Pharmacology Flashcards
MOA of warfarin
Inhibits Vitamin K reductase enzyme (VKORC1) that reactivates oxidised Vitamin K -> Vitamin K remains oxidised leading to depletion of functional Vit K stores (reduced Vit K) leading to inability to further activate coagulation factors (factor II, VII, IX, X) hence prevents formation of new clots and extension of exisiting clots
What’s the reversal agent for Warfarin?
Vit K
State all the factors/proteins affected by Warfarin
Factors II, VII, IX, X
Protein C and S
ADRs of Warfarin (6)
1) GI (dyspepsia, N/V/D)
2) Hirsuitism
3) Thromboembolism (underwarfarinisation; DVT, PE, MI, Stroke)
4) Bleeding (ovewafarinisation; range from gum bleed, nose bleed to melena, hemoptysis)
5) Hepatitis (rare; risk factors: drugs, EtOH, fat)
6) Cutaneous necrosis (rare; as a result of other ADRs such as Calciphylaxis and Chloesterol microemboli; CKD is risk factor for Calciphylaxis)
Which clotting factor plunges the fastest with use of Warfarin? State the t1/2
Factor VII (t1/2 ~4-6h)
Explain why there may be an initial hypercoagulable state when a patient is first started on warfarin
Protein C and S (natural anticoagulants) are also reduced by warfarin -> might cause hypercoagulable state lasting 4-5 days
What are the absolute contraindications to Warfarin use? (Drug Pts; 8)
1) Hypersensitivity
2) Active bleeding
3) Recent traumatic surgery on enclosed places (e.g eye, CNS, heart)
4) Severe or malignant hypertension
5) Preeclampsia or Eclampsia
6) Severe renal or hepatic disease
7) Subacute bacterial endocarditis, pericarditis, or pericardial effusion
8) Inability to monitor treatment
Which Warfarin isomer is more potent?
S-isomer
Which antibiotics when used with Warfarin does not require pre-emptive dose adjustment?
Macrolides, Augmentin, Doxycycline
Which drugs when used with warfarin require pre-emptive dose adjustment? (state which are inducers/inhibitor also) (7)
Drugs that affect CYP2C9
Inducers:
1) Rifampicin (consider alt if possible)
2) Barbiturates
Inhibitors:
1) Bactrim
2) Ciprofloxacin
3) Amiodarone
4) Metronidazole (avoid use where possible)
5) Fluconazole
MOA of Dabigatran
Dabigatran and its acyl glucuronide metabolites are specific, reversible, competitive, non-peptide, direct thrombin inhibitor (factor IIa).
Dabigatran Etexilate (prodrug form)
What’s the reversal agent for Dabigatran and whats its MOA?
Idarucizumab. Binds dabigatran and its acyl glucuronide metabolites with higher affinity than the binding affinity of dabigatran to thrombin.
MOA of Rivaroxaban
Selectively, competitively, directly and reversibly inhibits factor Xa.
Also indirectly inhibits conversion of prothrombin to thrombin.
Reversal agent for Rivaroxaban
Andexanet Alfa (factor Xa decoy protein)
MOA of Heparin and explain the difference in activity between UFH and LMWH
- Potentiates the action of antithrombin III (AT III) and thereby inactivates thrombin.
- The active heparin molecules bind tightly to AT III and cause a conformational change, which exposes AT III’s active site for more rapid interaction with proteases.
- Heparin-ATIII complex inactivates a number of coagulation factors:
o Inactivates thrombin (factor IIa) and factors IXa, Xa, and XIa, XIIa.
o Thrombin is needed for the conversion of fibrinogen to fibrin.
o Without fibrin, clot formation is impeded.
LMWH has less effect on thrombin as it requires formation of a ternary heparin–antithrombin–thrombin complex which can be formed only by chains at least 18 saccharide units long.
