PhD215 Pharmacotherapy of Angina Pectoris & AMI Lecture 4 2024 PDF

NHN 4 November 2024  Learning Outcomes At the end of this lecture, you should be able to:  explain the basic pathophysiology of angina pectoris and acute myocardial infarction (AMI) that affect CVS;  describe angina pectoris and AMI in terms of their definition, causes & sympt...

NHN 4 November 2024  Learning Outcomes At the end of this lecture, you should be able to:  explain the basic pathophysiology of angina pectoris and acute myocardial infarction (AMI) that affect CVS;  describe angina pectoris and AMI in terms of their definition, causes & symptoms;  describe the treatment strategies (both non-pharmacological and pharmacological therapies) of angina and AMI;  discuss the pharmacological aspects of appropriate classes of drugs used in the treatment of angina and AMI (MOA, clinical uses, adverse effects);  determine the rationale use of drugs in treating angina and AMI.  Angina Pectoris  Medical term for temporary chest pain/discomfort due to coronary heart disease/coronary artery disease.  Is a symptom of underlying heart disease, the result of myocardial ischemia  reduction in O2 supply-demand ratio.  Commonly due to atherosclerosis/spasm of the coronary arteries.  New/recurring  early recognition and treatment may prevent MI.  2 main types of angina: 1. Reversible (stable) angina  when the heart works harder and needs more O2; pain goes away when heart demand. 2. Progressive (unstable) angina  when a plaque in one/more coronary arteries ruptures.  Coronary Artery Disease  Coronary arteries - mainly provide blood to the heart muscle. Over time, they can become hardened and clogged with plaque.  Coronary artery disease (CAD) occurs when the inside (the lumen) of one or more coronary arteries narrows, limiting the flow of O2-rich blood to surrounding heart muscle tissue.  Atherosclerosis: the process where a plaque build-up in the arteries causes the artery wall to get thick and stiff, which can lead to narrowing/complete blockage. If the build-up happens rapidly, there is a risk of myocardial infarction (MI).  Atherosclerosis At rest, a person with atherosclerosis of the coronary arteries may not face any problems. On the contrary, in physically active/emotionally extreme person with atherosclerosis where the heart work harder, there is insufficient blood flow to keep up with the increased workload. When heart muscle doesn’t receive enough O2 and nutrients, ischemia occurs, and chest pain and other symptoms may appear.  Risk Factors of Atherosclerosis Development Non-modifiable Modifiable  Age  Obesity  Gender  Smoking  Genetic  Hyperlipidemia  Diabetes mellitus  Physical inactivity  Arterial hypertension Pathophysiology of Angina Pectoris & AMI Pathophysiology of Angina Pectoris & Acute Myocardial Infarction (AMI) 1. The disease process begins when LDL (“bad” cholesterol) deposits cholesterol in the artery wall. 2. The body has an immune response to protect itself  sends white blood cells called macrophages to engulf the invading cholesterol in the artery wall. 3. When the macrophages are full of cholesterol, they are called foam cells because of their appearance. 4. As more foam cells collect in the artery wall, a fatty streak develops between the tunica intima and the media.  Pathophysiology of Angina Pectoris & AMI (cont’d) 5. If the process is not stopped, the fatty streak becomes a plaque, which pushes the intima into the lumen and narrowing the blood flow. 6. The plaque develops a fibrous coating on its outer edges. 7. But if cholesterol continues to collect in foam cells inside the plaque, the fibrous outer coating can weaken and eventually rupture. 8. Smaller arteries downstream from the rupture can quickly become blocked. Over time, a clot may develop at the rupture site and completely block the artery.  Types of Angina 1) Reversible (stable) angina:  Occur during physical activity / extreme emotion.  Symptoms usually develop gradually over time and follow a set pattern.  