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Pharmacology for Anaesthetists > Drugs affecting coagulation > Flashcards

Drugs affecting coagulation Flashcards

1
Q

What are the two different models used to explain how haemostasis occurs

A

The classical model (intrinsic and extrinsic pathway)

The cell based model (initiation, amplification, propogation)

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2
Q

Describe the classical model

A

Three elements:
1, Platelets
2. Coagulation cascade
3. Fibrinolysis

Subendothelial exposure –> vWF + platelet adhesion–> TXA2 (platelets) –> VC + platelet aggregation –> platelet plug interwoven with fibrinogen –> coagulation cascade to form cross linked fibrin and a stable clot.

Coagulation cascade:
Intrinsic and extrinsic pathway converge to activate factor 10 –> thrombin –> fibrin –> cross-linked plug

Intrinsic pathway

  • triggered by exposure to collagen
  • TENET: 12,11,9 + 8, Ca, PF3 –> 10
  • Lab measurement aPTT

Extrinsic pathway

  • triggered by leakage of tissue factors
  • 7 + 3 –> 10
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3
Q

How do constituents of arterial and venous thrombi compare?

A

Arterial –> Rely on more platelets

Venous –> Fibrin mesh predominates

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4
Q

What are the physiological inhibitors of the classic haemostatic model

A
  1. Anti-thrombin 3: inhibits: 10a, and 2a (and 12a, 11a and 9a)
  2. Protein C + Protein S: Deactivates 8 and 5
    (Protein C activated by thrombin-thrombomodulin complex)
  3. Thrombomodulin binds thrombin to activate protein C and inactivate thrombin bound
  4. t-PA: converts plasminogen –> plasmin (fibrinolysis)
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5
Q

Why was the cell based model developed

A

The classical model fails to effectively describe the haemostatic mechanisms on vivo (rather than in vitro).

E.g.
1. Factor 12 deficiency doesn’t result in increased bleeding tendency despite abnormal in vitro tests

  1. Factor 11 deficiency causes a bleeding tendency that is not closely related to in vitro tests
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6
Q

How does the cell based model differ from the classical model

A

The cell based model places greater importance on the interaction between specific cell surfaces and clotting factors.

The cell based model proposes that coagulation is the sum of 3 processes each occurring on different cell surfaces RATHER than as a cascade:
INITIATION
- damage –> cells bear TF on surface –> small amount thrombin generated –> platelets coated in activated co-factors
AMPLIFICATION
- Platelet surface covered in cofactors –> ^^ Thrombin and amplification
PROPOGATION
- Tissue factor bearing cells and platelets now coated with coagulation factors ^^^ Thrombin –> propogation

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7
Q

What is the mechanism of action of aspirin with regards to its use in cardiovascular disease? What minimum dose is required to achieve this effect? What is the maximum daily dose

A

Irreversible inhibition of cyclo-oxygenase by acetylation within the platelet –> reduced TXA2 –> increase cAMP –> reduced degranulation platelets and reduced vasoconstriction

Minimum dose = 75mg daily
Maximum daily dose = 4g (Toxic dose > 10g)

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8
Q

What is the significance of low dose aspirin (75mg)

A

At low does it is believed that aspirin selectively inhibits platelet COX whilst preserving vessel wall COX. This prevents TXA related VC and platelet aggregation while leaving the vessel wall synthesis of PGI2 unaltered and hence vasodilated.

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9
Q

What is the chemical name of aspirin

A

acetylsalicyclic acid

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10
Q

Describe the metabolic effects of aspirin

A

Usually have little significance but become significant in overdose.

ADULTS

  1. Initial respiratory alkalosis (direct stimulation resp. centres)
  2. Uncouple oxidative phosphorylation –> Increased O2 consumption + CO2 production but halted ATP production
  3. Interference with Krebs cycle enzymes –> ketoacidosis and lactic acidosis

CHILDREN
1. The resp. centre is depressed by rising aspirin levels –> Mixed resp acidosis + HAGMA

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11
Q

What is the consequence of uncoupling oxidative phosphorylation

A

Increased O2 consumption + CO2 production with halted ATP formation

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12
Q

What is the difference between haemoperfusion and haemodialysis

A

Haemoperfusion - blood comes into direct contact with various absorbant materials which means it can remove toxins despite protein binding and lipophilicity

Haemodialysis - there is a concentration gradient between the blood and the solvent across the dialysis membrane.

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13
Q

What are the common features of Aspirin overdose

A
  1. Nausea, vomiting and tinnitus
  2. Resp alkalosis
  3. HAGMA
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14
Q

What is the treatment of aspirin overdose

A

Supportive: ABCDE

  1. Activated charcoal
  2. Forced alkaline diuresis
  3. Haemofiltration/haemodialysis/Haemoperfusion
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15
Q

Can children under 12 receive aspirin? Explain the answer

A

Children under the age of 12 can receive aspirin only if specifically indicated. E.g. Juvenile arthritis (Still’s disease).

