IC3 Pharmacology of Antiplatelets, Anticoagulants, Fibrinolytics +

Question 1

What are the 4 stages of hemostasis & thrombosis?

Answer 1

1. Vasoconstriction
   - Endothelin release causes vasoconstriction
   - Reflex vasoconstriction
2. Pri Hemostasis
   - platelet adhesion (+vWF)
   - Shape change
   - platelets activated to release granules (ADP, TXA2)
   - recruitment
   - platelet plug
3. Sec hemostasis
   - tissue factor
   - phospholipid complex expression
   - thrombin activation
   - fibrin polymerization
4. Clot stabilization
   - platelet contraction
   - Factor XIII –> Covalent crosslinking of fibrin
   –> convert fibrin, stabilise fibrin, result in maturation of fibrin meshwork, trapping more platelets

Question 2

Which part of the hemostasis does antiplatelets tackle?

Answer 2

Antiplatelet drugs block platelet aggregation and primary haemostasis

Question 3

What are the adv and risk of using combi antiplatelets & ACG?

Answer 3

Advantage of using antiplatelet and anticoagulant combination

1. Tackle diff pathways
2. Greater effect with lower dose. Have stronger platelet effect but low adverse effect from each

Combi antiplatelet used in pts with high risk of thrombotic events (but use with caution, due to increase risk of bleeding and bruising)

Question 4

Name 5 antiplatelets and their class name

Answer 4

Antiplatelet agents:
1. Adenosine uptake and PDE3 inhibitor: Dipyridamole
2. COX-1inhibitor: Aspirin
3. ADP(P2Y12)receptor inhibitors, e.g: Clopidogrel, Ticagrelor
4. Glycoprotein IIb/IIIa inhibitors e.g.: Eptifibatide Tirofiban Abciximab

Question 5

What is the MOA of dipyridamole?

Answer 5

MECHANISMS OF ACTION:

1. Inhibits platelet activation and aggregation by ↑cAMP within platelets (and RBC):
   - Adenosine reuptake inhibitor → ↑ plasma adenosine activation of A2 receptors on platelets, since more adenosine is avail to bind to A2 receptor
   - Phosphodiesterase 3 (PDE3) inhibitor reducing cAMP degradation within platelets
2. Vasodilator as also inhibits adenosine reuptake and PDEs in vascular smooth muscle
   - Dose-limiting adverse effects limit clinical antiplatelet efficacy
   o At high doses it will bind to PDE in vascular smooth muscles and cardiac smooth muscles, lead to increase vasodilation and reflex tachycardia
   o Adjunct antiplatelet in combination with other antiplatelets (e.g., aspirin) and/or anticoagulants (e.g., warfarin) [rather than to increase the dose of dypiridamole]
   o Infused intravenously as an alternative to exercise for myocardial perfusion imaging.

Question 6

What is the PK of dipyridamole?

Answer 6

• Onset: Fast after oral administration (20-30 min) and peak effect (2 to 2.5 hours)
• Duration of action: Short (approx. 3 hours) –> gd since have rapid reversal in case of hemorrhage or bleeding
• Therefore, usually as modified-release preparation (to prolong the duration of drug)

Question 7

What is the ADR, CI and DDI of dipyridamole?

Answer 7

Headache, hypotension, dizziness, flushing, gastrointestinal (GIT) disturbance, diarrhoea, (nausea, vomiting)

CONTRAINDICATIONS & CAUTIONS:

• Contraindicated in patients with hypersensitivity to the drug
• Caution in hypotension or severe coronary artery disease
  o As induction of acute hypotension can trigger reflex tachycardia resulting in angina pectoris and ECG abnormalities and even MI

DRUG-DRUG INTERACTIONS:

• ↑Adenosine (antiarrhythmias): Increases cardiac adenosine levels and effects
• ↓Cholinesterase inhibitors: May aggravate myasthenia gravis
• Caution for bleeding when combined with heparin or other anticoagulants and antiplatelets.

Question 8

What is the MOA of aspirin?

