DRUG INTERACTIONS OF ANTIANGINAL DRUGS

BY KAMAL SIKANDAR

ANGINA PECTORIS
Angina is pain, "discomfort," or pressure localized in the chest that is caused by an insufficient supply of blood (ischemia) to the heart muscle. It is also sometimes characterized by a feeling of choking, suffocation, or crushing heaviness. This condition is also called angina pectoris.

TYPES OF ANGINAL ATTACKS

There are three types of angina: stable angina, unstable angina, and variant angina, also known as Prinzmetal's angina. Stable angina and unstable angina are the most common. Variant angina is less common. Stable Angina Stable angina can also be referred to as exertional angina. In stable angina, a coronary artery has been severely narrowed due to the buildup of plaque.

TYPES OF ANGINAL ATTACKS

Unstable Angina
It is a dangerous condition that requires emergency treatment. Unstable angina occurs more often in older adults and is a sign that a heart attack could occur soon. In fact, 10 to 20 percent of people with unstable angina symptoms will have a heart attack. Unlike stable angina, unstable angina can occur without physical exertion and is not relieved by rest or medicine. In most cases, the condition is caused by blood clots that partially or totally block a coronary artery.

TYPES OF ANGINAL ATTACKS

Variant Angina Variant angina is a rare angina type caused by a spasm in a coronary artery. This spasm causes the walls of the artery to tighten. In turn, this narrows the artery, causing the blood flow to the heart to slow or stop. Variant angina may occur in people with or without coronary heart disease.

TYPES OF ANGINAL ATTACKS

ANGINA DECUBITUS

It occurs in recumbent position and is not related to either rest or exertion. Gravitational forces shift fluid within the body with a resultant increase in ventricular volume which increases oxygen needs and produces angina decubitis.

ANTIANGINAL DRUGS
Management of angina depends on the type of angina and may include drug treatment, coronary artery bypass surgery, or percutaneous transluminal coronary angioplasty. Drugs are used both for the relief of acute pain and for prophylaxis to reduce further attacks; they include Organic nitrates Beta-antagonists (beta-blockers) Calcium-channel blockers. Ranolazine

DRUG INTERACATIONS OF ANTIANGINAL DRUGS

INTERACTIONS WITH ORGANIC NITRATES Nitrates cause vasodilation of the venous capacitance vessels by simulating the endothelium-derived relaxing factor (EDRF). Used to relieve both exertional and vasospastic angina by allowing venous pooling, reducing the pressure in the ventricles and so reducing wall tension and oxygen requirements in the heart. EXAMPLES- Glyceryl trinitrate(Nitroglycerine), isosorbid dinitrate, isosorbid mononitrate.

INTERACTIONS WITH ORGANIC NITRATES

INTERACTION WITH PHOSPHODIESTERASE-5 INHIBITORS--- Concurrent use of nitrates and sildenafil or tadalafil or vardenafil may cause potentially serious hypotension and myocardial infarction may be precipitated. Sildenafil should not be given within 24 hours of nitrates. INTERACTION WITH OTHER ANTIHYPERTENSIVES ( ACE INHIBITORS, CCBS, BB, AB, METHYLDOPA, CLONIDINE, VASODILATORS ,ARBS)--Enhanced hypotensive action when given concurrently.Monitoring is considered.

INTERACTION WITH ORGANIC NITRATES

INTERACTION WITH NSAIDS---Hypotensive effect of nitrates is antagonized by NSAIDS. INTERACTION WITH ANTI-ARRYTHMICS Effects of sublingual tablets of nitrates reduced by disopyramide.(Failure to dissolve under tongue owing to dry mouth). INTERACTION WITH ANTIDEPRESSENTS Enhanced hypotensive action when given with MAOI.Effects of sublingual tablets of nitrates is reduced by tricyclic related antidepressents .(Failure to dissolve under tongue owing to dry mouth).

INTERACTION WITH ORGANIC NITRATES

INTERACTION WITH ANTI-COAGULANTS---Infusion of glyceryl trinitrate reduces anticoagulant effect of heparins. INTERACTION WITH CORTICOSTEROIDS---Hypotensive effect of nitrates is antagonized by corticosteroides. INTERACTION WITH ERGOT ALKALOIDES--- Ergot alkaloids, by causing vasoconstriction, may theoretically antagonize the effects of nitrates. This combination should generally be avoided. Ergot alkaloids are considered contraindicated in patients with ischemic heart disease.

INTERACTION WITH ORGANIC NITRATES

INTERACTION WITH THROMBOLYTICS-- Coadministration of systemic or topical nitroglycerin and alteplase may reduce the thrombolytic efficacy of alteplase. Nitroglycerin may increase hepatic blood flow, causing increased metabolism of alteplase. Use with caution.

