Year 2 pharmacology

Question 1

Antiplatelet drugs:

Names

MOA

Indication

SE’s

Contraindications/ cautions/ interactions

Answer 1

• Aspirin:
  
  • MOA: Irreversibly inhibits COX –> reduced platelet production of TXA2 (platelet activator) –> at low doses selective inhibitor of COX1 within platelets - inhibition lasts for lifetime of circulating platelet (7-10 days)
  • Indications:
    
    • Thromboprophylaxis - post MI
    • Hx of MI/ angina/ intermittent claudication
    • following CABG
    • ACS - unstable
    • following coronary artery angioplasty or stenting
    • post TIA or thrombotic stroke to prevent recurrence
    • AF - if oral anticoagulation indicated.
  • SE’s:
    
    • Tinnitus
    • severe nausea/ vomiting
    • GI bleed/ ulceration
    • abdominal pain/ indigestion / heartburn
    • headache
    • rash
  • Cautions:
    
    • Reye’s syndrome (not recommended under 16’s if experiencing flu/ chicken pox)
    • previous GI ulcer/ bleed
    • uncontrolled severe hypertension
    • previous hypersensitivity reaction with NSAID (e.g. bronchospasm, rhinnitis
    • careful if evidence of hepatic or renal impairment
  • Contraindication:
    
    • Pregnancy and breastfeeding
• Clopidogrel
  
  • Blocks ADP (P2Y12) receptor on platelet membrane –> prevents ADP dependent activation/expression of glycoprotien IIB/IIIa complex (binding site for fibrinogen) - prevents GP iib/iiia mediated platelet aggregation.
  • Indications:
    
    • used instead of aspirin in patients with contraindications
    • additive with aspirin in patients with acute MI - reduces mortality
    • pretreatment before stenting/ angioplasty
  • SE’s:
    
    • dyspepsia/ indigestion
    • rash
    • diarrhoea
    • risk of increased bleeding
  • Caution:
    
    • oral drug, metabolised by CYP enzymes - some variability in response due to different variations- some pts at risk of therapeutic failure
    • may interact with omeprazole as also metabolised by CYP2C19

Question 2

Anticoagulant - heparins

Name

MOA

Indications

Administration

SE

Cautions/ contraindications

Answer 2

• Heparin - unfractionated
• Names: LMWH - Dalteparin, Tinzaparin, Enoxaparin (heparin fragments) Synthetic (fondaparinux)
  
  • ​Often used instead of unfractionated
  • unfractionated reserved for renal failure - LMWH contraindicated
• MOA:
  
  • ​mixture of polysaccharides, acts immediately
  • binds to antithrombin - induces conformational change which increases its inhibitory activity
    
    • antithrombin binds to and inhibits thrombin, factors XIIa, XIa, Xa, IXa, VIIa
    • unfractionated can bind both antithrombin iii and thrombin - inhibit both factor II and Xa
    • Most importantly inhibits factor Xa (inhibit common pathway, inhibit coagulation).
    • LMWH small - only binds antithrombin iii- only inhibits factor Xa
• Administration:
  
  • Given intravenously or subcutaneously (not IM - would cause haematoma).
• Indication:
  
  • Prophylaxis of VTE and PE
  • Thromboprophylaxis in surgical patients/ pregnancy
• Contraindications:
  
  • haemorrhagic disorders/ haemophilia
  • peptic ulcer
  • cerebral haemorrhage
  • thrombocytopenia
• Caution:
  
  • elderly and severe HTN
• SE:
  
  • Bleeding
  • heparin induced thrombocytopenia
  • skin reactions
  • longer term use –> osteoporosis and hypoaldosteronism (consequent hyperkalaemia)

Question 3

Anticoagulant - coumarin

Name

MOA

Indication

Administration

SE

Cautions/contraindications

Answer 3

• Warfarin
  
  • MOA:
    
    • Inhibition of VKORC1 enzyme, needed for the posttranslational modification of vitamin K dependent coagulation factors 10, 9, 7, 2. (1972)
• Indication:
  