Answer 8

MECHANISMS OF ACTION:

• Irreversible non-specific COX inhibitor (COX-1 > COX-2)
• Inhibits platelet production of thromboxane A2 (TXA2)
• Irreversible: Once daily dosing is more effective than every 4 to 6h
• COX-1 > COX-2: Low dose (e.g., 75 to 325 mg loading dose or 40 to 160 mg daily) is more effective than a high dose (e.g., 500 mg to 1g)

Aspirin is an irreversible cyclooxygenase (COX) inhibitor

• COX-1 in platelets – Production of TXA2 (which promotes platelet aggregation) can only be restored by formation of new platelets (7-10days)
  o Platelets no nucleus, can’t make new cox enzymes
• COX-2 in endothelial cells – production of PGI2 (prostacyclin, which inhibits platelet aggregation) can be restored by synthesis of COX-2 enzymes (3-4hrs)
  o Have nucleus and can make new cox enzymes
  o Clearance of low dose aspirin is 3-4 hrs too, thus new cox enzymes + clearance of aspirin duration is the same → thus newly produced cox enzymes are not inhibited
  o Thus, take 3-4hrs to see sign. aspirin antiplatelet effect
• Low dose aspirin is better → since inhibition of COX-2 production of PGI2 counteracts antiplatelet effects of inhibiting COX-1 production of TXA2 → thus want to have as minimal effect on COX2

Question 9

What is the ADR, CI, DDI of aspirin?

Answer 9

ADVERSE EFFECTS:

• Upper gastrointestinal (UGI) events (e.g., gastric ulcers, bleeding)
  o Inhibits COX-1 production of protective prostaglandin in stomach
  o Low-dose aspirin for cardioprotective effects is associated with a 2-4x increase in UGI events
• Increased risk of bruising and bleeding

CONTRAINDICATIONS & CAUTIONS:

• Use with caution in patients with platelet and bleeding disorders.

DRUG-DRUG INTERACTIONS:
- Caution for bleeding when combined with other antiplatelets and anticoagulants.

Question 10

What is the GPIIb/IIIa receptor for and what happens when it is inhibited?

Answer 10

• ADP mediated increase in cell surface expression of active glycoprotein GPIIb/IIIa receptor
  o If inhibit this, would decrease platelet to platelet adhesion
  o Inhibit platelet aggregation and recruitment of platelets to the developing thrombus

Question 11

What is the MOA of ADP P2Y12 receptor inhibitors?

Answer 11

MECHANISMS OF ACTION

• ADP released from dense granules of platelets, acts on the ADP P2Y12 receptor and plays a central role in activating glycoprotein (GP) IIb/IIIa receptors and platelet recruitment and aggregation.
• Loading-dose regimens used to accelerate approach to steady-state (adv of P2Y12 inhibitors: faster onset of peak clinical onset)

Clopidogrel:

• is a prodrug with an active metabolite that irreversibly binds to the ADP binding site on the P2Y12 receptor
• Delayed onset (peak action 6-8 hours) and interindividual variability due to CYP2C19-mediated metabolism to produce active metabolite.
• Effects on platelet function last for the lifetime of the affected platelets, which is between 7 and 10 days.
• Prasugrel is also a prodrug that results in irreversible inhibition of the P2Y12 receptor, more potent and more dependent on CYP3A4, CYP2D6 metabolism

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

• Faster onset and peak effect than clopidogrel
• Recovery of platelet function depends on serum concentrations of ticagrelor and its active metabolites and takes 2 to 3 days (shorter duration).

P2Y12 inhibitor do NOT have reversal agents

Question 12

What is the ADR, CI, DDI of clopidogrel?

Answer 12

P2Y12 inhibitors - Clopidogrel
ADVERSE EFFECTS:

• Haemorrhage/bleeding, including intracranial bleeding, easy bruising, dyspepsia (~5 %), rashes (~5 %), bronchospasm and dyspnea, hypotension

CONTRAINDICATIONS & CAUTIONS:

• Contraindicated in patients with hypersensitivity to the drug
• Contraindicated in patients with active pathologic bleeding e.eg.peptic ulcer
• Caution in patients at risk of bleeding (e.g., risk of intracranial
  haemorrhage, trauma, surgery).
• Variant alleles of CYP2C19 (4 % to 40 %) associated with reduced metabolism to active metabolite and diminished antiplatelet response → thus increase use of prasugrel since less reliance on CYP2C19

DRUG-DRUG INTERACTIONS:

• Warfarin, NSAIDs, and salicylates(aspirin) may increase risk of bleeding
• Macrolides may reduce the antiplatelet effect
• Strong to moderate CYP2C19 inhibitors (e.g., PPIs, fluoxetine, ketoconazole, etc) may reduce the antiplatelet effect
• Rifampicins (inducer) may increase the antiplatelet effect

Question 13

What are the ADR, CI, DDI for ticagrelor?

