Antianginal drugs and drugs used in ischaemia - drdhriti

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

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  • 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( mariamnasrin2@gmail.com ) So that i can explain you more about me. thank Yours mariam.
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  • 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

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