Reye’s syndrome is an uncommon condition that has been linked to aspirin use in children.

Reye’s syndrome

  1. Widespread mitochondrial damage
  2. Liver: fatty changes –> hepatic failure with encephalopathy and cerebral oedema
  3. Mortality 40%
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16
Q

What is Reye’s syndrome

A

Reye’s syndrome is an uncommon condition that has been linked to aspirin use in children under 12 years of age.

Reye’s syndrome

  1. Widespread mitochondrial damage
  2. Liver: fatty changes –> hepatic failure with encephalopathy and cerebral oedema
  3. Mortality 40%
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17
Q

Where is aspirin absorbed and why?

A

Stomach

Its a weak acid with pKa of 3.0 –> therefore it is mostly unionized in the stomach pH ± 2.0 and absorbed readily.

pH in mucosal cells = 7.4. Therefore ion trapping as aspirin becomes ionized at pH above its pKa (3.0)

Large surface area of small bowel allows further absorption of aspirin

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18
Q

What is the bioavailability of aspirin and why

A

50%

Half the aspirin is rapidly hydrolysed by hepatic and intestinal esterases to salicylate.

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19
Q

How is aspirin metabolized

A

Liver

  1. Hydrolysed by intestinal and liver esterases to salicylate
  2. Converted to salicyluric acid and glucoronide derivatives

Excreted in urine (enhanced under alkaline conditions) filtered but not re-absorbed as high pH in tubules maintains ionized state

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20
Q

What is dipyridamole and how does this drug affect coagulation

A
  1. PDE inhibitor –> increase cAMP –> Low calcium
  2. Prevents re-uptake of ADP
  3. Potentiates PGI2 effects
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21
Q

Summarise the uses of clopidogrel

A
  1. Post-coronary stent therapy (prevent failure)
  2. STEMI and NSTEMI (with aspirin)
  3. Atherothrombotic prevention in PVD
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22
Q

What is the mechanism of action of clopidogrel

A

Binds irreversibly to ADP receptor: P2Y 12 on platelets –> prevents Glycoprotein IIb/IIIa from transforming into its active form. Platelet activation and cross-linking is inhibited.

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23
Q

Is clopidogrel a drug?

A

No. It is a prodrug which is activated by cytochrome P450 system to form its active metabolite which blocks the P2Y12 ADP receptor irreversibly and prevents transformation of glycoprotein IIa/IIIb into active form hence preventing cross linking platelet aggregation

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24
Q

What is the dose of clopidogrel

A

300 - 600mg loading

75 mg daily

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25
Q

how long does it take for the antiplatelet effects of clopidogrel to occur

A

2 hours

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26
Q

How long to the antiplatelet effects of clopidogrel last and why

A

7 days (platelet life span). Due to IRREVERSIBLE binding to the P2Y12 receptor

Bleeding time completely normalized after 10 days

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27
Q

When is it safe to perform a neuraxial block in a patient who has taken clopidogrel?

A

After 7 days

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28
Q

Why does clopidogrel have a variable antiplatelet effect in different individuals

A

Cytochrome P450 metabolism

CYP3A4, CYP3A5 (primary isoenzymes

CYP2C19 (also involved)

  • significant genetic polymorphism
  • Result: increased/decreased metabolism into active metabolite.
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29
Q

How does omeprazole effect the antiplatelet effect of clopidogrel

A

Omeprazole inhibits CYP2C19 –> reduced metabolism of clopidogrel into active form –> reduced antiplatelet effect.

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30
Q

Can clopidogrel be reversed?

A

There is no specific reversal agent

A single dose of desmopressin for intracranial haemorrhage associated with aspirin/clopidogrel can be administered

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31
Q

What is the active metabolite of clopidogrel called

A

The clopidogrel thiol derivative

32
Q

What is the T1/2 elimination constant for clopidogrel and its active thiol derivative

A

Clopidogrel t1/2 = 6 hours

Thiol derivative t 1/2 = 30 minutes

33
Q

How is clopidogrel adminstered

A

PO

34
Q

Regarding Clopidogrel:

What is the risk reduction in unstable angina for MI
What is the risk reduction for prevention of stent thrombosis?

