Antiplatelets Anticoagulants This lecture begins with a review of the targeted system which in this case is haemostasis. LONG ASS FUCKEN LECTURE OMG
Lecture A: Review: Haemostasis
Lecture A objectives:
Provide an understanding of signalling molecular targets (eg what we want to target):
- Antiplatelets
- Anticoagulants
- Antifibrotics (antithrombotics)
Quick refresh
See: Platelets Coagulation To refresh, haemostasis involves platelets activation adhesion and aggragation into a clot, which is cemented into place by fibrinogen converting to fibrin in the cascade pathway
Intravascular thrombi…
- are the manifestations of many conditions: (Virchows triad)
- Atherosclerotic plaque rupture
- atrial fibrillation
- Valvular incompetence
- MI
- Hypokinetic ventricles
- trauma
- can lead to:
- Unstable angina and MI
- DVT Pulmonary embolism
- TIAs
- Stroke
Endogenous inhibitors of thrombosis
- Prostacyclin (PGI2) This is synthesised and secreted by endothelial cells (constantly in a non-injury state I think) and inhibits platelet aggregation and granule secretion. It does this via increasing platelet cAMP release and decreases platelet COX activity. Both of these decrease prothrombotic thromboxane (TxA2) production
- Antithrombin (circulating plasma protein) This simply inhibits coagulation
- Thrombomodulin and protein C These are present on endothelial calls which bind to and inactivate coagulation factors
Table of coagulants and anticoagulants (just cause)
| Anticoagulant (Found in typical endothelium) | Procoagulant (activated endothelium) |
|---|---|
| glycosaminoglycans (heparin-like?) | Tissue factor (?) |
| protein S | vWF |
| thrombomodulin (activates protein C) | Intracellular adhesion molecules |
| endothelial protein C receptors | thrombospondin |
| tissue factor pathway inhibitor | |
| prostacyclin, nitric oxide | |
Steps of haemostasis according to ivan sammut
Platelet adhesion sequence
i. Prostacyclin synthesis and secretion REDUCED allows ii. platelets to adhere to ECM iii. Aggregated platelets then generate thrombin
Platelet shape change
i. thrombin causes the platelets to change shape into activated form
Platelet granule release leading to aggregation and consolidation
thrombin also causes platelets to release more compound from granules to activatee other platelets
- TxA2 and ADP
- thromboxane is a potent vasoconstrictor (whichis bad in the brain or heart)
Fibrin Stabilisation
Thrombin also facilitates the conversion of fibrinogen to fibrin fibrin polymerises to form matrix and stablises aggregated platelets
both of these lead to fibrinogen receptor activation
Lecture B: Pharmacology of antiplatelets and anticoagulants
There are 3 ways to prevent Haemostasis and reduce thrombosis: 1. by reducing platelet aggregation 2. by reducing blood coagulation (fibrin formation) and 3. by increasing fibrin breakdown (fibrinolysis). Each of these mechanisms correspond to a drug class: Antiplatelets reduce platelet aggregation, anticoagulants reduce blood coagulation, and fibrinolytics increase fibrin breakdown. Some examples of each have been given.
Examples of drugs
Antiplatelets
- Aspirin
- Clopidogrel Anticoagulants
- LMWHs: like Enoxaparin
- Oral VKAs: Warfarin
- DOACs: Dabigatran, rivaroxaban (these have mainly replaced oral VKAs) Fibrinolytics: rtPAs (Alteplade) - drugs for IHD
1. Antiplatelets
our main antiplatelet is aspirin
Drug: oral low dose aspirin
Pharmacology
Pharmacodynamics:
Acetylsalicylate: nonselective COX inhibitor
Mechanism of action: Acetylsalicylate inhibits platelet aggregation and reduced risk of thrombus formation. It achieves this by irreversibly acetylating platelet cox reducing TXA2 production for lifetime of platelet (7-9 days)
How does it not affect endothelial COX-2 which makes PGI2?
A combination of rapid turnover of COX by endothelium (platelets don’t have transcription capability), and the fact the most of the aspirin doesn’t even reach it. As it is orally prescribed it is absorbed into the stomach vasculature and goes to the liver where esterase action deactivates acetylsalicylate through CYP2C9. however in the period before this it will irreversible disable the cox enzymes of passing platelets, which will retain this for the entirety of circulation. This is only the case in low dose aspirin
Most low dose aspirin is metabolised High doses of NSAIDs can lead to thrombosis risk (due to inhibition of cox2 whick makes prostacyclin)
Pharmacokinetics:
Metabolism: esterase action in liver breaks it down to salicylate which is broken down by hepatic/renal CYP2C9 and glucuronidation.
