Pharmacology of Haematology Drugs Flashcards
(53 cards)
1
Q
4 Main Phases of Hemostasis and Thrombosis
A
- Vasoconstriction
- Primary Hemostasis (Platelet Plug)
- Secondary Hemostasis (Coagulation Cascade)
- Clot Stabilization (Fibrin Plug)
2
Q
What happens during primary hemostasis?
A
- Platelet Adhesion to exposed collagen
- Platelet Activation
- Granule release ADP and Thromboxane A2
- Platelet Recruitment and Aggregation
- Platelet plug formation
3
Q
What happens during secondary hemostasis?
A
- Platelet phospholipid complex expression
- Tissue factors released
- Coagulation cascade
- Thrombin activation
- Fibrin polymerization
4
Q
What happens during clot stabilization?
A
- Platelet contraction and trap cells
- Covalent crosslinks and Fibrin network mesh
5
Q
3 Broad classifications of hematological drugs to prevent blood clots
- Phases that they target?
A
- Antiplatelets (Primary Hemostasis)
- Anticoagulants (Secondary Hemostasis)
- Fibrinolytics (Clot stabilization)
6
Q
Subclasses and route of administrations of antiplatelets
A
- Dipyridamole (Adenosine reuptake inhibitor)
- Aspirin (Irreversible COX Inhibitor)
- Clopidogrel and Ticagrelor (P2Y12 inhibitors)
7
Q
Subclasses and route of administrations of anticoagulants
A
- Warfarin (Vitamin K Antagonist)
- Direct-acting Oral Anticoagulants (DOACs)
- Parenterals (Heparin and LMWH)
- Hirudins
8
Q
Subclasses and route of administrations of fibrinolytics
A
- Recombinant tissue Plasminogen Activator (RtPA) - Alteplase
- Kinases (Urokinase)
9
Q
What is the MOA of Dipyridamole?
A
- Inhibition of adenosine reuptake by circulating platelets to increase A2 receptor activation by adenosine
- Inhibition of PDE3 activation to reduce cAMP degradation
- Increased levels of cAMP from these 2 inhibitions increase calcium levels
LEADS to
1. Inhibition of platelet activation / aggregation
2. Vasodilation
10
Q
How does the MOA of dipyridamole affect its clinical use (dosing and administration) and side effects?
A
- Adjunct medication to other antiplatelets or anticoagulants due to vasodilating effect that makes it dose limiting
- IV infusion for myocardial perfusion imaging
11
Q
PK characteristics of Dipyridamole and how it affects its action and formulation of drug
A
- Fast absorption and onset (20-30 min)
- Short duration of action - 3h (Modified release)
12
Q
ADR of dipyridamole
A
- Headache, dizziness, hypotension, flushing
- GI disturbances (N/V/D)
Due to vasodilatory effect
13
Q
Dipyridamole is contraindicated or used with caution in…
A
- Hypersensitivity
- Hypotension / Severe CAD
14
Q
Dipyridamole DDIs
A
- Adenosine
- Cholinesterase inhibitors (Aggravate myasthenia gravis)
- Heparin, anticoagulants and antiplatelets in combination
15
Q
What is the MOA of Aspirin?
A
- Irreversible COX inhibition
- COX-1 > COX-2
- COX-1: TXA2 production - Restored only by new platelet formation (7-10 days)
- COX-2: PGI2 production - Restored by synthesis of new COX enzyme (3-4h)
16
Q
Why does Aspirin have greater antiplatelet activity than NSAIDs?
A
Due to its irreversible COX inhibition (NOT the selectivity of COX-1 over COX-2)
17
Q
Why is Aspirin given low-dose for antiplatelet therapy? What is considered low vs high dose?
A
To ensure selective inhibition of COX-1 enzyme to reduce TXA2 production.
If high dose is given, the selective action is lost
Low-dose = 75-325 mg LD, 40-160 mg OD maintenance
High-dose = 500 mg - 1g
18
Q
ADR of Aspirin
A
- Bleeding and bruising
- Upper GI events due to COX inhibition that reduces PG production that protects the stomach lining (GI Ulcers and bleed)
19
Q
Contraindications of Aspirin
A
- Caution in bleeding disorders
20
Q
Aspirin DDI
A
Combination with other antiplatelets and anticoagulants
21
Q
MOA of P2Y12 Inhibitors
A
P2Y12 receptors are responsible for activation of glycoprotein IIa/IIIb needed for platelet recruitment and aggregation via fibrinogen
- Irreversible binding to ADP binding site of P2Y12 receptors - Clopidogrel
- Reversible binding to a non-ADP binding site of P2Y12 receptors to inhibit signaling pathway - Ticagrelor
22
Q
Why does clopidogrel have a delayed onset but longer duration of action than ticagrelor?