Answer 13

P2Y12 inhibitors - Ticagrelor

• Increase adenosine more in the lungs rather than the cardiac muscles or platelets → thus lead to dyspnea

ADVERSE EFFECTS:

• Haemorrhage/bleeding, including intracranial bleeding, easy bruising, bradycardia, dyspnea, cough (typical)

CONTRAINDICATIONS & CAUTIONS:

• Contraindicated in patients with hypersensitivity to the drug, severe hepatic impairment, and in breast-feeding women
• Contraindicated in patients with a history of intracranial haemorrhage or active pathologic bleeding (e.g., peptic ulcer)
• Caution in patients at risk of bleeding (e.g., peptic ulcer, trauma, surgery), elderly, and moderate hepatic failure

DRUG-DRUG INTERACTIONS:

• Anticoagulants, fibrinolytics, & long-term NSAIDs may ↑bleeding risk
• Aspirin doses >100 mg/day→ ↓ticagrelor effect but ↑bleeding risk
• CYP3A inducers (e.g., dexamethasone, phenytoin, etc) may ↓ticagrelor level and antiplatelet effect
• CYP3A strong inhibitors (e.g., clarithromycin, ketoconazole, etc) may ↑ticagrelor level and risk of adverse reactions

Question 14

Which stage of the hemostasis does ACG works on?

Answer 14

Anticoagulants block activation of fibrin polymerization and secondary haemostasis

Question 15

Name the 5 ACGs and their drug class.

Answer 15

Oral Anticoagulants

• Vitamin K antagonist:
  o Warfarin (activated II, VII, IX, X)
• Direct oral anticoagulants (DOACs) / Non-Vitamin K antagonists:
  o Dabigatran (IIa)
  o Rivaroxaban (Xa)

Parenteral Anticoagulants

• Heparin (activated II, X; IX, XI, XII)
• Low molecular weight heparin derivatives: LMWHs (Xa > IIa)

Question 16

What is the MOA of warfarin?
What is the target, what is the reversal agent, what are the clotting factors it targets?

Answer 16

Warfarin
The name vitamin K comes from the German word “Koagulations vitamin.”

• Active Vitamin K is oxidised to inactive Vitamin K in a step coupled to carboxylation of glutamic acid residues on coagulation factors II, VII, IX, and X.
• Carboxylation functionally activates the coagulation factors II, VII, IX, and X.
• Warfarin inhibits the Vitamin K reductase enzyme (VKORC1) that reactivates the oxidized Vitamin K. → thus more inactive vit K
• Reversal agent/antidote: Vitamin K can reverse the effect of warfarin.
  o Can use if bleeding due to excess warfarin
  o Means have FDI, have to balance diet and avoid excess vit K e.g. in vitamin supplement, kale, mustard, green and spinach

Question 17

What is the PK of warfarin? What metabolism do we have to look out for thus warranting us to do INR monitoring?

Answer 17

Warfarin PK

• Onset of action: Anticoagulation (Oral): 24-72 hours (delayed becos need to wait until all endogenous reserves of active vit K are depleted)
• Time to peak, plasma: Oral: 2 - 8 hours
• Full therapeutic effect: 5-7 days
• Duration: 2-5 days (Due to the long half-life of some of the coagulation factors. (e.g. Factor II[thrombin], T1/2 = 50 h) –> highly variable amongst individuals
• ABSORPTION (Oral): Rapid & complete
• METABOLISM: Hepatic, primarily via CYP2C9
• HALF-LIFE ELIMINATION: 20-60 hours; highly variable among individuals
• Genetic polymorphisms in 2 genes, CYP2C9 [metabolizer] and Vit K reductase complex subunit 1 (VKORC1) [target], accounts for most of the variability in response
• EXCRETION: Urine and faeces
• International normalized ratio (INR) and prothrombin time (PT) monitoring to titrate dose.

