Antianginal drugs and drugs used in ischaemia - drdhriti


Published on

A power point presentation on “Antianginal drugs and drugs used in ischaemia” suitable for undergraduate level MBBS students

Published in: Health & Medicine, Technology
1 Comment
  • Hello dear, My name is mariam nasrin, I know that this email will meet you in a good health and also surprisingly but God has his own way of bringing people together. Nice to Meet you I would appreciate if you can reply me back( ) So that i can explain you more about me. thank Yours mariam.
    Are you sure you want to  Yes  No
    Your message goes here
No Downloads
Total views
On SlideShare
From Embeds
Number of Embeds
Embeds 0
No embeds

No notes for slide
  • The coronary perfusion pressure is the difference between the aortic diastolic pressure and left ventricular end-diastolic pressure (LVEDP)
  • Balance between Oxygen and fatty acid for production of ATP in heart. When Oxygen reduces in heart (post ischemia) increased fatty acid oxidation for ATP production which require more oxygen --- more demand
  • Antianginal drugs and drugs used in ischaemia - drdhriti

    1. 1. Antianginal Drugs Dr. D. K. Brahma Associate Professor Department of Pharmacology NEIGRIHMS, Shillong
    2. 2. 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, tachypnoea and nausea • Primary cause: imbalance between myocardial oxygen demand and oxygen supplied by coronary vessels – This imbalance may be due to: 1. a decrease in myocardial oxygen delivery 2. 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
    3. 3. 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 – Duration of diastole – Coronary vascular resistance: determined by numerous factors: • Atherscelorosis • Intracoronary thrombi • Metabolic products that vasodilate coronary arterioles • Autonomic activity • Extravascular compression
    4. 4. Factors Affecting Myocardial Oxygen Demand • The major determinants of myocardial oxygen consumption include: 1. Ventricular wall stress • Both preload (end-diastolic pressure) and afterload (end- systolic pressure) affect ventricular wall stress 2. Heart rate 3. 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”
    5. 5. Types of Angina 1. Classical angina:  Stable 2. Variant or Prinzmetal`s angina  Unstable Myocardial infarction – what is it ? • Ischaemic necrosis of a portion of myocardium due to acute and complete occlusion of a coronary artery - due to coronary thrombosis
    6. 6. Stable Angina • Common form and 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: – Increasing myocardial blood flow by dilating coronary arteries and arterioles (increase oxygen delivery) – Decreasing cardiac load (preload and afterload: decrease oxygen demand) – Decreasing heart rate (decrease oxygen demand)
    7. 7. Unstable Angina • Unstable angina is also known as: – Preinfarction angina/Crescendo angina/angina at rest • Associated with a change in the character, frequency, and duration of angina in patients with stable angina, and episodes of 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 • May be associated with myocardial infarction • Therapeutic Goal: Inhibiting platelet aggregation and thrombus formation (increase oxygen delivery), decreasing cardiac load (decrease oxygen demand), and vasodilate coronary arteries (increase oxygen delivery)
    8. 8. Vasospastic Angina • Vasospastic angina (uncommon form) is also known as: – Variant angina/Prinzmetal's 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)
    9. 9. Coronary artery image • Coronary calibre changes in Classical and variant angina 1. Normal 2. Classical angina 3. Variant angina 1. 2. 3.
    10. 10. Classification of Antianginal Agents 1. Nitrates: a) Short acting (10 minutes): Glyceryl trinitrate (GTN and Nitroglycerine) - EMERGENCY b) Long acting (1 Hour): Isosorbide dinitrate, Isosorbide mononitrate, Erythrityl tetranitrate, Pentaerythritol tetranitrate 2. Calcium Channel Blockers: a) Phenyl alkylamine: Verapamil b) Benzothiazepin: Diltiazem c) Dihydropyridines: Nifedipine, Felodipine, Amlodipine, Nitrendipine and Nimodipine 3. Beta—adrenergic Blockers: Propranolol, Metoprolol, Atenolol and others 4. Potassium Channel openers: Nicorandil 5. Others: Dipyridamole, Trimetazidine, Ranolazine and oxyphedrine
    11. 11. Actions of Nitrates - GTN 1. Preload reduction:  Dilatation of veins more than arteries – peripheral pooling of Blood – decrease venous return  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
    12. 12. Actions of Nitrates - contd. 3. Increased Myocardial Perfusion:  Redistribution of coronary blood flow – facilitates entry of blood to Ischaemic area  However, total blood flow in coronary vessels is almost unchanged with Nitrates 4. Mechanism of angina relief:  Variant angina – coronary vasodilatation  Classical angina – reduction in Cardiac load  Increased exercise tolerance 5. Other actions: Cutaneous vasodilatation (flushing), meningeal vessels dilatation (headache) and decreased splanchnic and Renal blood flow (compensatory)
