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Drug Therapy for Coronary Atherosclerosis & it’s Repercussions Tay Ju Lee MD INTI Objective Ischemic Heart Disease Treatment of Angina Antithrombotic Anticoagulant Lipid-lowering Therapy Agents Drugs Ischemic Heart Disease Coronary blood flow is normally closely related to myocardial oxygen demand. Ischemic heart disease or coronary artery disease, alters coronary flow – mismatch between perfusion(supply) & demand. CAD occurs when there is a lack of oxygen to the myocardium usually due to coronary artery narrowing. Ischemic Heart Disease Ischemic disease may present as Unstable angina Def Acute Myocardial Infarction (MI) Chronic stable exertional angina Prinzmetal angina Vasospasm of coronary vessels. Pathophysiology Myocardial oxygen demand (MVO2) is determined by Heart rate Contractility Wall stress (intraventricular pressure) Ventricular volume Wall thickness during systole Pathophysiology Our heart is continuously beating Oxygen needs are high Blood delivers oxygen in diastole As heart rate increases, diastole shortens, heart demand for O2 increases. During systole, heart must contract with force that exceeds aortic pressure to eject blood. What happens when BP rises? Pathophysiology Coronary blood flow = 1/diameter vessel4 Critical loss of perfusion occurs when lesion extends across 70-80% of diameter. Ischemia causes abnormal contraction further increases burdens on remaining heart tissue. Severe coronary atherosclerosis increases sensitivity to catecholamines – vasocontriction Supply & Demand Factors affecting the balance of O2 supply and demand in angina What causes decreased O2 supply? ↓ Coronary blood flow ↓ Blood vessel caliber ↓ Perfusion pressure ↑Heart rate = decreased diastolic filling time ↑ Ventricular wall tension ( compression of intramyocardial vessels) Supply and Demand Increased O2 Demand ↑ Heart rate ↑ Myocardial contractility ↑ Ventricular wall tension ↑ Filling pressure (preload) ↑ Resistance to ejection (afterload) Coronary Steal A fixed stenosis can greatly affect collateral blood flow – Coronary steal During activity or exercise, well perfused tissue that is able to dilate will actually ‘steal’ blood away from areas of fixed stenosis, resulting in greater ischemia. Perfusion is compromised, vessels distal to area of fixed stenosis collapse. Coronary arteries are end-arteries. Clinical Presentation Angina Chest pain (angina) - Substernal Chest Pressure or sensation of heavy weight on chest. Burning sensation Feeling of tightness ST-depression on EKG Shortness of breath Radiating pain to LA/RA, lower neck/jaw Types of angina Exertional Pain usually at some predictable level of exertion, typically relieved with rest. Variant (Prinzmetal’s) angina Symptoms can occur at rest, not relieved by rest Unstable (Stable) angina angina – emergency Chest pain with minimal activity , increasing in frequency, severity & duration, present at rest. Often occurs prior to MI Treatment of Angina Treatment of Angina Relief of acute angina - Sublingual nitrates Stable angina - Prophylaxis(preventing anginal pain) Long-acting nitrates β-Blockers Calcium channel blockers Unstable angina – all of above for SA plus Aspirin Thrombin modulators Surgical management Coronary artery bypass graft CABG Percutaneous transluminal coronary artery angioplasty PTCA Nitrates Nitroglycerin, Isosorbide dinitrate, Isosorbide mononitrate Dilate arteries(higher dose) & veins(lower dose) Mechanism of action Nitrates work directly on vascular smooth muscle Nitrates reduce to nitric oxide, activating guanylate cyclase reducing GMP production reducing the amount of intracellular calcium available for contraction. Nitrates - Pathophysiology We thought nitrate improves redistribution of coronary blood flow to ischemic heart minimal Relief of angina is really due to ability to Reduce preload – Vasodilation of venous capacitance vessels reduced venous return to heart reduce Left