Question 18

What are the ADR, CI, DDI of warfarin?
Can it be used in pregnancy?

Answer 18

ADVERSE EFFECTS:

• Haemorrhage / bleeding
  o Signs include blood in stools or urine, melena, excessive bruising, petechiae, persistent oozing from superficial injuries, excessive menstrual bleeding
• Hepatitis (0.2% to 0.3%, rare but concerning)
  o Greatest risk: >60 years old, male, on warfarin < 1 month (early in treatment)
• Cutaneous necrosis (approx. 1 in 10,000, rare but severe ADR) and infarction of the breast, buttocks and extremities
  o Probably because of the reduced blood supply to adipose tissue
  o Typically 3 to 5 days after initiating treatment

CONTRAINDICATIONS & CAUTIONS:

• Contraindicated in patients with
  o Hypersensitivity to the drug
  o Active bleeding, risk of pathologic bleeding, after recent major surgery
  o Severe or malignant hypertension
  o Severe renal or hepatic disease
  o Subacute bacterial endocarditis, pericarditis, or pericardial effusion
• Contraindicated in pregnancy
  o Teratogen causing severe birth defects in the bone and CNS
  o Can cause haemorrhagic disorder in the fetus
• Caution in breast-feeding women
  o Crosses the placenta
• Caution in patients with
  o Diverticulitis, colitis, Mild or moderate hypertension, Mild or moderate renal or hepatic disease, Drainage tubes in any orifice

DRUG-DRUG & DRUG-FOOD INTERACTIONS:

• Paracetamol long-term therapy (> 2 weeks) at high doses (> 2g/day) may increase bleeding 0 –> warn pts about self-medication, high doses can cause hepatotoxicity
• ↑risk of bleeding
  o Numerous drugs (including allopurinol, NSAIDs, salicylates, PPI, metronidazole, etc)
  –> Competing for inhibiting CYP2C9 increase levels of warfarin and increase bleeding
  o Numerous traditional medicines, herbs, supplements, and foods (including gingko, ginseng, reishi mushrooms, cranberry juice, etc)
• ↓ efficacy of warfarin
  o Numerous drugs (including barbiturates, corticosteroids, spironolactone, thiazide diureticsetc)
  o Numerous traditional medicines, herbs, and supplements (including supplements containing vitamin K, green tea, vitamin K-rich foods, etc)

Regular international normalized ratio (INR) monitoring to ensure appropriate anticoagulant control.

Question 19

What is the MOA of dabigatran?
What is the reversal agent?

Answer 19

Dabigatran etexilate

• A prodrug that is rapidly converted to dabigatran.
• Dabigatran and its acyl glucuronide metabolites are competitive reversible non-peptide antagonists of thrombin (factor IIa).

Reversal agent: Idarucizumab
o For the reversal of dabigatran.
o Humanized monoclonal antibody fragment that binds dabigatran and its acyl glucuronide metabolites with higher affinity than the binding affinity of dabigatran to thrombin.
o Indicated for reversal of the anticoagulant effects of dabigatran for emergency surgery or urgent procedures and in life-threatening or uncontrolled bleeding.

Question 20

What is the MOA of rivaroxaban?
What is the reversal agent of rivaroxaban?

Answer 20

Rivaroxaban

• Competitive reversible antagonist of activated factor X (Xa).

Reversal agent: Andexanet alfa recombinant modified human factor Xa decoy protein for reversal of –xabans (and off-label LMWHs)

Question 21

What’s the PK difference between dabigatran and rivaroxaban?

Answer 21

Dabigatran vs rivaroxaban

1. IIa vs Xa
2. low F (need enteric coating) vs high F
3. 12-17hrs t1/2 vs 5-9hrs t1/2 (reverse faster)
4. Bleeding, gastrointestinal symptoms (dyspepsia, discomfort) vs bleeding
5. ↑risk of bleeding: antiplatelets, anticoagulants, fibrinolytics, NSAIDs, ketoconazole
   ↓reduce dabigatran level: rifampin
   vs
   ↑risk of bleeding: anitplatelets, anticoagulants, NSAIDs, P-glyco- protein (P-gp) & CYP3A4 inhibitors
   ↓rivaroxaban level: P-gp)& CYP3A4 inducers

Question 22

What is the MOA of heparin and LMWH?