Is not a life-threatening, but can lead to more serious condition (i.e. MI)  Only lasts for a few minutes, and can be improved by resting and/or taking glyceryl trinitrate (GTN)  Types of Angina 2) Progressive (unstable@crescendo) angina:  Blood supply to the heart is severely restricted.  Is a medical emergency  a sign that the blood supply to and the function of your heart is compromised, increasing your risk of having MI.  Symptoms develop rapidly and can persist even when at rest / asleep. Unrelieved with any intervention.  The symptoms of unstable angina are the same as those of stable angina, but they do not follow the usual pattern.  Occurs suddenly for the first time, but worsen over time. Prinzmetal angina (Coronary Artery Spasm)  Rare type, also known as variant angina / angina inversa  A temporary discomfort / pain caused by a spasm (constriction) in one/more of coronary arteries, which may prevent cardiac blood flow, reducing perfusion and causing ischemia.  Occurs while resting and during night to early morning.  Spasms can range from very minor to severe, and sometimes may completely block the blood supply to the heart.  Cold, stress, medicine, smoking, cocaine  Severe pain, may relieved by: exercise, spontaneously, or medications Risk Factors of Angina  Obesity  Diabetes  Hypertension  Smoking, stress  Sedentary lifestyle  Low HDL cholesterol  High LDL cholesterol  Older than 45 for men  Post-menopausal for women  Family history of heart disease  Symptoms of Angina  Symptoms of angina and MI are pretty similar.  People can have symptoms at different times (e.g. early in the morning/when resting/sleeping/in cold weather/after a heavy meal/after physical activity.  Include a dull pain, squeezing, uncomfortable pressure, fullness/heaviness feeling, or tightness in the centre of the chest.  Chest pain/discomfort that might spread to the arms, throat / neck, jaw, shoulders, stomach or back.  Feeling sick, unusual tiredness, light-headed, restlessness, nausea, fatigue, shortness of breath, sweating, and dizziness.  Generally unwell with pain/discomfort that feels like indigestion.  Treatment Goals 1) To reduce the frequency of angina episodes 2) To terminate acute anginal pain in progress *Anti-anginal medications only relieves symptoms and do not cure the underlying disorders.  Treatment Strategies 1) To reduce O2 requirement ( heart rate & contractility) 2) To increase O2 delivery ( perfusion of the myocardium by relaxing coronary arteries)  Non-Pharmacological Management  Treat hypertension  Treat hyperlipidaemia  Reduce stress levels as much as possible  Weight management, implement a medically supervised exercise plan  Healthy lifestyle and healthy eating, reduce dietary saturated fats to keep weight at an optimum level  Stop smoking, limit alcohol consumption, limit sodium intake  Eat food rich in potassium and magnesium (e.g. banana, beans spinach and tomatoes)  Pharmacological Management  Drug requirement:  determine by the frequency and intensity of anginal episodes  responsiveness of the patient to therapy  Angina attacks occur often = Nitrate + beta-blocker  Control is not adequate = Nitrate + BB + CCB (CCB to preload by dilating veins; additive effect on reduction of O2 demand)  If the drug therapy fails / coronary arteries are significantly occluded:  Coronary arterial bypass graft (CABG)  Percutaneous transluminal coronary angioplasty (PTCA)  Anti-anginal Drugs & Their Primary Therapeutic Actions O2 Supply – Demand Imbalance  Pharmacological Management Anti-anginal drugs:  Organic Nitrates  Isosorbide dinitrate  Isosorbide mononitrate  Nitroglycerine (glyceryl trinitrate, GTN)  Beta-blockers  Calcium Channel Blockers  Others: Thrombolytics  Organic Nitrates Nitrates & Nitrites It causes rapid reduction in myocardial O2 demand  rapid relief of angina MOA:  Nitrates are converted to nitric oxide (NO) in vascular smooth muscle.  NO activates guanylate cyclase that catalyzes formation of cyclic guanosine monophosphate (cGMP), thus Ca levels in vascular smooth muscle cells.  