Anti anginal drugs, uses, mechanism of action, adverse effects

Anti anginal drugs, uses, mechanism of action, adverse effects

• 1.
  ANTI- ANGINAL DRUGS DR. KARUN KUMAR JUNIORRESIDENT-I DEPARTMENT OF PHARMACOLOGY
• 2.
  What is Angina? ▪Symptom complex caused by transient myocardial ischemia and constitutes a “clinical syndrome” rather than a disease. ▪The term derives from the Latin angina ("infection of the throat") from the Greek ankhonē ("strangling"), and the Latin pectus ("chest"), and can therefore be translated as "a strangling feeling in the chest".
• 3.
  ▪Intermittent chest pain causedby transient, reversible, myocardial ischemia ▪Pain is relieved by rest or by taking nitrates.
• 4.
  PATHOPHYSIOLOGY ▪Imbalance between myocardial oxygen supplyand demand ▪Most common cause  Coronary atheroma (esp. in Left anterior descending artery)
• 5.
  Due to inadequacyof ischemic left ventricle, the end diastolic left ventricular pressure rises from about 5 to 25 mm Hg- produces subendocardial ‘crunch’ during diastole and aggravates the ischemia in this region.
• 6.
  SITE OF PAIN ▪Painis typically substernal ▪It is described as a constricting sensation, pressure like feeling or tightness in the chest and is frequently transmitted to the neck, left shoulder, left arm or lower jaw. ▪Occasionally, it radiates to the back or down the right arm.
• 7.
  TYPES ▪Typical/stable angina ▪Prinzmetal/Variant angina ▪Unstable/Crescendoangina ▪Angina with normal coronary arteries ▪Microvascular angina
• 8.
  STABLE ANGINA ▪Also knownas effort angina ▪It is usually associated with a fixed atherosclerotic narrowing (>=75%) of one or more coronary arteries ▪With this degree of critical stenosis, myocardial oxygen supply may be sufficient under basal conditions but cannot be adequately augmented to meet increased requirements
• 9.
  ▪Attacks are predictablyprovoked by exercise, emotion (anger, fear), sexual intercourse, and subside when the increased energy demand is withdrawn. ▪Stress test shows ST segment depression ▪Pain lasts from 30 seconds to 30 minutes and is relieved by rest or nitroglycerine
• 10.
  VARIANT ANGINA (VA) ▪Temporaryincrease in coronary vascular tone (vasospasm) causing a marked, but transient reduction in luminal diameter[1] ▪Patients are predominantly younger women[1] ▪It has been associated with vasospastic disorders such as Raynaud's phenomenon and migraine headaches.[1] 1. Keller KB, Lemberg L. Prinzmetal’s angina. Am J Crit Care. 2004;13(4):350-4
• 11.
  ▪As it isnot a "demand"- induced symptom, but rather a supply (vasospastic) abnormality, exercise treadmill stress testing is of no value in the diagnosis of VA. ▪The most sensitive and specific test for VA is the administration of ergonovine intravenously. ▪50 micrograms of Ergonovine is given at 5-minute intervals until a positive result or a maximum dose of 400 microg has been administered. ▪When positive, the symptoms and associated ST-segment elevation should be present.
• 12.
  ▪Nitroglycerin rapidly reversesthe effects of ergonovine if refractory spasm occurs. ▪Medical therapy classically employs vasodilator drugs, which include nitrates and calcium channel blockers. ▪Beta-Blockers and large doses of aspirin are contraindicated in VA.
• 13.
  UNSTABLE ANGINA ▪ Alsoknown 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
• 14.
  ▪It is characterizedby increased frequency of pain, precipitated by progressively less exertion; the episodes also tend to be more intense and longer lasting than stable angina ▪It is associated with plaque disruption ▪64% of all episodes occurring between 10 PM and 8 AM, this nocturnal preponderance being evident for episodes with or without a preceding increase in heart rate. [3] 3. Patel DJ, Knight CJ, Holdright DR, Mulcahy, Clarke D, Wright C et al. Pathophysiology of Transient Myocardial Ischemia in Acute Coronary Syndromes. 1996.
• 15.
  ANGINA WITH NORMALCORONARY ARTERIES ▪ 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% in men.[4] ▪ Randomized placebo-controlled studies have demonstrated that tricyclic antidepressants, beta-blockers, angiotensin-converting enzyme inhibitors, L-arginine, statins, and exercise may relieve symptoms, vascular dysfunction, or both; however, longer-term studies 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.
• 16.
  MICROVASCULAR ANGINA ▪Also knownas angina syndrome X. ▪Cardiac syndrome X defines patients with typical chest pain, transient ischaemic ST segment changes during effort and normal coronary angiograms[5] ▪It appears to be due to spasm in the tiny blood vessels of the heart arms, and legs[6] ▪Patients cope well with this type of angina and have very few 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
• 17.
