IC3: Pharmacology Flashcards
What are the 4 phases of hemostasis?
Vasoconstriction
Primary hemostasis
Secondary hemostasis
Clot stabilisation
What drugs should be used for the latter 3 stages of hemostasis?
Primary hemostasis - antiplatelets
Secondary hemostasis - anticoagulants
Clot stabilisation - fibrinolytics
What are the 3 classes of antiplatelets and their respective drugs?
Adenosine uptake and PDE3i - dipyridamole
COX-1 inhibitor - aspirin
ADP P2Y12 inhibitors - clopidogrel, ticagrelor
Explain the MOA of dipyridamole
Dipyridamole inhibits adenosine reuptake, increasing plasma adenosine activation of A2 receptors on platelets, which then increases cAMP levels which inhibit platelet activation and aggregation
It also inhibits PDE3, hence reducing cAMP degradation in platelets
Explain the main side effect of dipyridamole and why this occurs
Hypotension (dose-limiting SE) as dipyridamole acts as a vasodilator and inhibits adenosine reuptake and PDEs in vascular smooth muscle as well
Explain the MOA of aspirin
Aspirin is an irreversible cyclooxygenase (COX) inhibitor, inhibiting COX-1 more than COX-2 at lower doses
COX-1 (platelets) normally produces TXA2 which promotes platelet aggregation (effects for 7-10d)
COX-2 (endothelial cells) expresses PGI2 which inhibits platelet aggregation (effects for 3-4h)
What is the main side effect for aspirin
Upper GI events (gastric ulcers, bleeding), as aspirin inhibits COX-1 production of protective PGs in the stomach
Why is ADP P2Y12 important in platelet aggregation?
Platelets release ADP from their granules which act on the P2Y12 receptor, which plays an important role in activating GP IIb/IIIa receptors
Explain how clopidogrel works
Clopidogrel is a prodrug whereby the active metabolite (metabolised by CYP2C19) irreversibly binds to the ADP binding site of P2Y12
Explain how ticagrelor works
Ticagrelor and its metabolites binds reversibly at an allosteric site of P2Y12
What are the main contraindications to clopidogrel and ticagrelor? (2 + 1 for ticagrelor)
Hypersensitivity
Pathological bleeding (eg. PUD)
Severe hepatic impairment for ticagrelor
DDIs for clopidogrel (6)
warfarin
NSAIDs
salicylates
macrolides
PPI
CYP2C19 inhibitors
DDIs for ticagrelor (6)
anticoagulants
fibrinolytics
long-term NSAIDs
aspirin (>100mg/day)
CYP3A4 inducers
CYP3A34 strong inhibitors
What are the 3 classes of anticoagulants?
VKA - warfarin
DOACs - dabigatran (DTI, IIa), rivaroxaban (Xa)
Parenteral ACs - heparin, LMWH (enoxaparin)
How is vitamin K used in the coagulation pathway?
Active vitamin K is oxidised to inactive vitamin K to carboxylate glutamic acid residues on factors II, VII, IX and X
What is warfarin’s MOA
Warfarin inhibits vitamin K reductase that normally reactivates oxidised vitamin K
What are the 2 genetic polymorphisms implicated in warfarin use?
CYP2C19
VKORC1
What are the 3 main side effects of warfarin?
Bleeding
Hepatitis
Cutaneous necrosis
DDIs with warfarin? (10)
Paracetanol
allopurinol
NSAIDs
salicylates
PPIs
metronidazole
barbituates
corticosteroids
spironolactone
thiazides
CI for warfarin (5)
hypersensitivity
active bleeding
HTN
renal or hepatic disease
pregnancy
What is dabigatran etexilate’s MOA
Dabigatran etexilate is a prodrug that is rapidly converted to dabigatran, and dabigatran and its acyl glucuronide metabolites are competitive reversible non-peptide antagonists of thrombin (factor IIa)
What are the adverse effects of dabigatran (2)
bleeding
GI symptoms (dyspepsia, abd discomfort)
What is the reversal agent for dabigatran and what is its MOA?
Idarucizumab, binds dabigatran and its acyl glucuronide metabolites with higher affinity than dabigatran binds to thrombin
What is the MOA of rivaroxaban?
Rivaroxaban is a competitive reversible antagonist of activated factor Xa
What is the reversal agent for rivaroxaban?
Andexanet alfa
Explain the general MOA of parenteral anticoagulants (heparin, LWMH)
They potentiate the action of antithrombin III (causing conformational change)
The heparin-AT III complex inactivates coagulation factors IIa, IXa, Xa, XIa and XIIa (mainly IIa and Xa)
Compare between LMWH enoxaparin and heparin (2)
Enoxaparin is more selective for factor Xa (less for factor IIa)
Enoxaparin causes a lower instance of thrombocytopenia
What are the main 2 side effects of heparin?
