ANTI-ANGINAL DRUGS

PROF.VINOD BHARDWAJ

ANTI-ANGINAL DRUGS• ANTI-ANGINAL DRUGS • ANGINA PECTORIS:- IS A PAIN SYNDROME DUE TO INDUCTION OF AN

ADVERSE OXYGEN SUPPLY/DEMAND SITUATION IN A PORTION OF THE MYOCARDIUM.(FIG)

• TWO PRINCIPAL FORMS ARE RECOGNIZED: • A). CLASSICAL ANGINA (COMMON FORM):ATTACKS ARE

PREDICATABLY (STABLE ANGINA) PROVOKED BY EXERCISE, EMOTION, EATING OR COITUS AND SUBSIDE WHEN THE INCREASED ENERGY DEMAND IS WITHDRAWN. THE UNDERLYING PATHOLOGY IS SEVERE ARTERIOSCLEROTIC AFFLICTION OF LARGER CORONARY ARTERIES (CONDUCTING VESSELS) WHICH RUN EPICARDIALLY AND SEND PER FORATING BRANCHES TO SUPPLY THE DEEPER TISSUE.

ANTI-ANGINAL DRUGS• THE CORONARY OBSTRUCTION IS FIXED; BLOOD FLOW

FAILS TO INCREASE DURING INCREASED DEMAND DESPITE LOCAL FACTORS MEDIATED DILATATION OF RESISTANCE VESSELS AND ISCHAEMIC PAIN IS FELT.

• DUE TO INADEQUACY OF ISCHAEMIC LEFT VENTRICLE, THE END DIASTOLIC LEFT VENTRICULAR PRESSURE RISES FROM 5 TO ABOUT 25 mmHg -> PRODUCES SUBENDOCARDIAL ‘CRUNCH’ DURING DIASTOLE (BLOOD FLOW TO THE SUBENDOCARDIAL REGION OCCURS ONLY DURING DIASTOLE) AND AGGRAVATES ISCHAEMIA IN THIS REGION.(FIG.)

ANTI-ANGINAL DRUGS

• DRUGS THAT ARE USEFUL, PRIMARILY REDUCE CARDIAC WORK (DIRECTLY BY ACTING ON HEART OR INDIRECTLY BY REDUCING PRELOAD HENCE, END DIASTOLIC PRESSURE, AND AFTERLOAD.

• THEY MAY ALSO CAUSE FAVOURABLE REDISTRIBUTION OF BLOOD FLOW TO THE ISCHAEMIC AREAS.

ANTI-ANGINAL DRUGS• B). VARIANT / PRIZMETAL’S/UNSTABLE ANGINA

(UNCOMMON FORM):• ATTACKS OCCUR AT REST OR DURING SLEEP AND ARE

UNPREDICATABLE & ARE DUE TO RECURRENT LOCALIZED (OCCASIONALLY DIFFUSE) CORONARY VASOSPASM WHICH MAY BE SUPERIMPOSED ON ARTERIOSCLEROTIC CORONARY ARTERY DISEASE. ABNORMALLY REACTIVE AND HYPERTROPHIED SEGMENTS IN THE CORONARY ARTERIES HAVE BEEN DEMONSTRATED. DRUGS ARE AIMED AT PREVENTING AND RELIEVING THE CORONARY VASOPASM.

ANTI-ANGINAL DRUGS• UNSTABLE ANGINA WITH RAPID INCREASE IN

DURATION AND SEVERITY OF ATTACKS IS MOSTLY DUE TO RUPTURE OF AN ATHEROMATOUS PLAQUE, ATTRACTING PLATELET DEPOSITION AND PROGRESSIVE OCCLUSION OF THE CORONARY ARTERY; OCCASIONALLY WITH ASSOCIATED CORONARY VASOSPASM.

• ANTIANGIAL DURGS RELIEVE CARDIAC ISCHAEMIA BUT DO NOT ALTER THE COURSE OF CORONARY ARTERY PATHOLOGY, HENCE, NO PERMANENT BENEFIT IS AFFORDED.

ANTI-ANGINAL DRUGS• CLASSIFICATION OF ANTI-ANGINAL DRUGS:• 1. NITRATES OR NITROVSODILATORS:

(A). SHORT ACTING:-- GLYCERYL TRINITRATE (GTN, NITROGLYCERINE)(B). LONG ACTING:-

- ISOSORBIDE DINITRATE (SHORT ACTING BY SUBLINGUAL ROUTE),

- ISOSORBIDE MONONITRATE, - ERYTHRITYL TETRANITRATE, - PENTA ERYTHRITOL TETRAINTRATE.

ANTI-ANGINAL DRUGS2. ΒETA - BLOCKERS:• - PROPRANOLOL, • - METOPROLOL,• - ATENOLOL

3. CALCIUM CHANNEL BLOCKERS:(a). PHENYLALKYLAMINE:• - VERAPAMIL. (b). BENZOTHIAZEPINES:• - DILTIAZEM( c ). DIHYDROPYRIDINES:• - NIFEDIPINE,• - FELODIPINE,• - AMLODIPINE,• - NITRENDIPINE,• - LACIDIPINE,• - BENIDIPINE,• - LERCANIDIPINE

ANTI-ANGINAL DRUGS4. POTASSIUM CHANNEL OPENER:

- NICORANDIL 5. MISCELLANEOUS DRUGS:

- DIPYRIDAMOLE, - RANOLAZINE- TRIMETAZIDINE. - OXYPHEDRINE

CLINICAL CLASSIFICATION OF ANTI-ANGINAL DRUGS:• A. DRUG USED SUBLINGUALLY TO ABORT OR TERMINATE

AN ACUTE ATTACK: - GTN (SUBLINGUALLY)- ISOSORBIDE DINITRATE (SUBLINGUALLY).

• B. USED FOR CHRONIC PROPHYLAXIS: ALL OTHER DRUGS GIVEN ORALLY.

ANTI-ANGINAL DRUGSNITROVASODILATORS: THESE AGENTS ARE PRODRUGS THAT ARE SOURCES OF NITRIC OXIDE (NO). NO ACTIVATES THE SOLUBLE ISOFORM OF GUANYLYL CYCLASE, THEREBY INCREASING INTRACELLULAR LEVELS OF CYCLIC GMP. IN TURN, THIS PROMOTES THE DEPHOSPHORYLATION OF THE MYOSIN LIGHT CHAIN AND THE REDUCTION OF CYSTOLIC (Ca2+) AND LEADS TO THE RELAXATION OF SMOOTH MUSCLE CELLS IN A BROAD RANGE OF TISSUES.

• THE NO-DEPENDENT RELAXATION OF VASCULAR SMOOTH MUSCLE LEADS TO VASODILATION. NO-MEDIATED GUANYLYL CYCLASE ACTIVATION INHIBITS PLATELET AGGREGATION AND ALSO RELAXES SMOOTH MUSCLE IN THE BRONCHI AND GASTROINTESTINAL (GI) TRACT .

ANTI-ANGINAL DRUGS• THE BROAD BIOLOGICAL RESPONSE TO NITROVASODILATORS

SUGGESTS THE EXISTENCE OF ENDOGENOUS NO-MODULATED REGULATORY PATHWAYS;

• MORE THAN A CENTURY AFTER THE THERAPEUTIC USE OF NITROVASODILATORS, THE ENZYMES RESPONSIBLE FOR ENDOGENOUS NO SYNTHESIS WERE ISOLATED AND CHARACTERIZED. THE ENDOGENOUS SYNTHESIS OF NO IN HUMANS IS CATALYZED BY A FAMILY OF NO SYNTHASES THAT OXIDIZE THE AMINO ACID L-ARGININE TO FORM NO.

• THERE ARE THREE DISTINCT MAMMALIAN NO SYNTHASE ENZYME ISOFORMS TERMED NNOS, ENOS, AND INOS , AND THEY ARE INVOLVED IN PROCESSES AS DIVERSE AS NEUROTRANSMISSION, VASOMOTION, AND IMMUNOMODULATION. IN SEVERAL VASCULAR DISEASE STATES, PATHWAYS OF ENDOGENOUS NO-DEPENDENT REGULATION APPEAR TO BE DERRANGED.

ANTI-ANGINAL DRUGS

NITRATES (GTN AS PROTOTYPE):• ALL ORGANIC NITRATES SHARE THE

SAME ACTION; DIFFER ONLY IN TIME COURSE. THE ONLY MAJOR ACTION IS DIRECT NONSPECIFIC SMOOTH MUSCLE RELAXATION.

ANTI-ANGINAL DRUGS

• THE MOST PROMINENT ACTION IS EXERTED ON VASCULAR SMOOTH MUSCLE.

• NITRATES DILATE VEINS MORE THAN ARTERIES - > PERIPHERAL POOLING OF BLOOD - > DECREASED VENOUS RETURN - > PRELOAD ON HEART IS REDUCED - > END DIASTOLIC VOLUME & VENTRICULAR SIZE & PRESSURE ARE REDUCED - > DECREASED CARDIAC WORK - > DECREASED OXYGEN DEMAND.