Risks and ADRS:
Due to overcooking:
- Haemorrhage
- Gastric ulceration and blooding
- Reyes syndrome (if used with viral illness) (esp in children)
General NSAID side effects (incl. aspirin)
GI mucosa
Prostaglandin E2 leads to more mucus secretion, more bicarb, and more mucosal blood flow. All of this is decreased with NSAID cox-1 inhibition which results in peptic ulcers and GI bleeding
Kidney
Prostaglandin E2 and prostacyclin lead to afferent arteriolar vasodilation (increasing GFR) leading to increased Na and water excretion. NSAID COX1 and 2 inhibition will lead to, NA and water retention, Hypertension, and Haemodynamic acute kidney injury
Cardiovascular
COX-1 makes thromboxane and COX-2 makes prostacyclin. These have 2 different effects. when vascular effect of NSAIDs or aspirin is greater than platelet effect stroke and MI infarct can result
Interactions:
Other notes
Drug: Clopidogrel
Pharmacology
Pharmacodynamics:
Mechanism of action: This is a noncompetitive ADP receptor blocker. It therefore prevents GPIIb-IIIa receptor reducing platelet activation by preventing fibrinogen receptor from being primed
Pharmacokinetics:
prodrug so metabolised to CYPC19 CYP3A4 CYP2C9 and CYP2B6
Indications:
Used when patient cannot tolerate aspirin
Contraindications:
Risks and ADRS:
Interactions:
This drug is valuable when on its own and combined with aspirin.
Other notes
2. Anticoagulants
These drugs prevent thrombi from forming and include
- UF heparin (iv)
- Low molecular weight heparin: Enoxaparin s.c. (Clexane)
- VKAs: warfarin (oral)
- DOACS: DabigatraN, Rivaroxaban.
These drugs are used for patients with increased thrombotic risk:
- prolonged immobility (look at virchows triad)
- acute MI
- Coronary artery bypass artery (CABG)
- angioplasty
Heparin
Heparin is a naturally occurring antithrombotic which also exist in drug form. There are 2 main types: unfractionated (UF) heparin, and Lowmolecular weight heparin
Drug: Unfractionated Heparin
Pharmacology
Pharmacodynamics:
Mechanism of action: Reduces formation of fibrin via increasing the action of antithrombin binding with both prothrombin (Xa) and thrombin (IIa)
Pharmacokinetics:
Administration: given via IV due to how large the molecule is Clearance: half life of this drug is 30 mins to an hour
Risks and ADRS:
Danger of haemorrhage or thrombocytopenia leading to necrosis
Interactions:
see overdose for chelation agent
Overdose:
Can reverse with chelation, as a heparin antagonist is protamine sulphate which bindss with it to form an inactive complex
Other notes
Drug: LMWH (low molecular weight heparin) Enoxaparin
Trade name: Clexane
Pharmacology
Pharmacodynamics:
Mechanism of action Facilitates antithrombin binding to prothrombin but not thrombin
Pharmacokinetics:
Administration: subcutaneously so patients can even do it themselves. Always adjusted to body weight. do not give iv or im Distribution: increased bioavailability when compared with UF heparin Metabolism: Excretion: Half life is 4-6 hours (longer than heparin) and is eliminated in urine (so you need a patient with good renal function)
Indications:
Its really fast so used to
- prevent DVT (prophylaxis) post op immobile patients etc
- treat DVT - bridging therapy with warfarin
- coronary syndromes (sometimes)
Contraindications:
Risks and ADRS:
if overcooked haemorrhage bruising
elevated AST ALT and hyperkalaemia
thrombocytopenia not generally considered major
Interactions:
Other notes
not as reversible with protamine sulphate as with UF hepatin action is assessed using antifactor Xa activity
Vitamin K and its antagonists
The name is originally german (Vitamin Koagulation). Vitamin K is needed for the activation (or production? idk) of factors X, IX, VII, II (1972). Vitamin K is present in the diet and a number of vitamin replacement products. So ask patient about supplements
Drug: Warfarin
derived from coumarin (rat poison)
Pharmacology
Pharmacodynamics:
S-isomer of warfarin competitively inhibits Vit k epoxide reductase which recharges Vitamin K into its active form. This prevent factors 1972 from being formed (or activated idk).
In short warfarin prevents formation of fibrin
Pharmacokinetics:
Administration: orally Distribution peak blood conc reached in 1-8 hours but does not coincide with therapeutic effect. To measure effects you must use INR, not blood warfarin level. Warfarin has a very low TI. You want to maintain INR at 2-3 Metabolism: S-warfarin (active one) metabolised through CYP 2C9, R-warfarin Metabolised by CYP 1A2 and 3A4 Excretion
Indications:
to prevent thrombosis
- after surgery
Risks and ADRS:
- Major haemorrhagic risk at high INR
- warfarin can cause inhibition of protein C and S which can induce microvasculature thrombosis
- gi tract loss
- bruising
- teratogen
- skin necrosis
Interactions
Warfarin interacts with just about everything which makes it really unstable
Overdose
Administer vitamin k and or factor concentrates (PCC!)
Other notes
Dabigatran is not good with valvular disease or prothetic valves which is why warfarin is still used
DOACs (covered more in drugs for IHD)
These are direct thrombin inhibitors
Drug: Dabigatran
Pharmacology
Pharmacodynamics:
Mechanism of action: Direct Thrombin inhibitor
Pharmacokinetics:
Mainly cleared through renal clearance. therefore patient must have good renal function. this is checked before prescription and then annually
Indications:
Indicated for DVTs PE prophylaxis and treatment venous thromboembolism post arthroplasty CAD and PAD
Contraindications:
Not great for valvular AF or mechanical valve thrombus formation
Risks and ADRS:
fewer adverse effects then warfarin, drug effect directly propertional to dose so we don’t need to take INR
Overdose:
Can be reversed with mAb - idarucizumab