Antianginal drugs and drugs used in ischaemia - drdhriti


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Antianginal drugs and drugs used in ischaemia - drdhriti

  1. 1. Antianginal Drugs and Other Anti-ischaemic Drugs Department of Pharmacology NEIGRIHMS, Shillong
  2. 2. Learning Objectives!• Know the Basics of the Disease of Angina Pectoris• Know the major classes of drugs used to treat angina and their clinically important mechanisms of action• Know the basic Pharmacology of each class of antianginal drugs• Know the major contraindications, toxicities, and drug interactions of each class of antianginal drugs• Know the drugs of choice for treating different forms of angina• Know which antianginal drug combinations
  3. 3. What is angina?• Angina pectoris is a Syndrome characterized by sudden severe pressing substernal chest pain or heaviness radiating to the neck, jaw, back and arms. It is often associated with diaphoresis, tachypnea and nausea• The primary cause of angina is an imbalance between myocardial oxygen demand and oxygen supplied by coronary vessels – This imbalance may be due to: • a decrease in myocardial oxygen delivery • an increase in myocardial oxygen demand • or both• The discomfort abates when supply becomes adequate for demand. Typically angina lasts for seconds to minutes, up to 15 minutes – Classically angina is not associated with ischemic cell death
  5. 5. Factors affecting Myocardial Oxygen Delivery• Coronary artery blood flow is the primary determinant of oxygen delivery to the myocardium – Myocardial oxygen extraction from the blood is nearly complete, even at rest• Coronary blood flow is essentially negligible during systole and is therefore determined by: – Perfusion pressure during diastole (aortic diastolic pressure) – Duration of diastole – Coronary vascular resistance: Coronary vascular resistance is determined by numerous factors including: • Atherscelorosis • Intracoronary thrombi • Metabolic products that vasodilate coronary arterioles • Autonomic activity • Extravascular compression
  6. 6. Factors AffectingMyocardialOxygen Demand• The major determinants of myocardial oxygen consumption include: – Ventricular wall stress • Both preload (end-diastolic pressure) and afterload (end-systolic pressure) affect ventricular wall stress – Heart rate – Inotropic state (contractility) – Myocardial metabolism (glucose vs fatty acids)• A commonly used non-invasive index of myocardial oxygen demand is the “double product”: – [Heart rate] X [Systolic blood pressure] – Also known as the “rate pressure product”
  7. 7. Types of Angina1. Classical angina:  Stable  Unstable2. Variant or Prinzmetal`s angina Myocardial infarction – what is it ? • Acute and complete occlusion of a coronary artery • Due to coronary thrombosis
  8. 8. Stable Angina• Stable angina (common form) is also known as: – Exertional angina/Typical or classic angina/Angina of effort/Atherosclerotic angina• The underlying pathology is usually atherosclerosis (reduced oxygen delivery) giving rise to ischemia under conditions where the work load on the heart increases (increased oxygen demand)• Anginal episodes can be precipitated by exercise, cold, stress, emotion, or eating• Subendocardial crunch developes• Therapeutic goals: Increase myocardial blood flow by dilating coronary arteries and arterioles (increase oxygen delivery), decrease cardiac load (preload and afterload; decrease oxygen demand), decrease heart rate (decrease oxygen demand), [alter myocardial metabolism?]
  9. 9. Subendocardial Crunch - Image
  10. 10. Unstable Angina• Unstable angina is also known as: – Preinfarction angina – Crescendo angina – Angina at rest• Caused by recurrent episodes of small platelet clots at the site of a ruptured atherosclerotic plaque which can also precipitate local vasospasm• Associated with a change in the character, frequency, and duration of angina in patients with stable angina, and episodes of angina at rest• May be associated with myocardial infarction• Therapeutic Goal: Inhibit platelet aggregation and thrombus formation (increase oxygen delivery), decrease cardiac load (decrease oxygen demand), and vasodilate coronary arteries (increase oxygen delivery) and Statins
  11. 11. VasospasticAngina• Vasospastic angina (uncommon form) is also known as: – Variant angina – Prinzmetals angina• Caused by transient vasospasm of the coronary vessels• Attack occurs even at rest or during sleep• Usually associated with underlying atheromas, abnormally reactive or hypertrophied segments in coronary artery• Chest pain may develop at rest• Therapeutic rationale: Decrease vasospasm of coronary vessels (calcium channel blockers are efficacious in >70% of patients; increase oxygen delivery)
  12. 12. Coronary 1.artery imageCoronary calibrechanges in Classicaland variant angina – 1. Normal 2. Classical angina 2. 3. Variant angina 3.
