart disease are due, in part, to the inhibition of the breakdown of kinins, which are important regulators of prostaglandin and nitric oxide synthesis. Such inhibition promotes vasodilation and afterload reduction. Aspirin may block these beneficial effects by inhibiting cyclo-oxygenase (COX) and prostaglandin synthesis to cause vasoconstriction, decreased cardiac output and worsening heart failure. Effects on renal function : Both NSAIDs and ACE inhibitors alone can cause renal impairment. In patients whose kidneys are underperfused, they may cause further deterioration in renal function when used together. Hyperkalaemia : Both ACE inhibitors and NSAIDs (rarely) can cause hyperkalaemia, often with associated renal impairment. The risk may be increased when both drugs are used together.

5. ACE inhibitors + Azathioprine Interaction : Anaemia has been seen in patients given azathioprine and enalapril or captopril. Leucopenia occasionally occurs with captopril and azathioprine. Mechanism : 

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Anaemia : The anaemia appears to be due to suppression of erythropoietin by the ACE inhibitors, and azathioprine may cause patients to be more susceptible to this effect. Leucopenia : Uncertain. Additive bone marrow suppression?

6. ACE inhibitors + Beta-blockers Interaction : No clinically important adverse interactions have been seen between propranolol and cilazapril, quinapril, or ramipril, and between trandolapril and unnamed beta-blockers. Mechanism : No important adverse interaction seems to occur, and the combination of these ACE inhibitors and propranolol may be clinically useful. 7. ACE inhibitors + Calcium channel blockers Interaction : No clinically important adverse interactions have been seen between lisinopril, moexipril, or trandolapril and nifedipine; between benazepril or captopril and amlodipine; between ramipril and felodipine; or between spirapril and nicardipine. Mechanism : A number of products combining an ACE inhibitor with a calcium channel blocker are available. In the UK, the British National Formulary states that use of such combinations may increase the range of adverse effects, and that they should be used only for those patients stabilised on the individual components in the same proportions. 8. ACE inhibitors + Capsaicin Interaction : An isolated report describes cough in a woman taking an ACE inhibitor each time she used a topical cream containing capsaicin. Clinical evidence, mechanism, importance and management : A woman of 53 who had been maintained on an unnamed ACE inhibitor for several years, complained of cough each time she applied Axsain, a cream containing 0.075% capsaicin, to her lower extremities. Whether this reaction would have occurred without the ACE inhibitor was not determined, but pre-treatment with an ACE inhibitor is known to

enhance the cough caused by inhaled capsaicin. This potential interaction is probably of little general clinical importance. 9. ACE inhibitors + Cimetidine Interaction : No clinically important adverse interactions have been seen between cimetidine and captopril, enalapril, fosinopril, moexipril, quinapril or spirapril. Cimetidine modestly reduced the absorption of temocapril. Clinical evidence, mechanism, importance and management : Cimetidine in healthy subjects did not appear to alter the pharmacokinetics or pharmacological effects of captopril or enalapril, or the pharmacokinetics of quinapril or fosinopril. The makers of moexipril say that no important pharmacokinetic interaction occurred with cimetidine. The makers of spirapril briefly note in a review that cimetidine did not alter the plasma concentrations of spirapril or its active metabolite spiraprilat. None of these pairs of drugs appears to interact to a clinically relevant extent, and no special precautions appear to be necessary. Preliminary findings suggest cimetidine 400 mg twice daily had no effect on the metabolism of temocapril 20 mg daily in 18 healthy subjects, but the absorption was reduced 26%.The clinical relevance of this is uncertain, but check that the effects of temocapril remain adequate if cimetidine is added. 10. ACE inhibitors + Clonidine Interaction : There is some evidence that the effects of captopril may be delayed when patients are switched from clonidine. 1 Note that sudden withdrawal of clonidine may cause rebound hypertension. 11. ACE inhibitors + Garlic Interaction : An isolated report describes marked hypotension and faintness in a patient on lisinopril when garlic was added. Clinical evidence, mechanism, importance and management : A man whose blood pressure was 135/90 mmHg while on 15 mg lisinopril daily began to take 4 mg garlic daily (Boots odourless garlic oil capsules). Within 3 days he became faint on standing and was found to have a blood pressure of 90/60 mmHg. Stopping the garlic restored his blood pressure to 135/90 mmHg within a week. The garlic on its own did not lower his blood pressure. The reasons are not known. This seems to be the first and only report of this reaction, so its general importance is small. There seems to be nothing documented about garlic and any of the other ACE inhibitors. 12. ACE inhibitors + Haemodialysis membranes

