ANTI-ANGINAL DRUGS

DR. KARUN KUMAR

JUNIOR RESIDENT-I

DEPARTMENT OF PHARMACOLOGY

What is Angina ?

▪Symptom complex caused by transient myocardial ischemiaand constitutes a “clinical syndrome” rather than a disease.

▪ The term derives from the Latin angina ("infection of thethroat") from the Greek ankhonē ("strangling"), and theLatin pectus ("chest"), and can therefore be translated as "astrangling feeling in the chest".

▪ Intermittent chest paincaused by transient,reversible, myocardialischemia

▪Pain is relieved by rest or bytaking nitrates.

PATHOPHYSIOLOGY▪ Imbalance betweenmyocardial oxygensupply and demand

▪Most common cause Coronary atheroma(esp. in Left anteriordescending artery)

Due to inadequacy of ischemicleft ventricle, the end diastolicleft ventricular pressure risesfrom about 5 to 25 mm Hg-produces subendocardial‘crunch’ during diastole andaggravates the ischemia in thisregion.

SITE OF PAIN

▪Pain is typically substernal

▪ It is described as a constrictingsensation, pressure like feeling ortightness in the chest and isfrequently transmitted to the neck,left shoulder, left arm or lower jaw.

▪Occasionally, it radiates to theback or down the right arm.

TYPES

▪ Typical/stable angina

▪Prinzmetal/Variant angina

▪Unstable/Crescendo angina

▪Angina with normal coronary

arteries

▪Microvascular angina

STABLE ANGINA▪Also known as effort angina

▪ It is usually associated with a fixed atheroscleroticnarrowing (>=75%) of one or more coronary arteries

▪With this degree of critical stenosis, myocardial oxygensupply may be sufficient under basal conditions but cannotbe adequately augmented to meet increased requirements

▪Attacks are predictably provoked by exercise, emotion(anger, fear), sexual intercourse, and subside when theincreased energy demand is withdrawn.

▪Stress test shows ST segment depression

▪Pain lasts from 30 seconds to 30 minutes and is relieved byrest or nitroglycerine

VARIANT ANGINA (VA)▪ Temporary increase in coronary vascular tone (vasospasm)causing a marked, but transient reduction in luminaldiameter[1]

▪Patients are predominantly younger women[1]

▪ It has been associated with vasospastic disorders such asRaynaud's phenomenon and migraine headaches.[1]

1. Keller KB, Lemberg L. Prinzmetal’s angina. Am J Crit Care. 2004;13(4):350-4

▪As it is not a "demand"- induced symptom, but rather asupply (vasospastic) abnormality, exercise treadmill stresstesting is of no value in the diagnosis of VA.

▪ The most sensitive and specific test for VA is theadministration of ergonovine intravenously.

▪50 micrograms of Ergonovine is given at 5-minute intervalsuntil a positive result or a maximum dose of 400 microghas been administered.

▪When positive, the symptoms and associated ST-segmentelevation should be present.

▪Nitroglycerin rapidly reverses the effects of ergonovine ifrefractory spasm occurs.

▪Medical therapy classically employs vasodilator drugs,which include nitrates and calcium channel blockers.

▪Beta-Blockers and large doses of aspirin are contraindicatedin VA.

UNSTABLE ANGINA▪ Also known as crescendo angina or pre-infarction angina

▪ It has at least one of these three features:[2]

1) It occurs at rest (or minimal exertion), usually lasting >10 min;

2) It is severe and of new onset (i.e., within the prior 4–6 weeks);

3) It occurs with a crescendo pattern (i.e., distinctly more severe,prolonged, or frequent than previously).

2. Daniel, 2010. http://kardzmed.com/kardz/health-life/item/240-angina-pectoris

▪ It is characterized by increased frequency of pain,precipitated by progressively less exertion; the episodes alsotend to be more intense and longer lasting than stableangina

▪ It is associated with plaque disruption

▪64% of all episodes occurring between 10 PM and 8 AM,this nocturnal preponderance being evident for episodeswith or without a preceding increase in heart rate. [3]

3. Patel DJ, Knight CJ, Holdright DR, Mulcahy, Clarke D, Wright C et al. Pathophysiology ofTransient Myocardial Ischemia in Acute Coronary Syndromes. 1996.