Intracellular calcium is required for the contraction of vascular smooth muscle, Ca  venodilation/vasodilation  Thus,  preload,  workload,  O2 demand ischemia  Therapeutic Indications 1. Sublingual NTG: Mainstay for acute treatment of angina  rapid onset of action & clinical efficacy:  Exertional angina  Venodilation with resulting  venous return   of intracardiac volume result in  wall tension  preload, and heart workload =  myocardial O2 demand.  Prinzmetal’s Angina  relaxes the smooth muscle of the epicardial coronary arteries   coronary artery spasm  Unstable Angina  MOA are less well established: By dilating epicardial coronary arteries & simultaneously  myocardial O2 demand  ability to  platelet aggregation.  Therapeutic Indications (cont’d) 2. CHF associated with AMI 3. Control of blood pressure in hypertension associated with surgical procedures  to reduce the incidence of cardiac complications. 4. Production of controlled hypotension during surgical procedures  deliberate hypotension that reduces the mean arterial pressure between 50 and 65 mmHg in normal BP patients to minimizes blood loss in various operations.  Organic Nitrates 2 Major Effects on CVS 1) It causes vasodilation of the large vein (venodilation), resulting in pooling of blood in the veins preload (venous return to the heart), and workload of the heart =  myocardial O2 demand. 2) It dilates coronary vasculatures (arteries + arterioles) blood supply to the heart muscles.  Organic Nitrates Nitrates & Nitrites  Adverse effects (due to vasodilation): Flushing, dizziness, dilates arterioles (dose), reflex tachycardia (dose), tolerance, postural hypotension, lightheadedness, gastroesophageal reflux, headache  Contraindications:  Hypersensitivity reactions, severe anemia, hypotension, and hypovolemia.  Use cautiously in head injury/cerebral hemorrhage because they may intracranial pressure.  NTG/any other nitrate SHOULD AVOID sildenafil (Viagra) & other PDE5 inhibitors (for erectile dysfunction). Both drugs BP  profound, life-threatening hypotension.  Organic Nitrates Other Formulations  Buccal tablet (transmucosal) – place tablet between upper lip and gum or between cheek and gum  Sustained-released tablet – for prophylaxis use, given 3-8 hrs  Topical ointment apply to chest back abdomen  Transdermal patch (absorbed through skin)  Spray, inhalers  IV preparation – unstable angina, coronary vasospasm, hypertension, LVHF with AMI Other Formulations (cont’d)  Beta-Blockers  It suppresses the activation of the heart by blocking β-receptors  myocardial O2 consumption  It workload of the heart by CO &  BP  Useful in frequency and severity of angina attacks  Some may be contraindicated with asthmatic patients (e.g., non-selective β-blockers)  Calcium Channel Blockers  CCB inhibit the entrance of Ca into cardiac & smooth muscle cells  Vasodilation (coronary and peripheral arteries)  smooth muscle tone & vascular resistance  contractility  Clinical uses: Effective in prophylactic therapy and reduces the frequency of angina episodes.  MOA: Blocks Ca access to cells, contractility + conductivity of the heart, O2 demand  Agents: Amlodipine, Nifedipine, Felodipine, Verapamil, Diltiazem  Adverse Effects: BP, bradycardia, cause A-V block, headache, abdominal discomfort (constipation, nausea), peripheral edema  Thrombolytic Drugs  Thrombosis (blood clot formation)  significant physiological response that limits hemorrhage caused by large or tiny vascular injuries.  Thrombi can occur in any vascular system and can be immediately life-threatening:  coronary thrombi  myocardial infarctions  cerebrovascular thrombi  strokes  pulmonary thrombi  respiratory and cardiac failure  Thrombolytic drugs dissolve dangerous intravascular clots to prevent ischemic damage by improving blood flow.  Thrombolytics’ efficacy depends on the clot’s age. Older clots have more fibrin cross-linking, more compacted, more resistant  difficult to dissolve.  Thrombolytic Drugs  Also known as fibrinolytic drug, clot-lysing drug, and clot buster.  