Interaction : An anaphylactoid reaction (facial swelling, flushing, hypotension and dyspnoea) can occur in patients on ACE inhibitors within a few minutes of starting haemodialysis using high-flux polyacrylonitrile membranes (‘AN69 Hospal’). The reasons are not known. Use an alternative membrane or an alternative hypotensive agent. 13. ACE inhibitors + Interleukin-3 Interaction : Preliminary evidence indicates that marked hypotension can occur in patients on ACE inhibitors if given interleukin-3. Clinical evidence, mechanism, importance and management : Twenty-six patients with ovarian or small-cell undifferentiated cancers were treated with chemotherapy followed by recombinant human interleukin-3. Three of the 26 were taking ACE inhibitors (not named) and all three developed marked hypotension (WHO toxicity grade 2 or 3) within 1 to 4 h of the first interleukin-3 injection. Their blood pressures returned to normal when the ACE inhibitors were stopped while continuing the interleukin-3. When the interleukin-3 was stopped, they once again needed the ACE inhibitors to control their blood pressure. None of the other 23 patients showed hypotension except one who did so during a period of neutropenic fever. The authors of the report suggest (and present some supporting evidence) that the drugs act synergistically to generate large amounts of NO in the blood vessel walls. This relaxes the smooth muscle in the blood vessel walls causing vasodilatation and consequent hypotension. Information seems to be limited to this single report, but the interaction would appear to be established. Be alert for this reaction if interleukin-3 is used in any patient taking ACE inhibitors. More study is needed. 14. ACE inhibitors + Iron Interaction : Serious systemic reactions occurred in three patients given infusions of ferric sodium gluconate while taking enalapril. Oral ferrous sulphate may decrease absorption of captopril, but this is probably of little clinical importance. Mechanism : 

Intravenous iron : Uncertain. Intravenous iron causes a variety of systemic reactions including fever, myalgia, arthralgia, hypotension, nausea and vomiting which are believed to be due to the release of various inflammatory mediators such as bradykinin and substance P from tissues caused by toxic free radicals. The authors of the report suggest that ACE inhibitors like enalapril decrease the breakdown of these kinins so that the toxic effects of the iron become exaggerated.

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Oral iron : Reduced levels of unconjugated captopril in the plasma are probably due to reduced absorption resulting from a chemical interaction between ferric ions and captopril in the gastrointestinal tract.

15. ACE inhibitors + Loop or thiazide or related diuretics Interaction : The combination of captopril or other ACE inhibitors and loop or thiazide or related diuretics is normally safe and effective but ‘first dose hypotension’ (dizziness, lightheadedness, fainting,) can occur, particularly if the dose of diuretic is high and often associated with various predisposing conditions. A few cases of renal insufficiency, and even acute renal failure, have been reported in patients without renovascular disease when taking ACE inhibitors and diuretics, possibly associated with sodium depletion. Hypokalaemia may occur. Mechanism : 

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First dose hypotensive reaction : The first dose hypotension interaction is not fully understood. One suggestion is that if considerable amounts of salt and water have already been lost as a result of using a diuretic, the resultant depletion in the fluid volume (hypovolaemia) transiently exaggerates the hypotensive effects of the ACE inhibitor. Hypokalaemia : The cases of hypokalaemia are simply a result of the potassium-depleting effects of the diuretics. Impairment of renal function : Diuretic-induced sodium depletion may be a factor in the renal insufficiency and failure sometimes observed with ACE inhibitors.

