Drugs affecting blood Drugs Affecting Blood Treatment Anemia
Drugs affecting blood
Drugs Affecting Blood Treatment: Anemia Thrombosis Bleeding
Drugs are used to treat thrombotic disorders
Formation of a clot Clot formation requires platelet activation and aggregation, followed by formation of thrombin. This serum protease catalyzes the production of fibrin which, when cross-linked, stabilized the clot.
1. Resting platelets 2. Healthy, intact endothelium releases prostacyclin into plasma. - Prostacyclin binds to platelet membrane receptors, causing synthesis of c. AMP. Resting platelets Healthy, intact Endothelial cells Subendothelium Collagen fibers Inactive GP IIb/IIIa receptors - c. AMP stabilizes inactive GP IIb/IIIa receptors and inhibits release of granules containing platelet aggregation agents or Ca 2+ - Prostacyclin Nitrous oxide Endothelial cells
3. Platelet adhesion Resting platelets Activated platelets cover And adhere to exposed subendothelial surface of damaged endothelium Collagen fibers
4. Platelet activation Thromboxane A 2 ADP Serotonin PAF Chemical mediators released by platelets Activated platelets release chemical mediators
5. Platelet aggregation Platelets are recruited into the platelet plug Thromboxane A 2 ADP Serotonin PAF
Thrombin ADP Other mediators Thromboxane A 2 Granules Prostaglandin H Arachidonic acid Fibrinogen Thromboxane A 2 Thrombin ADP
8. Formation of plateletfibrin plug Prothrombin Thrombin Activation of coagulation factors in plasma Fibrinogen Heparin Platelet-fibrin clot Fibrin
9. Fibrinolysis Tissue plasminogen activator Plasminogen Plasmin Fibrin peptides
Classification 1) Platelet inhibitors 2) Anticoagulants 3) Trombolytic agents
Classification Platelet inhibitors: 1. Arachidonic acid pathway inhibitors Acethylsalycilic acid 2. Phosphodiesterase inhibitors Dipyridamole 3. ADP pathway inhibitors Ticlopidine, Clopidogrel, Ticagrelor 4. Glycoprotein IIb/IIIa inhibitors Abciximab, Tirofiban, Eptifibatide
1. Pletelet aggregation inhibitors They decrease the formation or the action of chemical signals that promote platelet aggregation.
Arachidonic acid pathway inhibitors Acethylsalycilic acid Mechanism of action It blocks thromboxane A 2 synthesis from arachidonic acid in platelets by irreversible inhibition of cyclooxygenase-1, a key enzyme in prostaglandin and thromboxane A 2 synthesis. The inhibitory effect is rapid and lasts for the life of the platelet – approximately 7 to 10 days.
Uses Prophylaxis of thromboembolism e. g. prevention of transient ischemic attack, ischemic stroke, myocardial infarction and venous thrombosis Prevention of ischemic events in patients with unstable angina pectoris. Following coronary artery bypass grafting. Following coronary artery angioplasty. Prosthetic heart valves. Chronic disseminated intravascular coagulation.
Adverse effects: 1. Gastro-intestinal disturbances: - nausea, vomiting, epigastric distress - ulcer 2. Bleeding 3. Bronchoconstriction 4. Reye syndrome 5. Interstitial nephritis, papillary necrosis, proteinuria, renal failure
Phosphodiesterase inhibitors Dipyridamole Mechanism of action 1) increases intracellular levels of cyclic AMP by inhibiting cyclic nucleotide phosphodiesterase; 2) inhibits thromboxane A 2 synthesis and may potentiate the effect of prostacyclin to antagonize platelet stickiness and therefore decrease platelet adhesion to thrombogenic surfaces.
Uses of dipyridamole Dipyridamole as a coronary vasodilator is employed to prophylactically treat angina pectoris (in combination with ASAc). Adjunctive therapy for prophylaxis of thromboembolism in cardiac valve replacement (with warfarin ). Secondary prevention of stroke and transient ischemic attack (with ASAc).
Side effects Headache Orthostatic hypotension Thrombocytopenia
ADP pathway inhibitors Ticlopidin, Clopidogrel, Ticagrelor Mechanism of action These drugs interfere with the binding of ADP to its receptors (subtype P 2 Y 12) on platelets and, thus, inhibit the activation of the GP IIb/IIIa receptors required for platelets to bind to fibrinogen and to each other.