3 main thrombolytics: 1) Streptokinase = 1st gen; Non-fibrin-specific agents 2) Urokinase plasminogen activator (uPA) = 1st gen; Non-fibrin-specific 3) Tissue plasminogen activator = 2nd & 3rd gen; Fibrin-specific agents  Clinical Uses:  acute ischemic stroke  IV catheter clots  intracardiac thrombus formation  arterial thrombosis  occlusion of indwelling catheters  deep vein thrombosis  acute peripheral arterial  blocked surgical bypass occlusion  acute myocardial infarction  cerebrovascular thrombotic  acute pulmonary embolism stroke  Thrombolytic Drugs Drug administrations: systemic administration through a peripheral IV local release by a catheter after navigating to the clot site  Adverse Effects:  Bleeding, cholesterol embolism, hypotension, allergic reactions, angioedema, anaphylactic shock, and reperfusion arrhythmias (when used in acute MI)  Bleeding complications  systemic fibrinogenolysis +lysis of normal hemostatic plugs  Excess bleeding in the brain (intracerebral hemorrhage) can be fatal in some case  Re-thrombosis can occur following thrombolysis, and therefore anticoagulants such as heparin, or antiplatelets such as aspirin are usually co-administered, and continued after thrombolytic therapy for some time.  Risk factors associated with hemorrhagic complications include elderly patients, uncontrolled hypertension, recent stroke or surgery, bleeding diathesis, and concurrent use of anticoagulants. *Patients must undergo neurologic and cardiovascular evaluation with strict BP monitoring every 15 minutes during and after drug infusion for at least 2 hrs, then half-hourly for 6 hrs and hourly for the next 16 hours after injection.  Contraindications  Patients with active internal bleeding, recent cerebrovascular accident/ structural cerebral vascular lesion, recent intracranial hemorrhage/intraspinal injury/trauma, intracranial neoplasm/arteriovenous malformation/aneurysm, known bleeding diatheses, ischemic stroke within 3 mths, aortic dissection, acute pericarditis, previous SK treatment within 6 mths, prolonged CPR (>10min)/recent major surgery, ischemic stroke history, dementia, peptic ulcer  Patients with severe uncontrolled hypertension: systolic BP>180 mmHg or diastolic BP>110 mmHg a delay in thrombolytic therapy increase morbidity.  Patients with hepatic impairment: due to the increased risk of bleeding due to coagulopathy.  Patients with renal impairment: due to the increased risk of bleeding due to hemostatic defects and bleeding tendencies.  Pregnancy: due to the increased risk of bleeding. May be used only when the benefits outweigh the increased risks of uterine bleeding  Breastfeeding: use tPA cautiously  has not been studied in nursing mothers.  1. Streptokinase (SK)  A purified fibrinolytic protein from ß-hemolytic streptococci antigenic.  SK is an indirect plasminogen activator of bacterial origin (not a protease/plasminogen activator and has no enzymatic activity)  Clinical Uses: FDA-approved for AMI, pulmonary embolism, DVT, arterial and venous thromboembolism.  Relatively low cost with good efficacy and safety – widely used worldwide.  MOA:  SK acts indirectly by forming an active complex with both fibrin-bound- and free- circulating-plasminogen, which then catalyse conversion of plasminogen to active plasmin, thus producing clot fibrinolysis along with fibrinogenolysis.  Also catalyse the degradation of fibrinogen, and the coagulation factors V and VII  Due to its lack of fibrin specificity, SK efficacy < tPA.  1. Streptokinase (cont’d)  SK - Adverse Effects:  SK-induced (dose-dependent) hypotension.  Intracranial hemorrhage < tPA.  Febrile episodes  Allergic hypersensitivity reactions (anaphylaxis), particularly with repeated treatment or in patients with a recent history of streptococcal infection *Re-administration of streptokinase within 6 months is not safe  high antigenicity and associated high antistreptococcal antibody titer. 2. Urokinase Plasminogen Activator (uPA)  Urokinase (Abbokinase®; UK) aka urinary-type PA (uPA)  serine protease released by epithelial cells that line excretory passages (e.g., renal tubules, mammary ducts). A physiologic thrombolytic usually produced by renal parenchyma, thus purified from human urine. Recombinant urokinase is also commercially available.  