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PR3154 (Haem) > Haem Pharmacology > Flashcards

Haem Pharmacology Flashcards

1
Q

What is the MOA of dipyridamole?

A

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)

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2
Q

How long does dipyridamole’s onset take?

A

20-30min

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3
Q

How long does dipyridamole’s peak effect take?

A

2-2.5h

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4
Q

How long is dipyridamole’s duration of action?

A

~3h

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5
Q

What are the adverse effects of dipyridamole?

A

headache, hypotension, dizziness, flushing, GI disturbance, N/V/D

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6
Q

What are the absolute and relative contraindications for dipyridamole?

A

Contraindicated in patients w hypersensitivity to the drug
Caution in hypotension or severe coronary artery disease

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7
Q

What are the DDIs with dipyridamole?

A

→ ↑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

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8
Q

What is the MOA of aspirin as an antiplatelet?

A

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

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9
Q

What are the adverse effects of aspirin?

A

→ Upper GI events (eg gastric ulcers, bleeding) – Inhibits COX-1 production of protective prostaglandin in stomach
→ Increased risk of bruising and bleeding

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10
Q

What is the MOA of clopidogrel?

A

Prodrug with active metabolite that irreversibly binds to ADP binding site on P2Y12 receptor - activate glycoprotein IIb/IIIa receptors and platelet recruitment & aggregation

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11
Q

What are the adverse effects of clopidogrel?

A
  • Haemorrhage/bleeding, including intracranial bleeding and easy bleeding
  • Dyspepsia, rashes, bronchospasm, dyspnea, hypotension
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12
Q

What are the absolute and relative contraindications for clopidogrel?

A
  • 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)
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13
Q

What are the DDIs for clopidogrel?

A
  • 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
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14
Q

What is the MOA of ticagrelor?

A

Ticagrelor and its metabolites bind reversibly at a different site (not ADP binding site) to inhibit G protein activation and signalling

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15
Q

What are the adverse effects of ticagrelor?

A
  • Haemorrhage/bleeding, including intracranial bleeding and easy bleeding
  • Bradycardia, dyspnea, cough
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16
Q

What are the absolute and relative contraindications for ticagrelor?

A
  • 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
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17
Q

What are the DDIs for ticagrelor?

A
  • 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)
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18
Q

What is the MOA of warfarin?

A
  • 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
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19
Q

How long does the onset of warfarin take?

A

24-72h

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20
Q

How long does it take for warfarin to peak in plasma?

A

2-8h

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21
Q

How long does it take for the full therapeutic effect of warfarin to show up?

A

5-7 days

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22
Q

How long is the duration of action of warfarin?

A

2-5 days

23
Q

How is warfarin metabolised?

A

Hepatically, mainly 2C9

24
Q

How is the elimination of warfarin?

A

T1/2 of 20-60h, highly variable among individuals, mostly due to genetic polymorphisms of CYP2C9 and VKORC1

Excreted by urine and faeces

25
Q

What are the adverse effects of warfarin?

A

→ 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)

26
Q

What are the absolute and relative contraindications for warfarin?

A

→ 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

27
Q

What drugs need to be precautionarily dose adjusted before concomitant administration with warfarin?

A

Bactrim (Co-trimoxazole): 25-50% reduction
Ciprofloxacin: 20-30% reduction

28
Q

What are some non-drug interactions with warfarin?

A

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)

29
Q

What is the MOA of Dabigatran Etexilate?

A

Prodrug that is rapidly converted to dabigatran – competitive reversible non-peptide antagonists of thrombin (factor IIa) along with its acyl glucuronide metabolites

30
Q

What is the antidote for Dabigatran?

A

Idarucizumab

31
Q

What is the MOA of Rivaroxaban?

A

Competitive reversible antagonist of factor Xa

32
Q

What is the antidote for Rivaroxaban?

A

Andexanet alfa – recombinant mab factor Xa decoy protein

33
Q

What is the bioavailability of Dabigatran?

A

3-7%

34
Q

What is the bioavailability of Rivaroxaban?

A

80-100%

35
Q

What is the peak action time of dabigatran?

A

3h

36
Q

What is the peak action time of rivaroxaban?

A

2.5-4h

37
Q

How is the metabolism of dabigatran?

A

largely excreted unchanged

38
Q

How is the metabolism of rivaroxaban?

A

hepatic

39
Q

What is the half-life of dabigatran?

A

12-17h (3-5 days to reverse effects)

40
Q

What is the half-life of rivaroxaban?

A

5-9h (1-2 days to reverse effects)

41
Q

How is dabigatran excreted?

A

Via urine

42
Q

How is rivaroxaban excreted?

A

Urine (66%), faeces (28%)

43
Q

What are the adverse effects of dabigatran?

A

bleeding, GI symptoms

44
Q

What are the adverse effects of rivaroxaban?

A

bleeding

45
Q

What are the DDIs of dabigatran?

A

↑bleeding risk: antiplatelets, anticoagulants, fibrinolytics, NSAIDs, ketoconazole
↓ efficacy: Rifampin

46
Q

What are the DDIs of rivaroxaban?

A

↑bleeding risk: antiplatelets, anticoagulants, NSAIDs, P-gp and CYP3A4 inhibitors
↓ efficacy: Pgp, CYP3A4 inducers

47
Q

What is the MOA of heparin and the LMWHs?

A

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

48
Q

What are the adverse effects of heparin and the LMWHs?

A

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)

49
Q

What are the absolute and relative contraindications for heparin and LMWHs?

A

→ 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)

50
Q

What is the MOA of alteplase?

A

Recombinant tissue plasminogen activators
Bind preferentially to clot-associated plasminogen, activating plasmin at the clot

51
Q

What are the adverse effects of alteplase?

A

→ Haemorrhage/bleeding
→ Ventricular arrhythmias, hypotension, edema
→ Cholesterol embolization, venous thromboembolism
→ Hypersensitivity and anaphylaxis

52
Q

What are the antidotes for alteplase?

A

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

53
Q

What are the absolute and relative contraindications of alteplase?

A

→ 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

54
Q

What are the DDIs of alteplase?

A

→ ↑bleeding risk w antiplatelets (esp dipyridamole, aspirin), anticoagulants (esp warfarin, heparin)
→ ↓alteplase level with nitroglycerin

PR3154 (Haem) (5 decks)

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