Uses 1) in preventing cerebrovascular and cardiovascular as well as peripheral vascular disease 2) in stent insertion during a myocardial infarction
Adverse effects Neutropenia Bleeding G. I. T : nausea, dyspepsia, diarrhea. Allergic reactions. Thrombocytopenic purpura frequent, because this drugs can inhibit cytochrome P 450 Clopidogrel more potent, but causes fewer adverse reactions
Glycoprotein IIb/IIIa inhibitors Abciximab, Eptifibatide, Tirofiban Mechanism of action Abciximab inhibits platelet aggregation by preventing the binding of fibronigen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. Tirofiban (non peptide drug) and Epitafibatide (peptide drug) act by occupying the site on glycoprotein IIb/ IIIa receptor that is required to bind the platelet to fibrinogen ( act as fibrinogen like mimetic agents).
Glycoprotein IIb/IIIa inhibitors Abciximab, Eptifibatide, Tirofiban Uses Abciximab is given i. v. along with Heparin or ASAc as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complication. Tirofiban and Eptifibatide are given intravenously for the reduction of incidence of thrombotic complications during coronary angioplasty
Adverse effects Abciximab may cause bleeding Drug-induced thrombocytopaenia Ishemic disorders of myocardium or brain
Arachidonic acid Aspirin Clopidogrel ticlopidine ADP Thromboxane stimulates (from activated platelets) inhibit P 2 Y receptor TXA 2 recep clotting Ca 2+ Lowers c. AMP Increased c. AMP clotting Prevents clotting Gp. IIb-IIIa Eptifibatide Receptor for Abciximab fibrinogen and Tirofiban platelet adhesion 19. 12. 17 Dipyridamole (prevents breakdown by phosphodiesterase)
Classification Anticoagulants: 1. Direct acting Dependent on AT III - heparins (Heparin, LMW heparins: Enoxaparin, Fraxiparine, Dalteparin sodium) - factor Xa inhibitors (Fondaparinux) Independent of AT III - factor Xa inhibitors (Rivaroxaban) - thrombin inhibitors (Dabigatrana etexilate ) 2. Indirect acting coumarins Warfarin
Heparin Mechanism of action Heparin acts indirectly by binding to antithrombin III and causes a conformational change thereby activating AT-III. Antithrombin III inhibits clotting factor proteases, Thrombin (IIa), Xa, and others by forming stable complexes and inhibits the clot formation.
Uses Heparin is the major antithrombotic drug for the treatment of deep vein thrombosis and embolism and pulmonary embolism. Venous thrombosis prevention - post surgical Acute myocardial infarction Arterial thrombosis Prevention of clotting in medical devices (catheters, hemodialysis, heart lung machines) It is anticoagulant of choice for treating pregnant women with venous thromboembolism, because it does not cross the placenta.
Adverse effects of Heparin 1) bleeding complications (hemorrhage); 2) heparin-induced thrombocytopenia; 3) hypersensitivity reactions ( chills, fever, urticaria or anaphylactic shock are possible). 4) Osteoporosis (long-term) 5) Hyperkalemia 6) Rebound ischaemia Thest effects may be managed by treating with Protamine sulfate (antagonist of Heparin).
Contraindications 1) hypersensitivity; 2) bleeding disorders 3) recent trauma 4) Intra-Cranial Hemorrhage 5) Bacterial Endocarditis
Low molecular weight Heparin Mechanism of action - predominantly inhibit factor Xa by binding AT III Uses As heparin Side effects Less than heparin Advantages No need for laboratory monitoring Higher bioavailability Longer plasma half-life
Fondaparinux Mecanism of action By selectively binding to antithrombin III, potentiates the innate neutralization of factor Xa Uses for initial treatment of deep vein thrombosis and pulmonary embolism and for venous thromboembolism prevention in patients undergoing surgery for hip fracture or hip/knee replacement Side effects Bleeding Hepatotoxity
Rivaroxaban Mecanism of action Rivaroxaban is an orally available, small-molecule, active site-directed factor Xa inhibitor Uses treatment and prevention of deep vein thrombosis and pulmonary embolism and for the prevention of stroke in nonvalvular atrial fibrillation Side effects Bleeding Hepatotoxity
Dabigatrana etexilate Mecanism of action an oral direct thrombin inhibitor Uses for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation an alternative to Enoxparin for thromboprophylaxis in orthopedic surgery Side effects Bleeding GI: dyspepsia, abdominal pain, esophagitis, and GI bleeding
Warfarin Mechanism of action It inhibits the action of the enzyme vit Kepoxide reductase and prevent synthesis Vitamin K-dependent clotting factors (including factors: II, VII, IX and X) in the liver.
