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1997 Clinical pharmacology By Duy Thai

• In response to a vascular injury, there is: 1. Vasoconstriction 2. Platelet adhesion and activation Thrombus formation 3. Fibrin formation At the same time as the thrombus formation, there is also simultaneous activation of the fibrinolytic system. This ensures that the thrombus does not grow too large and is only transient - it will go away once the endothelium has healed. Disorders of haemostasis is concerned with inappropriate thrombus formation which leads to impaired blood flow.

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Definitions • Thrombus: • An aggregate of platelets and fibrin which occurs at the site of injury. • Embolus: • A portion of thrombus which has broken off from the primary site and impacted at a distant site Drugs used to treat haemostatic disorders • The drugs inhibit 1. Coagulation 2. Platelet adhesion and coagulation • The drugs promote: • Fibrinolysis ORAL ANTICOAGULANTS • Coumarin derivatives:. • Warfarin

Mechanism of action: • Prevents the activation of vitamin K dependent clotting factors (II, VII, IX and X) • These clotting factors are synthesised by the liver and converted into an active form via γ carboxylation (catalysed by vitamin K)

CH2 COOH COOH γ Carboxylation


Vit K (Hydroquinone)

Vit K (Epoxide form)

Warfarin • Warfarin is only active in vivo • Because it acts to inhibit a natural physiological process which only occurs in the liver. If you take a sample of blood, it already has the active coagulation factors, and so adding warfarin does not prevent coagulation of stored blood.

Pharmacokinetics: • There is a delayed onset of activity. • The effects of warfarin are only seen when the already active circulating coagulation factors are broken down. Any new ones which are made by the liver will be inactive. Warfarin does not affect the normal circulating active factors. • Orally active • Rapidly absorbed • Strongly bound to plasma proteins (approximately 99% is bound) • This means that there is a lot of drug interaction with other drugs which are bound to plasma proteins.
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1997 Clinical pharmacology By Duy Thai Factors affecting the activity of warfarin • Increase in warfarin activity • It is important to monitor the level of anticoagulation as too much can lead to haemorrhage 1. Vitamin K deficiency • Due to: • Decreased dietary intake (rare) • Reduced bile production • Resection/malabsorption at the terminal ileum • Less vitamin K is available, so there is less competetive inhibition of warfarin activity by vitamin K 2. Hepatic disease • Reduced production of clotting factors 3. Hypermetabolic states • e.g. Hyperthyroidism • Increased breakdown of active factors 4. Drug interactions A. Impaired platelet aggregation • E.g. When used in conjunction with aspirin B. Competition for binding • NSAIDs (including aspirin) are also highly plasma protein bound, and so tend to displace warfarin C. Inhibition of liver enzymes • By cimetidine, H2 antagonists • Less production of clotting factors • Decreased warfarin activity 1. Pregnancy • During pregnancy, there is an increased synthesis of clotting factors in the mother • However, the foetus is very sensitive to warfarin (because it has a limited ability to synthesis clotting factors) and so it is possible that bleeding can occur in the foetus. 2. Drug interaction • Induction of liver enzymes which increase the synthesis of clotting factors (e.g barbituates) • Vitamin K supplements Adverse effects of warfarin • Haemorrhage • Often bleeding in the bowel • Necessary to titrate the dose • To treat this effect, often try to reverse the action of warfarin by taking oral vitamin K, which slows things down a bit. • Also give Phytomeradione (IV) as a vitamin K analogue • INJECTABLE ANTICOAGULANTS Heparin

Properties • Low molecular weight forms of heparin • Is a natural long chain mucopolysaccharide found in most cells of the body • Specific arrangement of sulphate groups (high negative charge), therefore not absorbed well from the GIT Mechanism of action • Promotes the action of antithrombin III • Heparin binds to antithrombin III and changes its conformation. thus exposing an active site • The activated antithrombin III + Heparin complex inactivates active clotting factors 1000 times more rapidly than antithrombin III on its own • Low molecular weight heparin has more specificity towards affecting factor Xa Side effects • Never given intramuscularly because it can lead to haemorrhage in the muscle (given IV or subcutaneously) • Thrombocytopenia (often transient and mild) • Low molecular weight heparin has less effects on platelet number • Osteoporosis (only occurs with long term use of heparin - Greater than 6 months) • Heparin is only used for short periods (for acute treatment - NOT long term prophylaxis)

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1997 Clinical pharmacology By Duy Thai DRUGS INHIBITING PLATELET AGGREGTION Platelet membrane PLA2 Arachidonic acid COX TxA2 Stimulates other platelets to become pro aggregatory Also causes vasoconstriction Ca2+ Shape change

Adhesion & aggregation • • Platelets also release 5HT and ADP, which are also proaggregatory Therapy: • Use low dose aspirin (100 - 150 mg per day, which is half the dose required for aspirin to be analgesic. • Aspirin inhibits COX, thus reducing the amount of TxA2 produced in platelets • However, COX is also required for the formation of PGI2, which is produced by the endothelium and is antiaggregatory. • The advantage of using aspirin is that it allows the endothelium to make PGI2 because the endothelium is still able to regenerate COX. Platelets, being anucleate, do not have the capacity to regenerate COX (which is irreversibly inhibited) THROMBOLYTICS XIIa (involved in the formation of fibrin as well) tPA (tissue plasminogen activator)




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Breaks down fibrin tPA analogues: • Streptokinase • Derived from bacteria • Can only be used once since it is antigenic. • The first time it is used, the body will mount an immune response, making antibodies to it. • Streptokinase is the first line of treatment due to its cost ($200 per dose compared to $2000 per dose for alteplasej • Urokinase • Drived from human urine • Alteplase • Identical to human tPA therefore no antibodies are made against it Used to treat thrombosis in coronary arteries Used acutely to treat someone with a myocardial infarct because it enhances the body’s ability to break down the thrombus. The window of opportunity for streptokinase is 3 hours • This means that it must be given within 3 hours of the attack starting. otherwise it is too late to prevent damage The window of opportunity for alteplase is 6 hours.

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1997 Clinical pharmacology By Duy Thai Therapeutic uses of the drugs • Venous side • Thrombus occurs due to stasis • The thrombus is mainly formed from fibrin (less platelet contribution) • Acute - use heparin • Chronic - warfarin • Used for: • Mitral valve stenosis - turbulence leading to thrombus • Prosthetic ‘valves - prevent coagulation of valves due to an abnormal surface • Atrial fibrillation • Deep vein thrombosis • Arterial side • More platelet involvement • Anticoagulants less effective • Aspirin - used acutely and chronic • Thrombolytics in myocardial infarct

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