ANGINA WITH NORMAL CORONARYARTERIES▪ Normal or nonobstructive coronary disease at angiography is not

uncommon and occurs in 10% of women presenting with ST-segment elevation myocardial infarction compared with 6% inmen.[4]

▪ Randomized placebo-controlled studies have demonstrated thattricyclic antidepressants, beta-blockers, angiotensin-convertingenzyme inhibitors, L-arginine, statins, and exercise may relievesymptoms, vascular dysfunction, or both; however, longer-termstudies evaluating cardiac event rates need to be performed.[4]

4. Bugiardini R, Bairy CNM. Angina with “normal” coronary arteries:a changing philosophy. JAMA.2005;293(4):477-84.

MICROVASCULAR ANGINA▪Also known as angina syndrome X.

▪Cardiac syndrome X defines patients with typical chest pain,transient ischaemic ST segment changes during effort andnormal coronary angiograms[5]

▪ It appears to be due to spasm in the tiny blood vessels ofthe heart arms, and legs[6]

▪Patients cope well with this type of angina and have veryfew long-term side effects[6]

5. Kaski JC, Perez RF. Rev Esp Cardiol. 2002;55 Suppl 1:10-6.

6. http://www.texasheartinstitute.org/hic/topics/cond/angina.cfm

MANAGEMENTNON-PHARMACOLOGIC MEASURES

A)Explanation and reassurance

B)Do not smoke

C) Aim for ideal body weight

D)Take regular exercise (May promotecollateral vessels)

E) Avoid severe exertion and vigorousexercise

F) Correction of established risk factors

PRINCIPAL THERAPEUTIC GOAL

Heart rate

Contractility

Preload

Afterload

Beta blockers

Calcium channel

blockers (CCBs)

Organic nitrates

Calcium channel

blockers

Coronary blood

flow

Regional

myocardial

blood flow

Vasodilators (esp.

CCBs), statins, anti-

thrombotics, stents,

angioplasty, CABG

surgery

Oxygen

demand

Oxygen

supply

Balance

Ischemia

=

>

Agents decreasing myocardial oxygen

demand Agents increasing myocardial blood flow

MEDICAL MANAGEMENT

▪1) ACUTE ATTACK:- NITROGLYCERIN AND ISOSORBIDEDINITRATE

▪2) FIRST LINE DRUGS:- NITRATES AND BETA BLOCKERS

▪3) SECOND LINE DRUGS:- CALCIUM CHANNEL BLOCKERSAND POTASSIUM CHANNEL OPENERS

NITRATES▪A) CLASSIFICATION:-

▪ i) Short acting:- Glyceryl trinitrate[GTN] (sublingual), Isosorbide dinitrate[IDN] (sublingual), Amyl nitrite (shortest acting)

▪ ii) Long acting:- Isosorbide dinitrate (oral), Isosorbidemononitrate, Erythritol tetranitrate, Pentaerythritoltetranitrate (longest acting)

B) PREPARATION AND DOSE:- GTN (Angised)-0.5 mg tab.; IDN (Sorbitrate) -5, 10 mg tab.

MECHANISM OF ACTIONRapidly denitrated in smooth muscle cell

Nitric oxide released

Activation of guanylyl cyclase

Increased cyclic guanosine monophosphate (cGMP)

Dephosphorylation of myosin light chain kinase (MLCK)

CORONARY STEAL PHENOMENON

ADVERSE EFFECTS▪ These are mostly due to vasodilatation[7]

▪Headache is the most common side effect of nitrates; oftendose-related and reported by up to 82% of patients inplacebo-controlled trials[8]

▪Nearly 10% of patients are unable to tolerate nitrates due todisabling headaches or dizziness[8]

▪Other adverse effects are tachycardia, orthostatichypotension and methemoglobinemia[7]

▪Rashes are rare, though relatively more common withpentaerythritol tetranitrate[7]

7. Tripathi KD. Antianginal and other anti-ischaemic drugs. In: Tripathi M, editor. Essentialsof Medical Pharmacology. 7th ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd;2013. p. 542.

