Drug Pharmacology Flashcards
Aspirin
Class:
Acetic acid derivitve
antiplatelet agent
Use:
ACS / Stroke - antiplatelet
anti pyretic
analgesic
Action:
COX inhibition ( irreversible)
COX 1 inhibition -> Dec Thromboxane A2 (TXA2) -> dec platelet aggregation
Duration of effect:
7 days.
Dynamics
CNS: Anti-inflammatory effects, antipyretic ( decreased prostaglandin)
CVS: antiplatelet effect mediated by inhibition of TXA2 production
Adverse effects:
Resp: in over dose - respiratory alkalosis ( by direct stimulation of resp centre) followed by metabolic acidosis. May also cause bronchospasm ( over expression of leukotrienes)
GI: Gastritis/ GU ulceration ( COX1 inhibition - decreased mucus and bicarb secretion)
CNS: tinnitus in OD
Haem: inc r/o bleeding, prolonged bleeding time
Can cause Reyes syndrome in children
Kinetics:
A: well absorbed orally but high first pass metabolism = PO bioavilabiltiy 50%. pKA of 3.
D: >90% PB bound to albumin ( LIKE OTHER NSAIDS) but paracetamol is 10% PB.
M: Rapid esterase hydrolysis to salicylate which is active. Salicylate is conjugated in liver.
Saturable metabolism so aspirin obeys Zero order kinetics in overdose
E: inactive metabolites excreted in urine - enhance excretion by ion trapping with alkalinisation!
Aspirin can be dialysed out.
Clopidogrel
Class:
Antiplatelet
Action:
Pro drug -> active metabolite is an irreversible P2Y12 ADP receptor antagonist
Prevents ADP mediated platelet activation
Prevents aggregation (by inhibiting activation of GPIIb/IIIa complex on platelet surface.
T1/2: 1/24.
DOA: 7/7
Dynamics:
CVS: Inhibits platelet activation and aggregation irreversibly
Adverse Effects:
Bleeding time prolonged
Aplastic anaemia / thrombocytopenia
Pancytopenia can occur
Kinetics:
A: rapid absorption but poor oral bioavailability
D: 98% protein bound to albumin. Very Large Vd.
M: pro drug which is extensively metabolised in the liver. Involves esterases and conjugation. Only 2% is metabolised to active form. CYP2C19
E: inactive metabolites excreted in urine
Drug interactions: PPIs e.g. Omeprazole are enzyme inhibitors - prevent conversion of clopidogrel to its active form!
Ticagrelor MOA
Reversible P2Y12 receptor antagonist (clopidogrel is an irreversible example) prevents platelet activation and aggregation. T1/2 ~8 hours
Given BD. T1/2 ~ 7-8 hours
Hepatic metabolism and biliary excretion
Tirofiban MOA
Class:
Antiplatelet
Use:
ACS, peri-angiography
Unstable angina
Action:
GPIIb/IIIa complex inhibitor - prevents platelet aggregation
Route:
IV infusion
Onset / duration of action:
Fast onset
Short acting
T1/2 2 hours
Dynamics:
Prevents platelet aggregation and clot formation
Prolongs bleeding time.
Kinetics:
A: given IV
D: moderate protein binding - 60%
M: limited metabolism
E: renal excretion largely unchanged
MOA of Rasburicase
Recombinant urate oxidase
Promotes urate clearance by degradation to more soluble allatonin in tumour lysis syndrome
Can cause hypersensitivity reactions
Mechanism of Heparin Resistance
*Low ATIII - genetic or acquired (nothing for Heparin to bind)
*Low heparin concentration ( binding to acute phase proteins e.g. in systemic inflammation)
*Enhanced clearance ( e.g. massive splenomegaly)
*Factitious resistance i.e. line not connected
Warfarin
Class:
Coumarin derivitive
Use:
DVT/PE, Mechanical HV, AF
Action:
Vit K antagonist, inhibits Vit K reductase
Prevents activation of Vit Dependent FII,FVII, FIX + FX (prevents Vit K mediated carboxylation)
*Circulating factors not affected so take ~ 72 hours to take effect
Dynamics:
Initial procoagulant phase ( inhibits protein C+S)
bleeding risk, tetarogenic
Kinetics:
A: 100% PO bioavailable, oral
D: highly albumin bound, small Vd
M: Hepatic CYP2C9
E: Renal excretion. T/12 36 hours, Terminal T1/2 1 week.
