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Anaesthetic FRCA Primary - eLFH Pharmacology > eLFH - Drugs acting in the Bloodstream > Flashcards

eLFH - Drugs acting in the Bloodstream Flashcards

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1
Q

Location of tissue factor

A

Injured endothelium

Tissue factor bearing fibroblasts and monocytes

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2
Q

Cross section of vessel wall

A
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3
Q

Coagulation cascade

A
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4
Q

Part of coagulation cascade represented by PT (prothrombin time)

A

Extrinsic pathway

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5
Q

Part of coagulation cascade represented by APTT (activated partial thromboplastin time)

A

Intrinsic pathway

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6
Q

Three overlapping stages of cell based coagulation model

A

Initiation

Amplification

Propagation

Note: Also Adhesion / Aggregation of platelets occurs

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7
Q

Initiation phase of coagulation definition

A

Formation of Prothrombinase

Tissue factor and Factor VII are key for this stage

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8
Q

Amplification phase of coagulation definition

A

Activation of platelets

Various factors but Thrombin (Factor IIa) is key for this stage

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9
Q

Propagation phase of coagulation definition

A

Massive Thrombin burst

Thrombin converts fibrinogen to fibrin - results in stable fibrin clot

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10
Q

Initiation phase process

A

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

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11
Q

Scaffold for coagulation complexes to bind onto platelet

A

Externalisation of phosphatidylserines on platelet plasma membrane

This externalisation occurs during Initiation phase

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12
Q

Amplification phase process

A

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

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13
Q

Propagation phase process

A

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

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14
Q

Adhesion and Aggregation of platelets process

A

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

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15
Q

How many molecules of Thrombin are generated from one Prothrombinase complex

A

1000 molecules

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16
Q

Warfarin mechanism of action

A

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

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17
Q

Warfarin pharmacokinetics

A

99% plasma protein bound

Metabolised by liver almost entirely

Metabolites excreted in urine and faeces

Elimination half life 35 to 45 hours

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18
Q

Mechanisms by which significant drug reactions occur with warfarin

A

Displacement from plasma proteins

Liver induction / inhibition

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19
Q

Drugs which potentiate Warfarin effects by inhibition of metabolism

A

Alcohol

Metronidazole

Erythromycin

Ciprofloxacin

Allopurinol

Cimetidine

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20
Q

Drugs which potential Warfarin effects by displacing it from plasma proteins

A

NSAIDs

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21
Q

Drugs with inhibit Warfarin effects by enzyme induction

A

Barbiturates

Rifampicin

Carbamazepine

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22
Q

Drugs which inhibit Warfarin effects by decreasing fat soluble vitamin absorption