  13. 13. Antianginal AgentsThree major classes of agents are used individually or in combination to treat angina: 1. Organic nitrates: • Vasodilate coronary arteries • Reduce preload and aferload 2. Calcium channel blockers: • Vasodilate coronary arteries • Reduce afterload • The non-dihydropyridines (verapamil and diltiazem) also decrease heart rate and contractility 3. Beta-adrenergic blockers: • Decrease heart rate and contractility - decrease in cardiac work and O2 consumption • Improve myocardial perfusion due to decrease in heart rate – decreased in ventricular wall tension • Exercise tolerance
  14. 14. Classification of Antianginal Agents1. Nitrates: a) Short acting (10 minutes): Glyceryl trinitrate (GTN and Nitroglycerine) - EMERGENCY b) Long acting (1 Hour): Isosorbide dinitrate, Isosorbide mononitrate, Erythrityl tetranitrate, Pentaerythritol tetranitrate2. Calcium Channel Blockers: a) Phenyl alkylamine: Verapamil b) Benzothiazepin: Diltiazem c) Dihydropyridines: Nifedipine, Felodipine, Amlodipine, Nitrendipine and Nimodipine3. Beta—adrenergic Blockers: Propranolol, Metoprolol, Atenolol and others4. Potassium Channel openers: Nicorandil5. Others: Dipyridamole, Trimetazidine, Ranolazine and oxyphedrine
  15. 15. Nitrates• All Nitrates share same action – only difference is on Pharmacokinetic properties (duration of action)• Hepatic first-pass metabolism is high and oral bioavailability is low for nitroglycerin (GTN) and isosorbide dinitrate (ISDN) – Sublingual or transdermal administration of these agents avoids the first-pass effect• Isosorbide mononitrate is not subject to first-pass metabolism and is 100% available after oral administration• Hepatic blood flow and disease can affect the pharmacokinetics of GTN and ISDN
  16. 16. NitratesPharmacokineticcomparison: • Bioavailability: NG: Below 1% IDN: 20% ISMN: 100% • Plasma clearance: NG: 50L/min IDN: 4L/min ISMN: 0.6L/min
  17. 17. Organic Nitrates - MOA• All of these agents are enzymatically converted to free radical nitric oxide (NO) in the target tissues – NO is a very short-lived endogenous mediator of smooth muscle contraction and neurotransmission• Veins and larger arteries appear to have greater enzymatic capacity than resistance vessels, resulting in greater effects in these vessels – arterioles, veins, aorta and coronary arteries• NO activates a cytosolic form of guanylate cyclase in smooth muscle – Activated guanylate cyclase catalyzes the formation of cGMP which activates cGMP-dependent protein kinase – Activation of this kinase results in phosphorylation of several proteins that reduce intracellular calcium and hyperpolarize the plasma membrane causing relaxation
  18. 18. Mechanism of Action of Nitrovasodilators Nitrates become denitrated by glutathione S-transferase to release Nitric Oxide activates Guanylate Cyclase* converts GTP cGMP activates cGMP-dependent protein kinase Activation of PKG results in phosphorylation of several proteins that reduce intracellular calcium causing smooth muscle relaxation
  19. 19. Actions of Nitrates - GTN1. Preload reduction:  Dilatation of veins more than arteries – peripheral pooling of Blood – decrease venous return  Will lead to reduction in preload – decreased end diastolic size – decrease in fibre length  Less wall tension to develop for ejection (Laplace`s law) – less oxygen consumption and reduction in ventricular wall pressure (crunch abolished)2. Afterload reduction:  Some amount of arteriolar dilatation – Decrease in peripheral Resistance (afterload reduction) – reduction in Cardiac work (also fall in BP)  Standing posture – pooling of Blood in legs – reflex tachycardia (prevented by lying down and foot end raising)  However in large doses opposite happens – marked fall in BP – reflex tachycardia – increased cardiac work – precipitation of angina
  20. 20. Actions of Nitrates - contd.3. Increased Myocardial Perfusion:  Dilatation of bigger conducting coronary arteries all over the heart + dilatation of autoregulatory ischemic vessels due to ischaemia + normal tone of non-ischaemic zone vessels – Redistribution of blood in Myocardium to ischemic zone  However total blood flow in coronary vessels is almost unchanged with Nitrates4. Mechanism of angina relief:  Variant angina – coronary vasodilatation  Classical angina – reduction in Cardiac load  Increased exercise tolerance5. Other actions: Cutaneous vasodilatation (flushing occurs), meningeal vessels dilatation (headache) and decreased renal blood flow