ventricular filling pressure reducing myocardial oxygen demand. Reduce afterload – Vasodilation of arteries decreased peripheral vascular resistance Decreases work of heart - no coronary steal effect. Nitroglycerin Administration Intravenous, sublingual, topical, lingual spray & chewable tablets – quick & short acting Transdermal & oral tablets - long-acting control Tolerance to nitrates occurs quickly - 8 hours free of drug per day – sleep. Nitroglycerin Sublingual niroglycerin Keep in tight brown glass bottle – Short half-life 3 mths. Dissolves under tongue in 30 seconds, tingling Relief 1-2 minutes - drug action enhanced by sitting, leaning forward & deep inhalation May give another dos in 5 mins Third dose – no relief, pt having an MI Take before activity, PT Nitrates-therapeutic concerns Reflex tachycardia Dizziness, orthostatic hypotension & weakness Precautions against falls is warranted Avoid thermal modalities – which increase pooling in lower legs Long-term nitrate use associated withabnormal hemoglobin, methemaglobin both compromise oxygen delivery. β-Blockers β-Blockers are used as initial therapy for stable angina with nitroglycerin Clinical use Decrease myocardial oxygen demand by Decreasing contractility Decreasing exertional tachycardia Titrate so resting HR within 75% of rate producing chest pain. Avoid in pt with bradycardia, asthma, hypotension & heart block. Calcium Channel Blockers Calcium initiates contraction in cardiac and smooth muscle. CCB’s block that causing reduced contractility of heart and vasodilation. Calcium channels in heart are L-type – produces long & large high threshold current - during upstrokes AV & SA nodes (Phase 1 & 2) T-type – produces short, small & low threshold current – during diastolic depolarization (Phase 4) Calcium Channel Blockers Dihydropyridines – nifedipine & amlodipine Vasodilation Phenethyl alkylamines – verapamil Benzodiazepine - diltiazem Both decreases cardiac contractility Preventing chest pain in stable angina Used in preventing chest pain in variant angina Calcium Channel Blockers Unwanted effects – extension of therapeutic effects Dizziness Flushing of skin Hypotension Reflex tachycardia Peripheral edema Verapamil & Diltiazem Heart block & Bradycardia Heart failure Constipation. Therapeutic Regimens β-Blockers & nitrates are used together effectively - β-Blockers reduce reflex tachycardia produced by nitrates Nitrates & CCB’s are effective for treatment of variant angina, prevention of coronary vasospasm. Thrombosis & Antithrombotic therapy Thrombosis Haemostasis is the arrest of blood loss from damaged blood vessels and is essential to life. It involves vasoconstriction adhesion and activation of platelets fibrin formation. http://www.youtube.com/watch?v=9QVTHDM90i o&feature=related Antithrombotic agents Drugs that affect hemostasis affects Platelet function – Antiplatelet Agents Aspirin ADP receptor antagonists Glycoprotein Iib/IIIa receptor blockers Dipyridamole Blood coagulation (fibrin formation) – Anticoagulants Heparin Low Molecular Weight Heparin Warfarin Fibrin removal - Thrombolysis Alteplase Anti-platelet agents Aspirin Used in unstable & stable angina to lower risk of MI. Preventing stable thrombosis from rupture causing unstable angina leading to MI Used in prevention of strokes. MOA inhibits COX blocking conversion of arachidonic acid to prostaglandin H2 This reduces Thromboxane A2 Inhibits platelet aggregation for platelet lifespan - 8 days Aspirin Pharmacokinetics Loading dose 325 mg, daily 80mg Chewable tablets for patient with chest pain who may be having an MI Normal platelet function occurs after 36 hrs due to new platelet release Can be combined with other antiplatelet agents Aspirin Adverse Bleeding & GI irritation Tinnitus and CNS toxicity at higher doses Bronchoconstriction – aspirin sensitive asthma PT effects avoids Deep tissue work Friction massage Vigorous mobilization Watch for bruising, joint swelling and bleeding which