ANTI-ANGINAL DRUGS

• THE DECREASE IN END DIASTOLIC PRESSURE ABOLISHES THE SUBENDOCARDIAL CRUNCH BY RESTORING THE PRESSURE GRADIENT ACROSS VENTRICULAR WALL DUE TO WHICH SUBENDOCARDIAL PERFUSION OCCURS DURING DIASTOLE.

• IT IS THROUGH THIS ACTION ON PERIPHERAL VEINS THAT NITRATES EXERT MAJOR BENEFICIAL EFFECTS IN CLASSICAL ANGINA.

ANTI-ANGINAL DRUGS

• NITRATES ALSO PRODUCE SOME ARTERIOLAR DILATATION -> SLIGHTLY DECREASE TOTAL PERIPHERAL RESISTANCE (T.P.R.) OR AFTERLOAD ON HEART - > BP FALLS SOMEWHAT, SYSTOLIC MORE THAN DIASTOLIC (REFLEX SYMPATHETIC ACTIVITY TENDS TO MAINTAIN DIASTOLIC BP).

• THIS ACTION CONTRIBUTES TO THE REDUCTION OF CARDIAC WORK WHICH IS DIRECTLY PROPORTIONAL TO AORTIC IMPEDANCE.

ANTI-ANGINAL DRUGS

• IN THE ARTERIAL TREE, NITRATES PREFERENTIALLY RELAX BIGGER CONDUCTING (ANGIOGRAPHICALLY VISIBLE) CORONARY ARTERIES THAN ARTERIOLES OR RESISTANCE VESSELS WITHOUT AFFECTING THE AUTOREGULATORY VASODILATATION IN THE SUBENDOCARDIAL ISCHEMIC ZONE.

ANTI-ANGINAL DRUGS• THIS PATTERN OF ACTION MAY CAUSE FAVORABLE

REDISTRIBUTION OF BLOOD FLOW TO ISCHAEMIC AREAS IN ANGINA PATIENTS. DILATATION OF CONDUCTING VESSELS ALL OVER BY NITRATE ALONG WITH ISCHAEMIA INDUCED DILATATION OF AUTOREGULATORY RESISTANCE VESSELS ONLY IN THE ISCHAEMIC ZONE INCREASES BLOOD FLOW TO THIS AREA; WHILE IN THE NON –ISCHAEMIC ZONES, RESISTANCE VESSELS MAINTAIN THEIR TONE & BLOOD FLOW DOES NOT INCREASE, RATHER, MAY DECREASE TO COMPENSATE FOR INCREASED FLOW TO ISCHAEMIC ZONE.

• IN FACT, NITRATES DO NOT APPRECIABLY INCREASE TOTAL CORONARY FLOW IN ANGINA PATIENTS.

ANTI-ANGINAL DRUGS• THE DILATOR EFFECT ON LARGER CORONARY VESSELS

IS THE PRINCIPAL ACTION OF NITRATES BENEFITING VARIANT ANGINA BY COUNTER ACTING CORONARY SPASM.

• IN CLASSICAL ANGINA, UNDOUBTEDLY, THE PRIMARY ACTION IS TO REDUCE CARDIAC WORK BY ACTION ON PERIPHERAL VASCULATURE, THOUGH INCREASED BLOOD SUPPLY TO ISCHAEMIC AREA MAY CONTRIBUTE.

• EXERCISE TOLERANCE OF ANGINA PATIENTS IS INCREASED BECAUSE THE SAME AMOUNT OF EXERCISE CAUSE LESSER AUGMENTATION OF CARDIAC WORK.

ANTI-ANGINAL DRUGS• NITRATES HAVE NO DIRECT STIMULANT OR

DEPRESSANT ACTION ON HEART. THEY DILATE CUTANEOUS ARTERIOLES (ESPECIALLY OVER FACE AND NECK - > FLUSHING) AND MENINGEAL VESSELS -> HEADACHE.

• SPLANCHNIC & RENAL BLOOD FLOW DECREASES TO COMPENSATE FOR VASODILATATION IN OTHER AREAS. THEY TEND TO DECONGEST LUNGS BY SHIFTING BLOOD TO SYSTEMIC CIRCULATION.

• BRONCHI, BILIARY TRACT AND ESOPHAGUS ARE RELAXED; EFFECT ON INTESTINE, URETER AND UTERUS IN VARIABLE AND INSIGNIFICANT.

ANTI-ANGINAL DRUGS• MOLECULAR MECHANISM OF ACTION OF

NITROVASODILATORS:• ORGANIC NITRATES ARE RAPIDLY DENITRATED

ENZYMATICALLY ( BY NO SYNTHEASES) IN THE SMOOTH MUSCLE CELL TO RELEASE THE REACTIVE FREE RADICAL NITRIC OXIDE (NO) WHICH ACTIVATES CYTOSOLIC GUANYLYL CYCLASE - > INCREASED C-GMP CAUSES DEPHOSPHORYLATION OF MYOSIN LIGHT CHAIN KINASE (MLCK) THROUGH A C-GMP-DEPENDENT PROTEIN KINASE (FIG. 11.4).

ANTI-ANGINAL DRUGS

• REDUCED AVAILABILITY OF PHOSPHORYLATED (ACTIVE) MLCK INTERFERES WITH ACTIVATION OF MYOSIN IT FAILS TO INTERACT WITH ACTIN TO CAUSE CONTRACTION. CONSEQUENTLY, RELAXATION OCCURS. RAISED INTRACELLULAR C-GMP MAY ALSO REDUCE Ca2+ ENTRY -> CONTRIBUTING TO RELAXATION.

ANTI-ANGINAL DRUGS

• PHARMACOKINETICS:• ORGANIC NITRATES ARE LIPID SOLUBLE WELL

ABSORBED FROM BUCCAL MUCOSA, INTESTINES AND SKIN.

• ALL EXCEPT ISOSORBIDE MONONITRATE UNDERGO EXTENSIVE BUT VARIABLE FIRST PASS METABOLISM IN LIVER.

• THEY ARE RAPIDLY DENITRATED BY A GLUTATHIONE REDUCTASE.

ANTI-ANGINAL DRUGS• ADVERSE EFFECTS: THESE ARE MOSTLY DUE TO

VASODILATATION. • FULLNESS IN HEAD, THROBBING HEADACHE; SOME

DEGREE OF TOLERANCE DEVELOPS ON CONTINUED USE.

• FLUSHING, WEAKNESS, SWEATING, PALPITATION, DIZZINESS AND FAINTING; THESE ARE MITIGATED BY LYING DOWN AND ACCENTUATED BY ERECT POSTURE AND ALCOHOL.

• METHEMOGLOBINEMIA: IS NOT MARKED WITH CLINICALLY USED DOSES.

• RASHES ARE RARE.

ANTI-ANGINAL DRUGS• TOLERANCE ATTENUATION OF HAEMODYNAMIC AND

ANTIISCHAEMIC EFFECT OF NITRATES OCCURS IF THEY ARE CONTINUOUSLY PRESENT IN THE BODY.

• THIS TOLERANCE WEANS OFF RAPIDLY (WITHIN HOURS)WHEN THE BODY IS FREE OF THE DRUG. CLINICALLY, NO SIGNIFICANT TOLERANCE DEVELOPS ON INTERMITTENT USE OF SUBLINGUAL GTN FOR ATTACKS OF ANGINA. HOWEVER, IT MAY BECOME IMPORTANT WHEN GTN IS USED ORALLY, TRANSDERMALLY OR BY CONTINUOUS I.V. INFUSION ROUND THE CLOCK.

ANTI-ANGINAL DRUGS

• THE MOST PRACTICAL WAY TO PREVENT NITRATE TOLERANCE IS TO PROVIDE NITRATE FREE INTERVALS EVERY DAY.

• SILDENAFIL CAUSES DANGEROUS POTENTIATION OF NITRATE ACTION: SEVERE HYPOTENSION, MI AND DEATHS ARE ON RECORD.

• ADDITIVE HYPOTENSION, IS ALSO POSSIBLE WHEN NITRATE IS GIVEN TO PATIENT RECEIVING OTHER VASODILATORS.

ANTI-ANGINAL DRUGSINDIVIDUAL COMPOUNDS: • 1.GLYCERYL TRINITRATE: IT IS A VOLATILE LIQUID WHICH IS

ABSORBED ON THE INERT MATRIX OF TABLET. THE SUBLINGUAL ROUTE IS USED WHEN TERMINATING AN ATTACK OR ABORTING AN IMMINENT ONE IS THE AIM. IT ACTS WITHIN 1-2MIN (PEAK BLOOD LEVEL IN 3-6MIN) BECAUSE OF DIRECT ABSORPTION INTO SYSTEMIC CIRCULATION (BYPASSING LIVER WHERE ALMOST 90% IS METABOLIZED).

• PLASMA t1/2 IS 2 MIN, DURATION OF ACTION DEPENDS ON THE PERIOD IT REMAINS AVAILABLE FOR ABSORPTION FROM BUCCAL MUCOSA.

• THE REMAINING PART OF THE TABLET MAY BE SPIT OR SWALLOWED WHEN NO LONGER NEEDED.