8. Thadani U, Rodgers T. Side effects of using nitrates to treat angina. Expert Opin Drug Saf.2006;5(5):667-74.

TACHYPHYLAXIS AND CONTRAINDICATIONS

▪ Tolerance can develop to nitrates on chronic use (NOT seenwith sublingual use). Thus, for clinical use, at least 8 hoursof drug free period per day is required.

▪Administration of nitrates is contraindicated withconcomitant use of phosphodiesterase-5 inhibitors used forthe treatment of erectile dysfunction, as combinationtherapy may lead to profound hypotension and evendeath.[8]

BETA BLOCKERSA) CLASSIFICATION:-

i) Non-selective:-Propranolol, Sotalol, Timolol, Pindolol,Labetalol, Carvedilol

ii) Cardioselective:-Metoprolol, Atenolol, Acebutolol,Bisoprolol, Esmolol, Betaxolol, Celiprolol, Nebivolol

B) Preparation and Dose:-Pindolol(Visken)-10, 15 mg tab.;Dose-10-30 mg per day; Metoprolol(Betaloc)-25, 50, 100 mgtab.; Dose-100-400 mg day

MECHANISM OF ACTION

▪Reduction of heart rate and blood pressure Decreasedmyocardial oxygen consumption Improved exercisetolerance

▪Beta-Blockers provide similar clinical outcomes and areassociated with fewer adverse events than calciumantagonists in randomized trials of patients who have stableangina.[9]

9. Heidenreich PA, McDonald KM, Hastie T, Fadel B, Hagan V, Lee BK, et al., 1999. Meta-analysis of trials comparing beta-blockers, calcium antagonists, and nitrates for stableangina. JAMA. 1999;281(20):1927-36

ADVERSE EFFECTS1. Bradycardia

2. Bronchoconstriction

3. Claudication

4. Plasma lipid profile altered

5. Vivid dreams and nightmares

6. Reduced sensitivity to hypoglycemia

7. Fatigue

8. Erectile dysfunction

CONTRAINDICATIONS1. Asthma

2. Chronic obstructivepulmonary disease

3. Diabetes mellitus

4. Severe bradycardia

5. Bradycardia-tachycardiasyndrome (variant of sicksinus syndrome)

6. Atrioventricularblockade

7. Unstable leftventricular failure

8. Prinzmetal’s angina

9. Peripheral vasculardisease

CALCIUM CHANNEL BLOCKERS A) CLASSIFICATION:-

i) Phenylalkylamine:-Verapamil

ii) Benzothiazepine:-Diltiazem

iii) Dihydropyridines:- Nifedipine, Felodipine, Amlodipine,Nitrendepine, Nimodipine, Lacidipine, Lercanidipine,Benidipine, Isradipine, Nicardipine, Nisoldipine

B) Preparations and Dose-Verapamil(Calaptin)–40, 80 mgtab., Dose – 40-160 mg TDS oral; Diltiazem(Dilzem) – 30, 60mg tab., Dose – 30-60 mg TDS-QID oral

MECHANISM OF ACTIONBlock voltage gated L-type calcium channels

Drugs bind more effectively to open channels and inactivated channels

Reduces the frequency of opening in response to depolarization

Decrease in transmembrane calcium current

Decrease in contractility throughout the heart and decrease in sinus node pacemaker rate and atrioventricular node conduction velocity

ADVERSE EFFECTS▪Well tolerated, associated with few side effects.