    13. 13. Mechanism of Action of Nitrovasodilators Nitric Oxide activates converts Guanylate Cyclase* GTP cGMP activates cGMP-dependent protein kinase Activation of PKG results in dephosphorylation of several proteins that reduce intracellular calcium causing smooth muscle relaxation Nitrates become denitrated by glutathione S-transferase to release Dephosphorylaton of MLCK
    14. 14. Pharmacokinetics - Nitrates • All Nitrates share same action – only Pharmacokinetic differences • All are highly lipid soluble and absorbed well from bccal mucosa, orally and skin • Rapidly denitrated by glutathione reductase and mitochondrial aldehyde dehydrogenase • Hepatic first-pass metabolism is high and oral bioavailability is low for nitroglycerin (GTN) and isosorbide dinitrate (ISDN) – Sublingual or transdermal administration - 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
    15. 15. GTN ISDN 5-ISMN Half-life (min) 3 10 280 Plasma clearance (L/min) 50 4 0.1 Apparent volume of distribution (L/kg) 3 4 0.6 Oral bioavailability (%) < 1 20 100 Property Comparison of Pharmacokinetic Properties of Nitrates
    16. 16. Nitrates - ADRs • Due to excessive vasodilatation - Orthostatic hypotension, Tachycardia, Severe throbbing headache, Dizziness, Flushing and Syncope • Methaemoglobinemia • Rashes - rare • Contraindicated in patients with elevated intracranial pressure • Drug Interaction: 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)
    17. 17. 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
    18. 18. 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
    19. 19. Nitrates – Therapeutic Uses 1. Angina pectoris: Classical and variant Types 2. Acute Coronary syndromes: Unstable angina and associated with MI (Combination Drugs) 3. Myocardial Infarction: In evolving MI : IV administration is useful in relieving – 3 things: chest pain, congestions of chest and reducing the infarct size favouring blood supply to ischemic zone 4. CHF and LVF: Pooling of blood 5. Biliary colic: Sl administration 6. 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)
    20. 20. Role of Beta-blockers • No coronary vasodilatation like the nitrovasodilators or calcium channel blockers - beta-blockers are important in the treatment of angina • Instead coronary flow reduced – beta2 effect • But, Coronary flow to ischaemic area not reduced: – Redistribution and decrease in ventricular wall tension • Improve myocardial perfusion by slowing heart rate (more time spent in diastole) • less O2 consumption (decreased HR, Inotropy and mean BP)
    21. 21. Role of 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 – pretreatment with Nitrates or CCB – Avoid abrupt withdrawal • ADRs and CI: – May exacerbate heart failure – Contraindicated in patients with asthma – Precaution in 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)
    22. 22. Calcium Channels 1. Voltage Sensitive Channels (- 40mV) 2. Receptor operated Channel (Adr and other agonists) 3. Leak channel (Ca++ATPase) o Voltage sensitive Calcium channels are heterogenous (membrane spanning funnel shaped): o L-Type (Long lasting current) – SAN, AVN, Conductivity, Cardiac and smooth muscle o T-Type (Transient Current) – Thalumus, SAN o N-Type (Neuronal) – CNS, sypmathetic and myenteric plexuses
    23. 23. Calcium Channel Blockers 1) Phenylalkylamines: Verapamil 2) Dihydropyridines: • 1st generation: Nifedepine • 2nd generation: Nicardipine, nimodipine, Felodipine, Isradipine • 3rd generation: Amlodipine 3) Benzothiazepines: Diltiazem 4) Diarylaminopropylamine ethers: Bepridil 5) Benzimidazole-substituted tetralines: Mibefradil
    24. 24. 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 1. Decreased intracellular Ca++ in arterial smooth muscle results in relaxation (vasodilatation) -> decreased cardiac afterload (aortic pressure) 2. Little or no effect on venous beds -> no effect on cardiac preload (ventricular filling pressure) DHPs have the highest vascular SM relaxant action 3. Additional Mechanism: Release of NO – inhibit cAMP PDE – increased SM cAMP • 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 except bronchial, uterine, biliary, vesical and intestinal
    25. 25. Effects on Cardiac Cells • Negative Inotropic, Chronotropic and Dromotropic • Negative inotropic effect (myocardial L-type channels) – WMC and ventricular fibres • Negative chronotropic /dromotropic effects (L- and T-type channels) • Verapamil and diltiazem shows such effects but not DHPs • Verapamil, diltiazem, and mibefradil depress SA node and AV conduction – depression of pacemaker and conduction • Dihydropyridines have minimal direct effects on SA node and AV conduction – more selective for vascular smooth muscles • Magnitude and pattern of cardiac effects depends on the class of Ca++channel blocker Recovery Resting Activated Inactivated Nonconducting of C++ conducting Ca++ NC Ca++