ANTI-ANGINAL DRUGS• SUSTAINED RELEASE ORAL CAPSULES CONTAINING

MUCH LARGER AMOUNTS OF GTN CAN BE USED FOR CHRONIC PROPHYLAXIS.

• NITROGLYCERINE IS READILY ABSORBED FROM THE SKIN. A TRANSDERMAL PATCH IN WHICH THE DRUG IS INCORPORATED INTO A POLYMER BONDED TO ADHESIVE PLASTER HAS BEEN DEVELOPED WHICH PROVIDES STEADY DELIVERY FOR 24 HOURS. HOWEVER, DEVELOPMENT OF TOLERANCE AND DEPENDENCE MAY JEOPARDIZE ITS VALUE. IT IS ADVISED THAT THE PATCH BE TAKEN OFF FOR 8 HOURS DAILY.

ANTI-ANGINAL DRUGS

• INTRAVENOUS INFUSION OF GTN PROVIDES RAPID, STEADY, TITRATABLE PLASMA CONCENTRATION FOR AS LONG AS DESIRED.

• IT HAS BEEN SUCCESSFULLY USED FOR : - UNSTABLE ANGINA,- CORONARY VASOPASM, - LVF ACCOMPANYING MI, - HYPERTESION DURING CARDIAC

SURGERY, ETC.

ANTI-ANGINAL DRUGS

• 2.ISOSORBIDE DINITRATE :• IT CAN BE USED SUBLINGUALLY AT THE TIME

OF ATTACK (SLIGHTLY SLOWER IN ACTION THAT GTN, PEAK IN 5-8 MIN)

• USED ORALLY FOR CHRONIC PROPHYLAXIS. THE t 1/2 IS 40 MIN, BUT SUSTAINED RELEASE FORMULATION MAY AFFORD PROTECTION FOR 6-10 HOURS.

ANTI-ANGINAL DRUGS• 3.ISOSORBIDE MONONITRATE : • THIS IS AN ACTIVE METABOLITE OF ISOSORBIDE

DINITRATE. WHEN ADMINISTERED ORALLY, IT UNDERGOES LITTLE FIRST PASS METABOLISM.

• BIOAVAILABILITY IS HIGH, INTERINDIVIDUAL DIFFERENCES ARE MINIMAL AND IT IS LONGER ACTING (t1/2 4-6 HR).4. ERYTHRITYL TETRANITRATE, 5. PENTA ERYTHRITOL TETRAINTRATE.THESE ARE LONGER ACTING NITRATES USED ONLY FOR CHRONIC PROPHYLAXIS.

ANTI-ANGINAL DRUGSTHERAPEUTIC USES OF NITROVASODILATORS:1.ANGINA PECTORIS: NITRATES ARE EFFECTIVE IN CLASSICAL AS WELL AS

VARIANT ANGINA.- FOR ABORTING OR TERMINATING AN ATTACK, SUBLINGUAL GTN TABLET OR ISOSORBIDE DINITRATE IS TAKEN ON ‘AS AND WHEN REQUIRED’ BASIS. - SINCE DENTAL PROCEDURES ARE OFTEN AN EMOTIONAL STRESS, ANGINAL ATTACK MAY BE PRECIPITATED. SUBLINGUAL GTN TABLET SHOULD BE READILY AVAILABLE TO ABORT/TERMINATE SUCH AN ATTACK ON THE DENTAL CHAIR. - NITRATES INCREASE EXERCISE TOLERANCE AND POSTPONE ECG CHANGES OF ISCHAEMIA. - LONGER ACTING FORMULATIONS (ORAL, TRANSDERMAL) OF GTN OR OTHER NITRATES ARE USED ON REGULAR SCHEDULE FOR CHRONIC PROPHYLAXIS. NITRATES ARE EFFECTIVE IN UNSTABLE ANGINA AS WELL. HOWEVER, ANTIPLATELET DRUGS ARE THE PRIMARY MEASURE IN UNSTABLE ANGINA.

ANTI-ANGINAL DRUGS

2. IN ACUTE CORONARY SYNDROMES: THESE ARE CHARACTRIZED BY RAPIDLY WORSENING CARDIAC STATUS OF THE PATIENT BY CONDITIONS SUCHAS UNSTABLE ANGINA AND NON-ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION (NSTEMI).THESE NECESSITATE AGGRESSIVE & EFFECTIVE THERAPY TO PREVENT FURTHER CORONARY OCCLUSION,INCREASE CORONARY BLOOD FLOW, AND DECREASE MYOCARDIAL STRESS BY DECREASING OXYGEN DEMAND.

ANTI-ANGINAL DRUGS

• NITROVASODILATORS ARE EFFECTIVE BY:• - DECREASING PRE-LOAD (MYOCARDIAL

WORKLOAD IS DECREASED),• - INCREASING CORONARY BLOOD FLOW

(CORONARY VASODILATATION & REVERSAL OF CORONARY SPASM IF PRESENT),

• - DECREASING MYOCARDIAL STRESS BY DECREASING ITS OXYGEN DEMAND.

ANTI-ANGINAL DRUGS• INITIALLY GTN IS GIVEN SUBLINGUALLY, BUT IF PAIN PERSISTS

AFTER THREE TABLETS AT 5 MIN. INTERVALS , I.V INFUSION OF GTN IS STARTED.

• THE ROLE OF NITRATES IS HOWEVER LIMITED TO CONTROL OF PAIN, BECAUSE NO BENEFIT IS DISCOVERED IN DECREASING MORTALITY OR MORBIDITY.

• ANTIPLATELET DRUGS LIKE ASPIRIN, CLOPIDOGREL, GPIIb/IIIa RECEPTOR ANTAGONISTS AND HEPARIN AND A BETA BLOCKER ARE THE PRIMARY MEASURES IN THESE CONDITIONS.

• OTHER MEASURES IN UNSTABLE ANGINA ARE THROMBOLYTICS, CORONARY ANGIOPLASTY WITH STENTS CARRYING SUITABLE DRUGS AND CORONARY BYPASS SURGERY

ANTI-ANGINAL DRUGS• 3. MYOCARDIAL INFARCTION: ADMINISTRATION OF

CAREFULLY TITRATED I.V. INFUSION OF GTN, WITHOUT CAUSING HYPOTENSION & TACHYCARDIA, IS FREQUETLY USED IN A PATIENT OF EVOLVING ACUTE M.I. BECAUSE SUCH A PATIENT IS BENEFITED BY:

• - THE RELIEF OF THE ISCHEMIC PAIN,• - DECREASE IN PULMONARY CONGESTION,• - LIMITING THE AREA OF NECROSIS BY FAVORABLY

ALTERING THE OXYGEN BALANCE IN THE MARGINAL PARTIALLY ISCHEMIC ZONE OF MYOCARDIUM, AS A CONSEQUENCE OF PRELOAD REDUCTION.

ANTI-ANGINAL DRUGS• NITRATES AFFORD RELIEF BY VENOUS POOLING OF BLOOD

REDUCED VENOUS RETURN (PRELOAD) DECREASED END DIASTOLIC VOLUME AND LEFT VENTRICULAR WALL TENSION IMPROVEMENT IN LEFT VENTRICULAR FUNCTION.

• INTRAVENOUS GTN IS THE PREPARATION OF CHOICE FOR EMERGENCY USE, BUT THE RATE OF INFUSION MUST BE GUIDED BY CONTINUOUS HAEMODYNAMIC MONITORING TO AVOID HYPOTENSION & TACHYCARDIA.

• THE ECG SIGNS, ARRHYTHMIAS AND EARLY MORTALITY MAY ALSO BE REDUCED. NITRATE THERAPY IN THE POST INFARCTION PERIOD DOES NOT ALTER MORTALITY, BUT IT CAN BE USED FOR RELIEF OF ANGINA.

ANTI-ANGINAL DRUGS• PROPER PATIENT SELECTION IS IMPORTANT, GTN

SHOULD NOT BE ADMINISTRERED IF:• - SYSTOLIC B.P. IS < 90 mm Hg.• - H.R IS <50 OR >100 min.• - RIGHT VENTRICULAR INFARCTION IS SUSPECTED,• - HYPOTENSION CAUSED BY GTN LIMITS THE USE

OF BETA BLOCKER WHICH HAS MORE BENEFICIAL & SALUTARY RESULTS THAN GTN.

• - PATIENT HAS TAKEN SILDENEFIL IN PAST 24 HRS.

ANTI-ANGINAL DRUGS4. IN C.H.F & ACUTE L.V.F:

NITRATES AFFORD RELIEF IN SUCH PATIENTS BY VENOUS POOLING OF BLOOD, WHICH CAN BE ACCENTUATING BY SITTING THE PATIENT IN PROPPED UP POSITION -> REDUCED VENOUS RETURN -> DECREASED END-DIASTOLIC VOLUME AND LEFT VENTRICULAR WALL TENSION -> IMPROVEMENT OF LEFT VENTRICULAR FUNCTION BY LAPLACE LAW & DECREASE IN PULMONARY CONGESTION.- I.V. GTN IS A DRUG OF CHOICE IN THESE PATIENTS BUT NEEDS CAREFUL HEMODYNAMIC MONITORING & CONTROL OF THE RATE OF I.V. INFUSION.