  MANAGEMENT NON-PHARMACOLOGIC MEASURES A)Explanation andreassurance B)Do not smoke C)Aim for ideal body weight D)Take regular exercise (May promote collateral vessels) E) Avoid severe exertion and vigorous exercise F) Correction of established risk factors
• 18.
  PRINCIPAL THERAPEUTIC GOAL Heartrate 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
• 19.
  MEDICAL MANAGEMENT ▪1) ACUTEATTACK:- NITROGLYCERIN AND ISOSORBIDE DINITRATE ▪2) FIRST LINE DRUGS:- NITRATES AND BETA BLOCKERS ▪3) SECOND LINE DRUGS:- CALCIUM CHANNEL BLOCKERS AND POTASSIUM CHANNEL OPENERS
• 20.
  NITRATES ▪A) CLASSIFICATION:- ▪i) Shortacting:- Glyceryl trinitrate[GTN] (sublingual), Isosorbide dinitrate[IDN] (sublingual), Amyl nitrite (shortest acting) ▪ii) Long acting:- Isosorbide dinitrate (oral), Isosorbide mononitrate, Erythritol tetranitrate, Pentaerythritol tetranitrate (longest acting) B) PREPARATION AND DOSE:- GTN (Angised)-0.5 mg tab.; IDN (Sorbitrate) -5, 10 mg tab.
• 21.
  MECHANISM OF ACTION Rapidlydenitrated in smooth muscle cell Nitric oxide released Activation of guanylyl cyclase Increased cyclic guanosine monophosphate (cGMP) Dephosphorylation of myosin light chain kinase (MLCK)
• 23.
  CORONARY STEAL PHENOMENON
• 24.
  ADVERSE EFFECTS ▪These aremostly due to vasodilatation[7] ▪Headache is the most common side effect of nitrates; often dose-related and reported by up to 82% of patients in placebo-controlled trials[8] ▪Nearly 10% of patients are unable to tolerate nitrates due to disabling headaches or dizziness[8]
• 25.
  ▪Other adverse effectsare tachycardia, orthostatic hypotension and methemoglobinemia[7] ▪Rashes are rare, though relatively more common with pentaerythritol tetranitrate[7] 7. Tripathi KD. Antianginal and other anti-ischaemic drugs. In: Tripathi M, editor. Essentials of 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.
• 26.
  TACHYPHYLAXIS AND CONTRAINDICATIONS ▪Tolerancecan develop to nitrates on chronic use (NOT seen with sublingual use). Thus, for clinical use, at least 8 hours of drug free period per day is required. ▪Administration of nitrates is contraindicated with concomitant use of phosphodiesterase-5 inhibitors used for the treatment of erectile dysfunction, as combination therapy may lead to profound hypotension and even death.[8]
• 27.
  BETA BLOCKERS A) 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 mg tab.; Dose-100-400 mg day
• 28.
  MECHANISM OF ACTION ▪Reductionof heart rate and blood pressure  Decreased myocardial oxygen consumption  Improved exercise tolerance ▪Beta-Blockers provide similar clinical outcomes and are associated with fewer adverse events than calcium antagonists in randomized trials of patients who have stable angina.[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 stable angina. JAMA. 1999;281(20):1927-36
• 29.
  ADVERSE EFFECTS 1. 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
• 30.
  CONTRAINDICATIONS 1. Asthma 2. Chronicobstructive pulmonary disease 3. Diabetes mellitus 4. Severe bradycardia 5. Bradycardia-tachycardia syndrome (variant of sick sinus syndrome) 6. Atrioventricular blockade 7. Unstable left ventricular failure 8. Prinzmetal’s angina 9. Peripheral vascular disease
• 31.
  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 mg tab., Dose – 40-160 mg TDS oral; Diltiazem(Dilzem) – 30, 60 mg tab., Dose – 30-60 mg TDS-QID oral
• 32.
  MECHANISM OF ACTION Blockvoltage 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
• 34.
  ADVERSE EFFECTS ▪Well tolerated,associated with few side effects. ▪In recent trials ▪Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) ▪International Verapamil Slow-Release/Trandolapril Study (INVEST) ▪Controlled Onset Verapamil Investigation of Cardiovascular Endpoints (CONVINCE) study no association with precipitation of cardiovascular events found. [10]
• 35.
  ▪Dihydropyridines may causereflex tachycardia, flushing, headache, and ankle swelling. Diltiazem and verapamil depress cardiac conduction and cause bradycardia, and should not be given to people with heart block or treated with 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 College of Physicians (UK); 2011.
• 36.