Answer 22

Parenteral (IV or SC) anticoagulants: Heparin & LMWHs
MECHANISM OF ACTION:
UFH

• 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-AT III complex inactivates a number of coagulation factors:
  o Inactivates thrombin (factor IIa) and factors IXa, Xa, and XIa, XIIa.
  o Intrinsic and final common pathway
  o Thrombin is needed for the conversion of fibrinogen to fibrin.
  o Without fibrin, clot formation is impeded.
  o Good at blocking surface contact triggered coagulation

Low molecular weight heparins (LMWHs) e.g., enoxaparin, are more selective for factor Xa and to a lesser extent factor IIa

• Mainly final common pathway

Question 23

How are heparin and LMWH administered?

Answer 23

IV or SC (parenteral)

Question 24

What’s the difference btw heparins and LMWH? e.g.PK

Answer 24

ADMINISTERED: IV, subcutaneously
FEATURES HEPARIN LMWHs
Molecular weight (Da) 15,000 ~5000
Bioavailability (% ) 30 86-98
t1/2 (h) 1 4
Renal excretion No Yes
Thrombocytopenia <5% <1%

Question 25

Why is LMWH favoured over heparins?

Answer 25

1. Longer half-life
2. higher bioavailability
3. Not associated with HIT

Question 26

What is the ADR, CI, DDI of heparin & LMWH?
What is the reversal agent of heparin?

Answer 26

ADVERSE EFFECTS:

• Bleeding (in 1-5 % of patients treated with IV heparin)
  o Anticoagulant effect disappears within hours of discontinuation (due to short t1/2)
  o Reversal agent: Protamine sulfate IV infusion to reverse effects of heparin
   5-kDa cationic polypeptide derived from salmon sperm
   Highly basic peptide stably binds negatively charged heparin and neutralizes anticoagulant properties of heparin
   **Incomplete reversal for LMWHs **
• Increased risk of epidural or spinal haematoma and paralysis in patients receiving epidural or spinal anaesthesia or spinal puncture
• Heparin-induced thrombocytopenia (low platelet count)
  o Binds to platelet factor 4 (PF4) on activated platelet surface
  o IgG antibody against the heparin-PF4 complex
  o Lower risk with LMWHs

PREGNANCY:

• Unlike warfarin, heparin and LMWH do not cross the placenta, and have not been associated with fetal malformations.
• Preferred in pregnancy than warfarin

CONTRAINDICATIONS & CAUTIONS:

• Contraindicated in patients with:
  o Hypersensitive to heparins or pork products (cross reactivity)
  o Active major bleeding
  o Thrombocytopenia or antiplatelet antibodies
• Caution in:
  o Elderly patients
  o Risk of bleeding(hematoma), 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)

DRUG-DRUG, DRUG-HERB & DRUG-FOOD INTERACTIONS:

• ↑risk of bleeding: anitplatelets, anticoagulants, fibrinolytics, NSAIDs, SSRIs
• ↑risk of bleeding: with various herbs/foods, including chamomile, fenugreek, garlic, ginger, ginkgo, ginseng.

Question 27

Describe the endogenous process of fibrinolysis?

Answer 27

Endogenous thrombolysis:

• tPA activates conversion of plasminogen to plasmin
• enzyme that mediates fibrinolysis
• depolymerizing and breaking down the meshwork
• allows RBC and platelets trapped in clot to be slowly released back into bloodstream

Question 28

When do weuse fibrinolytics and why only in specific situations?

Answer 28

Fibrinolytics:

• Risk/Danger: broken down too quickly, clot can break up too fast in clumps rather than by gradual release ofRBC and platelets trapped in the clot, risk of circulating and causing embolism
• Thus, only use when pre-existing clots are causing an imminent death / irreversible damage e.g. thrombotic stroke, pulmonary embolism
• Other conditions e.g. DVT, allow endogenous tPA to degrade the clot and treat them with ACG aggressively to prevent the growth of the clot

Question 29

Why are the -teplase preferred over the other fibrinolytics?