ANTI-ANGINAL DRUGS

5. BILIARY COLIC: SUBLINGUAL GTN OR ISOSORBIDE DINITRATE EFFECTIVELY COUNTERS THE BILIARY SPASM INDUCED BY OPIOIDS OR DISEASE STATES.

6. ESOPHAGEAL SPASM: SUBLINGUAL GTN PROMPTLY RELIEVES PAIN. NITRATES TAKEN BEFORE MEALS FACILITATE FEEDING IN ESOPHAGEAL ACHALASIA BY REDUCING ESOPHAGEAL TONE.

ANTI-ANGINAL7. CYANIDE POISONING: NITRATES GENERATE

METHAEMOGLOBIN WHICH HAS HIGH AFFINITY FOR CYANIDE RADICAL AND FORMS CYANOMETHAEMOGLOBIN. CYTOCHROME AND OTHER OXIDATIVE ENZYMES ARE THUS PROTECTED FROM CYANIDE. HOWEVER, CYNAMTHEMOGLOBIN MAY AGAIN DISSOCIATE TO FORM CYANIDE, THEREFORE SODIUM THIOSULFATE IS GIVEN TO FORM SOD. THIOCYANATE WHICH IS POORLY DISSOCIABLE AND IS ECRETED IN URINE. AN EARLY TREATMENT IS NECESSARY & THE ANTIDOTES SHOULD BE REPEATED AS NEEDED.

ANTI-ANGINAL• HEMOGLOBIN• SODIUM NITRITE ( 10 ml.OF 3%

SOLUTION, I.V.)• METHEMOGLOBIN• CYANIDE• CYNOMTHEMOGLOBIN• SOD. THIOSULPHATE(50ml. OF

25% SOLUTION, I.V.)• METHEMOGLOBIN + SOD. THIOCYANATE

(EXCRTETED IN URINE)

ANTI-ANGINAL• ΒETA BLOCKERS:• THESE DRUGS DO NOT DILATE CORONARIES OR OTHER BLOOD

VESSELS; TOTAL CORONARY FLOW IS RATHER REDUCED DUE TO BLOCKADE OF DILATOR Β2- RECEPTORS. HOWEVER, FLOW TO THE ISCHAEMIC SUBENDOCARDIAL AREA IS NOT REDUCED BECAUSE OF FAVOURABLE REDISTRIBUTION AND DECREASE IN VENTRICULAR WALL TENSION.

• THEY ACT BY:- REDUCING CARDIAC WORK AND- O2 CONSUMPTION (DECREASED HEART RATE, INOTROPIC STATE AND MEAN BP). THIS IS MARGINAL AT REST. MORE IMPORTANTLY, THEY LIMIT INCREASE IN THESE MODALITIES THAT OCCURS DURING EXERCISE OR ANXIETY (DUE TO ANTIADRENEGIC ACTION ON HEART).

ANTI-ANGINAL• ALL ΒETA BLOCKERS ARE NEARLY EQUALLY EFFECTIVE IN

DECREASING FREQUENCY AND SEVERITY OF ATTACKS AND INCREASING EXERCISE TOLERANCE IN CLASSICAL ANGINA.

• CARDIOSELECTIVE AGENTS (ATENOLOL & METOPROLOL) ARE PREFERRED OVER NONSELECTIVE Β1 + Β2 BLOCKERS (PROPRANOLOL) WHICH MAY WORSEN VARIANT ANGINA.

• LONG –TERM Β BLOCKER THERAPY LOWERS RISK OF SUDDEN CARDIAC DEATH AMONG ISCHAEMIC HEART DISEASE PATIENTS. ΒETA - BLOCKERS ARE TO BE TAKEN ON A REGULAR SCHEDULE; NOT ON ‘AS AND WHEN REQUIRED’ BASIS.THE DOSE HAS TO BE INDIVIDUALIZED. ABRUPT WITHDRAWAL AFTER CHRONIC USE MAY PRECIPITATE SEVERE ATTACKS, EVEN M.I.

ANTI-ANGINAL

• IN UNSTABLE ANGINA & NON ST-ELEVATION M.I: THE BETA BLOCKERS ARE ROUTINELY EMPLOYED UNLESS CONTRAINDICATED. HOWEVER, SHOULD BE ADMINISTERED ONLY AFTER STARTING NITRATE WITH OR WITHOUT Ca++ CHANNEL BLOCKER TO COUNTERACT ANY CORONARY VASOSPASM INDUCED BY BETA BLOCKER, WHICH MAY WORSEN THE UNSTABLE ANGINA.

ANTI-ANGINAL

• BETA BLOCKERS REDUCE MYOCARDIAL OXYGEN DEMAND AND AFFORD ADDITIONAL BENEFIT BY REDUCING THE RISK OF IMPENDING M.I AND OR SUDDEN CARDIAC DEATH.

ANTI-ANGINAL

• CALCIUM CHANNEL BLOCKERS: VERAPAMIL WAS THE FIRST DRUG OF THIS GROUP TO BE DEVELOPED, WHICH ACTS BY BLOCKING THE Ca++ ION CHANELS. A LARGE NUMBER OF CHEMICALLY DIVERSE Ca++ CH. BLOCKERS HAVE BEEN DEVELOPED WHICH CAN BE PUT INTO THREE CLASSES:

• I. PHENYLALKYLAMINES: e.g. VERAPAMIL(HYDROPHILIC).• II. DIHYDROPYRIDINES: e.g., NIFEDEPINE (LIPOPHILIC).• III. BENZOTHIAZEPINES: e.g., DILTIAZEM (HYDROPHILIC).• THE DIHYDROPYRIDINES (DHPs) ARE THE MOST POTENT

OF ALL THE Ca++ CH. BLOCKERS.

ANTI-ANGINAL• CALCIUM CHANNELS: THREE TYPES OF CALCIUM CHANNELS ARE

PRESENT IN SMOOTH MM AND OTHER EXCITABLE CELLS:• I. VOLTAGE SENSITIVE Ca++ CHANNELS.• II. RECEPTOR OPERATED Ca++ CHANNELS.• III. LEAK CHANNELS.• THE VOLTAGE SENSITIVE Ca++ CHANNELS ARE HETEROGENOUS

AND THREE MAJOR SUBTYPES ARE KNOWN : L-TYPE, T-TYPE AND N-TYPE. EVEN THE SMOOTH MM. L-TYPE CHANNELS DIFFER AS THE VASCULAR AND NONVASCULAR TYPES, AND THEIR DISTRIBUTION MAY BE HETEROGENOUS IN DIFFERENET PART OF THE VASCULAR BED. THE L-TYPE Ca++ CHANNELS ARE SO NAMED BECAUSE THEY ARE SENSITIVE TO LONG LASTING CURRENT.

ANTI-ANGINAL• ONLY THE VOLTAGE SENSITIVE L-TYPE Ca++ CHANNELS

ARE BLOCKED BY THE THREE CLASSES OF THE Ca++ CHANNEL BLOCKERS.

• PHARMACOLOGICAL ACTIONS:• THE COMMON PROPERTY OF ALL THE THREE CLASSES OF

C.C.Bs. IS TO INHIBIT Ca++ MEDIATED SLOW CHANNEL COMPONENT OF THE ACTION POTENTIAL IN SMOOTH mm. AND CARDIAC mm. CELLS.

• THE TWO MOST IMPORTANT ACTIONS OF THE CCBs ARE:• I. SMOOTHN mm. RELAXATION (MAINLY VASCULAR)• II. NEGATIVE CHRONOTROPIC, INOTROPIC AND

DROMOTROPIC ACTION ON HEART.

ANTI-ANGINAL

• ACTION ON SMOOTH mm.:• SMOOTH MUSCLES DEPOLARISE PRIMARILY BY

INWARD Ca++ ION MOVEMENT THROUGH VOLTAGE SENSITIVE Ca++ CHANNELS.

• THESE Ca++ IONS TRIGGER RELEASE OF MORE Ca+ IONS FROM SARCOPLASMIC RETICULUM AND INTRACELLULAR STORES AND TOGATHER BRING ABOUT EXCITATION-CONTRACTION COUPLING THROUGH PHOSPHORYLATION OF MYOSIN LIGHT CHAIN.

ANTI-ANGINAL

• CCBs CAUSE SMOOTH MM RELAXATION BY DECREASING AVAILABILITY OF INTRACELLULAR FREE Ca++ IONS.

• CCBs MARKEDLY RELAX ARETERIOLES BUT HAVE ONLY MILD EFFECTS ON VEINS.

• EXTRAVASCULAR SMOOTH MM. OF BRONCHI, GIT, BILIARY, VESICAL AND UTERUS ARE ALSO RELAXED.

ANTI-ANGINAL• THE DIHYDROPYRIDINES (NIFEDEPINE) HAVE THE

MOST MARKED SMOOTH MM. RELAXANT AND VASODILATOR ACTION.

