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

eLFH - Drugs acting in the Bloodstream Flashcards

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
Q

Management of warfarin overdose / high INR

A

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

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26
Q

Dosing of vitamin K for warfarin reversal

A

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

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27
Q

Contraindication to warfarin and why

A

Pregnancy

Warfarin crosses placenta and causes foetal haemorrhage

Also causes birth defects - Foetal warfarin syndrome

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28
Q

Anticoagulation alternative used in pregnancy

A

LMWH

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29
Q

Heparin structure

A

Mucopolysaccharide

Derived from porcine intestinal mucosa

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30
Q

Molecular weight of commercially produced heparin

A

12 to 15 kDa

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31
Q

Heparin mechanism of action

A

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
Q

What is antithrombin III

A

Plasma serine protease inhibitor

33
Q

Unfractionated heparin route of administration

A

SC or IV

Not absorbed orally due to size and negative charge

34
Q

Unfractionated heparin pharmacokinetics

A

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
Q

Unfractionated heparin metabolism

A

Metabolised by hepatic heparinase

Products excreted in urine

36
Q

Structure of low molecular weight heparins (LMWH)

A

Short chain polysaccharides

Produced by fractionation (depolymerisation) of heparin

37
Q

Average molecular weight of LMWH

A

< 8000 Da

38
Q

LMWH mechanism of action

A

Full anti-Xa action

Less anti-IIa action due to shorter chain lengths

39
Q

Half life of LMWH

A

2-3x longer than unfractionated heparin due to lower affinity for heparin binding proteins

40
Q

LMWH monitoring

A

Factor Xa assays

41
Q

Advantages of LMWH compared with unfractionated heparin

A

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
Q

Most common adverse reactions to heparin

A

Haemorrhage

Hyperkalaemia

Hypotension

43
Q

Heparin induced thrombocytopenia definition

A

Immune mediated thrombocytopenia

Heparin sulphate is recognised as foreign

44
Q

HIT mechanism

A

Heparin binds to platelet factor 4 stimulating IgG antibody formation

This predisposes to thrombosis

45
Q

Incidence of HIT for patients on Heparin / LMWH

A

3%

46
Q

Time scale of platelet count drop in HIT

A

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
Q

Alternative anticoagulants that can be used in patients with HITs

A

Danaparoid - SC or IV

Fondaparinux - SC

48
Q

Danaparoid features

A

Factor Xa inhibitor

Heparinoid similar to LMWH

49
Q

Danaparoid adverse effects

A

Low platelets

Asthma exacerbation

50
Q

Fondaparinux features

A

Synthetic pentasaccharide - similar to heparin

Substantially lower risk of HIT as no affinity for platelet factor 4

Does not require therapeutic monitoring

51
Q

Fondaparinux mechanism of action

A

Factor Xa inhibitor

52
Q

Fondaparinux excretion

A

Renally excreted

Half life 21 hours

Avoid in renal failure

53
Q

Rivaroxaban features

A

Similar to oral heparin

Once daily dosing

Doesn’t need therapeutic monitoring

54
Q

Rivaroxaban mechanism of action

A

Factor Xa inhibition

55
Q

Protamine reversal of heparins

A

Only partial reversal as only fully reverses anti-IIa activity

Anti-Xa activity only partially reversed

56
Q

Aspirin mechanism of action

A

Inhibits COX enzymes in platelet

Prevents formation of thromboxane A2

Therefore reduced glycoprotein IIb/IIIa activation and reduced vasoconstriction

57
Q

Clopidogrel mechanism of action

A

Blocks ADP induced platelet activation pathway (P2Y12ADP)

Prevents ADP from activating the common pathway

Irreversible platelet effects

58
Q

Glycoprotein IIb/IIIa antagonists mechanism of action

A

Block GP IIb/IIIa receptor

Prevents receptor binding to fibrinogen and therefore inhibits platelet adherence

59
Q

Glycoprotein IIb/IIIa antagonists examples

A

Tirofiban

Abciximab

60
Q

Cyclo-oxygenase (COX) isoenzymes

A

COX 1

COX2 - inducible in response to tissue injury

See diagram for roles of each

61
Q

Aspirin effects on COX 1 vs COX 2

A

50 - 100x more effective against COX 1

Therefore higher doses required to achieve anti-inflammatory effects

62
Q

Platelet turnover following aspirin treatment

A

Normal platelet turnover 10% per day

Normal platelet function will return 7 to 10 days post aspirin treatment as new platelets are formed

63
Q

Aspirin pharmacokinetics

A

Well absorbed orally

Weak acid with pKa of 3

85% plasma protein bound - mainly to albumin

Half life 15 - 20 mins

64
Q

Aspirin metabolism

A
65
Q

Aspirin overdose pathophysiology

A

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
Q

Symptoms of aspirin overdose

A

Tachycardia
Pyrexia
Blurred vision
Hyperventilation

67
Q

Treatment of aspirin overdose

A

Activated charcoal

IV Fluid resus

Alkalinisation of urine with sodium bicarbonate - enhances salicylate removal from blood

Haemodialysis

68
Q

Clopidogrel pharmacokinetics

A

Prodrug - activated by oxidation of the thiophene ring by cP450

Elimination half life ~ 8 hours

69
Q

When to stop clopidogrel pre-surgery

A

7 days prior to surgery

As irreversible platelet effects so need new platelet production

70
Q

Role of Dual Antiplatelet Therapy

A

Clopidogrel and Aspirin work synergistically - but thus produce severe intraoperative haemorrhage

71
Q

Administration of Glycoprotein IIb/IIIa antagonists

A

Given as loading dose followed by 12 hour infusion

72
Q

Duration of action of Glycoprotein IIb/IIIa antagonists

A

Effects are seen up to 48 hours after cessation of infusion

73
Q

Dipyridamole effects

A

Antiplatelet - inhibits platelet adhesion to vessel wall

Vasodilating effects - particularly in coronary arteries

74
Q

Dipyridamole excretion

A

Excreted by biliary tree - subject to enterohepatic circulation

Terminal half life of 10 hours

75
Q

Dipyridamole (possible) mechanisms of action

A

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 (10 decks)

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