A
- Interindividual variability in CYP2C19 mediated metabolism of clopidogrel - platelet function recovery time takes 7-10 days
- Reversible binding - platelet function recovery time takes 2-3 days
23
Q
ADR of Clopidogrel
A
- Haemorrhage / Bleeding / Bruising (Intracranial hemorrhage)
- Hypotension
- Dyspepsia
- Rash
- Bronchospasm
- Dyspnea
24
Q
Contraindications of Clopidogrel
A
- Hypersensitivity
- Active pathological bleeding
- Patients with Bleeding risk (Caution)
- Variant alleles of CYP2C19
25
Clopidogrel DDI
Safety DDI - May increase risk of bleeding
* Warfarin
* NSAIDs and salicylates
Efficacy DDI
* Macrolides (Reduce effect)
* Strong to moderate CYP2C19 inhibitors - PPIs, fluoxetine, ketoconazole (Reduce effect)
* Rifamycins (Increase effect)
26
Ticagrelor ADR
1. Haemorrhage / Bleeding / Bruising (Intracranial bleed)
2. Bradycardia
3. Dyspnea
4. Coughing
27
Ticagrelor Contraindications
1. Hypersensitivity
2. Active pathological bleeding
3. Patients with bleeding risk
4. Elderly
5. Moderate hepatic failure
28
Ticagrelor DDI
Safety DDI - Bleeding risks
1. Anticoagulants
2. Fibrinolytics
3. Long-term NSAIDs
4. Aspirin doses >100 mg/day reduce ticagrelor effect but ↑ bleeding risk
Efficacy DDI
1. CYP3A inducers (e.g., dexamethasone, phenytoin) - Reduced effect
2. CYP3A strong inhibitors (e.g., clarithromycin, ketoconazole, etc) - Increased effect
29
What is the MOA of warfarin?
Inhibit activation of coagulation factors II, VII, IX, X
* Inactive coagulation factors have glutamic acid residues that are carboxylated and activated by Vitamin K (hydroquinone) which is oxidized and converted to its inactive form (epoxide)
* Vitamin K epoxide reductase is responsible for converting Vitamin K back into its active form
* Warfarin inhibits the activity of VKORC1
30
What can warfarin be reversed by and how does it affect its use?
Vitamin K
1. Reversal agent for MOA
2. DDIs and Food drug interactions
3. Monitoring of INR and PT due to interindividual variability of VKORC1 enzyme expression
31
PK Characteristics of Warfarin
1. Hepatic metabolism by CYP2C9 primarily
2. Rapid absorption and onset
3. Half-life duration of action depends on half-life of coagulation factors (e.g. II - 50h)
4. Gene polymorphism - CYP2C9 and VKORC1 (Interindividual variability)
32
Warfarin ADR
1. Bleeding, Hemorrhage (Signs in stools, urine, melena, bruising, petechiae, menstruation)
2. Hepatitis
3. Cutaneous necrosis and infarction at breast, buttocks, extremities (3-5 days after initiation)
33
Contraindications of Warfarin
Contraindications
1. Hypersensitivity
2. Severe renal / hepatic disease
3. Severe / malignant hypertension
4. Active bleeding, risk of bleed
5. After recent major surgery
6. Pregnancy
Cautions
1. Breastfeeding
2. Diverticulitis, colitis
3. HTN, renal, hepatic (Mild-moderate)
4. Draining tubes in any orifice
34
Warfarin DDI
Safety DDI - Bleed
1. Paracetamol long term therapy > 2wks at high doses > 2g/day
2. NSAIDs, salicylates
3. PPI
4. Metronidazole
5. Allopurinol
6. TCM, herbs, food - Gingko, ginseng, cranberry juice, reishi mushroom
Efficacy DDI - Reduced
1. Barbiturates
2. Corticosteroids
3. Spironolactone and thiazides
4. Vitamin K rich foods, green tea
35
MOA of DOACs
Competitive Reversible antagonists
1. Dabigatran - Inhibit Factor IIa
2. Rivaroxaban - Inhibit Factor Xa
36
Reversal agents of DOACs
1. Idarucizumab - Dabigatran etexilate
2. Andexanet Alfa (Decoy protein) - Rivaroxaban
37
PK Characteristics of Dabigatran vs Rivaroxaban
Both have rapid onset of action
Bioavailability:
* Rivaroxaban > Dabigatran
Metabolism:
* Rivaroxaban - Hepatic
* Dabigatran - Excreted unchanged
Half-life:
* Dabigatran (12-17h) > Rivaroxaban (5-9h)
38
DOAC ADRs
1. Bleeding
2. GI symptoms for Dabigatran
39
DOAC DDIs
Safety DDI - Bleeding risk
1. Antiplatelets, anticoagulants, fibrinolytics
2. NSAIDs
3. Ketoconazole (Dabigatran)
4. Pgp and CYP3A4 inhibitors (Rivaroxaban)
Efficacy DDI - Reduced
1. Rifampin (Dabigatran)
2. Pgp and CYP3A4 inducers (Rivaroxaban)
40
What is the Heparin and LMWH MOA?
