Flashcards in Drugs And Haemostasis Deck (43)
What is haemostasis ?
Stopping blood flow
What are the 3 natural mechanisms for haemostasis ?
Smooth muscle present in vessel walls spasm and constrict the vessel reducing the diameter of the vessel
It can reduce blood flow for about 30 mins
Describe platelet plug
Damaged vessels can expose collagen causing platelets to rapidly adhere and become sticky and irregular in shape and they swell
The activated platelets de granulate causing the release of many substances which activate more platelets and impede blood flow
Platelet surface has protease receptors which can be activated by thrombin causing de granulation
Uses proteolytic enzymes and cofactors
An in Vivo and an in vitro coagulation cascade
What factors convert prothrombin into thrombin ?
Xa and Va
What is Bernard-soulier syndrome ?
Rare autosomal recessive disease
Platelets don't stick to vessel wall causing bleeding
What is classic haemophilia ?
Haemophilia a - deficiency in factor 8
Haemophilia b - deficiency in factor 9
What causes hypercoagulabilty disorder ?
Factor 5 Leiden mutation
What acquired defects can cause coagulopathies ?
Vitamin k deficiency
Pregnancy - there is an increase in coagulation factors - excessive coagulability can lead to miscarriage
What are the 2 for a of vitamin K ?
K1 - phylloquinone, made in plants
K2- menaquinones, made in bacteria
What does vitamin k do ?
Converts glutamate into gamma-carboxyglutamate by adding a carboxyl group
This is important for the formation of clotting factors - prothrombin, factor 7, 9 and 10 and proteins c, s and z
Why do newborns get a vitamin k injection ?
Because their gut flora is not established so it improves their coagulability
What gastrointestinal disorders can cause a vitamin k deficiency ?
Prolonged antibiotic therapy
What are the characteristics of an ideal anticoagulant ?
Administered orally once a day
Predictable dose response and kinetics
Low rate of bleeding
No routine monitoring required
Wide therapeutic window
No dose adjustments required
Little interactions - food/drugs
Low non specific pla a protein bindi
Inhibition of both free and clot bound coagulation factors
What is warfarin a synthetic derivative of ?
What is the mechanism of action of warfarin ?
Interferes with vit k metabolism and prevents formation of functional coagulation factors
What are the medical uses of warfarin ?
What are the pharmokinetics of warfarin ?
Very long half life - 20-60 hours - makes it difficult to determine dose
Often co administered with heparin
How is warfarin controlled ?
aPTT assay - activated partial thromboplastin time
Can be reversed by vit k injection or in sever cases with prothrombin complex
What are the complications of warfarin ?
Narrow therapeutic range - monitoring and tailoring
Drug to drug interactions - antibiotics, aspirin, statins and antidepressants
- aspirin causes excessive bleeding and antibiotics exacerbate effects o warfarin on gut flora
Drug to diet interactions- brocolli, green leafy beg and liver - these food reduce actions of warfarin
What are the 2 main benefits of warfarin ?
Cheap to produce
What is heparin ?
Strongly negatively charged glycosaminoglycan made up of variably surfaced repeating disaccharide units
What is heparin derived from ?
Mucosal tissue of porcine intestine or bovine lungs
Large molecular mass range 3-50kDa
What are the 3 other examples of the drug heparin ?
Enoxaparin and dalteparin and tinzaparin
What is the mechanism of action of heparin ?
Prevents thrombus formation and extension of existing blood clots
Binds to antithrombim and enhances its inhibitory capacity
No effet on thrombus bounds thrombin
What are the medical uses of heparin ?
During surgery for coronary bypass
Which antithrombim does heparin bind to ?
Antithrombim 3 inhibiting factors 7a, 2 and 2a
What are the pharmokinetics of heparin ?
Administered intravenously or subcutaneously - sub cuntaneous is for continuous treatment
Short half life -1hour
How is heparin controlled ?
Monitored by laboratory assay - aPTT
What is an adverse effect of heparin and how are overdoses treated ?
Haemorrhage and can transiently decrease platelet number
Protamine sulphate is used for overdoses
- used to be taken from shark sperm but now there is a recombinant form
What are the 2 types of thrombin inhibitors ?
Bivalent - derived from hirudin a leech anticoagulant
- leprudin, bivalirudin and desinudin
Univalent- synthetic compounds derived to fit active site of thrombin
- argatroban, melagatran, dabigatran
What are the advantages of direct thrombin inhibitors ?
Don't rely on interactions with endogenous anticoagulant mechanisms
Inhibit both coagulation and platelet activation by thrombin
How are DTIs controlled ?
No means established
Ecarin( venom of saw scaled viper which activates prothrombin) clotting time
Why was melagatran withdrawn from the market ?
Because it causes liver toxicity
What do anti platelet drugs do ?
Decrease platelet activation and thrombus formation
Very effective in arterial circulation where thrombi are platelet rich and anticoagulants are less effective
Able to act at numerous pathways
What are the 3 classes of anti platelet drugs ?
ADP receptor antagonists
Glycoproteins 2b-3a antagonists
What drugs are often used to treat acute coronary syndrome ?
Clopidogrel, ABCIXIMAB and TIROFIBAN
What is thrombolysis ?
Breakdown of blood clots by pharmacological means - clot busting
They stimulate fibrinoloysis by infusion of proteins which generate active plasmin
What is the mechanism of action of thrombolytic agents ?
Stimulate conversion of endogenous plasminogen to plasmin skin lyses blood clots relaxing fibrin degradation products
What are the medical uses of thrombolytic agents ?
How is antithrombolytic agents controlled ?
Infused intravenously with heparin for 24-48 hours
Can cause haemorrhage