ADR of Heparin (3)
1) Bleeding
o Anticoagulant effect disappears within hours of discontinuation
2) Increased risk of epidural or spinal haematoma and paralysis in patients receiving epidural or spinal anaesthesia or spinal puncture
3) Heparin-induced thrombocytopenia (low platelet count)
o Binds to platelet factor 4 (PF4) on activated platelet surface -> development of IgG antibody against the heparin-PF4 complex
o Lower risk with LMWHs
MOA of Dipyridamole
1) Inhibits platelet activation and aggregation by ↑cAMP within platelets by 2 ways:
o Inhibits adenosine reuptake into platelets and RBC -> ↑ plasma adenosine activation of A2 receptors on platelets -> inhibits platelet aggregation and activation
o Inhibits Phosphodiesterase 3 (PDE3) -> reducing cAMP degradation within platelets -> ↑cAMP leads to further inhibition of platelet aggregation and activation
2) Vasodilator effect as it also inhibits adenosine reuptake and PDEs in vascular smooth muscle (biggest concern if used as antiplatelet)
o Results in dose-limiting adverse effects that limit clinical antiplatelet efficacy -> hence normally used as adjunct antiplatelet in combination with other antiplatelets (e.g., aspirin) and/or anticoagulants (e.g., warfarin)
ADRs of Dipyridamole (2)
1) Vasodilator side effects (dizziness, flushing, headache, hypotension)
2) GI side effects (N/V/D)
MOA of Aspirin
Irreversible COX inhibitor (COX-1 > COX-2)
Inhibition of COX-1: Inhibits platelet production of thromboxane A2 (TXA2) hence inhibiting platelet aggregation
Inhibition of COX-2: inhibits endothelial cell production of PGI2 (Prostacyclin) hence promoting platelet aggregation
Inhibition of TXA2 by platelets take longer time to recover as production can only be restored with production of new platelets (takes 7-10 days). Hence, if given at low doses, effects of COX-2 inhibition wears off, allowing for production of Prostacyclin to resume resulting in overall antiplatelet effect.
But since low dose is given OD, not all platelets are inhibited -> need 2-3 days of continuous daily administration to achieve maximum antiplatelet effect
ADR of Aspirin (2)
1) Upper gastrointestinal (UGI) events (e.g., gastric ulcers, bleeding)
o Inhibits COX-1 production of protective prostaglandin in stomach
- PGI decreases acid secretion and increases bicarb and mucus secretion
2) Increased risk of bruising and bleeding
MOA of Clopidogrel
Clopidogrel is a prodrug with an active metabolite (produced by CYP2C19 metabolism) that irreversibly binds to the ADP binding site on the P2Y12 receptor hence blocking ADP mediated ↑ in cell surface expression of GPIIb-IIIa, decreasing platelet to platelet adhesion and aggregation
MOA of Ticagrelor
Same MOA as clopidogrel except that it binds at different site of ADP receptor and exhibits reversible binding. Still inhibits G protein activation and signalling
ADR of Clopidogrel (4)
- Haemorrhage/bleeding, including intracranial bleeding, easy bruising
- Dyspepsia (~5%)
- Rashes (~5%)
- Hypotension
ADR of Ticagrelor (4)
- Haemorrhage/bleeding, including intracranial bleeding, easy bruising
- Adenosine effects: Bradycardia, Cough, Dyspnea (ABCD)
MOA of Alteplase
Breaks down fibrin cross-linkages to reverse clot stabilisation
ADRs of Alteplase (6)
- Haemorrhage/bleeding
- Ventricular arrhythmias, hypotension, oedema
- Cholesterol embolization, venous thromboembolism
- Hypersensitivity and anaphylaxis
What drugs are associated with Aplastic Anemia via dose dependent drug toxicity?
Cancer chemotherapies, radiotherapies, PO chloramphenicol
What drugs are associated with Aplastic Anemia via idiosyncratic means (toxic metabolites) (2)
Carbamazepine, phenytoin
What drugs are associated with Immune Thrombocytopenia? (5)
1) Heparin
2) Sulphonamides
3) Carbamazepine
4) Phenytoin
5) Glycoprotein IIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban)
Read through DTSY notes for more
What drugs are typically associated with Agranulocytosis?