16. ACE inhibitors + Minoxidil or Sodium nitroprusside Interaction : The hypotensive effects of captopril and either minoxidil or sodium nitroprusside appear to be synergistic. Clinical evidence, mechanism, importance and management : In healthy subjects, sodium nitroprusside infusion caused a greater fall in blood pressure (mean arterial pressure 8 mmHg lower) when given with oral captopril. In 4 patients on a betablocker and a diuretic, the addition of both minoxidil and captopril produced satisfactory control of blood pressure, when the addition of each drug individually was not effective. Moreover, the minoxidil dose needed to be reduced. It has been suggested that captopril blunts the rise in plasma renin activity caused by the vasodilators. Care should be taken when combining these drugs to avoid excessive hypotension. 17. ACE inhibitors + Moracizine

Interaction : Moracizine causes some moderate alterations in the pharmacokinetics of free captopril, but these are unlikely to be clinically important. Clinical evidence, mechanism, importance and management : In a preliminary report, 19 normal subjects were given 250 mg moracizine 8-hourly or 50 mg captopril 8hourly, either alone or together, for a total of 22 doses. When taken together the pharmacokinetics of the moracizine and total captopril remained unchanged, but the maximum serum levels of the free captopril and its AUC decreased by 32 and 14% respectively. The half-life of the free captopril was shorted by 44%. These modest changes are unlikely to be clinically relevant. There seem to be no reports of adverse reactions when both drugs have been used together. 18. ACE inhibitors + Pergolide Interaction : An isolated report describes severe hypotension in a patient on lisinopril when given pergolide. Clinical evidence, mechanism, importance and management : A man successfully treated for hypertension with 10 mg lisinopril daily experienced a severe hypotensive reaction within four hours of taking a single 0.05-mg dose of pergolide for periodic leg movements during sleep. He needed hospitalisation and treatment with intravenous fluids. It is not clear whether this patient was extremely sensitive to the pergolide or whether what occurred was due to an interaction, but it would now seem prudent to monitor the concurrent use of pergolide and ACE inhibitors, or other antihypertensives. The authors of this report suggest that the initial dose of pergolide should be 0.025 mg. 19. ACE inhibitors + Potassium-sparing diuretics Interaction : Combining ACE inhibitors with potassium-sparing diuretics (amiloride, spironolactone, triamterene) can result in clinically relevant or severe hyperkalaemia, particularly if other important risk factors are present. Mechanism : ACE inhibitors reduce the levels of aldosterone, which results in the retention of potassium. This would be expected to be additive with the potassiumretaining effects of amiloride, spironolactone and triamterene leading to hyperkalaemia, but usually only if other risk factors are present (see ‘Importance and management’ below). 20. ACE inhibitors + Potassium supplements and salt substitutes Interaction : ACE inhibitors maintain serum potassium levels so that potassium supplements are not normally needed. Hyperkalaemia is therefore a possibility if potassium supplements or potassium-containing salt substitutes are given, particularly in those patients where other risk factors are present such as decreased renal function.

Mechanism : The potassium-retaining effects of ACE inhibitors (due to reduced aldosterone levels) are additive with increased intake of potassium, particularly when there are other contributory factors such as poor renal function. 21. ACE inhibitors + Probenecid Interaction : Probenecid decreases the renal clearance of captopril, but this is probably not clinically important. Enalapril serum levels are raised by probenecid. Clinical evidence, mechanism, importance and management : Steady-state levels of unchanged and total captopril were slightly increased (14% and 36%) by the use of probenecid in healthy subjects. Renal clearance of unchanged captopril decreased by 44%, but total clearance was reduced by only 19%. These moderated changes are unlikely to be clinically important. Probenecid 1 g twice daily for 5 days increased the AUC of enalapril and enalaprilat by about 50% after a single 20-mg dose in 12 healthy subjects. Renal clearance of enalapril decreased 73%. A moderate increase in the hypotensive effects might be expected, but there do not appear to be any reports of adverse effects. 22. ACE Inhibitors + Rifampicin (Rifampin) Interaction : An isolated report describes a rise in blood pressure in one hypertensive patient attributed to an interaction between enalapril and rifampicin. Rifampicin may reduce the plasma levels of the active metabolites of imidapril and spirapril. Mechanism : The general importance of these interactions is uncertain. The isolated reports with enalapril suggest minor clinical relevance. The makers of spirapril did not consider the modest pharmacokinetic changes to be clinically relevant. However, the makers of imidapril state that rifampicin might reduce the antihypertensive efficacy of imidapril, but this awaits clinical assessment.