    26. 26. Relative Cardiovascular Effects of Calcium Channel Blockers - (Goodman & Gilman) Verapamil ++++ ++++ +++++ +++++ Diltiazem +++ ++ +++++ ++++ Nifedipine +++++ + + 0 Nicardipine +++++ 0 + 0 Compound Coronary vasodilatation Suppression of cardiac contractility Suppression of SA node Suppression of AV node
    27. 27. Adverse effects • Verapamil: – Nausea, constipation and bradycardia – Headache, flushing and oedema – less common – Hypotension and tachycardia - less common – Precipitation of CHF in pre-existing patients – Increase in plasma digoxin level – Contraindicated in 2nd and 3rd degree heart block • Diltiazem: Same as Verapamil
    28. 28. Adverse effects – contd. • DHP – immediate release forms e.g. Nifedepine: – Palpitation, flushing ankle oedema, hypotension, headache and drowsiness – Diuresis – Higher incidence of frequency of angina – Higer incidence of mortality – Voiding difficulty (relaxed bladder Vs increased urine) • Nifedipine may increase mortality in patients with myocardial ischemia – Cause increase in angina frequency (myocardial Ischaemia) – Cerebral Ischaemia – rapid bringing down of BP – Bladder relaxation – voiding difficulty – Decrease in Insulin release
    29. 29. CCBs - Pharmacokinetics • High oral absorption, but high first pass metabolism (except amlodipine) – inter and intra individual variation and highly plasma protein bound • Extensively distributed in tissues and highly metabolized in liver and excreted in urine, eliminated in 2 - 6 Hrs (except amlodipine) Drug Bioavailability % Vd (L/kg) Active metabolite Elim half life(hr) 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
    30. 30. Desired Therapeutic Effects of Calcium Channel Blockers for Angina • Improve oxygen delivery to ischemic myocardium – Vasodilate coronary arteries – 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)
    31. 31. CCBs – Therapeutic Uses 1. 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 a reduce O2 consumption by direct effect – do not aggravate angina  MI - Verapamil/Diltiazem as alternative to β-blockers  Variant angina: Benefited by reducing the arterial spasm
    32. 32. CCBs – Therapeutic Uses – contd. 2. Hypertension 3. Cardiac arrhythmia 4. Hypertrophic Cardiomyopathy: verapamil 5. Nifedipine – Preterm labour (?) and Raynaud`s disease; Verapamil - migraine and nocturnal leg cramps
    33. 33. 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 2. Acute Prophylaxis: GTN 15 minutes before a period of increased activity – exercise, sexual activity etc. – lasts for upto 2 Hrs 3. 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) • Beta blocker + nitrates or slow acting DHP + beta blocker (no diltiazem or verapamil) • CCB + Nitrates • In severe cases - nitrates+ CCBs + beta blockers
    34. 34. Combination Therapy of Angina • Use of more than one class of antianginal agent can reduce specific undesirable effects of single agent therapy Nitrates Alone Reflex Increase Decrease Decrease Reflex increase Decrease Beta-Blockers or Channel Blockers Alone Decrease* Decrease Increase Decrease* Increase Nitrates Plus Beta-Blockers or Channel Blockers Decrease Decrease None or decrease None None Undesireable effects are shown in italics * Dihydropyridines may cause the opposite effect due to a reflex increase in sympathetic tone Heart Rate Afterload Preload Contractility Ejection time Effect
    35. 35. Potassium Channel Openers – Nicorandil • Minoxidil and diazoxide • 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 – epicardial and deep • 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
    36. 36. Pharmacotherapy of MI 1. Aim:  Emergency life saving management of the patient (ICU)  Subsequent Treatments 2. Pain, anxiety and apprehension: Morphine, Pethidine parenteral 3. Oxygenation: assisted respiration 4. Maintenance of Blood Volume, tissue perfusion and microcirculation: slow IV fluid with saline 5. Correction of acidosis: Sodibicarb IV 6. Prevention of Arrhythmia: Beta blockers early (arrhythmia and infarct size) 7. Pump Failure: Furosemide, GTN IV/Nitroprusside and Dobutamine 8. Prevention of Thrombus extension and thrombo-embolism: Aspirin and oral anticoagulants 9. Thrombolysis and reperfusion: Streptokinase, urokinase etc. 10. Prevention of Remodelling 11. Prevention of future attacks: beta-blockers, aspirin, anti-hyperlipidemia
    37. 37. 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: 1) Non-haemorrhagic stroke 2) Intermittent claudication 3) Trophic leg ulcers 4) TIA 5) To improve memory, vertigo and tinnitus etc. after CVA
    38. 38. 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 – short question