Answer 29

Recombinant variants of t-PA are produced by recombinant DNA technology.

• Recombinant tissue plasminogen activator (r-tPA) drugs end in -teplase e.g., alteplase
  o Differ from native t-PA by having longer plasma half-lives that allow convenient intravenous dosing
  o An advantage of –teplases over urokinase and streptokinase is that the –teplases bind preferentially to clot-associated plasminogen, activating plasmin at the clot

Question 30

What are the ADR, CI, DDI of -teplases?
What are the reversal agents of -teplases?

Answer 30

Alteplase
ADVERSE EFFECTS:

• Haemorrhage/bleeding
• Ventricular arrhythmias, hypotension, oedema (can be monitored and managed)
• Cholesterol embolization, venous thromboembolism (due to embolism)
• Hypersensitivity and anaphylaxis (rare but severe)

Anti-fibrinolytic agents (antidotes) such as tranexamic acid and aminocaproic acid:

• Compete for the lysine binding sites on plasminogen and plasmin –> thus blocking their interaction with fibrin.
• Used to reverse states of excessive fibrinolysis.

CONTRAINDICATIONS & CAUTIONS:

• Contraindicated in patients with active bleeding, prior intracranial haemorrhage, or recent (within the last 3 months) intracranial or intraspinal surgery, serious head injury, or stroke.
• Caution in patients with major surgery within 10 days, risk of bleeding (e.g., peptic ulcer), cerebrovascular disease, mitral stenosis, atrial fibrillation, acute pericarditis or subacute bacterial endocarditis

DRUG-DRUG INTERACTIONS:

• ↑risk of bleeding – antiplatelets (especially dipyridamole and aspirin), and anticoagulants (especially warfarin and heparin).
• ↓ alteplase level – Nitroglycerin

Question 31

What are the 4 drug-induced haematological disorders? What are the drugs that induce them?
What are the possible treatments?

Answer 31

Drug-induced Haematological Disorders

1. Aplastic Anaemia
   a. Drugs that induce – chemotherapies, chloramphenicol, CBZ, phenytoin
   b. Treatment – immunosuppressants, GM-CSF, G-CSF, IL-14 (withdraw, transfusion of erythrocytes and platelets, HSCT)
2. Immune Thrombocytopenia
   a. Drugs that induce – heparin, CBZ, phenytoin, sulphonamides, GP IIb/IIIa inhibitors (eptifibatide)
   b. Treatment – immunosuppressants (withdraw, platelet transfusion)
3. Agranulocytosis / Neutropenia
   a. Drugs that induce – clozapine, thioamides (anti-hyperthyroidism), B-lactam
   b. Treatment – GM-CSF, G-CSF (withdraw)
4. Immune Haemolytic Anaemia
   a. Drugs that induce – methyldopa, quinidine, penicillins, cephalosporins, streptomycin, cisplatin, oxaliplatin, b-lactamase inhibitor
   b. Treatment – steroids, immunoglobulins, rituximab (withdraw, RBC transfusion, hemodialysis for acute renal failure)

Question 32

List / What are the supportive care drugs for leukemia, myelodysplastic syndromes, lymphoma? (For haemotological disorders that arise from these conditions)

Answer 32

Haematological Drugs for Supportive Care (Leukaemia, Myelodysplastic syndromes, lymphoma)

1. Anaemia
   a. Nutrients:
   i. Iron – Ferrous sulphate, Fe sucrose
   ii. Vit B12 – hydroxocobalamin
   iii. Folic acid
   b. Erythropoiesis-stimulating agents (ESA)
   i. Darbepoietin alfa, epoietin alfa
2. Neutropenia
   a. Recombinant G-CSF – filgrastim, pegfilgrastim (PEG covalently linked to G-CSF)
   b. Recombinant GM-CSF – sargramostim
3. Thrombocytopenia
   a. Recombinant IL-11 – Oprelvekin
   b. Fc fusion protein thrombopoietin receptor agonist – romiplostim
   c. Oral non-peptide thrombopoietin receptor agonist – eltrombopag

Question 33

What nutrients are deficient in microcytic anaemia and megaloblastic anaemia? What process are inhibited

Answer 33

Nutrient Deficient:
Microcytic anaemia – Fe deficiency –> inhibits Hg synthesis
Megaloblastic anaemia – VitB12 / Folic acid deficiency –> inhibit DNA synthesis

Question 34

What is the name, ROA, ADR of Iron drugs? What is the reversal agent?