  • Prophylaxis of emobolisation in rheumatic heart disease (rheumatic fever damaged heart valves), and atrial fibrilliation (stroke prophylaxis)
  • prophylaxis after insertion of prosthetic heart valve
  • prophylaxis and tx of venous thrombosis and PE
  • TIA
• Administration - Oral
• SE’s:
  
  • increased bleeding/ haaemorrhage
  • rarer - alopecia, nausea, vomiting
  • teratogenicity in women of childbearing age
• Contraindications:
  
  • first/ third trimester pregancy (generally avoid in pregnancy - teratogenic and can cause intracranial haemorrhage in baby during delivery)
• caution:
  
  • ​ in hepatic and renal impairment - hepatotoxicity (rare)
  • metabolised by CYP2C9 - polymorphic therefore variability in response
  • many drug interactions - especially with other NSAIDs (aspirin) and antibiotics/ carbmazepine/ rifampacin
• Requires monitoring with INR - baseline prothrombin time at initial dose, then determined daily/ 2 days in early tx, then longer intervals, then up to every 12 weeks.
• Aim for 2-4 INR
• INR= normalised PT compared to mean normal prothrombin time

Question 4

Anticoagulants - direct factor Xa inhibitors

Names

MOA

Indication

Administration

SE

Cautions/ contraindications

Answer 4

• Names: Apixaban, Edoxaban, Rivaroxaban - DOAC
• MOA:
  
  • direct inhibition of factor Xa in coagulation cascade
• Indication:
• prophylaxis of stroke from atrial fibrillation
• prophylaxis of DVT/ PE and treatment
• Atherothrombotic event prophylaxis -ACS (with raised cardiac markers) or peripheral artery disease
• Administration:
  
  • oral
• SE:
  
  • bleeding/ menorrhagia
  • anaemia
  • dizziness
  • headache
  • nausea/ GI discomfort/ vomiting
  • diarrhoea/ constipation
  • Skin reactions
  • renal impairment
• Contraindication/ cautions:
  
  • ​teratogenic- avoid in pregnancy
  • avoid in breastfeeding
  • renal and hepatic disease

Question 5

Anticoagulant - direct thrombin inhibitor

Name

MOA

Indication

administration

SE

caution/ contraindications

Answer 5

• Dabigatran
• MOA:
  
  • Direct inhibition of thrombin
• Indication:
  
  • Prophylaxis of venous VTE post surgery
  • Tx of DVT/PE in higher risk pts
  • Prophylaxis stroke and systemic embolism in AF
• Administration:
  
  • Oral
• SE’s:
  
  • Abnormal hepatic function
  • Diarrhoea/ nausea/ vomiting
  • anaemia and haemorrhage
• Contraindications/ cautions:
  
  • Avoid in pregnancy and breastfeeding (possible teratogenicity)
  • avoid in hepatic or renal impairment
    *

Question 6

Thromblytics and Fibrinolytics:

Names

MOA

Indication

SE

Contraindications/ cautions

Answer 6

• Names:
  
  • Streptokinase
  • Urokinase
  • Alteplase
• MOA:
  
  • Streptokinase:
    
    • activation of plasminogen -> releases plasmin
    • proteolytic breakdown of thrombus fibrin (and fibrinogen, factor ii, V and VIII)
  • Alteplase (recombinant tPA and urokinase (both serine proteases)
    
    • Activates plasminogen -> release plasmin
• Indication:
  
  • MI and ischaemic stroke
  • Lysis of pulmonary emboli/ DVT
• Administration - IV
• SE’s:
  
  • Main hazard = bleeding –> GI haemorrhage and haemorrhagic stroke (treat with tranexamic acid, fresh plasma or coagulation factors)
    
    • Streptokinase can cause allergic reaction and low grade fever, hypotension by burst of plasmin formation and kinins
  • Anaphylactic reaction, MI, angina, haemorrahage and haemorrhagic stroke, HF, hypotension, nausea and vomiting
• Cautions/ contraindications:
  
  • streptokinase useful for IV acute MI response, additive with aspirin BUT Antibodies develop after 4 days of initial dose, then cannot be used again
  • Caution in AF and embolic complication, HTN
  • Contraindication -> active internal bleeding, haemorrhagic CVD, pregnancy, uncontrolled HTN, recent trauma or invasive surgery