Bleeding
Heparin-induced thrombocytopenia
What is the reversal agent for heparin and what is its MOA
Protamine sulfate IV infusion, stably binds to heparin and neutralises its anticoagulant property
Explain how heparin-induced thrombocytopenia is caused
Heparin binds to platelet factor 4 (PF4) on activated platelet surface, causing the body to form IgG antibodies against the heparin-PF4 complex (lower risk of thrombocytopenia with LMWHs)
DDIs with heparin/LMWH (5)
Antiplatelets
Anticoagulants
Fibrinolytics
NSAIDs
SSRIs
Explain how endogenous thrombolysis occurs and how it stops
Tissue-type plasminogen activator binds to plasminogen and converts it to plasmin
tPA is inactivated when it binds to plasminogen activator inhibitor-1 and subsequently destroyed in the liver
What are the benefits of using alteplase over urokinase and streptokinase
they bind preferentially to clot-associated plasminogen, activating plasmin at the clot itself
When are fibrinolytics indicated?
Fibrinolytics are only used to treat existing clots causing iminent risk of irreversible damage or death (eg. thrombotic stroke or pulmonary embolism)
What are the two reversal agents for fibrinolytics (rtPA)?
Tranexamic acid and aminocarpoic acid, which compete for the lysine binding sites on plasminogen and plasmin, blocking their interaction with fibrin
What are the contraindications for fibrinolytics (rtPA)? (4)
active bleeding
hemorrhage
surgery
stroke
DDIs with fibrinolytics? (2)
antiplatelets (dipyridamole, aspirin)
anticoagulants (warfarin, heparin)
What are the 4 main drug-induced blood dyscrasias?
Aplastic anemia
Immune thrombocytopenia
Agranulocytosis
Hemolytic anemia
What are the causes of aplastic anemia (2 x 2)
Dose-dependent direct drug toxicity caused by cancer chemotherapies and chloramphenicol
Idiosyncratic (toxic metabolites) caused by carbamazepine and phenytoin
5 management strategies for aplastic anemia
Withdraw the causative drug whenever possible
Immunosuppressants
Transfusion of erythrocytes and platelets may be done
Other drugs such as granulocyte-macrophage colony-stimulating factor (GM-CSF) sargramostim, and granulocyte CSF (G-CSF) filgrastim, and interleukin-14 may be given
Hematopoietic stem cell transplantation may be necessary
5 drugs that can cause immune thrombocytopenia
heparin
sulfonamides
carbamazepine
phenytoin
GP IIb/IIIa inhibitors (eptifibatide)
3 management strategies for thrombocytopenia
- Withdraw the causative drug whenever possible
- Immunosuppressants are used
- Platelet transfusions can be given if there is clinically significant bleeding
What are the 3 classes of agranulocytosis
- Direct drug toxicity caused by thiamazole, chlorpromazine, ticlopidine, busulfan, zidovudine
- Toxic metabolite caused by clozapine, carbimazole
- Immune mediated (hapten or complement) caused by beta-lactam antibiotics, propylthiouracul
3 management strategies for agranulocytosis
- Withdraw the causative drug whenever possible
- Prophylactic administration of hematopoietic growth factors such as GM-CSF sargramostim and G-CSF filgrastim may be done as well
- Routine (weekly) monitoring of WBC count, particularly for patients treated with clozapine
Main causes of immune (3) and non-immune (1) hemolytic anemia
Immune hemolytic anemia
- Drug induced true autoantibody production caused by methyldopa
- Innocent bystander (immune complex) autoantibody production caused by quinine and quinidine
- Hapten induced hemolysis caused by penicillins, cephalospirins, streptomycin
Non-immune hemolytic anemia
- Protein adsorption caused by cisplatin, oxaliplatin and beta-lactamase inhibitors
5 management strategies for hemolytic anemia
- Withdraw the causative drug whenever possible
- RBC transfusion for pts with very low hemoglobin
- Hemodialysis may be required for those in acute renal failure
- Steroids and immunoglobulins have been used in serious cases
- For autoimmune hemolytic anemia, rituximab (human anti-CD20 monoclonal antibody) can be used
What should you give for iron-deficient anemia?
Iron can be given orally (ferrous sulfate) or parenterally (iron sucrose)
What is the main adverse effect with giving iron for IDA?
Hemochromatosis
What reversal agents can be given for iron overdose?
Deferoxamine (parenteral)
Deferasirox (oral)
What should you give for vitamin B12 deficiency?
hydroxocobalamin
What is contraindicated for folic acid deficiency?
untreated B12 deficiency (treat B12 first)
What are the adverse effects of treating with folic acid? (2)
Bitter/bad taste
Nausea
What are the DDIs with folic acid? (5)
Anticonvulsants, lithium, MTX, aspirin, bactrim
What are the 3 ESAs that can be given in anemia?
dabepoetin alfa
epoetin alfa
methoxy PEG-epoetin beta
What are the main adverse effects of ESAs? (2)
hypertension
thrombosis
What drugs can be given for neutropenia? (2)
G-CSF filgrastim with HSC mobiliser plerixafor
GM-CSF sargramostim
What is the prominent adverse effect for G-CSF (filgrastim)?
Bone pain
What are the three drugs that can be given for thrombocytopenia
Oprelvekin (recombinant IL-11)
Romiplostim (thrombopoietin agonist)
Eltrombopag (thrombopoietin agonist)
What is the main adverse event for thrombocytopenia drugs?
thromboembolic events