A

Unstable angina MI –> 18%

Stent thrombosis –> 30 %

35
Q

How long is clopidogel usually prescribed for post percutaneous transluminal coronary angioplasty (PTCA)? How long is aspirin given for

A

3 to 12 weeks

Aspirin for life

36
Q

What is the increased bleeding risk associated with dual antiplatelet therapy

A

40% increased

37
Q

What type of surgery should be performed whilst a patient is on clopidogrel

A

Life or Limb only

38
Q

Describe successful management of patients with a drug-eluting coronary stent presenting for elective, non-cardiac surgery

A
  1. Stop clopidogrel at 5 days preop
  2. Admit 3 days preop
  3. Tirofiban and UFH infusion until 6 hours preop
  4. Restart clopidogrel day 1 postop
  5. Continue aspirin throughout
39
Q

By how much does one unit of pooled platelets raise the platelet count

A

± 5000 platelets/microliter

Normal platelets > 150 000 platelets / microliter

VEry small increase relative to normal platelet numbers

40
Q

What are the functional platelet count targets for surgery/spinal anaesthesia, epidural and eye/neurosurgery

A

Spinal anaesthesia and surgery: Plts > 50 000

Epidural: Plts > 80 000

Eye/Neurosurgery: Plts > 100 000

41
Q

Where does heparin naturally occur in the body

A

Lungs
Liver
Mast cells
Arterial walls

42
Q

Compare the molecular weight of unfractionated heparin and low molecular weight heparin

A

UFH: 15 000 Da

LMWH: 5 000 Da

43
Q

How does heparin act

A
  1. INHIBITION OF COAGULATION
    - Enhances formation of antithrombin III - thrombin complex: Inhibits: 2a, 10a, 12a, 11a, 9a
  2. INHIBIT PLATELET AGGREGATION
  3. INCREASE LIPOPROTEIN LIPASE
    - reduces plasma turbidity
  4. INCREASE VASCULAR PERMEABILITY
44
Q

What are the uses of heparin

A
  1. PROPHYLAXIS VTE
  2. RX ACS and UNSTABLE ANGINA
  3. RX critical peripheral arterial occlusion
  4. PRIME extracorporeal circuits
45
Q

How is heparin administered.

Describe dosages: Prophylaxis and full anticoagulation as during cardiopulmonary bypass

A

IV or SC
Adult dose for prophylaxis: 5000 IU SC 8 - 12 hrly

For full anticoagulation: 300IU/kg or 3mg/kg

46
Q

What is the onset of action and half life of heparin vs LMWH

A

Onset: immediate
T1/2 UFH = 1 hour
T1/2 LMWH = 4.5 hours

47
Q

What are LMWH and what are their advantages compared to UFH

A

Fragments from depolymerization of heparin and have a MW of 5000 Da

LMWH (vs. UFH)

  • More effective in inhibiting Xa
  • Less effective in potentiating antithrombin III

Advantages

  • Single daily dose (longer half life)
  • Require less monitoring
  • Less effect on platelets
  • Reduced risk of HIT (heparin induced thrombocytopaenia)
  • Reduced affinity for vWF
48
Q

What prolongs aPTT and TT

A

Heparin

49
Q

Why do LMWH not need routine monitoring and when they are monitored how is this done?

A

More predictable plasma level and do not need monitoring routinely

If monitoring necessary: anti-Xa assay.

50
Q

Is aPTT prolonged by LMWH

A

No

51
Q

What are the side effects of heparin

A
  1. Haemorrhage
  2. HIT
  3. Hypotension (rapid infusion)
  4. Osteoporosis
  5. Alopecia
52
Q

What do you understand by heparin induced thrombocytopaenia

A

Two types:

Type 1. NON-IMMUNE

  • Within 4 days of starting therapy
  • Returns to normal without stopping therapy
  • Unknown clinical significance

Type 2. IMMUNE

  • More severe
  • Occurs 5 - 14 days after starting therapy
  • 50% develop serious THROMBOSIS ± PE
  • High mortality (PE)
  • Formation of a complex formed between:

HEPARIN - Platelet Factor 4 - IgG –> Platelet aggregation and thrombosis

53
Q

How is the effect of heparin reversed

A

Protamine sulphate

- Basic cationic protein obtained from the sperm of fish

54
Q

How much protamine is required to reverse heparin. How long does this reversal take

A

1mg reverse 100IU of heparin

55
Q

Is protamine fully effective in reversing LMWH

A

No. But it can still be administered for partial reversal

56
Q

What is the dosing regimen for protamine administration and reversal of enoxaparin

A

Time from last enoxaparin:
< 8hrs: 1mg protamine for every 1mg enoxaparin
> 8 and < 12 hrs: 0.5 mg protamine for every 1 mg enoxaparin
12 - 24 hours –> ? need for reversal depending on dose received and renal function

57
Q

What is Warfarin? How does Warfarin act?

A

Warfarin is an Oral anticoagulant which is a derivative of coumarin.

