Blood Thinning Drugs and Antihyperlipidemic Agents PDF

Cardiovascular system’ drugs: Anticoagulants, Antiplatelet and Thrombolytic Agents + Dyslipidemia Drugs By Dr. Jawza Almutairi HPT 316 Third Semester/ 1444 H Anticoagulant, Antiplatelet and Thrombolytics Agents Objectives - To differentiate between anticoagulant, antiplatelet and thrombolytic...

Cardiovascular system’ drugs: Anticoagulants, Antiplatelet and Thrombolytic Agents + Dyslipidemia Drugs By Dr. Jawza Almutairi HPT 316 Third Semester/ 1444 H Anticoagulant, Antiplatelet and Thrombolytics Agents Objectives - To differentiate between anticoagulant, antiplatelet and thrombolytics - To each drug groups know mechanism of action To differentiate between different types of thrombolytic drugs. - To describe indications, side effects and contraindications of these drugs. - To recognize the mechanisms, uses and side effects of them. Clot IN ten all 45 É Thrombf Clot treat prevent I 41,63 Important Definitions Hemostasis u Is the body’s process of stopping bleeding in a blood vessel. u Normal hemostasis involves a complex process of extrinsic and intrinsic factors. Thrombus u Is defined as blood clot which may form in any vessel, artery, or vein when blood flow is impeded. Drugs used in thrombosis: b Clot Ischemia Atherosclerosis Antiplatelet Classification of antiplatelet 1. Arachidonic acid pathway inhibitors Aspirin (acetylsalicylic acid) Aspirin is the only NSAID that irreversibly exhibits antithrombotic efficacy. MOA: u Irreversible inhibition of cyclooxygenase enzyme(COX-1) è THUS inhibits thromboxane (TXA2) synthesis in platelets B. u Low-dose aspirin (81mg enteric coated tablet/day) is the most common dose used to prevent a heart attack or a stroke. 1. Arachidonic acid pathway inhibitors Aspirin (acetylsalicylic acid) Indications: - Prophylaxis of thromboembolism e.g. prevention of transient ischemic attack, ischemic stroke and myocardial infarction. - Prevention of ischemic events in patients with unstable angina pectoris. - Can be combined with other antiplatelet drugs (clopidogrel)or anticoagulants (heparin). SE: • Risk of peptic ulcer.àbc they inhibit the prostaglandins synthesis. • Increase incidence of GIT bleeding 2. Adenosine diphosphate (ADP) receptor inhibitors Ticlopidine & Clopidogrel MOA: These drugs specifically and irreversibly inhibit ADP receptor. which is required for platelets activation thus prevent platelet aggregation. u giving orally. u Pro-drugs, they have to be activated in the liver. 2. Adenosine diphosphate (ADP) receptor inhibitors Ticlopidine & Clopidogrel SE: u Sever neutropenia (with Ticlopidine) (lowWBCs) \agranulocytosis, èèCBC should be done monthly during treatment. Importantly, Less side effects (less neutropenia), clopidogrel it is rarely associated with neutropenia and Bioavailability isunaffectedbyfood. Clopidogrel has replaced ticlopidine. u Bleeding (prolong bleeding time). u G.I.T: nausea, dyspepsia, diarrhea. u Allergic reactions. Drug Interaction: Inhibit CYTP450 causing increase in plasma levels of drugs such as phenytoin and carbamazepine.(Antiepileptic drugs) 2. New Adenosine diphosphate (ADP) receptor inhibitors Prasugrel & Ticagrelor Both have more rapid onset of action than clopidogrel. Both drugs donot need hepatic activation.(notprodrugs!) 3. Glycoprotein IIb/IIIa receptor inhibitors Abciximab, Tirofiban & Eptifibatide MOA: inhibit GP IIb/IIIa receptor. Glycoprotein IIb/ IIIa receptor is required for platelet aggregation with each other and with fibrinogen and von Willbrand factor. - They are given IV. - Used For the reduction of incidence of thrombotic complications during coronary angioplasty (PCI). 4. Phosphodiesterase inhibitors Dipyridamole MOA: (It is a vasodilator). u it Inhibits phosphodiesterase (an enzyme that normally breakdown cAMP) thus increases cAMP causing decreased synthesis of thromboxane A2 and other platelet aggregating factors. u Given orally. SE - Headache. - Postural hypotension.àbc it is a vasodilator. vann w factor Summary reffered thromoxane prevent Anticoagulant Emergency in somecases 1st the theorld Thrombie Act on the factor Coagulation pathways: undirect 080 O O O Direct O Endogenous inhibitors of coagulation: factors Ttheliver g Anticoagulants indications: • In myocardial infarction, • Deep venous thrombosis. • Peripheral arterial emboli, pulmonary embolism • Also used in blood transfusions and dialysis procedures. 