1) Antipsychotics -> phenothiazines e.g Clozapine
2) Antibiotics -> β-lactam, sulfonamides e.g Bactrim
3) Antithyroid -> Methimazole, Propylthiouracil (PTU)
See DTSY for more
What are some common drugs associated with Hemolytic Anemia? (8)
1) Paracetamol
2) ACEi
3) β-lactam
4) Fluroquinolone
5) Thiazide
6) Rifampicin
7) Methyldopa
8) NSAID
See DTSY list for more
What are some common drugs that are associated with oxidative hemolytic anemia?
1) Vit C
2) Metformin
3) Nitrofurantoin
4) Bactrim
See DTSY list
List the hematological drugs used for suppportive therapy for anemia
1) Nutrients (Vit B12, Folic Acid, Iron)
- Rescue tx for Fe overload: Parenteral deferoxamine or oral deferasirox iron chelators
2) Erythropoiesis Stimulating Agents (ESAs)
List the hematological drugs used for suppportive therapy for neutropenia
1) Granulocyte colony-stimulating factors (G-CSF) e.g Filgrastim (-gra- = granulocyte) +- hematopoietic stem cell mobiliser (Plerixafor)
2) Granulocyte-macrophage colony-stimulating factors (GM-CSF) e.g Sargramostim (-gra-m- = granulocyte + macrophage)
GM-CSF has broader spectrum effect but less well tolerated compared to G-CSF
List the hematological drugs used for suppportive therapy for thrombocytopenia
1) Megakaryocyte growth factors/ Platelet-Stimulating Agents (PSAs)
o More potent but more ADR as they stimulate more cell types
Examples:
* Recombinant Interleukin-11 (-elve-) E.g Oprelvekin
* Fc-fusion protein thrombopoietin receptor agonist E.g Romiplostim
* Oral non-peptide thrombopoietin (growth factor for thrombocytes) receptor agonists E.g Eltrombopag
Which genetic polymorphisms of Warfarin are most prevalent in SG?
VKOR1, CYP2C9
When would pgx testing for warfarin be beneficial? (5)
Testing beneficial when initiating, but NOT to be done when maintenance dose is already known:
o For those requiring ≤21mg/week or ≥49mg/week
o Existing clot: left ventricular thrombus
o Outpatient commencement of Warfarin
o DDI
o Questionable adherence
State the potential MOA of Wafarin DDI with antimicrobials and its impact on INR
More disruption of gut bacteria = Less menadione (different types of Vit K) from gut? -> less Vit K = less activation of clotting factor -> Increases INR (blood take longer time to clot)
State what happens to INR in the various Drug Disease interactions:
a) Liver impairment
b) Fluid retention
c) Fever
d) Thyroid disease
a) Liver impairment = ↓ clotting factor synthesis + ↓ warfarin metabolism -> ↑ sensitivity to warfarin -> ↑ INR
b) Depend on location that is more affected by fluid retention (gut vs liver)
o In acute fluid retention, usually will see INR blip followed by INR dropping
- Liver congestion affect clotting factor synthesis hence INR ↑
- Edematous gut affect Warfarin absorption -> INR ↓
c) Fever = Increased metabolism and clotting disorders in sepsis -> INR ↑
d)
* Hyperthyroidism increases clotting factor turnover -> decrease in concentration of clotting factors -> ↑ INR
* Opposite for hypothyroid
DDI mechanisms of Apixaban
CYP, P-gp, BCRP
DDI mechanisms of Dabigatran
P-gp
DDI mechanisms of Rivaroxaban
CYP, P-gp, BCRP, OATP (OAT3)
Herbal DDI of DOACs (3)
1) St. Johns Wort (P-gp, BCRP and CYP3A4 inducer) should NOT be used with DOACs -> loss of DOAC function
* If cannot convince patient to stop, switch from DOAC to Warfarin
2) Ginko (antiplatelet effect) and Ginseng (can either induce or inhibit depending on strain) also have interactions with Warfarin
Which drugs should not be used with DOACs? (3)
Rifampicin, Valproic acid, Carbamazepine
What are examples of potent dual inhibitors (CYP3A4 and P-gp) that should not be used with Rivaroxaban and Apixaban? (3)
Azoles
Clarithromycin
Ritonavir