  CONTRAINDICATIONS ▪ In patientswith unstable angina, immediate-release short-acting calcium channel blockers can increase the risk of adverse cardiac events and therefore are contraindicated.[12] ▪ Calcium channel blockers do not reduce the risk of initial or recurrent infarction or death when given routinely to patients with acute myocardial infarction or unstable angina.[13] 12. Katzung BG. Vasodilators and the treatment of angina pectoris. In: Katzung BG, Masters SB, 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 infarction and unstable angina: an overview. BMJ. 1989;299(6709):1187-92.
• 37.
  POTASSIUM CHANNEL OPENERS A)CLASSIFICATION:- Nicorandil, Pinacidil, Cromakalim, Minoxidil, Diazoxide B) Preparation:-Nicorandil(Nikoran)5,10mg tabs.;Dose–5-20 mg BD Nicorandil inhibits rest and effort angina unresponsive to usual doses of calcium antagonist and oral nitrate.[14]
• 38.
  Use Resistant angina Adverse effects Flushing,palpitation, weakness, headache, dizziness, nausea, vomiting Drug interactions Sildenafil
• 39.
  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 of mitochondrial KATP channels (Ischaemic preconditioning is a phenomenon in which brief periods of ischaemia and reperfusion exert a cardioprotective effect on subsequent total vascular occlusion) 14. Araki H, Hayata N, Matsuguchi T, Nakamura M. Effects of nicorandil on rest and effort angina unresponsive to combination therapy with a calcium antagonist and oral nitrate. Clin Ther. 1987;9(2):174-82.
• 40.
  OTHER ANTI-ANGINAL DRUGS 1.DIPYRIDAMOLE:- It inhibits platelet aggregation by potentiating PGI2 and increasing cAMP in platelets. It is not useful as an anti-anginal drug (“coronary steal”) but 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. Preparation is Persantin (25, 75, 100 mg tab.) and dose is 25 - 100 mg TDS
• 41.
  2. TRIMETAZIDINE It isused as an add on medication to conventional therapy in angina and post-MI patients. Mechanism of action It causes inhibition of mitochondrial enzyme long chain 3-ketoacyl thiolase (LC-3KAT)  Reduces fatty acid metabolism in myocardium and increases glucose metabolism  Shift back of substrate to glucose decreases oxygen demand.
• 42.
  Side effects aregastric burning, dizziness, fatigue, muscle cramps. Other uses are visual disturbances, tinnitus, Meniere’s disease. Preparation:-Flavedon 20 mg tabs.; Dose- 20 mg TDS
• 43.
  3. RANOLAZINE It isa newer antianginal drug used in prophylaxis of angina Mechanism of action-It acts by reducing a late sodium current (INa) that facilitates calcium entry via the sodium-calcium exchanger  Decreased intracellular calcium concentration  Decreased cardiac contractility and work It also inhibits LC-3KAT
• 44.
  Adverse effects -Dizziness, weakness, constipation, postural hypotension, headache and dyspepsia. Drug interactions – Avoided in patients taking CYP3A4 inhibitors. Preparation - Ranozex 0.5 g SR tab.; Dose – 0.5 – 1 gm BD as SR tab
• 45.
  4. IVABRADINE It hasbeen introduced recently. Uses- a) Chronic stable angina with sinus rhythm (patients in whom beta blockers are contraindicated or they are intolerant to beta blockers) b) Inappropriate sinus tachycardia
• 46.
  Mechanism of action-Relativelyselective If sodium channel blocker that reduces cardiac rate by inhibiting the hyperpolarization-activated sodium channel in the sinoatrial node Preparation – Ivabrad (5, 7.5 mg tab.) Dose – Initially 5 mg BD, increase if needed to 7.5 mg BD
• 47.
  5. OXYPHEDRINE It improvesmyocardial metabolism so that heart can sustain hypoxia better. Preparation – Ildamen (8, 24 mg tab.) Dose – 8-24 mg TDS oral 6. FASUDIL Rho-kinase plays an important role in calcium sensitization for vascular smooth muscle (VSMC) contraction and may be involved in the inappropriate coronary vasoconstriction during exercise-induced myocardial ischemia.[15]
• 48.
  It is aninhibitor of smooth muscle Rho kinase which reduces coronary vasospasm in experimental animals. In clinical trials in patients with coronary artery disease, it has improved performance in stress tests. 15. Shimokawa H, Hiramori K, Iinuma H, Hosoda S, Kishida H, Osada H et al. Anti-anginal effect of fasudil, a Rho-kinase inhibitor, in patients with stable effort angina: a multicenter study. J Cardiovasc Pharmacol. 2002;40(5):751-61.
• 49.