  21. 21. Nitrates - ADRs• The major acute adverse effects of nitrates are due to excessive vasodilatation – Orthostatic hypotension – Tachycardia – Severe throbbing headache – Dizziness – Flushing – Syncope• Organic nitrates are contraindicated in patients with elevated intracranial pressure• Sildenafil (Viagra) and other PDE-5 inhibitors used for erectile dysfunction can potentiate the actions of nitrates because they inhibit the breakdown of cGMP (they should not be taken within 6 hours of taking a nitrovasodilator)
  22. 22. Nitrate Tolerance• Continuous or frequent exposure to nitrates can lead to the development of complete tolerance• The mechanism of tolerance is not completely understood: – May be related to the enzymes involved in converting the nitrates to NO – or to the enzyme that produces cGMP• Industrial (occupational) exposure to organic nitrates has been associated with “Monday disease” and physical dependence manifest by variant angina occurring 1-2 days after withdrawal
  23. 23. Nitrates – Individual agents• Glyceryl trinitrate (GTN, Nitroglycerine): – Rendered nonexplosive by adsorbing in inert matrix of a tablet – Stored in a tightly closed Glass container• Formulations: Oral, SL, IV and ointment 1) SL (0.5 mg) – to terminate an Ongoing attack • Crushed under the tongue and spread over the buccal mucosa • Action starts within 1-2 minutes • Effects disappear within minutes but its metabolite – dinitrate stays (1 hr) 2) IV transfusion: in acute AMI 3) Patches: Ointment and patches – at night application
  24. 24. Nitrates – Therapeutic Uses1. Angina pectoris: Classical and variant Types2. Acute Coronary syndromes: Unstable angina and associated with MI (Combination Drugs)3. Myocardial Infarction: IV administration is useful in relieving congestions of chest and favouring blood supply to ischemic zone4. CHF and LVF: Pooloing of blood5. Biliary colic: Sl administration6. Oesophageal spasm: Reduction in oesophageal tone (achalasia)7. Cyanide Poisoning: Nitrates counter cyanide by producing Methaemoglobin – then Cyanomethaemoglobin (Sod. Thiosulfate is given to form Sod. Thiocyanate)
  25. 25. Beta-blockers• Though most beta-blockers do not cause coronary vasodilatation like the nitrovasodilators or calcium channel blockers, beta-blockers are important in the treatment of angina because of their effects on the heart• Desired effects of beta-blockers – Reduce myocardial oxygen consumption by reducing contractility and heart rate • Reducing cardiac output also reduces afterload • Some b-blockers can cause vasodilatation directly or by acting as a-blockers – Improve myocardial perfusion by slowing heart rate (more time spent in diastole)
  26. 26. Beta-blockers – contd.• Benefits: – Decreased frequency and severity of attacks – Increased exercise tolerance (classical angina) – cardioselectives are preferred (coronary spasm due to alpha-blockade) – Lowers sudden cardiac death – Routinely used in UA and with MI• ADRs and CI: – May exacerbate heart failure – Contraindicated in patients with asthma – Should be used with caution in patients with diabetes since hypoglycemia-induced tachycardia can be blunted or blocked – May depress contractility and heart rate and produce AV block in patients receiving non-dihydropyridine calcium channel blockers (i.e. verapamil and diltiazem)
  27. 27. Calcium Channels1. Voltage Sensitive Channels (- o Voltage sensitive Calcium 40mV) channels are2. Receptor operated Channel (Adr heterogenous (membrane and other agonists) spanning funnel shaped):3. Leak channel (Ca++ATPase) o L-Type (Long lasting current) – SAN, AVN, Conductivity, Car diac and smooth muscle o T-Type (Transient Current) – Thalumus, SAN o N-Type (Neuronal) – CNS, sypmathetic and myenteric plexuses
  28. 28. Calcium Channel Blockers• Five major classes of Ca++ channel blockers are known with diverse chemical structures: 1) Benzothiazepines: Diltiazem 2) Dihydropyridines: Nicardipine, nifedipine, nimodipine, amlodipine, and many others • There are also dihydropyridine Ca++-channel activators (Bay K 8644, S 202 791) 3) Phenylalkylamines: Verapamil 4) Diarylaminopropylamine ethers: Bepridil 5) Benzimidazole-substituted tetralines: Mibefradil
