Dr. Laila M. Matalqah Ph.D. Pharmacology Antiplatelet, Anticoagulant, & Thrombolytic Agents General Pharmacology M212 Dr. Laila M. Matalqah Ph.D. Pharmacology

Coagulation Thrombus: A clot that adheres to a vessel wall Embolus: is an intravascular clot that floats in the blood Blood Coagulation: generates thrombin , consists of two pathways: the extrinsic and the intrinsic systems. Thrombotic & thromboembolic disease is common. It has severe & serious consequences Myocardial infarction Stroke Deep vein thrombosis Pulmonary embolism

Coagulation process Clotting factors: II, VII, IX, X, XI, XII inhibitors of coagulation factors: protein C, protein S, antithrombin III, and tissue factor pathway inhibitor.

Anticoagulants Vitamin K antagonists: coumarin anticoagulants e.g., warfarin Thrombin inhibitors: heparin low-molecular-weight heparins (LMWH) e.g., Dalteparin and Enoxaparin Direct Thrombin inhibitor: dabigatran etexilate

Vitamin K antagonists: Warfarin Inhibit synthesis of vitamin k dependent clotting factors: II, VII, IX, and X Antidote of warfarin is vitamin K or fresh frozen plasma . Narrow therapeutic index Therapeutic uses: Prophylactically, Deep Vein Thrombosis (DVT) Pulmonary Embolism (PE) Acute Myocardial Infarction (AMI) Prosthetic Heart Valves (INR: 2.5- 3.5) Atrial Fibrillation (AF)

Warfarin: PK Oral administration Bioavailability almost 100% Plasma protein binding: 99% Monitored by INR: 2-3 sulfonamides, can displace Warfarin and lead to increase its activity Warfarin C/I: pregnancy , crosses the placental barrier (teratogenic) Metabolized by CYP450 (inhibitor and inducer interaction) T1/2: 40 hrs

Warfarin Monitoring 1) The Prothrombin Time (PT) test The normal prothrombin time is 12-14 seconds 2) The International normalized ratio (INR) Where ISI: the international sensitivity index which relates the sensitivity of a given thromboplastin to the WHO reference

Warfarin Drug interaction: Inhibitors of warfarin metabolism: increase activity Cimetidine, Chloramphenicol, Cotrimoxazole, Metronidazole Inducer of warfarin metabolism: decrease activity Barbiturates, Rifampin Inhibition of platelet aggregation (Aspirin): increase activity ADR: Bleeding: treated by withdrawal of the drug and administration of oral vitamin K1 Skin lesions and necrosis Purple toe syndrome

Thrombin inhibitors MOA: Heparin and LMWH binding to antithrombin – Heparin inactivation of : Thrombin (IIa) and factor Xa, while LMWHs inactivate factor Xa only. Heparin given I.V or S.C , LMWH (enoxaparin and dalteparin): S.C Heparin and LMWHs are the anticoagulants of choice for treating pregnant women , with prosthetic heart valves or venous thromboembolism. Heparin (Not LMWH) need monitoring by activated partial thromboplastin time (aPTT) is 1.5- to 2.5-fold that of the normal control (30 sec)

Thrombin inhibitors Uses: TT of Acute PE, Acute DVT ADR of heparin Bleeding complication : antidote protamine sulfate Hypersensitivity reactions Thrombocytopenia (heparin- induced thrombocytopenia)

Direct Thrombin inhibitor: dabigatran etexilate prodrug of the active moiety: dabigatran Orally does not require routine monitoring (INR) Alternative to warfarin: for prevention of stroke in patients with atrial fibrillation.

THROMBOLYTIC DRUGS Alteplase (tPA), Reteplase, Streptokinase, Urokinase MOA: convert plasminogen to plasmin, which, in turn, cleaves fibrin, thus lysing thrombi Administered intravenously (I.V) Uses: Acute myocardial infarction (AMI), Acute PE, Acute DVT ADR: hemorrhage (GIT and brain bleeding) C/I: pregnancy, brain tumor, head trauma, intracranial bleeding, and metastatic cancer.

Aminocaproic acid and tranexamic acid Fibrinolytic states can be controlled by the administration of aminocaproic acid or tranexamic acid. Both agents are synthetic, orally active, and excreted in the urine, and they inhibit plasminogen activation. Tranexamic acid is 10 times more potent than aminocaproic acid. A potential side effect is intravascular thrombosis.

Platelet Aggregation Inhibitors Aspirin : inhibits thromboxane A2 synthesis- preventing platelet aggregation. 2. Ticlopidine & clopidogrel: inhibit activation of GP IIb/IIIa receptors required for platelets to bind to fibrinogen 3. Dipyridamole: a coronary vasodilator, is used prophylactically to treat angina pectoris. Uses: prevention of stroke

Anti-hyperlipidemias

Hyperlipidemias Coronary heart disease (CHD) associated with: Elevated Plasma lipoproteins: low-density lipoprotein (LDL) cholesterol and triacylglycerols (TG) Low levels of high-density lipoprotein (HDL) cholesterol

Antihyperlipidemia Drugs HMG CoA reductase inhibitors (Statins) Lovastatin simvastatin pravastatin atorvastatin Niacin (nicotinic acid) The fibrates Fenofibrate gemfibrozil Bile acid–binding resins Cholestyramine Colestipol colesevelam

HMG CoA reductase inhibitors (Statins) MOA: inhibit de novo cholesterol synthesis by inhibiting 3-hydroxy-3- methylglutaryl coenzyme, the rate-limiting step in cholesterol synthesis. Uses: Lower LDL, TG and Cholesterol oral administration ADR: Liver: increase serum transaminase levels Muscle: Myopathy and rhabdomyolysis Drug interactions: increase warfarin levels. Thus, it is important to evaluate INR frequently. Contraindications: pregnancy and in nursing mothers, children or teenagers.

Fibrates MAO: increasing lipoprotein lipase – decrease TG, LDL, VLDL and increase HDL USES: treatment of hypertriacylglycerolemias Orally ADR: Lithiasis: increase biliary cholesterol excretion- formation of gallstones Muscle: Myositis Drug interaction: displace warfarin Plasma protein – increase warfarin activity

Bile acid–binding resins MOA: bind to bile acids, resin/bile acid complex is excreted in feces--- lowering the bile acid concentration causes hepatocytes to increase conversion of cholesterol to bile acids Orally ADR: GI disturbances, such as constipation, nausea, and flatulence. Impair the absorption of the fat- soluble vitamins (A, D, E, and K).

Bile acid–binding resins Decrease absorption of tetracycline, digoxin, warfarin, pravastatin, aspirin, and thiazide diuretics, Therefore, these drugs should be taken at least 1–2 hours before, or 4–6 hours after bile acid–binding resins.