INHIBITS VITAMIN K EPOXIDE REDUCTASE complex 1
- Inhibits the synthesis of vitamin k dependent clotting factors: 2,7, 9, 10. Protein C, Protein S.

58
Q

How long does warfarin take to work and why

A

Up to 3 days

Warfarin has no effect on the circulating clotting factors

59
Q

What are the side effects of warfarin

A
  1. Haemorrhage
  2. Teratogenecity
  3. Drug interactions
60
Q

What are the important drug interactions of Warfarin

NB Potentiation and inhibition of effects of warfarin

A

POTENTIATION OF WARFARIN effects

  1. Other anticoagulant drugs –> Increase bleeding risk
    - NSAIDS
    - heparin
  2. Highly protein bound drugs –> displace warfarin from protein binding sites –> higher free drug level –> increased bleeding risk
    - NSAIDS
    - Oral hypoglycaemics
    - Diuretics
    - Amiodarone
  3. Broad spectrum antibiotics potentiate warfarin effects
  4. Reduced Vit K intake potentiate warfarin effects
  5. Cimetidine potentiate warfarin effects

INHIBITION OF WARFARIN effects

  1. Induction of CYP450: Barbiturates and phenytoin
  2. Oestrogens: increase production of Vit K dependent clotting factors
61
Q

How is warfarin therapy monitored

A

PT

Measure of factor 7 from extrinsic pathway and the factors of the final common pathway

62
Q

What is INR

A

The international normalized ratio

(PT patient / PT control)^international sensitivity index value

The international sensitivity index value is provided by the manufacturer

63
Q

How is the anticoagulant effect of warfarin reversed

A

Rapid reversal FFPs

Slower reversal: vitamin K

64
Q

What is abciximab

A

Monoclonal antibody with a high affinity for the platelet glycoprotein IIb/IIIa receptor. This blocks the final common pathway of platelet aggregation.

65
Q

What is the half life of abciximab and for how long does it remain in circulation with residual activity

A

T1/2 is 20 minutes

Remains bound in circulation for 15 days with come residual activity

66
Q

Give two more examples of Glycoprotein IIb/IIIa inhibitors

What is their mechanism of action

A

Abciximab
Eptifibitide
Tirofiban

Glycoprotein IIb/IIIa inhibitor –> blocking the final common pathway of platelet aggregation.

They do not block:

  1. Platelet adhesion
  2. Secretion platelet products
  3. Inflammatory effects
  4. Secretion of thrombin
67
Q

How do fibrinolytic agents work?

A

Stroptokinase
Urokinase
Alteplase

Activate the fibrinolytic system by forming a complex with plasminogen –> plasmin –> enzymatic degradation of the fibrin clot

68
Q

Is there a contraindication to regional and neuraxial blockade for a patient on aspirin or NSAIDS

A

No

69
Q

How long prior to neuraxial anaesthesia should clopidogrel be stopped?

A

7 days preoperatively

70
Q

How long should regional/neuraxial anaesthesia be delayed if unfractionated heparin has been administered SC

A

Minimum of 4 hours.

UFH infusion can start 1 hour after the block

71
Q

When should intravenous UFH be stopped and started before and after neuraxial blockade

A

Stop 4 hours before

Start 1 hour afterwards

72
Q

When should the IV catheter be removed

A

4 hours after last dose or the infusion has ended

73
Q

How long should LMWH be witheld prior to regional anaesthesia

And when can LMWH be recommenced subsequent to regional anaesthesia

A

Therapeutic dose clexane 1 mg.kg 12 hourly

Stop > 24 hours before
Start > 4 hours after

Prophylactic dose clexane 1mg/kg daily

Stop > 12 hours prior
Start > 12 hours afterwards

74
Q

Describe the pharmacokinetics of aspirin

A

A: Stomach (unionized) and SI (Surface Area)
D: High PB 90%. Saturable. Increased free at high doses
M: Hepatic –> Salicylate. Saturable –> 0 order in OD
E: Salicylate + metabolites in urine. t1/2 15 mins

75
Q

Describe the pharmacokinetics of clopidogrel

A

A: Intestinal
D: Highly PB
M: CYP450
E: 50% Renal. 50% faeces. T1/2 8 hours

76
Q

Name the IIB/IIIa receptors. How long before normal platelet function resumes after disconstinuation of each of these drugs

A

Abciximab - 24 - 48 hours

Ebtifibitide - 4 - 8 hours
Tirofiban - 4 - 8 hours

77
Q

Which anticoagulants are safe and used in pregnancy. Which cannot be used in pregnancy

A

LMWH < 36 weeks gestation
UFH > 36 weeks gestation

Cannot use NOACS or Warfarin in 1st trimester
(exception: mechanical heart valves)

Pharmacology for Anaesthetists (37 decks)

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