Inhibition of intrinsic pathway - Good for tubings (Contact)
* Potentiates antithrombin III and inactivates thrombin
1. Heparin-ATIII complex inactivates Factors IIa, IXa, Xa, XIa, XIIa
2. LMWH selective inhibition of Xa > IIa
41
What is the advantage of lower molecular weight of heparin?
1. Good Bioavailability
2. Longer Half-life
3. Lower Incidence of thrombocytopenia
4. IV and SC administration favored over continuous infusion of heparins
42
Heparin ADRs
1. Bleeding
2. Heparin-induced thrombocytopenia (Low platelet count due to PF4 binding causing IgG Ab activity) - Prefer LMWH
3. Risk of epidural or spinal hematoma and paralysis in patients receiving epidural or spinal anesthesia or spinal puncture
43
Reversal Agent of Heparin
Protamine sulfate - Highly basic peptide that binds to negatively charged heparin and neutralizes anticoagulant properties
Note: Incomplete reversal for LMWH
44
Can heparin be used in pregnancy?
Yes. Does not cross placenta, not associated with fetal malformations.
45
Contraindications and cautions in heparin and LMWH
Contraindicated in patients with:
- Hypersensitive to heparins or pork products
- Active major bleeding
- Thrombocytopenia or antiplatelet antibodies
Caution in:
- Elderly patients
- Risk of bleeding, including patients with prosthetic heart valves, major surgery, regional or lumbar block anaesthesia, blood dyscrasias, recent childbirth, pericarditis or pericardial effusion, renal insufficiency (for LMWHs)
46
Heparin DDI and DFI
Increased bleeding risk:
1. Antiplatelets, anticoagulants, fibrinolytics
2. NSAIDs, SSRIs
3. Various herbs/foods - chamomile, fenugreek, garlic, ginger, ginkgo, ginseng.
47
MOA of fibrinolytics
Conversion of plasminogen to plasmin needed to dissolve the clot by breaking down fibrin cross links to reverse clot stabilization
48
How do -teplases differ from endogenous tPA
Recombinant variant of tPA = Longer half-lives
More convenient IV dosing
49
What are the advantages of -teplases over kinases?
Preferential binding to clot-associated plasminogen
50
Alteplase ADRs
1. Bleeding, hemorrhage
2. VTE, Cholesterol embolization
3. VA, Hypotension, Edema
4. Anaphylaxis
51
Antidotes of alteplase - How do they reverse the effect?
1. Tranexamic acid
2. Aminocaproic acid
Compete for lysine binding sites on plasminogen and plasmin to prevent fibrin interaction
52
Contraindications and cautions for alteplase use
Contraindicated:
1. Patients with active bleeding
2. Prior intracranial haemorrhage
3. Recent (within the last 3 months) intracranial or intraspinal surgery, serious head injury, or stroke.
Caution:
1. Patients with major surgery within 10 days
2. Risk of bleeding (e.g., peptic ulcer)
3. Cerebrovascular disease, mitral stenosis, AF, acute pericarditis or subacute bacterial endocarditis
53
Alteplase DDIs
1. Antiplatelet, anticoagulant
2. Nitroglycerin (Reduce efficacy)