1. Heparin and LMWH Derivatives Heparin, Enoxaparin sodium MOA: u Inhibit the formation of thrombin and fibrin by activating antithrombin III. u Antithrombin III then inactivates factors IXa, Xa, XIa, and XIIa resulting in prevention of a stable fibrin clot. factor 8 10 Heparin cannot be taken orally or IM. Why?? u Heparin is not absorbed from the GITàIt should be administratedby IVor SC injection but not IM as it causes haematomas at the injection site. (bc muscles are rich in BV) 1. Heparin and LMWH Derivatives Heparin, Enoxaparin sodium u Does not cross placenta, there fore,it is the drug of choice as an anticoagulant during pregnancy. a u It require regularly monitor aPTT (activated partial thromboplastin time: a test to measure how long it take for clot to form, this test determin the effectiveness of the therapy ). SE: Ø Bleeding > antidote is protamine sulfate Ø Thrombocytopenia (rare but severe) Ø Osteoporosis on long-term use Ø Hypersensitivity reaction include local irritation when heparin is given by SC injection to rarely anaphylactoid reaction. 2. Direct thrombin inhibitors Hirudin, Lepirudin MOA: Exert their effect by direct binding to thrombin. u This direct effect is rapid & potent. u Not associated with thrombocytopenia. u Recombinant hirudin “Lepirudin” is used as IV anticoagulant in patients with HIT (Heparin-induced thrombocytopenia) Afar hipri n 3. Vitamin K (Fat soluble vitamins) Antagonist Coumarin (Warfarin) MOA: u Inhibits vitamin K epoxide reductase, thus interferes with the manufacturing of vitamin K dependent clotting factors by the liver resulting in depletion of clotting factors II (prothrombin), VII, IX, and X. 5 u u 8 factors t has a slow offset of action, 3-4 days until effect is seen. à Because it does not have any effect on already-synthesized coagulation factors; therefore, the therapeutic effects are not seen until these factors are depleted I Uses as (prophylaxes): Warfarin is used to prevent the progression or recurrence of acute deep vein thrombosis or pulmonary embolism after initial heparin treatment. 1 J 3. Vitamin K (Fat soluble vitamins) Antagonist Coumarin (Warfarin) u Its contraindicator in Pregnancy à as it can cross the placental barrier and cause Teratogenicity abortion (1st months), hemorrhagic disorder (later stages) in the fetus and birth defects. SE: u The most common site of bleeding is the GI tract. u hypersensitivity. u Narrow therapeutic range u loss of effectiveness > thromboembolism u High dose > bleeding 3. Vitamin K (Fat soluble vitamins) Antagonist Coumarin (Warfarin) SE: u Need to monitor INR (international normalization ratio) > adjust dose normal people u The average time range for blood to clot is about 10 to 13 seconds. A number higher than that range means it takes blood longer than usual to clot. A number lower than that range means blood clots more quickly than normal. u In healthy people an INR of 1.1 or below is considered normal. An INR range of 2.0 to 3.0 is generally an in cardiovascular Pt ratio effective therapeutic range for people taking warfarin for disorders such as atrial fibrillation or a blood clot in the leg or lung. 3. Vitamin K (Fat soluble vitamins) Antagonist Coumarin (Warfarin) Drug interaction: u Metabolized by liver u Enzyme inducers (e.g. phenobarbital) > loss of effectiveness > required larger dose Enzyme inhibitors (e.g. omeprazole) > increase risk of bleeding > require dose reduction lipid sum y agent): Inhibition of Cholystyramine (dyslipidaemia drug absorption from GIT u u u VitK, and oral contraceptives: Increase in synthesis of aclotting factors; É waffrin 3. Vitamin K (Fat soluble vitamins) Antagonist Coumarin (Warfarin) What do you do in case of warfarin associated bleeding? u Stop the drug u IV injection of vitamin K ( (the antidote of warfarin) u Fresh frozen blood Thrombolytic Anticoagulants Vs. Thrombolytics Ø Anticoagulants are used to prevent the formation and extension of a thrombus. Ø Thrombolytic drugs or called fibrinolytic drugs dissolve blood clots that have already formed within a blood vessel. Mechanism of Action of thrombolytic drugs They have common mechanism of action by stimulating plasminogen active inactive activation via converting plasminogen (proenzyme) to plasmin (active enzyme) ® lysis of the insoluble fibrin clot into soluble derivatives. Plasmin: is a nonspecific protease capable of breaking down fibrin as well as other circulating proteins, including fibrinogen, factor V, and factor VIII. gAtival Types of thrombolytic drugs Non-fibrin specific u Streptokinase, Anistreplase and Urokinase Fibrin specific u Alteplase, Reteplase and Tenecteplase Non-fibrin vs fibrin Specific Thrombolytics Non-Fibrine: u binds equally to circulating and non-circulating plasminogen. u produces breakdown of clot (local fibrinolysis) and circulating plasminogen and other plasma proteins thus cause an unwanted (systemic fibrinolysis) leading to bleeding. Fibrin Specific: u Selective in action (clot or fibrin specific) u