  29. 29. Effects on Vascular Smooth Muscle• Ca++ channel blockers inhibit mainly L-type• Little or no effect on receptor-operated channels or on release of Ca++ from SR• “Vascular selectivity” is seen with the Ca++ channel blockers – Decreased intracellular Ca++ in arterial smooth muscle results in relaxation (vasodilatation) -> decreased cardiac afterload (aortic pressure) – Little or no effect of Ca++-channel blockers on venous beds -> no effect on cardiac preload (ventricular filling pressure) – Specific dihydropyridines may exhibit greater potencies in some vascular beds (e.g.- nimodipine more selective for cerebral blood vessels, nicardipine for coronary vessels) – Little or no effect on nonvascular smooth muscle
  30. 30. Effects on Cardiac Cells• Magnitude and pattern of cardiac effects depends on the class of Ca++channel blocker • Negative inotropic effect (myocardial L-type channels) – Reduced inward movement of Ca++ during action potential plateau phase – Dihydropyridines have very modest negative inotropic effect – Mibefradil (T-type) has no negative inotropic effect • Negative chronotropic/dromotropic effects (L- and T- type channels) – Verapamil, diltiazem, and mibefradil depress SA node and AV conduction – Dihydropyridines have minimal direct effects on SA node and AV conduction (but they can cause reflex tachycardia)
  31. 31. Individual Drugs –Verapamil• Arteriolar dilatation and alpha blocking action – decrease in t.p.r – but modest lowering of BP• Direct Cardiac depressant action (countered by reflex effects of above)• Overall, decrease in HR, slowed AV conduction and increased coronary flow• Available as 40, 80, 120 etc. tabs and also injections• Drug Interactions: – Verapamil and beta blockers – sinus depression and conduction defects (asystole) – Gigoxin – digitalis toxicity (by decreasing excretion) – Quinidine – Cardiac depresion
  32. 32. Relative Cardiovascular Effects of Calcium Channel Blockers - (Goodman & Gilman)Compound Coronary Suppression Suppression Suppression vasodilatation of cardiac of of contractility SA node AV nodeVerapamil ++++ ++++ +++++ +++++Diltiazem +++ ++ +++++ ++++Nifedipine +++++ + + 0Nicardipine +++++ 0 + 0
  33. 33. Adverse effects• Adverse effects are typically direct extensions of their therapeutic effects and are relatively rare – Minor adverse effects • Nausea , constipation and bradycardia (Verapamil) • Hypotension, dizziness, edema, flushing (more with DHPs) – Major adverse effects: • Depression of contractility and exacerbation of heart failure • AV block, bradycardia, and cardiac arrest – ppt of CCF• Patients with ventricular dysfunction, SA node or AV conduction disturbances, WPW syndrome, and systolic blood pressures below 90 mm Hg should not be treated with verapamil or diltiazem• Immediate-release forms of dihydropyridines (Nifedipine) may increase mortality in patients with myocardial ischemia – longer acting Nifedipine is used – Also cause increase in angina frequency – Cerebral Ischaemia – rapid bringing down of BP – Bladder relaxation – voiding difficulty – Decrease in Insulin release
  34. 34. CCBs - Pharmacokinetics• High oral absorption, but high first pass metabolism (except amlodipine) – individual variation and highly plasma protein bound• Extensively distributed in tissues and metabolized in liver and excreted in urine, eliminated in 22-6 Hrs (except amlodipine) Drug Bioavailability Vd (L/kg) Active Elim half life(hr) % metabolite Verapamil 15-30 5.0 Y 4-6 Diltiazem 40-60 3.0 Y 5-6 Nifedepine 30-60 0.8 M 2-5 Felodipine 15-25 10.0 None 12-18 Amlodipine 60-65 21.0 None 35-45
  35. 35. Desired Therapeutic Effects of Calcium Channel Blockers for Angina• Improve oxygen delivery to ischemic myocardium – Vasodilate coronary arteries – May inhibit platelet aggregation – Particularly useful in treating vasospastic angina• Reduce myocardial oxygen consumption – Decrease afterload (no effect on preload) – Non-dihydropyridines also lower heart rate and decrease contractility – (* Dihydropyridines may aggravate angina in some patients due to reflex increases in heart rate and contractility)
  36. 36. CCBs – Therapeutic Uses1. Angina Pectoris:  Reduce frequency and severity of Classical and Variant angina  Classical angina • reduction in cardiac work by reducing afterload • Increased exercise tolerance • Coronary flow increase – less significant (fixed arterial block) • But: short acting DHPs cause Myocardial Ischaemia – WHY? - due to decreased coronary blood flow secondary to fall in mean BP, reflex tachycardia and coronary steal • Verapamil/Diltiazem are better (reduce O2 consumption by direct effect)  MI - Verapamil/Diltiazem as alternative to β-blockers  Variant angina: Benefited by reducing the arterial spasm2. Hypertension3. Cardiac arrhythmia4. Hypertrophic Cardiomyopathy: verapamil5. Nifedipine – Preterm labour (?) and Raynaud`s disease; Verapamil - migraine and nocturnal leg cramps