INTERACTIONS WITH BETA BLOCKERS

Beta blockers are used in the prophylaxis of exertional angina by reducing the work the heart is allowed to perform below the level that would provoke an angina attack. They cannot be used in vasospastic angina and can precipitate heart failure. Agents include either cardioselectives such as Bisoprolol or metoprolol, or non-cardioselectives such as carvedilol and propranolol.

INTERACTIONS WITH BETA BLOCKERS

INTERACTION WITH CALCIUM CHANNEL BLOCKERS--- DILTIAZEMPatients with pre-existing ventricular failure or conduction abnormalities have developed serious and potentially life threatening bradycardia. NIFEDIPINE OR NISOLDIPINE---ISOLATED CASES OF SEVERE HYPOTENSION AND HEART FAILURE HAVE BEEN SEEN. VERAPAMIL---COMBINATION CAN BE BENEFICIAL,SERIOUS CARDIODEPRESSION SOMETIMES OCCUR. Combination with felodipine,isradipine,nicardipine appears to be useful and safe.

INTERACTIONS WITH BETA BLOCKERS

INTERACTION WITH CYCLOSPORIN---CARVEDILOL can cause a small to moderate rise in cyclosporine levels(requiring gradual cyclosporine dose reduction of 20% over about 3 months, to maintain levels within therapeutic range.

INTERACTIONS WITH BETA BLOCKERS

INTERACTION WITH CO-ARTEMETHER----LUMEFENTRINE IN CO-ARTEMETHER SIGNIFICANTLY INHIBIT CYP2D6 WHICH IS METABOLIZING ENZYME OF METOPROLOL RESULTING IN INCREASE BLOOD LEVELS OF METOPROLOL AND CAUSING MARKED BETA BLOCKADE. INTERACTIONS WITH CONTRACEPTIVES----OESTROGENS CAN RAISE BLOOD PRESSURE AND ANTAGONIZE EFFECT OF BETA BLOCKERS. BLOOD LEVELS OF METOPROLOL ARE INCREASED IN WOMEN TAKING ORAL CONTRACEPTIVES BUT ITS CLINICAL SIGNIFICANCE IS SMALL.

INTERACTIONS WITH BETA BLOCKERS

INTERACTION WITH DIGOXINIn general beta blocker and digoxin appear not to interact. However there is always risk of additive bradycardia. Carvedilol appears to increase bioavailability of Digoxin.(14% increase in AUC in adults and may be doubling of levels in children). INTERACTION WITH DISOPYRAMIDE----Severe bradycardia has been described and combination should generally be avoided.

INTERACTIONS WITH BETA BLOCKERS

INTERACTION WITH CIMETIDINE---Cimetidine alters pharmacokinetics of some beta blockers resulting in increase levels of metoprolol,nebivolol,pindolol and propranolol requiring dosage adjustment where needed. INTERACTION WITH HYDRALAZINE---Plasma levels of propranolol,metoprolol and oxprenolol are increased by hydralazine but an increase in adverse effects does not seems to have been reported.

INTERACTIONS WITH BETA BLOCKERS

INTERACTION WITH ERGOT DERIVATIVES---Combination is generally safe but cases of peripheral vasoconstriction have been reported following concurrent use. INTERACTION WITH FLECAINIDE---Combination causes additive cardiac depressant effects. Careful monitoring for bradycardia is recommended.

INTERACTIONS WITH BETA BLOCKERS

INTERACTION WITH INOTROPES AND VASOPRESSORS-----The hypertensive effect of adrenaline can be markedly increased in patients taking non-selective beta blocker propranolol. A severe and potentially life threatening hypertensive reaction occur.Cardioselective beta blocker interact minimally.

INTERACTIONS WITH BETA BLOCKERS

INTERACTION WITH PHENOBARBITAL---Plasma level and effects of beta-blockers that are mainly metabolized by liver(e.g., metoprolol,timolol,alprenolol) are reduced by the barbiturates. INTERACTION WITH PHOSPHODIESTERASE-5 INHIBITORS---Vardenafil modestly prolongs the QT interval(by 5 to 10 milliseconds),its use with class 3 antiarrythmics such as sotalol should be avoided. INTERACTION WITH TERBINAFINE---Terbinafine inhibit CYP2D6 and hence increases the plasma level of metoprolol,carvedilol,propranolol,nebivolol and timolol.

INTERACTIONS WITH BETA BLOCKERS

INTERACTION WITH PROPAFENONE----Plasma metoprolol and propranolol levels can be markedly raised(2 to 5 folds) by propafenone.Toxicity may develop. INTERACTION WITH QUINIDINE---Marked bradycardia and orthostatic hypotension may occur when given in combination with atenolol,propranolol,timolol etc. INTERACTION WITH SSRIs---Concurrent use of metoprolol with Citalopram or Escitalopram result in doubling of plasma level of metoprolol which may decrease its cardioselectivity.