UK is non-antigenic (> expensive than SK)  allows repeated dosing  Has limited clinical use due to low fibrin specificity  fibrinogenolysis (bleeding)  not used for thrombolysis in stroke treatments.  Clinical uses: Acute massive pulmonary embolism, catheter-directed treatment of AMI, DVT, occluded catheters and peripheral vascular thrombus. Primarily indicated for patients allergic to SK  MOA: UK directly cleaves Arg-Val bond of plasminogen active plasmin.  A/Es: bleeding, fever and hypersensitivity/anaphylaxis (rare) 3. Tissue Plasminogen Activator (tPA)  Serine protease enzyme (tPA) released from the injured endothelium of the blood vessels.  Recombinant biotechnology has allowed tPA to be manufactured in labs  recombinant tissue plasminogen activators (rtPA).  Initially purified from the culture fluid of a stable human melanoma cell line.  tPA is relatively selective (fibrin-specific) for clot-bound plasminogen, but can still activate circulating plasminogen, thereby releasing plasmin, which can lead to the breakdown of circulating fibrinogen and cause an unwanted fibrinogenolysis.  tPA: Mechanism of Action 1) Injured vascular endothelial cells release plasminogen activators (tPA, uPA), activating fibrinolysis. 2) tPA binds to the surface of the fibrin-bound plasminogen at the thrombus site, activates the plasminogen and cleaves it to plasmin. 3) Plasmin breaks down fibrin to dissolve the blood clot into small soluble fragments (fibrin degradation products) that are then metabolized by the liver and kidney. 4) To prevent hypocoagulation, fibrinolysis is controlled by plasminogen activator inhibitors (PAIs; eg, PAI-1) and plasmin inhibitors (eg, α2-antiplasmin). 5) PAI-1 and α2-antiplasmin are serine protease inhibitors (serpin) responsible for regulating imbalances in coagulation and fibrinolysis. 3. Tissue Plasminogen Activator (tPA)  The gold standard treatment for acute ischemic stroke (AIS). IV injection of tPA is usually given within the first 3 hours of the onset of symptoms.  Due to tPA relative fibrin specificity, clot dissolution of circulating fibrinogen occurs with less breakdown than SK and UK.  tPA is preferred over SK for AMI treatment.  Contraindicated in patients with haemorrhagic stroke.  tPA has undergone various modifications to amplify its pharmacokinetics and pharmacodynamics, especially:  prolonging its short half-life in the circulation, and  further increase fibrin specificity to prevent unwanted fibrinogenolysis. 3. Tissue Plasminogen Activator (tPA)  Alteplase (Activase®; rtPA):  A recombinant form of normal human tPA. Has a short half-life (~5 - 30min), usually administered as an IV bolus followed by an infusion (60 mg IV bolus then 40 mg infusion over 2 hours).  Clinical Uses:  AIS (so far, only alteplase is FDA-approved),  STEMI,  acute massive pulmonary embolism, and  central venous access devices (CVAD)  A/Es: bleeding, stroke, bruising, pulmonary edema, arterial embolism, deep vein thrombosis, orolingual angioedema, intracranial hemorrhage, hypersensitivity, nausea/vomiting, seizure, ischemic stroke, sepsis, shock, and thromboembolism. 3. Tissue Plasminogen Activator (tPA)  Reteplase (Retavase®; rPA):  A genetically engineered (deletion mutant of rtPA), smaller derivative of recombinant tPA with:  enhanced fibrinolytic potency  rapid acting  longer action duration (15 min) Better than rtPA  lower bleeding tendency  Clinical Uses: AMI.  Reteplase is less fibrin specific than alteplase, with a longer half-life allowing simplified administration. 2 IV bolus injections over 2 min (10U each, 30 min apart). *An IV line is used for the bolus injection, and no other medication should be simultaneously injected/infused via the same line (incompatible with heparin). 3. Tissue Plasminogen Activator (tPA) Its rapid acting is better than rtPA due to:  a lower binding affinity to fibrin (about 5-fold) than native tPA  allows more free diffusion through the clot rather than surface- binding like tPA  increased resistance to PAI-1, thus allowing plasminogen to transform into clot dissolving plasmin  Reteplase – A/Es:  Bleeding, reperfusion arrhythmias, hypotension, nausea/vomiting, cardiogenic shock, muscle pain, allergic reaction, a reaction at the injection site, anemia, gastrointestinal/urogenital bleed, intracranial hemorrhage, cholesterol embolization. 