Binds preferentially to plasminogen at the fibrin surface (noncirculating) rather than circulating plasminogen in blood. u Risk of bleeding is less than non specific agents. u Activity is enhanced upon binding to fibrin. Thrombolytic u Therapeutic uses: Ø Acute myocardial infarction. Ø Acute ischemic stroke Ø DVT u Deepvainthrombosis Adverse effects: Bleeding (may dissolve beneficial clots), especially with non-fibrin specific agents Fibrinolytic Inhibitors Antiplasmin Aminocaproic Acid, tranexamic Acid and Aprotinin u Inhibit plasminogen activation and thus inhibit fibrinolysis and promote clot stabilization. Uses: ü Adjuvant therapy in hemophilia (inherited bleeding disorder) ü Fibrinolytic therapy-induced bleeding (antidote). ü Post-surgical bleeding ü These drugs work like antidotes for fibrinolytic drugs. Similar to Protamine (Antidote of the anticoagulant, heparin) or Vitamin K (Antidote of the oral anticoagulant warfarin). Dyslipidemia Drugs (Hypolipidemic Drugs ) Dyslipidemia Oddie Imbalances in lipid components u u High total cholesterol u High LDL cholesterol u Low HDL cholesterol u High triglycerides a Pt w bi g It’s the Significant risk factor for cardiovascular diseases; Heart disease and Stroke Physiology Lipid transport u Lipids are insoluble in water: Transported In plasma as complexes of lipid and proteins known as lipoproteins Lipoproteins: 3 major classes based on density u VLDL (Very Low Density Lipoprotein) u LDL (Low Density Lipoprotein) u HDL (High density Lipoprotein) Pathophysiology u The deposition and retention of cholesterol in the arterial walls are the central features of the pathogenesis in atherosclerosis Detection u If Fasting lipoprotein profile (total cholesterol > 200mg/dl, LDL cholesterol > 100mg/dl , HDL cholesterol < 40 mg/dl, triglycerides > 150mg/dl) Non-pharmacological Therapy (Lifestyle Changes) u Dietary therapy : Low consumption of saturated fat and cholesterol u Physical activity: Aerobic exercise 30 min/day for most days of the week u Weight reduction if overweight u Stop smoking Antihyperlipidemic agents Most commonly used lipid lowering drugs classes include: u HMG-CoA reductase inhibitors (statins) u Niacin u Fibrates u Bile acid–binding resins I-HMG-CoA reductase inhibitors u Simvastatin u Atorvastatin u Rosuvastatin u Pharmacodynamic: u Inhibit HMG-CoA (3-Hydroxy-3-methylglutaryl coenzyme A) reductase >> lower lipid levels by interfering with cholesterol synthesis. HMG-CoA reductase inhibitors Adverse reactions u u Most troublesome side effects are myalgia and occasionally lifethreatening rhabdomyolysis (at higher doses or with fibrates). Increase in liver enzymes. e f u Contraindicated in pregnancy, lactation and liver dysfunction u Drug interaction: increase the risk of bleeding when administered with warfarin. II. Fibrates u Fenofibrate. u Gemfibrozil. u in Pharmacodynamic: activate nuclear receptor [peroxisome proliferator–activated receptors (PPARs)] > regulates lipid metabolism. u Adverse effects: Ø Gastrointestinal upset, and diarrhea Ø Cholelithiasis (gall stones) with gemfibrozil. Ø Myositis the DNA II. Fibrates u Fenofibrate. u Gemfibrozil. u Drug interactions: Ps 1- Gemfibrozil is contraindicated with simvastatin (Myopathy and rhabdomyolysis) 2-Both fibrates may increase the effects of warfarin Ee 3- Fibrates should not be used in patients with severe hepatic or renal dysfunction or in patients with preexisting gallbladder disease b ok III. Bile-sequestering drugs 53 web wary idk joy u Pharmacodynamics: They combined with bile acids in the intestines Cholestyramine to form an insoluble compound that’s then excreted in feces. u With increased loss of bile acids , the liver uses cholesterol to manufacture more bile. This is followed by a decrease in cholesterol levels. u Adverse effects: ØConstipation ØDyspepsia ØFat (if severe occasionally result in fecal impaction). and flatulence. soluble vitamin deficiency ( A, D, K, E) Bile-sequestering drugs Drug interactionsu May bind with digoxin, thiazide diuretics and propranolol, resulting in decreased effects of these drugs. u Poor absorption of fat-soluble vitamin K can affect prothrombin time significantly, increasing the risk of bleeding. u May raise triglyceride levels > contraindicated in hypertriglyceridemia b Contraindication other between gab Drugs IV. Niacin u Mechanism of action: inhibits lipolysis in adipose tissue > reducing production of free fatty acids u Adverse effects: Ø Flush, nausea, vomiting Ø Inhibits tubular secretion of uric acid > hyperuricemia and gout Ø Impaired glucose tolerance (prediabetes) Ø Hepatotoxicity > should be avoided in hepatic disease A Igt Thank You u For ANY QUESTIONS: u ([email protected])