INTERACTIONS WITH BETA BLOCKERS

INTERACTION WITH RIFAMPICIN Rifampicin increases the loss of bisoprolol,carvedilol,metoprolol,propranolol, celiprolol from body and reduces their serum level(to small extent). INTERACTION WITH LIDOCAINE---The plasma level of lidocaine can be increased by the concurrent use of propranolol which has resulted in toxicity in selected cases. INTERACTION WITH NSAIDS---The antihypertensive effect of beta blocker can be reduced by NSAIDS.More significant increase in blood pressure is caused by indomethacine which is about 8 to 10 mm Hg.

INTERACTION WITH CALCIUM CHANNEL BLOCKERS

Calcium-channel blockers interfere with the inward movement of calcium ions through the slow channels in heart and vascular smooth muscle cell membranes, leading to relaxation of vascular smooth muscle. Calcium-channel blockers are used to improve exercise tolerance in patients with chronic stable angina due to coronary atherosclerosis or with abnormally small coronary arteries and limited vasodilator reserve. Calcium-channel blockers can also be used in patients with unstable angina with a vasospastic origin, such as Prinzmetal angina.

INTERACTION WITH CALCIUM CHANNEL BLOCKERS

INTERACTION WITH CALCIUM CHANNEL BLOCKER--Plasma level of both nifedipine and diltiazem are increased by concurrent use.This has been claimed to be advantageous but caution is advised. INTERACTION WITH FENTANYL----Coadministration with inhibitors of CYP450 3A4 i.e., DILTIAZEM may increase the plasma concentrations of fentanyl, which is primarily metabolized by the isoenzyme. Increased fentanyl concentrations could conceivably increase or prolong adverse drug effects and may cause potentially fatal respiratory depression.

INTERACTION WITH CALCIUM CHANNEL BLOCKERS

INTERACTION WITH CARBAMAZEPINE---Carbamazepine levels are increased by Diltiazem (up to 4 fold) and verapamil has cause increased carbamazepine toxicity. INTERACTION WITH ITRACONAZOLE--Itraconazole exhibits a dose-related negative inotropic effect which may be additive to those of calcium channel blockers (CCBs). In addition, both itraconazole and its major metabolite, hydroxyitraconazole, inhibit CYP450 3A4 metabolism and may interfere with the clearance of certain CCBs like the dihydropyridines (amlodipine, felodipine, isradipine, lacidipine, nicardipine, nifedipine, nimodipine, nisoldipine), diltiazem, and verapamil.

INTERACTION WITH CALCIUM CHANNEL BLOCKERS

INTERACTION WITH CICLOSPORIN--Diltiazem,verapamil,Nicardipine markedly raise serum ciclosporin levels. ciclosporin levels should be closely monitored and dosage reduction are necessary. INTERACTION WITH DIGOXIN---Diltiazem may cause increases in digoxin plasma levels although reports are conflicting. In addition, digoxin and diltiazem have additive effects in slowing AV conduction. Monitor for signs and symptoms of digoxin toxicity, checking digoxin levels when clinically necessary. INTERACTION WITH DISOPYRAMIDE---Profound hypotension and collapse has occurred in small number of patients taking both.Monitor concurrent use carefully.

INTERACTION WITH CALCIUM CHANNEL BLOCKERS

INTERACTION WITH DIURETICS---Mild to moderate inhibitors of CYP3A4 such as Verapamil and Diltiazem cause 2-fold increase in eplerenone levels which increases risk of hyperkalemia.Additive hypotensive effects occur with concurrent use. INTERACTION WITH FLECAINIDE---Although flecainide and verapamil have been used together successfully, serious and potentially life threatening cardiogenic shock and asystole have been seen in a few patients.

INTERACTION WITH CALCIUM CHANNEL BLOCKERS

INTERACTION WITH CIMETIDINE---Plasma level of diltiazem,isradipine and nifedipine are incraesed by cimetidine and it may be necessary to reduce their dosages. INTERACTION WITH MACROLIDES--Erythromycin markedly increases plasma levels of felodipine,nifedipine and verapamil and toxicity is seen in patients when given with erythromycin,clarithromycin and telithromycin.

INTERACTION WITH CALCIUM CHANNEL BLOCKERS

INTERACTION WITH NSAIDS---Studies have shown that NSAIDS elevated mean supine blood pressure by 5 mmHg. Indomethacin,ibuprofen and piroxicam produced the greatest increases.Aspirine and sulindac produced the smallest increases while effects of diclofenac,flurbiprofen and naproxen is intermediate.Effect is greater in elderly in those with high salt intake.Caution is exercised in NSAIDS use.