Answer 34

Iron

• Oral ferrous (Fe3+) salts e.g., ferrous sulphate
• Parenteral e.g., iron sucrose
• Minimal elimination in faeces, bile, urine and sweat –> therefore careful dosing required to avoid toxicity
• Adverse Effects / Toxicity:
  o Acute: Necrotizing gastroenteritis with vomiting, abdominal pain, and bloody diarrhoea followed by shock, lethargy, dyspnea, metabolic acidosis, coma and death.
  o Chronic: Haemochromatosis with iron deposited in heart, liver, pancreas and other organs → organ failure, death.
  o Reversal Agents: Parenteral deferoxamine or oral deferasirox iron chelators to treat overdose

Question 35

What is the name, ROA, ADR, PK of vit B12 drugs?

Answer 35

Vitamin B12 (cyanocobalamin)

• Parenteral (IM or SC) e.g., hydroxocobalamin
• Hydroxocobalamin precursor preferred to cyanocobalamin as –> protein binding so retained longer in circulation
• Oral not usually effective as deficiencies are usually caused by gastrointestinal malabsorption –> reduce F
• Excretion via bile and urine
• Excess stored in liver (normally 3 years supply stored)
• Elimination half-life: 26-31 hours (IV)
• Adverse Effects / Toxicity:
  o May cause photosensitivity, avoid direct exposure to sunlight
  o Injection site pain
  o Hypertension, hot flushing, arrhythmias secondary to hypokalaemia, gastrointestinal disturbances, dizziness, tremor, headache, paraesthesia, chromaturia, acneiform and bullous eruptions, rash and itching.
• Drug Interaction: PPIs may reduce oral absorption (but there’s already malabsorption)

Question 36

What is the ROA, F, ADR, DDI of folic acid supplement?

Answer 36

Folic Acid

• Absorption: Rapidly absorbed.
• Bioavailability: Approx 100% (for supplement); Peak plasma concentration: 1 hour.
• Metabolism: Metabolised in liver and plasma; converted to active metabolite, 5 methyltetrahydrofolate (5MTHF); undergoes enterohepatic circulation.
• Excretion: Via urine.
• Contraindications: Untreated cobalamin deficiency (including untreated pernicious anaemia or other causes e.g. lifelong vegetarians), malignant disease
• Special Precautions:
  o Folate-dependent tumours, haemolytic anaemia, alcoholism.
  o Women with pre-existing diabetes, obesity, family history of neural tube defects, or previous pregnancy affected by neural tube defect.
  o Not appropriate for monotherapy in pernicious, aplastic, or normocytic anaemias when anaemia is present with vitamin B12 deficiency.
  o Children. Pregnancy and lactation.
• Adverse Reactions: GI disorders –> Bitter or bad taste, nausea, abdominal distension, flatulence
• Immune system disorders: Rarely, allergic reactions (e.g. rash, pruritus, erythema, urticaria, dyspnoea, shock); allergic sensitization.
• Metabolism and nutrition disorders: Rarely, anorexia.
• Drug Interaction:
  o May reduce the plasma concentrations of anticonvulsants (e.g. phenytoin, phenobarbital, carbamazepine, valproic acid)
  o Enhances the efficacy of lithium
  o May decrease the therapeutic effect of methotrexate chemotherapy
  o Increased elimination with aspirin
  o Reduced absorption with sulfasalazine and triamterene
  o Chloramphenicol and sulfamethoxazole + trimethoprim may interfere with folate metabolism

Question 37

What are the names, ROA, t1/2, CI, ADR of ESA (erythopoiesis-stimulating agents)? Which ROA has the fatest onset?

