BDS 1st Year Pharmacology - Haematopoietics & Related Topics

Kathmandu University Board Exam Answers

Q1. Classify Anticoagulants with Examples. Write the Mechanism of Action and Uses of Heparin. [3+1+1 = 5]

Classification of Anticoagulants

1. Unfractionated Heparin (UFH) - e.g., Heparin sodium
2. Low Molecular Weight Heparins (LMWH) - e.g., Enoxaparin, Dalteparin
3. Fondaparinux - synthetic pentasaccharide
4. Direct Thrombin Inhibitors - Bivalirudin, Argatroban, Lepirudin
5. Factor Xa Inhibitors (parenteral) - Fondaparinux

1. Vitamin K Antagonists - Warfarin, Acenocoumarol
2. Direct Oral Anticoagulants (DOACs)
   • Direct thrombin inhibitors: Dabigatran
   • Factor Xa inhibitors: Rivaroxaban, Apixaban, Edoxaban

Mechanism of Action of Heparin

• Heparin binds to Antithrombin III (AT-III), causing a conformational change in AT-III that accelerates its inhibitory action by 1000-fold
• The heparin-AT-III complex inhibits thrombin (Factor IIa) and Factor Xa, and to a lesser extent Factors IXa, XIa, XIIa
• This prevents conversion of fibrinogen to fibrin, thus blocking clot formation
• Heparin also releases lipoprotein lipase from endothelial surfaces (responsible for its lipid-clearing effect)
• UFH requires a minimum chain length of 18 saccharide units to bridge AT-III and thrombin simultaneously

Uses of Heparin

1. Deep vein thrombosis (DVT) - treatment and prophylaxis
2. Pulmonary embolism (PE)
3. Acute coronary syndromes (unstable angina, STEMI) - alongside thrombolytics
4. Cardiopulmonary bypass surgery
5. Prevention of clotting in IV lines, dialysis circuits
6. Disseminated intravascular coagulation (DIC)
7. Bridging therapy when transitioning from oral anticoagulants

Q2. MOA of Aspirin as an Anticoagulant with its Two Adverse Effects [2+3 = 5]

Mechanism of Action of Aspirin as an Antiplatelet Agent

1. Platelet activation by thrombin, collagen, and ADP activates platelet membrane phospholipases, which liberate arachidonic acid from membrane phospholipids
2. Arachidonic acid is converted to Prostaglandin H2 by Cyclooxygenase-1 (COX-1)
3. Prostaglandin H2 is further metabolized to Thromboxane A2 (TXA2), which promotes platelet aggregation essential for hemostatic plug formation
4. