eLFH - Drugs acting in the Bloodstream Flashcards
Location of tissue factor
Injured endothelium
Tissue factor bearing fibroblasts and monocytes
Cross section of vessel wall
Coagulation cascade
Part of coagulation cascade represented by PT (prothrombin time)
Extrinsic pathway
Part of coagulation cascade represented by APTT (activated partial thromboplastin time)
Intrinsic pathway
Three overlapping stages of cell based coagulation model
Initiation
Amplification
Propagation
Note: Also Adhesion / Aggregation of platelets occurs
Initiation phase of coagulation definition
Formation of Prothrombinase
Tissue factor and Factor VII are key for this stage
Amplification phase of coagulation definition
Activation of platelets
Various factors but Thrombin (Factor IIa) is key for this stage
Propagation phase of coagulation definition
Massive Thrombin burst
Thrombin converts fibrinogen to fibrin - results in stable fibrin clot
Initiation phase process
Damage to endothelium exposes tissue factor (TF)
TF partially activates platelets
Expression of platelet glycoprotein 1b and Factor 9 + release of Von Willebrand Factor - attaches platelet to subendothelial collagen
Circulating Factor 7 attaches to TF
Factor 7a/TF complex activates Factors 9 and 10
Factor 9a migrates to platelet surface
Factor 10a forms complex with 7a/TF
Factor Xa/7a/TF complex activates Factor 5
Factor Xa separates and forms new complex Xa/Va (aka prothrombinase)
Remaining 7a/TF complex is inactivated by Tissue Factor Pathway Inhibitors
Scaffold for coagulation complexes to bind onto platelet
Externalisation of phosphatidylserines on platelet plasma membrane
This externalisation occurs during Initiation phase
Amplification phase process
Occurs on platelet surface
Prothrombinase converts prothrombin into small amounts of thrombin (Factor 2a)
Thrombin activates Factors 5, 8, 10 and 11
These factors fully activate the platelet
Thrombin also has some direct activating effect
Propagation phase process
Occurs on activated platelet surface
Activated platelet expresses Prothrombinase (Factor 5a/10a complex) and Tenase (Factor 8a/9a complex)
Thrombin Burst - Prothrombinase and Tenase cause massive conversion of Prothrombin to Thrombin
Thrombin converts Fibrinogen to Fibrin
Fibrin stabilises the clot
Adhesion and Aggregation of platelets process
Glycoprotein IIb/IIIa receptor responsible for binding to fibrinogen and platelet aggregation
Thromboxane A2 (TXA2) and ADP activate this receptor
TXA2 produced from arachidonic acid pathway inside platelets - initiated by platelet activation
TXA2 aids haemostasis through vasoconstricting effects
ADP secreted by activated platelets - binds to adjacent platelet receptors and activated the GP IIb/IIIa receptor through a common pathway
How many molecules of Thrombin are generated from one Prothrombinase complex
1000 molecules
Warfarin mechanism of action
Inhibits enzyme expoxide reductase
Expoxide reductase acts to regenerate active Vitamin K
Therefore Warfarin inhibits Vitamin K dependent factors 2, 7, 9, 10 as well as Protein C and S
Warfarin pharmacokinetics
99% plasma protein bound
Metabolised by liver almost entirely
Metabolites excreted in urine and faeces
Elimination half life 35 to 45 hours
Mechanisms by which significant drug reactions occur with warfarin
Displacement from plasma proteins
Liver induction / inhibition
Drugs which potentiate Warfarin effects by inhibition of metabolism
Alcohol
Metronidazole
Erythromycin
Ciprofloxacin
Allopurinol
Cimetidine
Drugs which potential Warfarin effects by displacing it from plasma proteins
NSAIDs
Drugs with inhibit Warfarin effects by enzyme induction
Barbiturates
Rifampicin
Carbamazepine
Drugs which inhibit Warfarin effects by decreasing fat soluble vitamin absorption
Cholestyramine
How long does it take Prothrombin levels to decrease by 50% with warfarin
~ 3 days
Shorter if patient is unwell or with drug interactions
Monitoring of warfarin
International Normalised Ratio
Ratio of patient’s prothrombin time to a normal control sample
PT is sensitive to Factors 2, 7 and 10
Management of warfarin overdose / high INR
Stop warfarin
FFP 15 ml/kg - does not fully reverse warfarin as factor 9 does not rise > 20%
Vitamin K
Prothrombin complex concentrate 30 - 50 units/kg for complete reversal
Dosing of vitamin K for warfarin reversal
1 mg will reverse effects within 12 hours
10 mg will saturate liver stores preventing re-warfarinisation
If non urgent, 5 mg Vit K usually given
Contraindication to warfarin and why
Pregnancy
Warfarin crosses placenta and causes foetal haemorrhage
Also causes birth defects - Foetal warfarin syndrome
Anticoagulation alternative used in pregnancy
LMWH
Heparin structure
Mucopolysaccharide
Derived from porcine intestinal mucosa
Molecular weight of commercially produced heparin
12 to 15 kDa
Heparin mechanism of action
Reversibly binds to and potentiates antithrombin III (ATIII)
ATIII mainly inhibits Factors 2, 9 and 10
ATIII also inhibits Factors 11, 12 and plasmin
Antiplatelet effects mediated through its effects on fibrin
What is antithrombin III
Plasma serine protease inhibitor
Unfractionated heparin route of administration
SC or IV
Not absorbed orally due to size and negative charge
Unfractionated heparin pharmacokinetics
Highly bound to plasma proteins such as fibrinogen and albumin
Low lipid solubility - does not cross blood brain barrier or placenta
Half life 30 - 60 mins
Unfractionated heparin metabolism
Metabolised by hepatic heparinase
Products excreted in urine
Structure of low molecular weight heparins (LMWH)
Short chain polysaccharides
Produced by fractionation (depolymerisation) of heparin
Average molecular weight of LMWH
< 8000 Da
LMWH mechanism of action
Full anti-Xa action
Less anti-IIa action due to shorter chain lengths
Half life of LMWH
2-3x longer than unfractionated heparin due to lower affinity for heparin binding proteins
LMWH monitoring
Factor Xa assays
Advantages of LMWH compared with unfractionated heparin
Once daily dosing
No need for APTT monitoring
Lower risk of Heparin Induced Thrombocytopenia
Less effect on thrombin but maintains same effect on Factor Xa
Most common adverse reactions to heparin
Haemorrhage
Hyperkalaemia
Hypotension
Heparin induced thrombocytopenia definition
Immune mediated thrombocytopenia
Heparin sulphate is recognised as foreign
HIT mechanism
Heparin binds to platelet factor 4 stimulating IgG antibody formation
This predisposes to thrombosis
Incidence of HIT for patients on Heparin / LMWH
3%
Time scale of platelet count drop in HIT
Usually 5 to 14 days after heparin first started
May occur within 24 hours if the patient previously received heparin within the last 3 months
Alternative anticoagulants that can be used in patients with HITs
Danaparoid - SC or IV
Fondaparinux - SC
Danaparoid features
Factor Xa inhibitor
Heparinoid similar to LMWH
Danaparoid adverse effects
Low platelets
Asthma exacerbation
Fondaparinux features
Synthetic pentasaccharide - similar to heparin
Substantially lower risk of HIT as no affinity for platelet factor 4
Does not require therapeutic monitoring
Fondaparinux mechanism of action
Factor Xa inhibitor
Fondaparinux excretion
Renally excreted
Half life 21 hours
Avoid in renal failure
Rivaroxaban features
Similar to oral heparin
Once daily dosing
Doesn’t need therapeutic monitoring
Rivaroxaban mechanism of action
Factor Xa inhibition
Protamine reversal of heparins
Only partial reversal as only fully reverses anti-IIa activity
Anti-Xa activity only partially reversed
Aspirin mechanism of action
Inhibits COX enzymes in platelet
Prevents formation of thromboxane A2
Therefore reduced glycoprotein IIb/IIIa activation and reduced vasoconstriction
Clopidogrel mechanism of action
Blocks ADP induced platelet activation pathway (P2Y12ADP)
Prevents ADP from activating the common pathway
Irreversible platelet effects
Glycoprotein IIb/IIIa antagonists mechanism of action
Block GP IIb/IIIa receptor
Prevents receptor binding to fibrinogen and therefore inhibits platelet adherence
Glycoprotein IIb/IIIa antagonists examples
Tirofiban
Abciximab
Cyclo-oxygenase (COX) isoenzymes
COX 1
COX2 - inducible in response to tissue injury
See diagram for roles of each
Aspirin effects on COX 1 vs COX 2
50 - 100x more effective against COX 1
Therefore higher doses required to achieve anti-inflammatory effects
Platelet turnover following aspirin treatment
Normal platelet turnover 10% per day
Normal platelet function will return 7 to 10 days post aspirin treatment as new platelets are formed
Aspirin pharmacokinetics
Well absorbed orally
Weak acid with pKa of 3
85% plasma protein bound - mainly to albumin
Half life 15 - 20 mins
Aspirin metabolism
Aspirin overdose pathophysiology
Aspirin uncouples oxidative phosphorylation - increases O2 consumption and CO2 production
Minute ventilation initially increases to maintain PaCO2 static
Respiratory alkalosis further stimulates ventilation via direct stimulation of respiratory centre
Impaired aerobic metabolism results in metabolic acidosis
Results in mixed acid base picture
Symptoms of aspirin overdose
Tachycardia
Pyrexia
Blurred vision
Hyperventilation
Treatment of aspirin overdose
Activated charcoal
IV Fluid resus
Alkalinisation of urine with sodium bicarbonate - enhances salicylate removal from blood
Haemodialysis
Clopidogrel pharmacokinetics
Prodrug - activated by oxidation of the thiophene ring by cP450
Elimination half life ~ 8 hours
When to stop clopidogrel pre-surgery
7 days prior to surgery
As irreversible platelet effects so need new platelet production
Role of Dual Antiplatelet Therapy
Clopidogrel and Aspirin work synergistically - but thus produce severe intraoperative haemorrhage
Administration of Glycoprotein IIb/IIIa antagonists
Given as loading dose followed by 12 hour infusion
Duration of action of Glycoprotein IIb/IIIa antagonists
Effects are seen up to 48 hours after cessation of infusion
Dipyridamole effects
Antiplatelet - inhibits platelet adhesion to vessel wall
Vasodilating effects - particularly in coronary arteries
Dipyridamole excretion
Excreted by biliary tree - subject to enterohepatic circulation
Terminal half life of 10 hours
Dipyridamole (possible) mechanisms of action
Phosphodiesterase inhibitor - potentiates action of prostacyclin
Directly stimulates release of prostacyclin
Inhibits metabolism and re-uptake of adenosine
Inhibits Thromboxane A2 synthetase - lowers TXA2 levels