Dabigatran
Class:
Direct thrombin inhibitor
Use:
Oral anticoagulan
Post orthopaedic vte prophylaxis
Presentation:
Prodrug
Twice daily dosing
Action:
Competitive thrombin inhibitor (FIIa)
Kinetics:
A: Prodrug - 100% bioavilability
D: low ~ 30% binding to albumin
M: minimally metabolised
E: mostly excreted unchanged by kidneys
Monitoring:
Can assess thrombin time and ecarin clotting time
Reversal:
Can be dialysed out
Idarucizumab (Praxabind) is a monoclonal Ab fragment which binds Dabigatran and neutralises it.
What is Idarucizumab? (Praxabind)
Idarucuzimab is a monoclonal Ab fragment which binds both free and thombin bound Dabigatran to neutralise it.
NB dabigatran can also be dialysed out
What is Bivalirudin
1) Bivalirudin is an intravenous direct thrombin inhibitor
2) It is one of a number of non-heparin options in the management of HIT and VITT
3) Bivalirudin is preferable in patients with critical illness, increased bleeding risk or have the potential for requiring urgent procedures, due to its shorter half life
4) APTT is used to monitor bivalirudin
5) Renal clearance (80%) - reduce dose in renal impairment.
*Can be dialysed out to reduce plasma levels in toxicity but no specific antidote
Alternative anticoagulation in HITT
1) Bivalirudin - direct thrombin inhibitor
2) Fondaparinux - parenteral (subcut) Xa inhibitor (once daily dosing) - Reduce dose in renal failure
3. Danaparoid - parenteral ( IV) Xa in inhibitor - useful in dialysis patients
Give short rationale for use of Novo 7
Novo 7 is a recombinant protein - factor VII
Uses: (most off licence)
*massive transfusion in life threatening bleeding
*massive trauma
*life threatening surgical bleeding when MTP used
*life threatening ICH
*haemophilia with bleeding
MOA:
*directly binds TF without need for cofactors - activated FX -> generates thrombin burst
*also promotes platelet aggregation
Evidence:
*initially developed for haemophilia
*encouraging case reports for trauma use
Trials:
Recombinant FVII in ICH - NEJM (2005) - associated reduction in volume of haematoma on CT at 24 hours.
- reduction in 30/7 mortality
Safety of Recombinant FVII in RCTs- NEJM (2010)
- increased r/o thromboembolic events, particularly arterial (coronary thrombosis)
TXA
Class: Antifibrinolytic ( lysine derivative)
Use: Trauma ( CRASH 2), epistaxis, menorrhagia, PPH, dental procedures
Action:
Competitively binds lysine binding sites on plasminogen -> prevents the conversion of plasminogen to active plasmin by tPA.
Therefore prevents fibrinolysis by plasmin
Dose:
Loading 1g
(Can also be nebulised / given as mouth wash/ orally)
Dynamics:
Reduced bleeding ( antifibrinolysis)
Thrombotic risk
Can cause hypotension
Kinetics:
A:some oral absorption
D: 3% PB - to plasminogen
M: no metabolism
E: excreted in urine unchanged
Evidence:
CRASH 2 (2010 )- reduced overall (non sig) mortality if TXA administered early in trauma
CRASH 3 (2019) - reduced mortality from mid-mod TBI if TXA given within 3 hours of onset
ATACAS-TXA (2017)- reduced use of transfusion products ifi TXA given for patients undergoing CABG
Describe how you would reverse warfarin
Can either promote new factor synthesis (Vit K) or replace factors which are depleted (FFP / Prothrombin X)
Agent depends on severity of coagulopathy and presence (or not) of bleeding.
* INR 4.5 – 10.0 and no bleeding: stop warfarin * INR 4.5 – 10.0 and high risk of bleeding: Vitamin K (1 – 2 mg orally or 0.5 – 1.0 mg iv). * Immediate reversal: Prothrombinex 25 – 50 iu/kg (Source of FII,IX,X, and small amount of FVII) * Acutely bleeding: high dose of Vitamin K - 5-10mg IV. It does not matter what the INR is. * Haemorrhage into a critical organ: 5-10mg of Vit K and prothrombinex 50.0 units/kg, and FFP 150–300mL.
FFP is generally reserved for situations when the prothrominex is not readily available. The maximum dose is 15ml/kg
What is andexanet alfa used for
Andexanet alpa =
* Recombinant modified Factor Xa which binds Xa inhibitors with greater affinity than native Fxa
*Not currently licensed in Aus
*Reversal of rivaroxaban/apixaban