▪ In recent trials

▪Antihypertensive and Lipid-Lowering Treatment to PreventHeart Attack Trial (ALLHAT)

▪ International Verapamil Slow-Release/Trandolapril Study(INVEST)

▪Controlled Onset Verapamil Investigation of CardiovascularEndpoints (CONVINCE) study

no association with precipitation of cardiovascular eventsfound. [10]

▪Dihydropyridines may cause reflex tachycardia, flushing,headache, and ankle swelling. Diltiazem and verapamildepress cardiac conduction and cause bradycardia, andshould not be given to people with heart block or treatedwith a β blocker. Verapamil may cause constipation.[11]

10. Eisenberg MJ, Brox A, Bestawros AN. Calcium channel blockers: an update. Am J Med.2004;116(1):35-43.

11. NICE Clinical Guidelines, No. 126. National Clinical Guidelines Centre (UK). Royal Collegeof Physicians (UK); 2011.

CONTRAINDICATIONS▪ In patients with unstable angina, immediate-release short-acting

calcium channel blockers can increase the risk of adverse cardiacevents and therefore are contraindicated.[12]

▪ Calcium channel blockers do not reduce the risk of initial orrecurrent infarction or death when given routinely to patients withacute myocardial infarction or unstable angina.[13]

12. Katzung BG. Vasodilators and the treatment of angina pectoris. In: Katzung BG, MastersSB, Trevor AJ, editors. Basic and Clinical Pharmacology. 12th ed. India: McGraw-Hill; 2012. p.205.

13. Held PH, Yusuf S, Furberg CD. Calcium channel blockers in acute myocardial infarctionand unstable angina: an overview. BMJ. 1989;299(6709):1187-92.

POTASSIUM CHANNEL OPENERS

A) CLASSIFICATION:- Nicorandil, Pinacidil, Cromakalim,Minoxidil, Diazoxide

B) Preparation:-Nicorandil(Nikoran)5,10mg tabs.;Dose–5-20mg BD

Nicorandil inhibits rest and effort angina unresponsive tousual doses of calcium antagonist and oral nitrate.[14]

Use

Resistant angina

Adverse effects

Flushing, palpitation, weakness, headache, dizziness,nausea, vomiting

Drug interactions

Sildenafil

MECHANISM OF ACTION▪ Activation of ATP sensitive potassium channels

Hyperpolarization of vascular smooth muscle

▪ NO donor Increased cGMP Relaxation of blood vessels

▪ Nicorandil is believed to exert cardioprotective action by stimulating‘ischaemic preconditioning’ as a result of activation ofmitochondrial KATP channels (Ischaemic preconditioning is aphenomenon in which brief periods of ischaemia and reperfusionexert a cardioprotective effect on subsequent total vascularocclusion)

14. Araki H, Hayata N, Matsuguchi T, Nakamura M. Effects of nicorandil on rest and effort angina unresponsiveto combination therapy with a calcium antagonist and oral nitrate. Clin Ther. 1987;9(2):174-82.

OTHER ANTI-ANGINAL DRUGS1. DIPYRIDAMOLE:-

It inhibits platelet aggregation by potentiatingPGI2 and increasing cAMP in platelets.

It is not useful as an anti-anginal drug(“coronary steal”) but is being employed for prophylaxis ofcoronary and cerebral thrombosis in post-MI and post-stroke patients, as well as to prevent thrombosis inpatients with prosthetic heart valves.

Preparation is Persantin (25, 75, 100 mg tab.)and dose is 25 - 100 mg TDS

2. TRIMETAZIDINEIt is used as an add on medication to conventional

therapy in angina and post-MI patients.

Mechanism of action

It causes inhibition of mitochondrial enzyme longchain 3-ketoacyl thiolase (LC-3KAT) Reduces fatty acidmetabolism in myocardium and increases glucosemetabolism Shift back of substrate to glucose decreasesoxygen demand.

Side effects are gastric burning, dizziness, fatigue,muscle cramps.

Other uses are visual disturbances, tinnitus,Meniere’s disease.

Preparation:-Flavedon 20 mg tabs.; Dose- 20 mgTDS

3. RANOLAZINE

It is a newer antianginal drug used in prophylaxis ofangina

Mechanism of action-It acts by reducing a latesodium current (INa) that facilitates calcium entry via thesodium-calcium exchanger Decreased intracellularcalcium concentration Decreased cardiac contractility andwork

It also inhibits LC-3KAT

Adverse effects - Dizziness, weakness, constipation,postural hypotension, headache and dyspepsia.

