Haem Pharmacology Flashcards
What is the MOA of dipyridamole?
Inhibits platelet activation and aggregation by
↑cAMP within platelets
→ Adenosine reuptake inhibitor – ↑plasma adenosine activation of A2 receptors on platelets (inc cAMP synthesis)
→ Phosphodiesterase 3 (PDE3) inhibitor
decreases cAMP degradation
within platelets
Also inhibits adenosine reuptake and
PDEs in vascular smooth muscle to
result in vasodilation
→ Dose-limiting adverse effects limit
clinical antiplatelet efficacy – thus
usually used as an adjunct platelet
in combination w other antiplatelets
(eg aspirin) and/or anticoagulants (eg warfarin)
How long does dipyridamole’s onset take?
20-30min
How long does dipyridamole’s peak effect take?
2-2.5h
How long is dipyridamole’s duration of action?
~3h
What are the adverse effects of dipyridamole?
headache, hypotension, dizziness, flushing, GI disturbance, N/V/D
What are the absolute and relative contraindications for dipyridamole?
Contraindicated in patients w hypersensitivity to the drug
Caution in hypotension or severe coronary artery disease
What are the DDIs with dipyridamole?
→ ↑Adenosine: inc cardiac adenosine levels and effects
→ ↓Cholinesterase inhibitors: may aggravate myasthenia gravis
→ Caution for bleeding when combined w heparin or other anticoagulants and antiplatelets
What is the MOA of aspirin as an antiplatelet?
Irreversible COX inhibitor (COX-1 > COX-2)
→ COX-1 produces thromboxane A2¬ in platelets, which promotes platelet aggregation, and can only be restored by formation of new platelets (takes 7-10 days since platelets have no nucleus)
→ COX-2 produces PGI2 in the endothelial cells, which inhibits platelet aggregation, can be restored by synthesis of new COX enzyme in the endothelial cells (takes 3-4h)
→ Aspirin inhibits COX-1 irreversibly (compared to other NSAIDs that inhibit reversibly)
→ Low dose is more effective than high dose – low dose allows for COX-1 inhibition with minimal COX-2 inhibition, as aspirin inhibits COX-1 more than COX-2
What are the adverse effects of aspirin?
→ Upper GI events (eg gastric ulcers, bleeding) – Inhibits COX-1 production of protective prostaglandin in stomach
→ Increased risk of bruising and bleeding
What is the MOA of clopidogrel?
Prodrug with active metabolite that irreversibly binds to ADP binding site on P2Y12 receptor - activate glycoprotein IIb/IIIa receptors and platelet recruitment & aggregation
What are the adverse effects of clopidogrel?
- Haemorrhage/bleeding, including intracranial bleeding and easy bleeding
- Dyspepsia, rashes, bronchospasm, dyspnea, hypotension
What are the absolute and relative contraindications for clopidogrel?
- Contraindicated in patients w hypersensitivity to the drug or active pathological bleeding
- Caution in patients at risk of bleeding (eg risk of intracranial haemorrhage, trauma, surgery)
- Variant alleles of CYP2C19 associated with reduced metabolism to active metabolite and diminished antiplatelet response (ticagrelor prefered)
What are the DDIs for clopidogrel?
- Warfarin, NSAIDs and salicylates may increase bleeding risk
- Macrolides may reduce antiplatelet effect
- Strong to moderate CYP2C19 inhibitors (eg PPIs, ketoconazole) may reduce antiplatelet effect
- Rifamycins may increase antiplatelet effect
What is the MOA of ticagrelor?
Ticagrelor and its metabolites bind reversibly at a different site (not ADP binding site) to inhibit G protein activation and signalling
What are the adverse effects of ticagrelor?
- Haemorrhage/bleeding, including intracranial bleeding and easy bleeding
- Bradycardia, dyspnea, cough
What are the absolute and relative contraindications for ticagrelor?
- Contraindicated in patients w hypersensitivity to the drug, severe hepatic impairment, breast-feeding women, Hx of intracranial haemorrhage or active pathologic bleeding
- Caution in patients at risk of bleeding, elderly and moderate hepatic failure
What are the DDIs for ticagrelor?
- Anticoagulants, fibrinolytics and long term NSAIDs may ↑bleeding risk
- Aspirin >100mg/day dec ticagrelor effect but inc bleeding risk
- Affected by CYP3A inducers (eg dexamethasone, phenytoin) & inhibitors (clarithromycin, ketoconazole etc)
What is the MOA of warfarin?
- Factors II, VII, IX and X are functionally activated by carboxylation of glutamic acid residues
- Carboxylation step is coupled to the inactivation of Vitamin K by a oxidation reaction
- Warfarin inhibits VKORC1, which reactivates the oxidised Vitamin K
How long does the onset of warfarin take?
24-72h
How long does it take for warfarin to peak in plasma?
2-8h
How long does it take for the full therapeutic effect of warfarin to show up?
5-7 days
How long is the duration of action of warfarin?
2-5 days
How is warfarin metabolised?
Hepatically, mainly 2C9
How is the elimination of warfarin?
T1/2 of 20-60h, highly variable among individuals, mostly due to genetic polymorphisms of CYP2C9 and VKORC1
Excreted by urine and faeces
What are the adverse effects of warfarin?
→ Haemorrhage/bleeding – melena, blood in stools/urine, excessive bruising, petechiae, persistent oozing from superficial injuries, excessive menstrual bleeding
→ Hepatitis (0.2-0.3%, Greatest risk in >60yo, males and/or on warfarin <1 month)
→ Cutaneous necrosis and infarction of breast, buttocks and extremities (Likely due to reduced blood supply to adipose tissue, Typically 3-5 days after initiating treatment)
What are the absolute and relative contraindications for warfarin?