Uses 1. the prevention and treatment of deep vein thrombosis and pulmonary embolism 2. stroke prevention 3. stroke prevention in the setting of atrial fibrillation and/or prosthetic heart valves 4. antiphospholipid syndrome 5. prevention of venous thromboembolism during orthopedic or gynecologic surgery
Adverse effects 1) bleeding disordes 2) thrombocytopenia 3) disease states (hepatic disease) 4) skin necrosis Contraindications The drug should never be used in pregnancy because it is teratogenic and can cause abortion.
Classification Trombolytic agents: Streptokinase, Urokinase, Alteplase, Tenecteplase
3. Thrombolytic drugs They activate directly or indirectly the conversion of plasminogen to plasmin
Streptokinase, one of the fist such agents to be approved, causes a systemic fibrinolytic state that can lead to bleeding problems.
Mechanism of action It is an extracellular protein purified from culture broth of Group C -hemolytic streptococci. It has no enzymic activity, instead it forms an active one-to-one complex with plasminogen which then converts uncomplexed plasminogen to the active enzyme plasmin
Uses of Streptokinase is approved for use in: 1) acute pulmonary embolism; 2) deep vein thrombosis; 3) acute myocardial infarction; 4) arterial thrombosis.
Adverse effects: 1) bleeding disorders; 2) hypersensitivity
Alteplase is a product of recombinant DNA technology (a serine protease originally derived from cultured human melanoma cells).
Mechanism of action Alteplase acts more locally on the thrombotic fibrin to produce fibrinolysis. Alteplase has a low affinity for free plasminogen in the plasma. Thus, Alteplase is said to be “fibrin selective” and low doses it has the advantage of lysing only fibrin, without unwanted degradation of other proteins – not able fibrinogen. This contrasts with Streptokinase, which acts on free plasminogen and induced a general fibrinolytic state. Tenecteplase is another recombinant t. PA with a longer half-life and greater binding affinity for fibrin than alteplase
Uses of Alteplase is approved for the treatment of: 1) myocardial infarction 2) massive pulmonary embolism 3) acute ischemic stroke Given within 12 hours of onset of symptoms of MI and 3 hours for embolic CVA for maximum effectiveness.
Adverse effects: Alteplase may cause bleeding complications, including gastrointestinal and cerebral hemorrages.
Urokinase Mechanism of action Urokinase is an enzyme capable of directly degradating both fibrin and fibrinogen. Urokinase was originally isolated from human urine, but is now obtained from cultures of human fetal renal cells. Urokinase is more expensive than Streptokinase and is usually employed in patients who are sensitive to Streptokinase.
Uses Like Streptokinase, Urokinase is effective in treating severe pulmonary embolism and deep vein thrombosis. Adverse effects The most important side effects of this drug therapy: bleeding complications
Drugs are used to treat bleeding
Classification Treatment of bleeding (Coagulants) : Antifibrinolytic agents (inhibitors of fibrinolysis): Aminocaproic acid, Tranexamic acid, Aprotinine Hemostatics: Fibrinogen, Vitamin K, Protamine sulfate (antagonist of Heparin), Thrombin, Clotting factors VIII, IX
Bleeding problems may have their origin in naturally occurring pathologic conditions such as hemophilia, or as a result of fibrinolytic states that may arise after gastro-intestinal surgery. The use of anticoagulants may also give rise to hemorrhaging.
Aminocaproic acid: inhibits plasminogen activation. A potential side effect is intravascular thrombosis. Vitamin K: A cofactor in complete synthesis several of the protein factors (II. VII, IX, X) by the liver. The response to Vitamin K is slow (24 hours).
Aprotinin is serine protease. It inhibits plasmin, activated protein C and thrombin as well as preserving platelet GP 1 b and IIb/IIIa. Aprotinin has been used in cardiac surgeries to reduce blood transfusion Side effects include allergic reaction and reversible renal impairment.
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