Cardiovascular Pharmacology PDF

Cardiovascular pharmacology PHARMACOLOGY OF Drugs Affecting Hemostasis & Drugs for CVA...

Cardiovascular pharmacology PHARMACOLOGY OF Drugs Affecting Hemostasis & Drugs for CVA Newman Osafo, B.Pharm., Ph.D. Department of Pharmacology, FPPS, CoHS, KNUST. [email protected] 8/22/22 1 Coagulation Cascade Reproduce following components of cascade: – Prothrombin -> thrombin Fibrinogen -> fibrin – Plasminogen -> plasmin 8/22/22 2 Drugs that affect Coagulation Thrombosis may occur in both arteries and veins Arterial thrombi cause disease by obstructing blood flow which can result in tissue ischemia or death Venous thrombosis is associated with venous stasis. A venous thrombus is less cohesive than an arterial embolus so venous emboli more prevalent Hemostasis Hemostasis is the prevention or stoppage of blood loss from an injured blood vessel. Process involves vasoconstriction, formation of a platelet plug, activation of clotting factors and growth of fibrous tissue into the blood clot making it more stable. Antiplatelet Drugs Arterial thrombi are composed primarily of platelets Antiplatelet drugs act by inhibiting platelet activation, adhesion, aggregation, or procoagulant activity. Include drugs that block platelet receptors for thromboxane, ADP, glycoprotein IIb/IIIa and phosphodiesterase inhibitors Platelet Inhibitors Inhibit the aggregation of platelets Indicated in progressing MI, TIA/CVA Side Effects: uncontrolled bleeding No effect on existing thrombi 8/22/22 6  Thromboxane A2 Inhibitors Work by inhibiting synthesis of prostaglandins. TA inhibitors work by acetylating cyclooxygenases, the enzyme in platelets that synthesizes thromboxane A2 (which causes platelet aggregation). ASA (aspirin) is example. It affects the platelets for the life of the platelet. NSAIDs not so useful as action wears off as drug wears off  Adenosine Diphosphate Receptor Antagonists Ticlopidine Inhibit platelet aggregation by preventing ADP-induced binding between platelets and fibrinogen. This reaction inhibits platelet aggregation irreversibly and persist for the lifespan of the platelet (9-10 days) Indicated in TIAs Adverse effects-neutropenia, diarrhea, skin rashes  Adenosine Diphosphate Receptor Antagonists Clopidogrel Fewer side effects than ASA or Ticlopidine indicated for patients with atherosclerosis for reduction of MI, stroke and vascular death Does not need reduction in those with renal problems  Used with aspirin and heparin and is contraindicated in clients who have recently received oral anticoagulants or IV dextran. Other contraindications include active bleeding, thrombocytopenia, history of stroke, surgery or trauma within past 6 weeks, uncontrolled hypertension or hypersensitivity.  Phosphodiesterase Inhibitors Cilostazol increases cAMP which then inhibits platelet aggregation and produces vasodilation. Drug reversibly inhibits platelet aggregation. Indicated for intermittent claudication. Contraindicated in patients with heart failure Most common SE is diarrhea and headache  Miscellaneous Dipyridamole inhibits platelet aggregation, but mechanism is unclear Used for prevention of thromboembolism after cardiac valve replacement and is given with Coumadin Anticoagulants Interrupt clotting cascade at various points – No effect on platelets Heparin & LMW Heparin (Lovenox®) warfarin (Coumadin®) 8/22/22 15 Heparin Endogenous – Released from mast cells/basophils Binds with antithrombin III Antithrombin III binds with and inactivates excess thrombin to regionalize clotting activity. – Most thrombin (80-95%) captured in fibrin mesh. Antithrombin-heparin complex 1000X as effective as antithrombin III alone 8/22/22 16 Heparin Measured in Units, not milligrams Indications: – MI, PE, DVT, ischemic CVA Antidote for heparin OD: protamine sulphate. – MOA: heparin is strongly negatively charged. Protamine is strongly positively charged. 