Pharmacology - Anticoagulation

Question 1

What types of antiplatelet agents are there and indications

Answer 1

1) inhibitors of prostaglandin synthesis: aspirin
2) inhibitors of ADP-induced platelet aggregation: clopidogrel, ticagrelor
3) blockers of platelet glycoprotein IIb/IIIa receptors: abciximab
4) phosphodiesterase inhibitors: dipyridamole

-indications for antiplatelets: IHD, TIA, CVA, post ACS intervention

Question 2

What is the mechanism of action of aspirin

Answer 2

irreversibly inhibits COX 1/2 enzyme
- causes reduced TXA2 (Cox1) which reduces platelet aggregation
- reduces prostaglandins (Cox2) involved in inflammation and pain signalling

Question 3

What is the mechanism of action of clopidogrel, pharmacokinetics and effects?

Answer 3

-inhibition of ADP-induced platelet aggregation by blocking the ADP receptor

-pharmacokinetics: prodrug, metabolised by liver to active metabolite, t1/2 0.5-1 hour
80% platelet activity inhibited in 5 hours of oral dose
50% excreted in urine, 50% excreted in faeces

• dose: loading of 300-600mg or 75mg daily
• duration of effect: 7-10 days
• adverse effects: bleeding, rash, diarrhoea, abdominal pain, reflux, gastric ulcers

Question 4

How does heparin work, how is it administered and what are some side effects

Answer 4

-mechanism:
binds to antithrombin III and enhances its activity
speeds up interaction between antithrombin III and factors 2, 9, 10 via conformational change
promotes inhibition of these factors by complexing with them

• administration: IV or SC, therapeutic vs prophylactic dose
• adverse effects: bleeding, allergy, allopecia, HIT

-reversal: protamine is highly charged and combines with negatively charged Heparin, causing inactivation
1mg protamine neutralises 100 units heparin and 1mg enoxaparin

Question 5

Compare LMWH and UFH

Answer 5

Low molecular weight (enoxaparin)
- short chains, only inhibits factor 10a, higher bioavailability, SC, longer half life
- reduced bleeding risk, lower risk of HIT, less frequent dosing, less monitoring
- needs renal adjustment

High molecular weight (heparin)
- unfractioned, inhibits 2a/9a/10a/11a, given IV/SC, short half life
- higher risk of HIT, aPTT monitoring required, needs continuous infusion
- readily reversible with protamine sulfate

Question 6

What are the types of thrombolytic agents

Answer 6

• mechanism: rapidly lyse thrombi by catalyzing the formation of plasmin from plasminogen
  1) streptokinase: synthesised from streptococci, needs loading and infusion, non-specific fibrinolytic action
  2) tPA: endogenous, activates plasminogen bound to fibrin (confines fibrinolysis), can be used as a push dose
• uses: AMI, unstable PE, acute ischaemic stroke
• adverse effects: haemorrhagic stroke (most common), GI bleed, allergy

Question 7

What is the mechanism of action of rivaroxaban

Answer 7

-mechanism: direct inhibitor of factor Xa

-pharmacokinetics: high oral bioavailability, small VOD, peak concentration in 2-4 hours, highly protein bound
2/3 metabolised by the liver, 1/3 excreted unchanged by kidney
substrate for P450 system, so drugs that inhibit CYP3A4 cause increased rivaroxaban effect

• advantages over warfarin: more rapid onset, wider therapeutic index, INR monitoring not required
• disadvantages compared to warfarin: need dose adjustment in renal failure, not suitable for dialysis patients
• can measure anti-factor Xa activity in bloods
• there is no specific antidote or reversal agent

Question 8

What is the mechanism of action and pharmacokinetics of warfarin and what products are used to reverse it

Answer 8

-mechanism: inhibits vitamin K epoxidereductase (normally converts vitamin K to its active form)
prevents the activation of vitamin K dependent clotting factors (2, 7, 9, 10, protein c/s)

• pharmacokinetics: 100% oral bioavailability, 99% protein bound, t1/2 36 hours, 8-12 hour delay in action
• reason for delay of onset: presence of active vitamin K before dose
• toxicity: crosses placenta, cutaneous necrosis, bleeding

-interactions: involved enzyme induction/inhibition of CYP2C9
medications that decrease INR (inducers) = rifampicin, barbiturates, phenytoin, carbamazapine
medications that increase INR (inhibitors) = amiodarone, metronidazole, fluconazole, aspirin, heparin

-reversal: vitamin K, FFP, prothrombin complex (contains factors 2, 9, 10)

Question 9

How long does it take vitamin K to work in reversing warfarin

Answer 9

24 hours

Question 10

Describe mechanisms by which drugs interact with warfarin

Answer 10

pharmacokinetic:
enzyme inhibitors causing increased INR, enzyme inducers causing decreased INR

pharmacodynamic:
synergism (aspirin affects platelet function), competitive antagonism (presence of vitamin K)