  37. 37. Pharmacotherapy of Angina Pectoris• Aim: 1. Relief and prevention of Individual attack; 2. Chronic Prophylaxis; 3. Measures to prevent Progression 1. Prevention of Individual attack: • Short acting Nitrate as and when required basis • GTN is the drug of Choice in all kinds of angina • Dose: 0.3 – 0.6 mg SL • If symptoms not relieved quickly – additional tabs at 5 min. interval (not more than 3 tabs at 5 minutes interval) • Discard the remnant tab soon relieved – hypotension • Acute Prophylaxis: GTN 15 minutes before a period of increased activity – exercise, sexual activity etc. – lasts for upto 2 Hrs2. Chronic Prophylaxis: • Monotherapy with either of the 3 groups of Drugs – depends on stage and associated cardiac disease • May be Nitrates/Ca++ blockers /beta-blockers – beta blockers are preferred • When Monotherapy fails: Go for combination of those Drugs (two drugs) • When Two Drugs fails – go for all above 3 drugs
  38. 38. Combination Therapy of Angina • Use of more than one class of antianginal agent can reduce specific undesirable effects of single agent therapy Beta-Blockers or Nitrates PlusEffect Nitrates Alone Channel Blockers Beta-Blockers or Alone Channel BlockersHeart Rate Reflex Increase Decrease* DecreaseAfterload Decrease Decrease DecreasePreload Decrease Increase None or decreaseContractility Reflex increase Decrease* NoneEjection time Decrease Increase None Undesireable effects are shown in italics * Dihydropyridines may cause the opposite effect due to a reflex increase in sympathetic tone
  39. 39. Additional Measures1. Hyperlipidemia, Diabetes and Hypertension - Statins2. Dietary Restriction – saturated fats3. Smoking cessation4. Lifestyle change – obesity reduction5. Physical exercise6. Daily intake of Vit. C and Vit. E7. Antiplatelete Drugs – Aspirin etc.
  40. 40. Potassium Channel Openers –Nicorandil, Pinacidil• Minoxidil and Diazoxide – older Drugs used in hypertension• MOA: – Activation of ATP sensitive K+ channel – hyperpolarization of vascular smooth muscle – relaxation of Smooth muscle – Also acts as NO donor and increases cGMP – Arterio-venous relaxation – Dilatation of all types of coronary vessels• Benefits in angina (equipotent to nitrates, beta blockers and Ca++ channel blockers) – Reduced angina frequency – Increased exercise tolerance – Ischaemic preconditioning for Myocardial stunning , arrhythmia and infarct size (Mitochondrial K+ATP channel opening)• ADRs: Flushing, palpitation, nausea, vomiting, aphthous ulcer• Dose: available as 5, 10 mg tabs and also injection
  41. 41. Pharmacotherapyof MI1. Aim:  Emergency life saving management of the patient (ICU)  Subsequent Treatments2. Pain, anxiety and apprehension: Morphine, Pethidine parenteral3. Oxygenation: assisted respiration4. Maintenance of Blood Volume, tissue perfusion and microcirculation: slow IV fluid with saline5. Correction of acidosis: Sodibicarb IV6. Prevention of Arrhythmia: Beta blockers early (arrhythmia and infarct size)7. Pump Failure: Furosemide, GTN IV/Nitroprusside and Dobutamine8. Prevention of Thrombus extension and thrombo-embolism9. Thrombolysis and reperfusion: Streptokinase, urokinase etc.10. Prevention of future attacks: beta-blockers, aspirin, anti-hyperlipidemia
  42. 42. Peripheral Vascular Disease – Pentoxiphylline (Trental)• Analogue of Theophylline – PDE inhibitor• Action: – Reduction of whole blood viscosity by improving the flexibility of RBCs – Improvement of passage of blood through microcirculation – No vasodilatation but improved circulation – Less chance of steal phenomenon• Kinetics: – Well absorbed in the GI tract, Metabolized in liver and via erythrocytes - some metabolites are active. Undergoes extensive 1st pass metabolism, excreted in urine• Available in tabs – 400 mg form and also injection• Uses: – Non-haemorrhagic stroke – Intermittent claudication – Trophic leg ulcers – TIA – To improve memory, vertigo and tinnitus etc. after CVA
  43. 43. What is Important?• Mechanism of action, therapeutic uses and ADRs of Nitrates• Role of Nitrates in Angina Pectoris• Role of Beta-blockers and Ca++ channel blockers in Angina Pectoris• Pharmacotherapy of Angina Pectoris• Pharmacotherapy of Myocardial Infarction• Potassium Channel Openers