Drug interactions – Avoided in patients takingCYP3A4 inhibitors.

Preparation - Ranozex 0.5 g SR tab.; Dose – 0.5 – 1gm BD as SR tab

4. IVABRADINE

It has been introduced recently.

Uses-

a) Chronic stable angina with sinus rhythm (patients in whombeta blockers are contraindicated or they are intolerant tobeta blockers)

b) Inappropriate sinus tachycardia

Mechanism of action-Relatively selective If sodiumchannel blocker that reduces cardiac rate byinhibiting the hyperpolarization-activated sodiumchannel in the sinoatrial node

Preparation – Ivabrad (5, 7.5 mg tab.)

Dose – Initially 5 mg BD, increase if needed to 7.5mg BD

5. OXYPHEDRINE

It improves myocardial metabolism so that heart cansustain hypoxia better.

Preparation – Ildamen (8, 24 mg tab.)Dose – 8-24 mg TDS oral

6. FASUDIL

Rho-kinase plays an important role in calciumsensitization for vascular smooth muscle (VSMC) contraction andmay be involved in the inappropriate coronary vasoconstrictionduring exercise-induced myocardial ischemia.[15]

It is an inhibitor of smooth muscle Rho kinasewhich reduces coronary vasospasm in experimental animals.

In clinical trials in patients with coronary arterydisease, it has improved performance in stress tests.

15. Shimokawa H, Hiramori K, Iinuma H, Hosoda S, Kishida H, Osada H et al. Anti-anginaleffect of fasudil, a Rho-kinase inhibitor, in patients with stable effort angina: a multicenterstudy. J Cardiovasc Pharmacol. 2002;40(5):751-61.

7. ALLOPURINOLExperimental evidence suggests that xanthine oxidase inhibitors reduce

myocardial oxygen consumption. Due to this fact, this class of inhibitors couldbecome a new treatment for ischaemia in patients with angina pectoris.[16]

The mechanism of the anti-ischemic effect of allopurinol could berelated to its reducing xanthine oxidase-induced oxidative stress.[17]

16. Noman A, Ang DS, Ogston S, Lang CC, Struthers AD. Effect of high-dose allopurinol onexercise in patients with chronic stable angina: a randomised, placebo controlled crossovertrial. Lancet. 2010;375(9732):2161-7.

17. Rajendra NS, Ireland S, George J, Belch JJ, Lang CC, Struthers AD. J Am Coll Cardiol.2011;58(8):820-8.

SURGICAL INTERVENTION▪PCI (Percutaneous CoronaryIntervention)

▪CABG (Coronary Artery BypassGraft)

STABLE ANGINA▪Drug of choice depends on individual patient’s response

▪ In hypertensive patients, monotherapy with either slow-release or long-acting calcium channel blockers or βblockers may be adequate

▪ In normotensive patients, long-acting nitrates may be suitable.

▪Combination therapy has been found to be more effective than monotherapy as can be clearly seen in the below mentioned clinical trials:-

a) The combination of a calcium antagonist and a beta-blocker is statistically more effective than eithermonotherapy.[18]

b) The combination of trimetazidine with beta-blockers orlong-acting nitrates significantly improves exercise stress testparameters and angina symptoms compared withplacebo.[19]

c) Trimetazidine is useful for combination therapy in patientswith stable angina insufficiently controlled by monotherapywith a beta-blocker.[20]

18. Klein WW, Jackson G, Tavazzi L. Efficacy of monotherapy compared with combinedantianginal drugs in the treatment of chronic stable angina pectoris: a meta-analysis. CoronArtery Dis. 2002;13(8):427-36.

19. Chazov EI, Lepakchin VK, Zharova EA, Fitilev SB, Levin AM, Rumiantzeva EG, Fitileva TB.Trimetazidine in Angina Combination Therapy--the TACT study: trimetazidine versusconventional treatment in patients with stable angina pectoris in a randomized, placebo-controlled, multicenter study. Am J Ther. 2005;12(1):35-42.