• VERAPAMIL IS SOMEWHAT WEAKER, FOLLOWED BY DILTIAZEM.

• NITRENDEPINE AND OTHER DHPs ALSO HAVE A NITRIC OXIDE GENERATING ACTION ON ENDOTHELIUM AND AN ADDITIONAL INHIBITORY ACTION ON c-AMP-PDEase RESULTING IN INCREASED SMOOTH MM c-AMP PRODUCING THEIR PREDOMINANT SMOOTH MM RELAXANT ACTION. RELEASED NO MAY ALSO HAVE ANTIATHERSCLEROTIC ACTION.

ANTI-ANGINAL

• ACTIONS ON HEART: NORMALLY, IN THE WORKING ATRIUM AND VENTRICLE FIBRES, Ca++ MOVES IN DURING THE PLATEAU PHASE OF ACTION POTNTIAL -> RELEASES MORE Ca++ FROM SARCOPLASMIC RETICULUM -> CONTRACTION OCCURS THROUGH BINDING TO TROPONIN -> ALLOWING INTERACTION OF ACTIN & MYOSIN.

• THE CCBs WOULD THUS HAVE A NEGATIVE INOTROPIC ACTION ON THE MYOCARDIUM.

ANTI-ANGINAL• THE ‘0’- PHASE DEPOLARIZATION IN S.A. NODE &

A.V.NODE IS LARGELY Ca++ MEDIATED AND AUTOMATICITY & CONDUCTIVITY OF THESE CELLS APPEARS TO BE DEPENDENT ON THE RATE OF RECOVERY OF THE Ca++ CHANNELS.

• -…………………RECOVERY-------------------------------• RESTING -> ACTIVATED -> INACTIVATED CH.• NON- CONDUCTS NON-• CONDUCTING Ca++ CONDUCTING

ANTI-ANGINAL• THE L-TYPE CHANNELS BOTH ACTIVATE AND

INACTIVATE SLOWLY. CONSEQUENTLY, Ca++ DEPOLARIZED CELLS (SA & AV NODE) HAVE A CONSIDERABLY LESS STEEP ‘0’ PHASE AND LONGER REFRACTORY PERIOD.

• THE RECOVERY PROCESS WHICH RESTORES THE CHANNEL TO THE FORM FROM WHICH IT CAN BE ACTIVATED AGAIN BY MEMBRANE DEPOLARIZATION IS DELAYED BY VERAPAMIL AND TO A LESSER EXTENT BY DILTIAZEM BUT NOT BY DHPs( THEY DO NOT PRODUCE NEGATIVE CHRONOTROPIC & DROMOTROPIC ACTIONS).

ANTI-ANGINAL

• THE CHANNEL BLOCKADE PRODUCED BY VERAPAMIL IS ENHANCED AT HIGHER RATES OF STIMULATION, THAT BY NIFEDEPINE IS INDEPENDENT OF THIS FREQUENCY AND THAT BY DILTIAZEM IS INTERMEDIATE.

• VERAPAMIL AND ALSO DILTIAZEM, THUS PRODUCE SLOWING OF SINUS RATE AND AV CONDUCTION AND CAUSE BRADYCARDIA, NIFEDEPINE DOES NOT.

ANTIANGINAL DRUGS

• THE RELATIVE POTENCIES OF THE THREE CLASSES OF CCBs TO BLOCK SMOOTH MM. SLOW CHANNELS ALSO DIFFERS AND DOES NOT PARRALEL HEART.

• DHPs ARE MORE SELECTIVE FOR SMOOTH MM L – CHANNELS AT CONCENTRATIONS WHICH CAUSE VASODILATATION, AND CAUSE NEGLIGIBLE NEGATIVE INOTROPIC ACTION.

• DILTIAZEM CAUSES LESS DEPRESSION OF CONTRACTILITY THAN VERAPAMIL.

ANTI-ANGINAL• PHARMACOKINETICS: ALL CCBs ARE ABSORBED 90 – 100% ORALLY.• PEAK OCCURS AT 1 – 3 HRS EXCEPT AMLODEPINE WHICH IS SLOW ACTING

WITH PEAK AT 6 – 9 HRS.• ORAL BIOAVAILABILITY DIFFERS PRODUCING GREAT INTER AND INTRA

INDIVIDUAL VARIATIONS OWING TO HIGH FIRST PASS METABOLISM, EXCEPT IN THE CASE OF AMLODEPINE WHERE IT IS MODEST AND LESS VARIABLE.

• ALL CCBs ARE HIGHLY PROTEIN BOUND AND ALL ARE HIGH CLEARANCE DRUGS AND HAVE EXTENSIVE TISSUE DISTRIBUTION.

• ALL ARE UPTO 90% METABOLIZED IN LIVER AND EXCRETED IN URINE. SOME METABOLITES ARE ACTIVE.

• ELIMINATION t1/2 RANGES FROM 2 – 6 HRS, BUT THAT OF AMLODEPINE IS EXCEPTIONALLY LONG, FOLLOWED BY LACIDIPINE, NITRENDIPINE & FELODEPINE.

• ON CHRONIC ADMINISTRATION VERAPAMIL INHIBITS ITS OWN METABOLISM AND THE BIOAVAILABILITY GETS DOUBLED AND t ½ PROLONGED.

ANTI-ANGINAL

• THERAPEUTIC USES OF CCBs:• THESE ARE SAFE IN ASTHMATICS AND

DIABETICS WHERE BETA BLOCKERS ARE CONTRAINDICATED.

• REBOUND INCREASE IN ANGINA AND B.P IS LESS MARKED WITH CCBs ON WITHDRAWAL AFTER CHRONIC USE AS IN THE CASE OF BETA BLOCKERS.

ANTI-ANGINAL

• THE IMPORTANT THERAPEUTIC USES ARE:• 1. CLASSICAL & VARIANT ANGINA.• 2. MYOCARDIAL INFARCTION.• 3. HYPERTENSION.• 4. CARDIAC ARRHYTHMIAS.• 5. HYPEETROPHIC CARDIOMYOPATHY.• 6. MISC: PREMATURE LABOUR, MIGRAINE,

NOCTURNAL LEG CRAMPS, P.V.Ds

ANTI-ANGINAL

• 1. ANGINA: ALL CCBs ARE EFFECTIVE IN REDUCING THE FREQUENCY & SECVEDRITY OF CLASSICAL AS WELL AS VARIANT ANGINA:

• REDUCE CARDIAC WORK BY DECREASING AFTERLOAD,

• INCREASE CORNARY BLOOD FLOW,• INCREASE EXERCIASE TOLERANCE.

ANTI-ANGINAL

• SHORT ACTING AND RAPIDLY ACXTING DHPs LIKE NIFEDEPINE CAN AGGRAEVATE MYOCARDIAL ISCHEMIA DUE TO DECREASED CORONARY BLOOD FLOW SECONDARY TO A DECREASE IN MEAN ARTERIAL B.P., REFLEX TACHYCARDIA AND CORONARY STEAL .

• DILTIAZEM & VERAPAMIL UNLIKELY TO DO SO AS THEY DIRECTLY DECREASE CARDIAC OXYGEN DEMAND AND PRODUCE LESS MARKED SYMPATHETIC STIMULATION.

ANTI-ANGINAL• MOREOVER, HIGH DOSE REGULAR SHORT ACTING

NIFEDEPINE FORMULATIONS ARE REPORTED TO INCREASE MORTALITY IN MI PATIENTS.

• THE SUDDEN RUSH OF SYMPATHETIC OVERACTIVITY PRODUCED BY EACH DOSE OF SUCH PREPARATIONS HAS BEEN HELD RESPONSIBLE FOR THIS DELETERIOUS EFFECT.

• THE SLOW AND LONG ACTING FORMULATIONS DO NOT HAVE THIS DISADVANTAGE.

• DILTIAZEM & VERAPAMIL REDUCE REINFARCTION & MORTALITY IN MI PATIENTS ALMOST COMPARABLE TO THAT OF BETA BLOCKERS PROVIDED THE PATIENTS HAVE UNCOMPROMISED LV-FUNCTION.

ANTI-ANGINAL• IN VARIANT ANGINA THE CCBs AFFORD BENEFIT

MAINLY DUE TO THEIR ABILITY TO REVERSE CORONARY VASOSPASM, THOUGH DECREASE OXYGEN DEMAND ALSO HELPS.

• THESE ARE DEFINITELY ADD ON DRUGS TO NITRATES IN VARIANT ANGINA.

• 2. MYOCARDIAL INFARCTION: THE CONSENSUS IS AGAINST THE USE OF CCBs IN MI.

• NEVERTHELESS VERAPAMIL & DILTIAZEM MAY BE USED FOR SECONDARY PROPHYLAXIS IN THOSE PATIENTS WHERE BETA BLOCKERS ARE CONTRAINDICATED.

ANTI-ANGINAL

• 3. HYPERTENSION: CCBs ARE NOW AMONGST THE FIRST LINE OF DRUGS FOR H.T.