3. Tissue Plasminogen Activator (tPA)  Tenecteplase (TNK-tPA®; TNK-tPA):  A genetically engineered mutant of the rtPA molecule with amino acid substitutions at three sites:  14-fold higher fibrin specificity  longer action duration (>15 min)  increased resistance to PAI-1 (80-fold) Better than rtPA  lower bleeding tendency  Clinical Uses: AMI.  As efficient as alteplase while exerting a lower risk of non-cerebral bleeding  Tenecteplase has higher fibrin specificity and a longer plasma half-life with final clearance, primarily through hepatic metabolism.  Administered based on weight and as a single IV bolus over 5 seconds 3. Tissue Plasminogen Activator (tPA)  These substitutions decrease plasma clearance, increase fibrin binding, and increase resistance to plasminogen activator inhibitor-1 (PAI-1).  Thus, these changes in human tissue plasminogen activator increase plasma half-life and fibrin specificity and decrease the inactivation of tenecteplase by PAI-1.  Tenecteplase – A/Es:  Bleeding, allergic reactions, anaphylaxis, cardiogenic shock, arrhythmias, atrioventricular block, pulmonary oedema, heart failure, cardiac arrest, recurrent myocardial infarction or ischemia, myocardial rupture, cardiac tamponade, pericarditis, pericardial effusion, mitral regurgitation, thrombosis, embolism and electromechanical disassociation. Antiplasmin: Tranexamic Acid (TXA)  TXA is a synthetic lysine analogue used as an antifibrinolytic to control and prevent bleeding in patients with haematological disorders.  Open heart surgery (Coronary Artery Bypass Graft) can  tPA plasma level, resulting in plasminogen activation and fibrinolysis that cause bleeding. TXA has prothrombotic (antifibrinolytic) effects that control bleeding with efficacy in major surgeries. Thus, used in life-threatening surgical complications to minimize bleeding in cardiac surgery.  Prothrombotic and proconvulsant effects of TXA  the risk of MI, stroke, and other thrombotic complications after cardiac surgery. But no convincing evidence was found.  Should not be introduced unless there is a life-threatening haemorrhage due to inhibiting intrinsic physiologic fibrinolytic activity, which may cause widespread thrombosis with potential end-organ damage at many sites. Antiplasmin: Tranexamic Acid (TXA)  MOA:  TXA competitively and reversibly inhibits plasminogen activation (via binding to lysine-binding site) to plasmin (enzyme that degrades fibrin clots, fibrinogen, and other plasma proteins, including the procoagulant factors V and VIII)  fibrinolysis inhibition and promotes clot stabilization.  TXA also directly (non-competitively) inhibits plasmin activity, and inhibits fibrinogenolysis at higher doses.  Clinical Uses: Adjuvant therapy in haemophilia; postsurgical bleeding; an antidote for fibrinolytic therapy-induced bleeding; hereditary angioedema; intraoperative use in cardiac surgeries to reduce perioperative blood loss and allogeneic blood transfusion; anti-fibrinolytic hemostatic use in severe haemorrhage (menstruation, surgery, or trauma); for short-term use in patients with haemophilia (2-8 days) to prevent or reduce bleeding following tooth extraction (via IV).  Myocardial Infarction  Myo = muscle; cardium = heart; infarction = tissue death  Definition: Irreversible cellular death/necrosis of cardiac muscle and surrounding tissue secondary to severe/prolonged ischemia and hypoxia.  Commonly known as heart attack.  It is an emergency situation, requiring prompt hospitalization in coronary care unit (CCU) and careful medical management.  >50% death associated with AMI occurs within 2 hours after the onset of the symptoms, and are attributed to ventricular arrhythmias.  