→ Contraindicated in patients w hypersensitivity to the drug, active bleeding, risk of pathologic bleeding, recent major surgery, severe or malignant HTN, severe renal or hepatic disease, subacute bacterial endocarditis, pericarditis or pericardial effusion
→ Contraindicated in pregnancy
- Teratogenic – can cause severe birth defects in bone and CNS
- Can cause haemorrhagic disorder in the fetus
→ Caution in breast-feeding women
→ Caution in diverticulitis, colitis, mild-moderate HTN, mild-moderate renal or hepatic disease, drainage tubes in any orifice
What drugs need to be precautionarily dose adjusted before concomitant administration with warfarin?
Bactrim (Co-trimoxazole): 25-50% reduction
Ciprofloxacin: 20-30% reduction
What are some non-drug interactions with warfarin?
Alcohol
→ Sudden binge: CYP inhibition, resulting in sudden INR “blip” increase
→ Chronic alcoholism: CYP induction, increasing warfarin metabolism, decreasing INR
Sudden increases in physical activity – increases warfarin metabolism, decreasing INR
Smoking – CYP induction, increasing warfarin metabolism, decreasing INR
Liver impairment – decreased clotting factor synthesis and warfarin metabolism, decreasing INR
Fluid retention
→ Absorption from oedematous gut – decreased INR
→ Liver congestion – increased INR
Thyroid disease
→ Hyperthyroidism – increased clotting factor turnover, increasing INR (and vice versa)
What is the MOA of Dabigatran Etexilate?
Prodrug that is rapidly converted to dabigatran – competitive reversible non-peptide antagonists of thrombin (factor IIa) along with its acyl glucuronide metabolites
What is the antidote for Dabigatran?
Idarucizumab
What is the MOA of Rivaroxaban?
Competitive reversible antagonist of factor Xa
What is the antidote for Rivaroxaban?
Andexanet alfa – recombinant mab factor Xa decoy protein
What is the bioavailability of Dabigatran?
3-7%
What is the bioavailability of Rivaroxaban?
80-100%
What is the peak action time of dabigatran?
3h
What is the peak action time of rivaroxaban?
2.5-4h
How is the metabolism of dabigatran?
largely excreted unchanged
How is the metabolism of rivaroxaban?
hepatic
What is the half-life of dabigatran?
12-17h (3-5 days to reverse effects)
What is the half-life of rivaroxaban?
5-9h (1-2 days to reverse effects)
How is dabigatran excreted?
Via urine
How is rivaroxaban excreted?
Urine (66%), faeces (28%)
What are the adverse effects of dabigatran?
bleeding, GI symptoms
What are the adverse effects of rivaroxaban?
bleeding
What are the DDIs of dabigatran?
↑bleeding risk: antiplatelets, anticoagulants, fibrinolytics, NSAIDs, ketoconazole
↓ efficacy: Rifampin
What are the DDIs of rivaroxaban?
↑bleeding risk: antiplatelets, anticoagulants, NSAIDs, P-gp and CYP3A4 inhibitors
↓ efficacy: Pgp, CYP3A4 inducers
What is the MOA of heparin and the LMWHs?
Potentiates the action of antithrombin III (AT III), inactivating thrombin
→ Active heparin molecules bind tightly to AT III and cause a conformational change, exposing active site of AT III for more rapid interaction with proteases
Heparin-AT III complex inactivates thrombin and factors IXa, Xa, XIa and XIIa
Low MW Heparins (eg enoxaparin) are more selective for factor Xa, and to a lesser extent factor IIa
What are the adverse effects of heparin and the LMWHs?
Bleeding (1-5% in patients treated w IV heparin)
→ Anticoagulant effect disappears within hours of discontinuation
→ Antidote: Protamine sulfate IV infusion (incomplete reversal for LMWH)
Increased risk of epidural or spinal haematoma and paralysis in patients receiving epidural or spinal anaesthesia or spinal puncture
Heparin-induced thrombocytopenia – binds to platelet factor 4 on activated platelet surface, which IgG antibody can bind to (lower risk with LMWH)
What are the absolute and relative contraindications for heparin and LMWHs?
→ Contraindicated with hypersensitivity to heparins or pork products (cross reactivity), active major bleeding, thrombocytopenia or antiplatelet antibodies
→ Caution in elderly, risk of bleeding (prosthetic heart valves, major surgery, region or lumbar block anaesthesia, blood dyscrasias, recent childbirth, pericarditis or pericardial effusion)
What is the MOA of alteplase?
Recombinant tissue plasminogen activators
Bind preferentially to clot-associated plasminogen, activating plasmin at the clot
What are the adverse effects of alteplase?
→ Haemorrhage/bleeding
→ Ventricular arrhythmias, hypotension, edema
→ Cholesterol embolization, venous thromboembolism
→ Hypersensitivity and anaphylaxis
What are the antidotes for alteplase?
Antifibrinolytic agents such as tranexamic acid and aminocaproic acid
→ Compete for lysine binding sites on plasminogen and plasmin, blocking their interaction with fibrin
→ Used to reverse states of excessive fibrinolysis
What are the absolute and relative contraindications of alteplase?
→ Contraindicated in patients w active bleeding, prior intracranial haemorrhage, or recent (within last 3 months) intracranial or intraspinal surgery, serious head injury or stroke
→ Caution in patients with major surgery within 10 days, risk of bleeding, cerebrovascular disease, mitral stenosis, atrial fibrillation, acute pericarditis, or subacute bacterial endocarditis
What are the DDIs of alteplase?
→ ↑bleeding risk w antiplatelets (esp dipyridamole, aspirin), anticoagulants (esp warfarin, heparin)
→ ↓alteplase level with nitroglycerin