• 4. CARDIAC ARRHYTHMIAS: • - VERAPAMIL & DILTIAZEM ARE HIGHLY EFFECTIVE

IN P.S.V.T. AND FOR CONTROLLING VENTRICULAR RATE IN SUPRAVENTRICULAR ARRHYTHMIAS.

• 5. HYPERTROPHIC CARDIOMYOPATHY: VERAPAMIL IS HIGHLY EFFECTIVE FOR ITS NEGATIVE INOTROPIC ACTION.

ANTI-ANGINAL• INDIVIDUAL CCBs:• 1. VERAPAMIL: • ARTERIOLAR DILATOR,• SOME ALPHA BLOCKING ACTION,• DECREASES TPR BUT B.P IS ONLY MODESTLY LOWERED,• PRONOUNCED & DIRECT CARDIAC NEGATIVE INOTROPIC ACTION,• H.R IS REDUCED,• A.V CONDUCTION IS SLOWED,• C.O. IS MAINTAINED BY SOME REFLEX SYMPATHETIC STIMULATION AND

DECREASE IN AORTIC IMPEDENCE,• CORONARY FLOW IS INCREASED,• BUT CARDIAC CONTRACTILITY IS MARKEDLY IMPAIRED IN CHF PATIENTS

SO CONTRAINDICATED. • DOSE: 40 – 160 mg TDS.

ANTI-ANGINAL• N, V, CONSTIPATION ARE MORE COMMON SIDE

EFFECTS BUT FLUSHING, HEADACHE AND ANKLE EDEMA ARE UNCOMMON.

• HYPOTENSION IS UNCOMMON.• TACHYCARDIA DOES NOT OCCUR.• CAN ACCENTUATE CONDUCTION DEFECTS, SO

CONTRAINDICATED IN 2ND AND 3RD DEGREE HEART BLOCKS.

• I.V. USE MAY CAUSE CARDIAC ARREST IN PATIENTS WITH SICK SINUS SYNDROME.

ANTI-ANGINAL

• DRUG INTERACTIONS OF VERAPAMIL:• - PRODUCES ADDITIVE SINUS DEPRESSION,

CONDUCTION DEFECTS, ASYSTOLE WITH BETA BLOCKERS.

• DECCREASES DIGITALIS EXCRETION, INCREASES ITS PLASMA CONCENTRATION TO TOXIC LEVELS.

• IT SHOULD NOT BE USED WITH DIRECT MYOCARDIAL DEPRESSANTS DRUGS LIKE QUINIDINE AND DISOPYRAMIDE

ANTI-ANGINAL• 2. DILTIAZEM:• LESS POTENT VASODILATOR THAN NIFEDEPINE &

VERAPAMIL.• MODEST DIRECT NEGATIVE INOTROPIC ACTION.• DIRECT DEPRESSANT ACTION ON S.A. & A.V. NODAL

CONDUCTION EQUAL TO VERAPAMIL.• USUAL DOSES CAUSE CONSISTENT FALL IN B.P WITHOUT

CHANGE IN HR OR BRADYCARDIA.• LARGE DOSES OR IV ADMINISTRATION DECREASES T.P.R.

MARKEDLY WITH REFLEX TACHYCARDIA.• DILATES CORONARIES.• DOSE: 30 – 60 mg TDS /QID.

ANTI-ANGINAL

• ADVERSE EFFECTS OF DILTIAZEM:• LOW INCIDENCE OF SIDE EFFECTS SIMILAR TO

VERAPAMIL.• INCREASES PLASMA DIGOXIN LEVELS.• CONTRAINDICATED IN PATIENTS OF SICK-

SINUS, A.V.NODAL OR MYOCARDIAL DISEASES.• ONLY LOW DOSES CAN BE GIVEN TO PATIENTS

RECEIVING BETA BLOCKERS.

ANTI-ANGINAL DRUGS• 3. NIFEDEPINE: • PROTOTYPE DIHYDROPYRIDINE CCB.• FAST & SHORTER ACTING.• VERY POTENT ARTERIOLAR DILATOR -> T.P.R DECREASES MARKEDLY ->

B.P FALLS ASSOCIATED WITH REFLEX TACHYCARDIA AND SYMPATHETIC OVERACTIVITY.

• HIGHER DOSES DIRECTLY DEPRESS THE HEART.• DOES NOT DEPRESS S.A OR A.V CONDUCTION.• REFLEX SYMPATHETIC STIMULATION PREDOMINATES -> TACHYCARDIA -

> INCREASED CONTRACTILITY, AND C.O. BECAUSE THERE IS NO DECREASE IN VENOUS RETURN WITH LOWERING OF AFTER LOAD.

• CORONARY BLOOD FLOW IS INCREASED. • IT HAS MILD NATRIURETIC ACTION BUT SIGNIFICANT DIURESIS DOES

NOT OCCUR.• DOSE: 5 – 20 mg. BD TO TDS, ORAL

ANTI-ANGINAL DRUGS• ADVERSE EFFECTS OF NIFEDEPINE:• FREQUENT SIDE EFFECTS ARE:• - PALPITATION,• - FLUSHING,• - ANKLE EDEMA,• - HYPOTENSION,• - HEADACHE,• - DROWSINESS, AND• - NAUSEA.• THESE ARE DOSE RELATED CAN BE MINMISED BY LOW

STARTIN DOSES, FRACTIONATION OF DOSES OR USING RETARD PREPARATION.

ANTI-ANGINAL DRUGS• OTHER SERIOUS SIDE EFFECTS ARE:• - PARADOXICAL AGGRAEVATION OF

ANGINA, • - HIGHER MORTALITY IN POST MI PATIENTS.• IT CAN BE SAFELY ADMINISTERED WITH BETA

BLOCKERS , DIGOXIN ETC.• IT CAN INCREASE URINE VOIDING DIFFICULTY IN

ELDERLY PATIENTS DUE ITS SMOOTH MM RELAXANT EFFECT ON URINARY BLADDER.

• IT DECREASES DIABETIC CONTROL BY INHIBITIN INSULIN RELEASE.

ANTI-ANGINAL DRUGS

• 4. FELODEPINE:• GREATER VASCULAR SMOOTH MM

SELECTIVITY THAN NIFEDEPINE.• LARGER TISSUE DISTRIBUTION,• LONGER t ½ .• EXTENDED RELEASE PREPARATION SUITABLE

FOR ONCE DAILY DOSING.• DOSE: 5 – 10 mg OD TO BD.

ANTI-ANGINAL DRUGS• 5. AMLODEPINE:• MOST DISTINCT DHP PHARMACOKINETICALLY.• COMPLETE BUT SLOW ORAL ABSORPTION.• PEAK IN 6 – 9 HRS., SO EARLY SIDE EFFECTS OF

VASODILATATION LIKE PALPITATION, FLUSHING, HEADACHE, POSTURAL DIZZINESS ARE LARGELY CIRCUMVENTED.

• HAS LESS VARIABLE FIRST PASS METABOLISM, AND CONSISTENT & HIGHER ORAL BIOAVAILABILITY.

• LARGE VOLUME DISTRIBUTION AND VERY LONG t ½ ,• DIURNAL FLUCTUATIONS IN BLOOD ARE MINIMAL & ACTION

EXTENDS TILL NEXT MORNING.• DOSE : 5 TO 10 mg OD.

ANTI-ANGINAL DRUGS• 6. NITRENDIPINE:• 10 – 30% ORALLY BIOVAILABLE,• t ½ 4 – 12 HRS.• RELEASES NITRIC OXIDE FROM ENDOTHELIUM.• INHIBITS c-AMP –PHOSPHODIESTERASE, AN

ADDITIONAL MECHANISM OF VASODILATOR ACTION.• VENTRICULAR CONTRACTILITY & AV CONDUCTION ARE

NOT DEPRESSED.• USED FOR H.T AND ANGINA.• DOSE : 5 TO 20 mg OD.

ANTI-ANGINAL DRUGS

• 7. LACIDIPINE:• HIGHLY VASOSELECTIVE.• ONCE DAILY DOSE• ATTAINS HIGHER CONCENTRATIONS IN

VASCULAR SMOOTH MM. MEMBRANE.• USED FOR HT ONLY.• DOSE: 4 mg OD.

ANTI-ANGINAL DRUGS• 8. NIMODIPINE:• LIPID SOLUBLE, ENTERS BRAIN, HIGHLY

CEREBROSELECTIVE.• APPROVED FOR PREVENTION AND TREATMENT

OF NEUROLOGICAL DEFICIT DUE TO CEREBRAL VASOSPASM FOLLOWING S.A.H OR RUPTURED CONGENITAL INTRACRANIAL ANEURYSMS.

• SIDE EFFECTS ARE HEADACHE, FLUSHING, DIZINESS, PALPITATION AND NAUSEA.

• DOSE : 30 – 60 mg 4 – 6 HOURLY FOR THREE WEEKS FOLLOWING S.A.H.

ANTI-ANGINAL DRUGS

• 9. LERCANIDIPINE:• SIMILAR TO NIFEDIPINE BUT LONGER ACTING,• PEAK IN 1.5 TO 3 HRS.• t½ IS 5 TO 10 HRS.• USED IN HT AND ANGINA.• DOSE : 10 TO 20 mg OD.