INTERACTION WITH CALCIUM CHANNEL BLOCKERS

INTERACTION WITH PHENOBARBITAL--PHENOBARBITAL decreases the levels of felodipine(bioavailability decreased by 90%),nifedipine(AUC reduced by 60%) and verapamil (bioavailability reduced by 5-fold).Other CCBS interact similarly.Monitor the outcome of concurrent use.Given the size of reduction it may be prudent to consider alternatives. INTERACTION WITH PHENYTOIN---Case reports describe phenytoin toxicity in patients given with diltiazem or nifedipine.Caution is exercised and phenytoin dose is decreased.

INTERACTION WITH CALCIUM CHANNEL BLOCKERS

INTERACTION WITH PROTEASE INHIBITORS Nelfinavir, saquinavir,ritonavir are predicted to increase the levels of calcium channel blockers that are substrate of CYP3A4.Undertake concurrent use with caution. INTERACTION WITH QUINIDINE---Verapamil ,diltiazem and nifedipine reduces the clearance of quinidine and quinidine toxicity developed.A reduction in dosage of quinidine(of up to 50%)may be needed to avoid toxicity.

INTERACTION WITH CALCIUM CHANNEL BLOCKERS

INTERACTION WITH RIFAMPICIN---The plasma level of diltiazem, nifedipine, verapamil, nimodipine, nisoldipine,isradipine are markedly reduced by rifampicin.They may become therapeutically ineffective unless their dosaages are raised.Manufacturers of nifedipine and nisoldipine contraindicate their use with rifampicin. INTERACTION WITH STATINS---Plasma levels of atorvastatin,lovastatin and simvastatin are markedly raised with diltiazem and verapamil.Statins should be started with lowest possible dose and than titrated upwards.Patients should be told to be alert for any signs of possible rhabdomyolysis(muscle tenderness,weakness,pain and dark coloured urine).

INTERACTION WITH CALCIUM CHANNEL BLOCKERS

INTERACTION WITH TACROLIMUS--verapamil,diltiazem and nifedipine causes moderate rise in the level of Tacrolimus.Tacrolimus levels should be monitored as a matter of routine and should be given special consideration while using CCBS. INTERACTION WITH TRICYCLIC ANTIDEPRESSENTS----Diltiazem and verapamil can increase plasma imipramine and nortriptyline levels.Dose is adjusted to avoid toxicity.

INTERACTION WITH CALCIUM CHANNEL BLOCKERS

INTERACTION WITH BETA BLOCKERS---Enhanced hypotensive effect,increased risk of AV block and bradycardia occur. With diltiazem and verapamil asystole,severe hypotension and heart failure may be precipitated.Dosage of both needs to be adjusted. INTERACTION WITH ANTIPSYCHOTICS---Enhanced hypotensive effect occur with concurrent use. Monitoring is considered. INTERACTION WITH ANTIMALARIALS---Increased risk of bradycardia when ccbs given with mefloquine.Monitoring is considered.

INTERACTION WITH CALCIUM CHANNEL BLOCKERS

INTERACTION WITH NITRATES Enhanced hypotension may occur.Monitoring is considered. INTERACTION WITH GRAPEFRUIT JUICE--Plasma levels of felodipine, isradipine, lacidipine, nifedipine, nisoldipine, nimodipine and verapamil are increased by grapefruit juice.

INTERACTION WITH RANOLAZINE

RANOLAZINE---On January 31, 2006, ranolazine was approved for use in the United States by the FDA for the treatment of chronic angina pectoris. It has very complicated mechanism of action.

INTERACTION WITH INHIBITORS OF CYP3A4-- Diltiazem Verapamil Ketoconazole and other azole antifungals Macrolide antibiotics Ritonavir Grapefruit products or grapefruit juice Increased level of ranolazine due to decreased metabolism.

INTERACTION WITH RANOLAZINE

INTERACTION WITH DIGOXIN---Ranolazine increases absorption of Digoxin resulting in increased level.Dosage needs to be adjusted. INTERACTION WITH METOPROLOL--Ranolazine inhibits CYP2D6 and thus decreases metabolism of metoprolol and increasing its plasma level.

REFRENCES
Meyler's Side Effects of Cardiovascular Drugs By J. K. Aronson Oxford HandBook of Clinical Medicine by Murray Longmore Essential psychopharmacology: the prescribes guide (2006) Applied therapeutics clinical use (2005) Haddad & Winchesters clinical management of poisoning 7 drug overdose (2007)

REFRENCES
GOODMAN & GILLMAN PHARMACOLOGICAL BASIS OF THERAPAEUTICS .Rang & Dale's Pharmacology, 5th Edition Desk Reference of Clinical Pharmacology, Second Edition

Drug Interactions Analysis and Management (2010) By Hansten and Horn A Manual of Adverse Drug Interactions by J.P. Griffin and P.F. D'Arcy Stocklays Drug Interaction Pocket Companion 9th Edition