A

Cholestyramine

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23
Q

How long does it take Prothrombin levels to decrease by 50% with warfarin

A

~ 3 days

Shorter if patient is unwell or with drug interactions

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24
Q

Monitoring of warfarin

A

International Normalised Ratio

Ratio of patient’s prothrombin time to a normal control sample

PT is sensitive to Factors 2, 7 and 10

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25
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
26
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
27
Contraindication to warfarin and why
Pregnancy Warfarin crosses placenta and causes foetal haemorrhage Also causes birth defects - Foetal warfarin syndrome
28
Anticoagulation alternative used in pregnancy
LMWH
29
Heparin structure
Mucopolysaccharide Derived from porcine intestinal mucosa
30
Molecular weight of commercially produced heparin
12 to 15 kDa
31
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
32
What is antithrombin III
Plasma serine protease inhibitor
33
Unfractionated heparin route of administration
SC or IV Not absorbed orally due to size and negative charge
34
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
35
Unfractionated heparin metabolism
Metabolised by hepatic heparinase Products excreted in urine
36
Structure of low molecular weight heparins (LMWH)
Short chain polysaccharides Produced by fractionation (depolymerisation) of heparin
37
Average molecular weight of LMWH
< 8000 Da
38
LMWH mechanism of action
Full anti-Xa action Less anti-IIa action due to shorter chain lengths
39
Half life of LMWH
2-3x longer than unfractionated heparin due to lower affinity for heparin binding proteins
40
LMWH monitoring
Factor Xa assays
41
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
42
Most common adverse reactions to heparin
Haemorrhage Hyperkalaemia Hypotension
43
Heparin induced thrombocytopenia definition
Immune mediated thrombocytopenia Heparin sulphate is recognised as foreign
44
HIT mechanism
Heparin binds to platelet factor 4 stimulating IgG antibody formation This predisposes to thrombosis
45
Incidence of HIT for patients on Heparin / LMWH
3%
46
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
47
Alternative anticoagulants that can be used in patients with HITs
Danaparoid - SC or IV Fondaparinux - SC
48
Danaparoid features
Factor Xa inhibitor Heparinoid similar to LMWH
49
Danaparoid adverse effects
Low platelets Asthma exacerbation
50
Fondaparinux features
Synthetic pentasaccharide - similar to heparin Substantially lower risk of HIT as no affinity for platelet factor 4 Does not require therapeutic monitoring
51
Fondaparinux mechanism of action
Factor Xa inhibitor
52
Fondaparinux excretion
Renally excreted Half life 21 hours Avoid in renal failure
53
Rivaroxaban features
Similar to oral heparin Once daily dosing Doesn't need therapeutic monitoring
54
Rivaroxaban mechanism of action
Factor Xa inhibition
55
Protamine reversal of heparins
Only partial reversal as only fully reverses anti-IIa activity Anti-Xa activity only partially reversed
56
Aspirin mechanism of action
Inhibits COX enzymes in platelet Prevents formation of thromboxane A2 Therefore reduced glycoprotein IIb/IIIa activation and reduced vasoconstriction
57
Clopidogrel mechanism of action
Blocks ADP induced platelet activation pathway (P2Y12ADP) Prevents ADP from activating the common pathway Irreversible platelet effects
58
Glycoprotein IIb/IIIa antagonists mechanism of action
Block GP IIb/IIIa receptor Prevents receptor binding to fibrinogen and therefore inhibits platelet adherence
59
Glycoprotein IIb/IIIa antagonists examples
Tirofiban Abciximab
60
Cyclo-oxygenase (COX) isoenzymes
COX 1 COX2 - inducible in response to tissue injury See diagram for roles of each
61
Aspirin effects on COX 1 vs COX 2
50 - 100x more effective against COX 1 Therefore higher doses required to achieve anti-inflammatory effects
62
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
63
Aspirin pharmacokinetics
Well absorbed orally Weak acid with pKa of 3 85% plasma protein bound - mainly to albumin Half life 15 - 20 mins
64
Aspirin metabolism
65
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
66
Symptoms of aspirin overdose
Tachycardia Pyrexia Blurred vision Hyperventilation
67
Treatment of aspirin overdose
Activated charcoal IV Fluid resus Alkalinisation of urine with sodium bicarbonate - enhances salicylate removal from blood Haemodialysis
68
Clopidogrel pharmacokinetics
Prodrug - activated by oxidation of the thiophene ring by cP450 Elimination half life ~ 8 hours
69
When to stop clopidogrel pre-surgery
7 days prior to surgery As irreversible platelet effects so need new platelet production
70
Role of Dual Antiplatelet Therapy
Clopidogrel and Aspirin work synergistically - but thus produce severe intraoperative haemorrhage
71
Administration of Glycoprotein IIb/IIIa antagonists
Given as loading dose followed by 12 hour infusion
72
Duration of action of Glycoprotein IIb/IIIa antagonists
Effects are seen up to 48 hours after cessation of infusion
73
Dipyridamole effects
Antiplatelet - inhibits platelet adhesion to vessel wall Vasodilating effects - particularly in coronary arteries
74
Dipyridamole excretion
Excreted by biliary tree - subject to enterohepatic circulation Terminal half life of 10 hours
75
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

Anaesthetic FRCA Primary - eLFH Pharmacology (11 decks)

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