ANTI-ANGINAL DRUGS

• 10. BENIDIPINE:• LONG ACTING DHP DUE TO ITS SLOW

DISSOCIATION FROM DHP RECEPTOR ON THE SMOOTH MM CELLS.

• USED FOR HT AND ANGINA.• DOSE: 4 TO 8 mg OD.

ANTI-ANGINAL DRUGS

POTASSIUM CHANNEL OPENERS:• MINOXIDIL AND DIAZOXIDE ARE K+ CHANNEL

OPENERS WHICH HAVE BEEN USED SINCE LONG IN SEVERE HYPER TENSION AND HYPERTENSIVE EMERGENCIES.

• NEWER K+ CHANNEL OPENERS LIKE NICORANDIL, PINACIDIL, CROMAKALIM AND OTHERS HAVE BEEN DEVELOPED RECENTLY.

ANTI-ANGINAL• SINCE INTRACELLULAR CONCENTRATION OF K+ IS MUCH HIGHER

(150mM) COMPARED TO EXTRA CELLULAR (4-5mM), K+ CHANNEL OPENING RESULTS IN OUTFLOW OF K+ IONS AND HYPERPLOARIZATION.

• THERE ARE MULTIPLE TYPES OF K+ CHANNELS:• - VOLTAGE DEPENDENT, • - Ca++ ACTIVATED,• - RECEPTOR OPERATED,• - ATP SENSITIVE, • - Na+ ACTIVATED AND• - CELL VOLUME SENSITIVE.• ALL OF WHICH SERVE DIVERSE FUNCTIONS AND EXHIBIT DIFFERENT

SENSITIVITIES TO DRUGS. AS SUCH K+ CHANNEL OPENERS EXHIBIT CONSIDERABLE DIVERSITY IN ACTIONS.

• THE MOST PROMINENT ACTION OF K+ CHANNEL OPENERS IS SMOOTH MUSCLE RELAXATION BOTH VASCULAR AS WELL AS VISCERAL.

ANTI-ANGINAL

• THE POTENTIAL CLINICAL USES OF THESE DRUGS ARE BASED PRIMARILY ON THIS PROPERTY OF K+ CHANNEL OPENERS.

• DIAZPXIDE AND SOME OTHER K+ CHANNEL OPENERS REDUCE INSULIN SECRETION, WHILE THE SULPHONYL UREA O.H.As CAUSE HYPOGLYCEMIA BY BLOCKING K+ CHANNELS IN PANCREATIUC BETA CELLS AND PROMOTING INSULIN RELEASE.

ANTI-ANGINALPOTENTIAL THERAPEUTIC USES OF K+ CHANNEL OPENERS AREFOLLOWING:• 1. ANGINA PECTORIS,• 2. HYPERTENSION,• 3. CONGESTIVE HEART FAILURE,• 4. MYOCARDIAL SALVAGE IN M.I.,• 5. ANTIHYPOGLYCEMIC IN INSULINOMA,• 6. ALOPECIA,• 7. BRONCHIAL ASTHMA,• 8. URINARY URGE INCONTRINENCE,• 9. P.V.D. ( RENAUD’S DISEASE, CEREBROVASCULAR),• 10. ERECTILE DYSFUNCTION, AND• 11. PREMATURE LABOUR.

ANTI-ANGINALNICORANDIL:• THIS NOVEL ANTIANGINAL DRUG ACTIVATES ATP SENSITIVE

K+ CHANNELS – > HYPERPOLARIZING VASCULAR SMOOTH MUSCLE .

• LIKE NITRATES IT ALSO ACTS AS A NO DONOR –> RELAXES BLOOD VESSELS BY INCREASING C-GMP.

• ARTERIAL DILATATION IS COUPLED WITH VENODILATATION.

• CORONARY FLOW IS INCREASED BY THE DILATATION OF BOTH EPICARDIAL CONDUCTING VESSELS AND DEEPER RESISTANCE VESSELS.

• NO SIGNIFICANT CARDIAC EFFECTS ON CONTRACTILITY AND CONDUCTION HAVE BEEN NOTED.

ANTI-ANGINAL• BENEFICIAL EFFECTS ON ANGINA FREQUENCY AND EXERCISE

TOLERANCE COMPARABLE TO NITRATES, ΒETA BLOCKERS AND C.C.Bs HAVE BEEN OBTAINED IN STABLE AS WELL AS VASOSPASTIC ANGINA.

• SIDE EFFECTS ARE:• FLUSHING,• PALPITATION, • WEAKNESS, • HEADACHE, • DIZZINESS, • MOUTH ULCERS,• NAUSEA AND • VOMITING.• DOSE: 5 TO 20O mg BD.

ANTI-ANGINAL• MITOCHONDRIAL K+ATP CHANNEL OPENING BY

NICORANDIL IS BELIEVED TO EXERT MYOCARDIAL PROTECTION BY A PROCES CALLED ISCHEMIC PRECONDITIONINGWHICH APPEARS TO REDUCE MYOCARDIAL STUNNING, ARRHYTHMIAS AND INFARCT SIZE WHEN A CORONARY ARTERY IS SUDDENLY BLOCKED.

• MYOCARDIAL RECOVERY FROM ISCHEMIC DAMAGE AFTER MI AS MEASURED BY LEFT VENTRICULAR WAKLL MOTION IS ALSO IMPROVED BY NICORANDIL.

ANTI-ANGINALMISCELLANEOUS ANTI-ANGINAL DRUGS:1. DIPYRIDAMOLE:• - IT IS A POWERFUL CORONARY DILATOR, AND INCREASES TOTAL

CORONARY BLOOD FLOW BY PREVENTING UPTAKE & DEGRADATION OF ADENOSINE WHICH IS A LOCAL MEDIATOR INVOLVED IN AUTO-REGULATION OF CORONARY FLOW IN RESPONSE TO ISCHEMIA.

• - IT DILATES RESISTANCE VESSELS AND ABOLISHES AUTOREGULATION AND HAS NO EFFECT ON LARGER CONDUCTING CORONARY VESSELS. –-- CARDIAC WORK IS NOT DECREASED BECAUSE VENOUS RETURN IS NOT REDUCED.

• - B.P. IS MINIMALLY ALTERED.• - IT DOES NOT AFFORD SYMPTOMATIC RELIEF OR AVERT E.C.G.

CHANGES OF ANGINA.

ANTI-ANGINAL

• THE PHARMACOLOGICAL SUCCESS BUT THERAPEUTIC FAILURE OF DIPYRIDAMOLE HAS BEEN EXPLAINED ON THE BASIS OF ‘CORONARY STEAL’ PHENOMENON.

• BY DILATING RESISTANCE VESSELS IN NON-ISCHAEMIC ZONE AS WELL, IT DIVERTS THE ALREADY REDUCED BLOOD FLOW AWAY FROM ISCHAEMIC ZONE.

ANTI-ANGINAL

• - DIPYRIDAMOLE INHIBITS PLATELET AGGREGATION.

• - THOUGH NOT USEFUL AS AN ANTIANGINAL DRUGS IT IS BEING EMPLOYED FOR PROPHYLAXIS OF CORONARY AND CEREBRAL THROMBOSIS IN POST MI AND POST-STROKE PATIENTS, AS WELL AS TO PREVENT THROMBOSIS IN PATIENTS WITH PROSTHETIC HEART VALVES.

• DOSE: 25 – 100 mg. TDS.

ANTI-ANGINAL2. TRIMETAZIDINE:• THIS NOVEL ANTIANGINAL DRUG ACTS BY NON-

HAEMODYNAMIC MECHANISMS. • THERE IS NO EFFECT ON DETERMINANTS OF

MYOCARDIAL O2 - CONSUMPTION, SUCH AS H.R. AND B.P., BOTH AT REST AS WELL AS DURING EXERCISE, BUT ANGINA FREQUENCY IS REDUCED AND EXERCISE CAPACITY IS INCREASED.

• IN NITRATE/ Β BLOCKER /CCB, ADDITION OF TRIMETAZIDINE FURTHER REDUCES ANGINAL ATTACKS AND INCREASES EXERCISE DURATION.

ANTI-ANGINAL• THE MECHANISM OF ACTION OF TRIMETAZIDINE IS NOT

KNOWN, BUT IT MAY IMPROVE CELLULAR TOLERANCE TO ISCHAEMIA BY FOLLOWING MECHANISMS:

• - INHIBITING MITOCHONDRIAL LONG CHAIN 3-KETOACYL-CoA-THIOLASE (LC3-KAT), A KEY ENZYME IN FATTY ACID OXIDATION -> THERBY REDUCINGFATTY ACID METABOLISM & INCREASING GLUCOSE METABOLISM IN MYOCARDIUM. ISCHEMIC MYOCARDIUM SHIFTS TO UTILIZING FATTY ACIDS AS SUNSTRATE -> INCREASING OXYGEN REQUIREMENT FOR THE SAME AMOUNT OF ATP GENERATED. SINCE OXIDATION OF FATTY ACIDS REQUIRESC MORE OXYGEN SHIFT BACK OF SUBSTRATE TO GLUCOSE WOULD REDUCE OXYGEN DEMAND. IT HAS BEEN LABELLED AS PFOX ( FATTY ACID OXIDATION PATHWAY) INHIBITOR.