may mean dose is too high. Antiplatelet agents Adenosine Diphosphate Receptor antagonists Ticlopidine & clopidogrel MOA Reduces the expression of GpIIb/IIIa receptors Clinical use Prevent recurrent stroke & Transient ischemic attacks (TIA) Prevent MI in acute coronary syndromes Used during stent placement to prevent thrombosis after PTCA Antiplatelet agents Glycoprotein Iib/IIIa receptor blockers Abciximab & tirofiban Used in angioplasty and prevent MI MOA Inhibit binding of fibrin and von Willebrand factor to glycoprotein recepters on platelet Platelet inhibition rapid, short duration 48 hrs Adverse effect Bleeding Anticoagulant agents Heparin MOA Binds to circulating antithrombin III to activate it. This complex neutralizes activated clotting factors Xa, !Xa, IIa (thrombin). Heparin’s major effect is inactivation of thrombin Unfractionated heparin has greater effect than LMWH, only this form can inhibit platelet aggregation. Heparin Clinical use IV in emergency, via continuous IV infusion halflife 30mins Subcutaneous – onset 1-2 hours Close monitoring with aPTT measures intrinsic pathway Heparin is used to prevent & treat Deep venous thrombosis Pulmonary embolism Arterial thrombosis in some cases of MI Prevent catheter clotting after certain surgeries Low Molecular Weight Heparin LMWH High anti-factor Xa activity compared to heparin Half-life 4 hrs, greater bioavailability & more predictable anticoagulant effect – less bleeding Limited effect on platelets SC q12hrs up to 6 wks after orthopedic surgery to prevent DVT or till mobile. Heparin Adverse effects Bleeding can be reversed with protamine sulfate, binds & inactivates heparin Heparin-induced thrombocytopenia paradoxically prothrombotic – monitor platelets Osteoporosis – long term >3mth treatment Warfarin Warfarin Oral anticoagulant that inhibits production of a reduced form of Vitamin K cofactor for synthesis of X, IX, VII, II in liver. Clinical indications Prevent & treat DVT & Acute MI, emboli from atrial fibrillation & prosthetic heart valves Warfarin Pharmacokinetics Highly bound to albumin 99% numerous drugs affect warfarin. Ingestion of large amount of green vegetables containing Vit K decreases warfarin’s effectiveness Onset of action 4-5 days, long half-life 36-40 hrs Monitored with INR goal dependent on type of treatment. Adverse effect Bleeding, treat with fresh frozen plasma Crosses placenta & highly teratogenic Pharmacological management DVT PE PAD Unstable angina & MI Please read pages101-103 Lipid-Lowering Drugs Lipid-Lowering Drugs HMG CoA Reductase Inhibitor (Statins) Pravastatin, atorvastatin, lovastatin, simvastatin (PALS) Statins competitively inhibit enzyme that catalyzes the rate-limiting step in synthesis of cholesterol Reduction in cholesterol causes compensatory increase in LDL receptors therefore LDL clearance. Statins Clinical use Statins reduce cardiac mortality, lowers the incidence of stroke & decrease mortality Atherosclerotic plaque stabilization Adverse effects Liver abnormalities – monitor liver enzymes Muscle pain Drug Interactions Lipid-Lowering Drugs Nicotinic Increases HDL, reduces LDL, decreasese TG Adverse effects – skin flushing Bile acid Acid – Binding Resins Cholestyramine & Colestipol Bind bile acids synthesized from cholesterol and prevent enterohepatic circulation GI intolerance limits widespread use. Lipid-Lowering Drugs Fibrates Gemfibrozil Alter lipoprotein metabolism by activating gene transcription of PPAR Increase Lipoprotein lipase activity – enhance elimination of TG Adverse effects – GI upset, increased risk of gallstones, increased risk of myositis when given with statin Lipid-Lowering Drugs Therapeutic concerns Muscle soreness & rhabdomyolysis especially when used in combination. PT should question pts about incidence of muscle soreness greater than what would be expected from PT. References Gladson, B (2006) Pharmacology for Physical Therapists. Rang et al (2007) Rang & Dale’s Pharmacology 6th Ed.