Answer 37

Drugs for Anaemias – Erythropoiesis-Stimulating Agents (ESAs)
Darbepoetin alfa, Epoetin alfa administered parenterally

• Mechanism of Clinical Action: Biosynthetic forms of erythropoietin
• Stimulate division and differentiation of erythroid (RBC lineage) progenitor cells
• Reticulocytes (immature RBC) are released from the bone marrow and mature into erythrocytes thereby regulating erythropoiesis
• Absorption:
  o IM: Slow;
  o SC: Slow and incomplete.
  o IV: Rapid
• Distribution: Concentrated in the liver, kidneys and bone marrow
• Metabolism: Limited degradation occurs
• Excretion: Mainly in faeces with small amounts in urine
  o Half-life (IV) Epoetin alfa: 4-13 hr; Darbepoetin alfa: 20-25 hr (longer t1/2)
  o Conjugation with polyethylene glycol (e.g., Methoxy polyethylene glycol-epoetin beta) prolongs half-life allowing 2 wks or 1 month dosing interval.
• Contraindications:
  o Uncontrolled hypertension, hypersensitivity (rare)
• Special Precautions
  o Hypertension; history of seizures; ischaemic vascular disease
  o Hepatic impairment, renal impairment, sickle cell anaemia
  o Pregnancy, lactation, children.
• Adverse Reactions
  o Hypertension, oedema; increased platelet count, thrombosis, stroke; hyperkalaemia; seizures; myalgia, arthralgia, limb pain; gastrointestinal effects including nausea and vomiting
  o Epoetin alfa: Pruritus
  o Darbepoetin alfa: Dyspnoea, cough, bronchitis

Question 38

What are the names, MOA, ADR, special precaution for GM-CSF/G-CSF?

Answer 38

Drugs for Neutropenia – Myeloid Growth Factors

• Granulocyte colony-stimulating factor (G-CSF)
  o Recombinant human G-CSF e.g. filgrastim
  o Filgrastim covalently conjugated with polyethylene glycol to extend half-live e.g., pegfilgrastim
  o Can be combined with hematopoietic stem cell mobiliser, plerixafor
• Granulocyte-macrophage colony-stimulating factor (GM-CSF)
  o Recombinant human GM-CSFe.g., sargramostim
• Mechanism of Clinical Action:
  o Stimulate myeloid progenitor cells
  o G-CSF
   Stimulates proliferation and differentiation of progenitors committed to neutrophil lineage and
   Additional activates phagocytic activity of mature neutrophils and prolongs their survival in circulation
  o GM-CSF broader spectrum effects than G-CSF additionally
  o Stimulates proliferation and differentiation of early and late granulocytic, erythroid and megakaryocyte progenitors
• Adverse Effects
  o G-CSF (e.g., filgrastim and pegfilgrastim) more frequently used than GM-CSF (e.g., sargramostim) as better tolerated
  o G-CSF causes bone pain, reversible when drug discontinued
  o GM-CSF causes fever, malaise, arthralgias, myalgias
  o Potentially Fatal:
   Severe sickle cell crisis, capillary leak syndrome, respiratory failure or acute respiratory distress syndrome (ARDS)
   Rarely, splenic rupture
• Special Precautions
  o Patient with pre-malignant or malignant myeloid condition, acute myeloid leukaemia; sickle-cell trait or disease, recent history of pneumonia or lung infiltrates, osteoporotic bone disease
  o Not indicated for use in chronic myeloid leukaemia or myelodysplastic syndrome

Question 39

What are the drugs for thrombocytopenia, their ADRs, and special precautions?

Answer 39

Drugs for Thrombocytopenias

• Megakaryocyte growth factors
• Mechanisms of clinical action
  o Recombinant interleukin-11 (IL-11) e.g., oprelvekin
  o Fc-peptide fusion thrombopoietin receptor agonist e.g., romiplostim
  o Orally active nonpeptide thrombopoietin receptor agonist e.g., eltrombopag
• Adverse Effects
  o Thromboembolic events
  o Oprelvekin: fluid retention, peripheral edema, dyspnea on exertion
• Special Precautions
  o With / history of cerebrovascular disease
  o RF for thromboembolism (e.g., advanced age, prolonged periods of immobilisation, malignancies, surgery/trauma, bleeding, obesity, smoking, contraceptives and hormone replacement therapy)
  o Eltrombopag: higher dose required for non-Asian ancestry (e.g., not Chinese, Koreans, Japanese, Taiwanese, Thai)
  o Oprelvekin: chronic HF or at risk of developing HF; and susceptibility to develop fluid retention