Lecture 4- Drugs Used In Bleeding Disorders Flashcards
Haemostasis
*haemostasis; arrest of blood loss from damaged blood vessels which is essential to survival
-main phenomena of haemostasis are= platelet adhesion + activation and blood coagulation
Thrombosis
*thrombosis; pathological condition resulting from inappropriate activation of haemostatic mechanisms;
-venous thrombosis= associated with stasis of blood; venous thrombus has a small platelet component and a large component of fibrin
-arterial thrombosis= associated with arthersclerosis = the thrombus has a large platelet component
-portion of a thrombus may break away, travel as an embolus and lodge downstream = causing ischaemia and infarction
Thrombosis
Thrombotic and thromboembolic disease could result in;
-myocardial infarction
-stroke
-deep vein thrombosis
-pulmonary embolus
*thrombus= clot that adheres to a vessel wall
*embolus= detached thrombus (floats in the blood) and may occlude blood vessels and deprive tissues of oxygen and nutrients
Thrombosis in intact endothelium
-platelets monitor the integrity of the endothelium
-in the absence of injury = resting platelets circulate freely
-nitric oxide + prostacyclin in intact endothelium= acts as inhibitors of platelet aggregation
-lower levels of prostacyclin = platelet aggregation
-circulating levels of thrombin and thromboxanes = low in the intact blood vessel
^ = platelet receptors for thrombin and thromboxanes are not occupied= inhibiting platelet activation + aggregation
Thrombosis in injured endothelium
-when the endothelium is injured= platelets adhere to its lining
-platelet activation triggers release of platelet granules containing mediators such as= adenosine diphosphate (ADP), thromboxane A2 (TXA2), serotonin, platelet-activation factor (PAF) and thrombin
-mediators bind to receptors on the membrane of resting platelets circulating nearby
-resting platelets become activated= begin to aggregate
Treatment of thrombosis
Main drugs;
- anticoagulants
- antiplatelet drugs
- fibrinolytic drugs
Anticoagulants
-inhibit clot formation
-do not dissolve clots that are already formed but prophylactically prevent formation of new clots
-they include;
*injectable anticoagulants (heparin + newer thrombin inhibitors)
*oral anticoagulants (warfarin and related compounds)
Heparin
-family of surfaced glycosaminoglycans (mucopolysaccharides)
-present together with histamine in the granules of mast cells
-heparin inhibits coagulation; both in vivo and vitro= activating antithrombin III (inhibits thrombin)
-not absorbed from the GIT because of its charge and large size= administered intravenously + subcutaneously
Side effects;
-bleeding complications-haemorrhage
-hypersensitivity reaction-chills, fever, urticaria or anaphylactic shock
-thrombosis- due to chronic/ intermittent administration
Warfarin + other vitamin K antagonists
-warfarin, nicoumalone, phenindione
^ block reduction of vitamin K epoxide
-reduced vitamin K epoxide = cofactor for synthesis of factors II (prothrombin), VII (precursor of tissue factor), IX and X
-warfarin= administered orally and requires monitoring using the international normalised ratio
-onset of action= hours = needed for degradation of factors that have already been synthesised
Antiplatelet drugs
*aspirin = inhibits cyclooxyrgenase irreversibly
-balance between prostacyclin (inhibitor of PA) and thromboxane (stimulant of PA), altered since the endothelium can synthesise more prostacyclin but platelets cannot synthesise more thromboxane
Antiplatelet drugs
*clopidogrel; pro-drug= inhibits platelet responses to adenosine diphosphate (ADP)
-antagonists of GPIIb/IIIa receptors include a monoclonal antibody (abciximab) + several oliogopeptides (tirofiban) since diff pathways of activation converge on GPIIb/IIIa receptors
*dipyridamole; phosphodiesterase inhibitors= used in addition to aspirin
Clinical uses of antiplatelet drugs
*aspirin= main drug relates mainly to arterial thrombosis
-acute myocardial infarction
-high risk of myocardial infarction, history of it and angina/intermittent claudication
-coronary artery bypass grafting
-unstable coronary syndromes (clopidogrel is added to aspirin)
-coronary artery angioplasty/ stenting (IV glycoprotein IIb/IIIa antagonists e.g. abciximab - used in patients in + to aspirin
-transient cerebral ischaemic attack (‘mini strokes’) / thrombotic stroke = prevent recurrence (dipyridamole + to aspirin)
-atrial fibrillation if oral anticoagulation is contraindicated
Fibrinolytic drugs
*streptokinase = acts to convert plasminogen to plasmin = cleaves fibrin losing thrombi
-used clinically to reopen (dissolve) occluded coronary artery in patients with acute myocardial infarction
*streptokinase= protein extracted from cultures of streptococci
^reduces mortality in acute myocardial infarction + this beneficial effect is additive with aspirin
Drugs used for bleeding disorders
-genetically determined deficiencies-haemophilia
-acquired clotting defects-liver disease, vit K deficiency and excessive oral anticoagulant therapy
-bleeding disorders require treatment with vitamin K
Vitamin K
-fat-soluble vitamin occurring naturally in plants
-essential for the formation of clotting factors II, VII, IX + X
Clinical use of Vit K;
*treatment and/or prevention of bleeding;
-from excessive oral anticoagulation (e.g. by warfarin)
-in babies; to prevent haemorrhagic disease of the newborn
*for vit K deficiencies in adults;
-spruce, coeliac disease and steatorrhoea
-lack of bile (e.g. with obstructive jaundice)