8/22/22 17  Low Molecular Weight Heparins Given subcutaneously in abdomen and do not require close monitoring of blood coagulation tests Still should follow platelet counts Dalteparin Enoxaparin warfarin (Coumadin®) Prothrombin (II), Proconvertin (VII), Christmas factor (IX) and Stuart-Prower factor (X) all require vitamin K dependent enzymes for their synthesis. Warfarin competes with vitamin K in the synthesis of these enzymes. Depletes the reserves of clotting factors. Delayed onset (~12 hours) due to existing factors 8/22/22 19  Warfarin Dosage reduction in patients with biliary tract disorders, liver disease, malabsorption syndromes, and hyperthyroidism. These conditions increase anticoagulant drug effects by reducing absorption of vitamin K or decreasing hepatic synthesis of clotting factors Has multiple, multiple drug interactions Counteract with vitamin K  Other anticoagulants Danaparoid — low molecular weight, heparin-like drug. Used in management of hip surgery, ischemic stroke or in those who cannot take heparin. Does not contain heparin. Lepirudin — used as heparin substitutes Fondaparinux –binds to clot bound factor Xa, inhibits thrombin productions  Other Anticoagulants cont. Trade and generic names Lepirudin Argatroban Fondaparinux Bivalirudin  Thrombolytics Given to dissolve thrombi Stimulate conversion of plasminogen to plasmin, an enzyme that breaks down fibrin (the framework of a thrombus) Used in severe thromboembolic disease such as MI, PE and ileofemoral thrombosis  Thrombolytics Goal is to re-establish blood flow and prevent tissue damage Also used to dissolve clots in arterial or venous cannulas or catheters Must obtain baseline INR, aPTT, platelet count and fibrinogen Will monitor labs 2-3 hours after thrombolytic treatment is instituted to determine efficacy Thrombolytics alteplase (tPA®, Activase®) Directly break up clots streptokinase (Streptase®) – Promote natural thrombolysis anistreplase (Eminase®) Enhance activation of plasminogen. reteplase (Retevase®) Reduce mortality from MI tenecteplase (TNKase®) Less systemic bleeding risk with Alteplase and other newer thrombolytics as compared with Streptokinase. However, haemorrhagic stroke risk with Alteplase is higher than Streptokinase. 8/22/22 25  Drugs Used to Control Bleeding Aminocaproic acid and tranexamic acid are used to stop bleeding caused by overdoses of thrombolytic agents Aprotinin indicated in patients undergoing CABG. Inhibits breakdown of blood clotting factors. Cholesterol Metabolism Cholesterol important component in membranes and as hormone precursor Synthesized in liver – Hydroxymethylglutaryl coenzyme A reductase – (HMG CoA reductase) dependant Stored in tissues for latter use Insoluble in plasma (a type of lipid) – Must have transport mechanism 8/22/22 27 Cholesterol Risk of Coronary artery disease linked to LDL levels LDLs are deposited under endothelial surface and oxidized where they: – Attracts monocytes -> macrophages – Macrophages engulf oxidized LDL Vacuolation into ‘foam cells’ – Foam cells protrude against intimal lining Eventually a tough cap is formed – Vascular diameter & blood flow decreased 8/22/22 28 Cholesterol Plaque cap can rupture Collagen exposed Clotting cascade activated Platelet adhesion Thrombus formation Embolus formation possible Occlusion causes ischemia 8/22/22 29  Overview of cholesterol panel Total cholesterol Desirable-less than 200 Borderline high—200-239 High—240 or greater LDL Desired 60 Low 100,000 Patient not on anticoagulants, no recent surgery or GI bleeding; no seizures at onset §Citicoline believed to improve clinical outcome following ischaemic stroke. Decreases death rate and disability post-CVA*. Management of Intracerebral Haemorrhage Rapid neuroimaging Intubation if necessary (CPR) Emergency haematoma evacuation External ventricular drainage Management of raised ICP BP and hyperglycaemia management Reversal of coagulopathy  Management of Subarachnoid haemorrhage Clipping Endovascular coiling Use of Tranexamic Acid/Aminocaproic acid to prevent rebleeding in the acute phase (