  7. ALLOPURINOL Experimental evidencesuggests that xanthine oxidase inhibitors reduce myocardial oxygen consumption. Due to this fact, this class of inhibitors could become a new treatment for ischaemia in patients with angina pectoris.[16] The mechanism of the anti-ischemic effect of allopurinol could be related 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 on exercise in patients with chronic stable angina: a randomised, placebo controlled crossover trial. 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.
• 50.
  SURGICAL INTERVENTION ▪PCI (PercutaneousCoronary Intervention) ▪CABG (Coronary Artery Bypass Graft)
• 51.
  STABLE ANGINA ▪Drug ofchoice depends on individual patient’s response ▪In hypertensive patients, monotherapy with either slow- release or long-acting calcium channel blockers or β blockers 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:-
• 52.
  a) The combinationof a calcium antagonist and a beta- blocker is statistically more effective than either monotherapy.[18] b) The combination of trimetazidine with beta-blockers or long-acting nitrates significantly improves exercise stress test parameters and angina symptoms compared with placebo.[19] c) Trimetazidine is useful for combination therapy in patients with stable angina insufficiently controlled by monotherapy with a beta-blocker.[20]
• 53.
  18. Klein WW,Jackson G, Tavazzi L. Efficacy of monotherapy compared with combined antianginal drugs in the treatment of chronic stable angina pectoris: a meta-analysis. Coron Artery 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 versus conventional 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: results of a randomized, double-blind, multicentre study (TRIMPOL II). TRIMetazidine in POLand. Eur Heart J. 2001;22(24):2267-74.
• 54.
  VARIANT ANGINA ▪ Calciumchannel blockers are extremely effective in preventing coronary spasm. The long-acting nitrate, nicorandil, and Rho-kinase inhibitor are also useful for inhibiting coronary artery spasm.[21] ▪ Stent implantation in patients with recurrent variant angina refractory to medical treatment may be an alternative treatment in carefully selected, clinically unstable patients.[22] 21. Kusama Y, Kodani E, Nakagomi A, Otsuka T, Atarashi H, Kishida H, et al. Variant angina and coronary artery spasm: the clinical spectrum, pathophysiology, and management. J Nippon Med Sch. 2011;78(1):4-12 22. Martí V, Ligero C, García J, Kastanis P, Guindo J, Domínguez de Rozas JM. Stent implantation in variant angina refractory to medical treatment. Clin Cardiol. 2006;29(12):530-3.
• 55.
  UNSTABLE ANGINA ▪Aggressive antiplatelettherapy with Aspirin and Clopidogrel is indicated. ▪In nonprior aspirin users, combination antithrombotic therapy with aspirin plus anticoagulation significantly reduces recurrent ischemic events in the early phase of unstable angina[23] ▪If PCI with stenting is required, glycoprotein (GP) IIb/IIIa inhibitors such as Abciximab, Eptifibatide or Tirofiban should be added.
• 56.
  ▪In addition, therapywith nitroglycerin and β blockers should be considered ▪Calcium channel blockers should be added in refractory cases ▪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. Combination antithrombotic therapy in unstable rest angina and non-Q-wave infarction in nonprior aspirin users. Primary end points analysis from the ATACS trial. Antithrombotic Therapy in Acute Coronary Syndromes Research Group. Circulation. 1994;89(1):81-8.
• 57.
  ▪ Consideration shouldbe given to measuring serum levels of a cardiac troponin (either T or I) and using intravenous GP IIb-IIIa inhibitors and low-molecular-weight heparin in the standard management of patients with unstable angina.[24] ▪ Nondrug therapies for unstable angina include intra-aortic balloon counterpulsation, 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. Redefining medical 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.
• 58.
  REFRACTORY ANGINA ▪Clinical trialshave shown that combined haemodynamic and metabolic treatment is more effective than combined haemodynamic therapy and is well tolerated.[26] ▪Haemodynamic agents are nitrates, β blockers and calcium channel blockers. ▪Metabolic agents such as Trimetazidine or L-carnitine are a new class of drugs that directly modify the use of energy substrates in the heart, lessening ischaemic injury and improving cardiac performance during ischaemia.[26]
• 59.
  ▪For patients withsevere angina pectoris not responding to combination therapy of a β-blocker with a nitrate, triple therapy may be of advantage, although the number of patients studied has been small.[27] 26. Jackson G. Combination therapy in angina: a review of combined haemodynamic treatment and the role for combined haemodynamic and cardiac metabolic agents. Int J Clin Pract. 2001;55(4):256-61. 27. W.E.M. Kok, F.C. Visser, and C.A. Visser. Combination and triple therapy in patients with stable angina pectoris not adequately controlled by optimal β-blocker therapy. Neth Heart J. 2002;10(11):455-461.
• 60.
  THANK YOU