Etiology:  Acute thrombus clot formation  following rupture of lipid-rich atherosclerotic plaque and platelet activation  A rare or coexisting cause is coronary artery spasm. Pathophysiology of AMI  Risk Factors of AMI  Smoking  Male gender  Hypertension  Increasing age  Hyperlipidemia  Diabetes mellitus  Family history of atherosclerotic arterial disease.  The disease risk becomes equal in both sexes after 80 years of age.  Between the ages of 45-54, men are 4 – 5 times as likely to develop an MI than women.  Symptoms of AMI One or more of the following may be present:  SOB  Arrhythmia, palpitation  Anxiety, weakness, fatigue  Hypotension or hypertension  Confusion, diaphoresis, pallor  Syncope, dizziness, light headedness  Nausea with or without vomiting (unexplained)  Chest pain (last at least 20 minutes, but may be shorter duration)  Diagnosis of AMI Require at least TWO of the following criteria:  A history of characteristic chest pain of ischaemic origin  Electrocardiograph (ECG) changes  Computed tomography coronary angiography (CTCA) / Chest X-ray to identify an intracoronary (IC) thrombus  Echocardiography - Structural and functional Imaging  Elevated cardiac enzymes (release of intracellular enzymes):  Aspartate aminotranferase (AST)  Creatine kinase myocardial band (CK-MB)  Lactate dehydrogenase (LDH)  Cardiac troponin I (cTnI)  BNP or NTproBNP (natriuretic peptides)  Goals of Therapy  Restoration of myocardial perfusion through thrombolytic therapy  Limit extension of myocardial necrosis  Reduction in myocardial O2 consumption  Control complications (pain, hypertension, CHF, arrhythmias)  Management Protocol A. General Measures  Hospitalization  Limit on visitor B. Analgesia  Adequate control of pain will reduced oxygen consumption and decrease levels of catecholamines.  It also helps to relief anxiety.  Morphine sulphate (drug of choice) C. Sedation  Given during the initial days following MI  Use benzodiazepine D. Oxygen therapy  To keep hemoglobin saturation above 90%  Administered at 2-4 liter/min nasal cannula  Management Protocol (cont’d) E. Antianginal drugs (NTG):  Use SL and IV nitroglycerine for pain relief (on arrival)  Agents useful are GTN, sodium nitroprusside etc.  MOA:  Nitrates are metabolized to nitric oxide in the vascular endothelium. Nitric oxide relaxes vascular smooth muscle and dilates the blood vessel lumen,  vasodilatation.  Vasodilator effect of nitroglycerine preload, and afterload, thus preventing left ventricular hypertrophy and CHF.  Management Protocol (cont’d) F. Thrombolytics  To open and restore blood flow to the occluded artery as soon as possible to prevent further tissue necrosis.  Drug: Streptokinase (sourced from beta-hemolytic streptococci; it’s a protein not an enzyme)  Drug Class: Thrombolytic agent  Mechanism of action: Make complex with plasminogen, which then converts plasminogen to the active enzyme plasmin, which then causes the lysis of fibrin thread.  Clinical uses: Acute pulmonary emboli, Deep venous thrombosis (DVT), Acute myocardial infarction  Side effects: Bleeding disorder, hypersensitivity (rashes, fever, anaphylaxis).  Management Protocol (cont’d) F. Anticoagulation (Heparin)  Heparin should be given to all patients who are not receiving thrombolytics.  Mechanism of Action:  Heparin binds reversibly with naturally circulating anticoagulant antithrombin III (heparin cofactor).  Heparin-Antithrombin III complex will instantly inactivate thrombin (IIa) and Xa by forming complexes with them. It can also inactivate factors IX, XI, XII and plasmin.  Side effects: Nose bleed, urinary bleeding, blood in stool, thrombocytopenia  Management Protocol (cont’d) F. Antiplatelet (Aspirin)  Aspirin 160-325mg (chewed) given concurrently with thrombolytic.  Aspirin should be continued every day through out life for prophylaxis.  Clopidogrel (Plavix) should be given to those who cannot tolerate aspirin.  MOA: Aspirin acts by irreversibly blocking the enzyme cyclooxygenase resulting in decreased thromboxane A2 production and platelet inhibition.  Management Protocol (cont’d) ACEIs:  Vasodilators reduce preload and after load, thereby reducing oxygen demand.  Most useful for MI patients with ejection fraction