ANTI-ANGINAL• - LIMITING INTRACELLULAR ACIDOSIS AND

Na+, Ca+ ACCUMULATION DURING ISCHEMIA,• - PROTECTING AGAINST O+ FREE RADICAL

INDUCED MEMBRANE DAMAGE. • TRIMETAZIDINE IS ABSORBED ORALLY, PARTLY

METABOLIZED AND LARGELY EXCRETED UNCHANGED IN URINE.

• TRIMETAZIDINE IS GENERALLY WELL TOLERATED; SIDE EFFECTS ARE: GASTRIC BURNING, DIZZINESS, FATIGUE AND MUSCLE CRAMPS AND REVERSIBLE PARKINSONISM.

ANTI-ANGINAL• STATUS OF TRIMETAZIDINE IN ISCHAEMIC HEART

DISEASE AND LONG-TERM SURVIVAL BENEFITS ARE NOT YET DEFINED. IT IS MOSTLY USED AS ADDITIONAL MEDICATION TO CONVENTIONAL THERAPY IN ANGINA AND POST – MI PATIENTS.

• OTHER USES OF TRIMETAZIDINE ARE:• - VISUAL DISTURBANCES,• - TINNITUS,• - MENIERE’S DISEASE,• - DIZZINESS

ANTI-ANGINAL• 3. RANOLAZINE:• NEW CONGENER LC3-KAT-INHIBITOR.• USED FOR CHRONIC ANGINA NOT RESPONDING TO OTHER DRUGS.• IT SPARES FATTY ACID OXIDATION & SHIFTS ATP PRODUCTION TO MORE OXYGEN

EFFICIENT CARBOHYDRATE OXIDATION.• ALSO INHIBITS LATE I-Na CURRENT IN MYOCARDIUM WHICH INDIRECTLY

FACILITATE Ca++ ENTRY. REDUCTION IN Ca++ OVERLOAD IN THE MYOCARDIUM DURIN ISCHEMIA MAY PLAY AN IMPORTANT ROLE IN THE CARDIOPROTECTION ACTION OF RANOLAZINE.. CAN BE USED AS MONOTHERAPY OR ADD ON THERAPY IN ANGINA.

• SLOW ORAL ABSORPTION.• PEAK IN 4 TO 6 HRS.• ORAL BIOAVAILABILITY 30 TO 40%. METABOLISED IN LIVER, EXCRETED IN URINE,

t ½ 7 HRS.• ADDED SIDE EFFECTS ARE POSTURAL HYPOTENSION, PROLONGATION OF QT-

INTERVAL WITH RISK OF TORSIDES DE POINTES. • DOSE : 0.5 TO 1.0 gm. BD.

ANTI-ANGINAL

• 4. OXYPHEDRINE:• IT IMPROVES MYOCARDIAL METABOLISM SO

THAT HEART CAN SUSTAIN HYPOXIA BETTER.• IT CAN DIMINISH OR ALTER TASTE

SENSATION.• DOSE : 8 TO 24 mg TDS

ANTI-ANGINAL

DRUG THERAPY IN MYOCARDIAL INFARCTION :• MYOCARDIAL INFARCTION (MI) IS ISCHAEMIC

NECROSIS OF A PORTION OF THE MYOCARDIUM DUE TO SUDDEN OCCLUSION OF A BRANCH OF CORONARY ARTERY. AN ACUTE THROMBUS AT THE SITE OF ATHEROSCLEROTIC OBSTRUCTION IS THE USUAL CASE.

ANTI-ANGINAL

• ABOUT ¼ PATIENTS DIE BEFORE THERAPY CAN BE INSTITUTED. THE REMAINING ARE BEST TREATED IN SPECIALIZED CORONARY CARE UNITY WITH CONTINUOUS MONITORING OF THE HAEMODYNAMIC PARAMETERS AND ECG GUIDE THE SELECTION OF DRUGS AND DOSAGE. THOSE WHO RECEIVE SUCH FACILITY CAN BE GREATLY BENEFITED BY DRUG THERAPY, WHICH ACCORDING TO INDIVIDUAL NEEDS IS DIRECTED TO FOLLOWING AIMS.

ANTI-ANGINAL1. PAIN, ANXIETY AND APPREHENSION:- OPIOID

ANALGESICS (MORPHINE/PETHIDINE), DIAZEPAM.2. OXYGENATION:- BY O2 INHALATION AND

ASSISTED RESPIRATION, IF NEEDED. 3. MAINTENANCE OF BLOOD VOLUME, TISSUE,

PERFUSION AND MICROCIRCULATION:- SLOW I.V. INFUSION OF SALINE/ LOW MOLECULAR WEIGH DEXTRAN (AVOID VOLUME OVERLOAD).

4. CORRECTION OF ACIDOSIS:- DUE TO LACTIC ACID PRODUCTION – SOD. BICARBONATE BY I.V. INFUSION.

ANTI-ANGINAL

5.PREVENTION AND TREATMENT OF ARRHYTHMIAS:- PROPHYLACTIC INFUSION OF Β BLOCKER AS SOON AS ATHE MI PATIENT IS SEEN AND ITS CONTINUATION FOR A FEW DAYS HAS BEEN SHOWN TO REDUCE THE INCIDENCE OF ARRHYTHMIAS AND MORTALITY. Β BLOCKERS USED EARLY IN EVOLVING MI CAN REDUCE THE INFARCT SIZE (MYOCARDIAL SALVAGE) AND SUBSEQUENT COMPLICATIONS.

ANTI-ANGINAL

• TACHYARRHYTHMIAS MAY BE TREATED WITH LIGNOCAINE, PROCAINAMIDE OR OTHER ANTIARRHYTHMICS. ROUTINE PROPHYLACTIC LIGNOCAINE INFUSION IS NOT RECOMMENDED NOW. BRADYCARDIA AND HEART BLOCK MAY BE MANAGED WITH ATROPINE OR ELECTRICAL PACING.

ANTI-ANGINAL

6.PUMP FAILURE:- THE OBJECTIVE IS TO INCREASE C.O. AND/OR DECREASE FILLING PRESSURE WITHOUT UNDULY INCREASING CARDIAC WORK OR REDUCING BP. DRUGS USED FOR THIS PURPOSE ARE:

• FUROSEMIDE:- INDICATED IF PULMONARY WEDGE PRESSURE IS > 20MM HG. IT DECREASES CARDIAC PRELOAD..

ANTI-ANGINAL• VASODILATORS:- ARTERIOLAR, VENOUS OR

COMBINED DILATOR IS SELECTED ACCORDING TO THE MONITORED HAEMODYNAMIC PARAMETERS. DRUGS LIKE GTN (I.V.), CAPTOPRIL, OR NITROPRUSSIDE HAVE BEEN MAINLY USED. INFUSED EARLY GTN MAY IN ADDITION LIMIT INFARCT SIZE AND REDUCE MORTALITY

• INOTROPIC AGENTS:- DOPAMINE OR DOBUTAMINE MAY BE NEEDED T AUGMENT THE PUMPING ACTION OF HEART AND TIDE OVER CRISIS.

ANTI-ANGINAL DRUGS7. PREVENTION OF THROMBUS EXTENSION,

EMBOLISM, VENOUS THROMBOSIS:- HEPARIN FOLLOWED BY ORAL ANTICOAGULANTS. HOWEVER, VALUE IS DISPUTED. ANY BENEFIT IS SHORT TERM; ANTICOAGULANTS ARE NOT PRESCRIBED ON LONG-TERM BASIS NOW.

8. THROMBOLYSIS:- FIBRINOLYTIC AGENTS, I.E., PLASMINOGEN ACTIVATORS- STREPTOKINASE/UROKINASE/ALTEPLASE TO ACHIEVE REPERFUSION OF THE INFRACTED AREA.

ANTI-ANGINAL DRUGS

9. PREVENTION OF REMODELING AND SUBSEQUENT CHF:- ACE INHIBITORS HAVE PROVEN EFFICACY AND AFFORD LONG TERM SURVIVAL BENEFIT.

ANTI-ANGINAL DRUGS

10. PREVENTION OF FUTURE ATTACKS:• PLATELET FUNCTION INHIBITORS –ASPIRIN GIVEN

ON LONG-TERM BASIS IS ROUTINELY PRESCRIBED.• Β BLOCKERS- REDUCE RISK OF REINFARCTION,

CHF AND MORTALITY. ALL PATIENTS NOT HAVING ANY CONTRAINDICATION ARE PUT ON A Β BLOCKER FOR AT LEAST 2 YEARS.

• CONTROL OF HYPERLIPIDAEMIA DIETARY SUBSTITUTION WITH UNSATURATED FAST, HYPOLIPIDEMIC DRUGS.

ANTI-ANGINAL DRUGS

• THANK YOU !