20. Szwed H, Sadowski Z, Elikowski W, Koronkiewicz A, Mamcarz A, Orszulak W, et al.Combination treatment in stable effort angina using trimetazidine and metoprolol: resultsof a randomized, double-blind, multicentre study (TRIMPOL II). TRIMetazidine in POLand. EurHeart J. 2001;22(24):2267-74.

VARIANT ANGINA▪ Calcium channel blockers are extremely effective in preventing

coronary spasm. The long-acting nitrate, nicorandil, and Rho-kinaseinhibitor are also useful for inhibiting coronary artery spasm.[21]

▪ Stent implantation in patients with recurrent variant anginarefractory to medical treatment may be an alternative treatment incarefully selected, clinically unstable patients.[22]

21. Kusama Y, Kodani E, Nakagomi A, Otsuka T, Atarashi H, Kishida H, et al. Variant anginaand coronary artery spasm: the clinical spectrum, pathophysiology, and management. JNippon Med Sch. 2011;78(1):4-12

22. Martí V, Ligero C, García J, Kastanis P, Guindo J, Domínguez de Rozas JM. Stentimplantation in variant angina refractory to medical treatment. Clin Cardiol.2006;29(12):530-3.

UNSTABLE ANGINA▪Aggressive antiplatelet therapy with Aspirin and Clopidogrelis indicated.

▪ In nonprior aspirin users, combination antithrombotictherapy with aspirin plus anticoagulation significantlyreduces recurrent ischemic events in the early phase ofunstable angina[23]

▪ If PCI with stenting is required, glycoprotein (GP) IIb/IIIainhibitors such as Abciximab, Eptifibatide or Tirofibanshould be added.

▪ In addition, therapy with nitroglycerin and β blockers shouldbe considered

▪Calcium channel blockers should be added in refractorycases

▪Primary lipid-lowering and angiotensin converting enzyme(ACE) inhibitor therapy should also be initiated.

23. Cohen M, Adams PC, Parry G, Xiong J, Chamberlain D, Wieczorek I, et al. Combinationantithrombotic therapy in unstable rest angina and non-Q-wave infarction in nonprior aspirinusers. Primary end points analysis from the ATACS trial. Antithrombotic Therapy in AcuteCoronary Syndromes Research Group. Circulation. 1994;89(1):81-8.

▪ Consideration should be given to measuring serum levels of acardiac troponin (either T or I) and using intravenous GP IIb-IIIainhibitors and low-molecular-weight heparin in the standardmanagement of patients with unstable angina.[24]

▪ Nondrug therapies for unstable angina include intra-aortic ballooncounterpulsation, percutaneous transluminal coronary angioplasty,and coronary-artery bypass surgery.[25]

24. Braunwald E, Califf RM, Cannon CP, Fox KA, Fuster V, Gibler WB, et al. Redefiningmedical treatment in the management of unstable angina. Am J Med. 2000;108(1):41-53.

25. Spinler SA, Davis LE. Advances in the treatment of unstable angina pectoris. Clin Pharm.1991;10(11):825-38.

REFRACTORY ANGINA▪Clinical trials have shown that combined haemodynamicand metabolic treatment is more effective than combinedhaemodynamic therapy and is well tolerated.[26]

▪Haemodynamic agents are nitrates, β blockers and calciumchannel blockers.

▪Metabolic agents such as Trimetazidine or L-carnitine are anew class of drugs that directly modify the use of energysubstrates in the heart, lessening ischaemic injury andimproving cardiac performance during ischaemia.[26]

▪For patients with severe angina pectoris not responding tocombination therapy of a β-blocker with a nitrate, tripletherapy may be of advantage, although the number ofpatients studied has been small.[27]

26. Jackson G. Combination therapy in angina: a review of combined haemodynamictreatment and the role for combined haemodynamic and cardiac metabolic agents. Int JClin Pract. 2001;55(4):256-61.

27. W.E.M. Kok, F.C. Visser, and C.A. Visser. Combination and triple therapy in patients withstable angina pectoris not adequately controlled by optimal β-blocker therapy. Neth Heart J.2002;10(11):455-461.

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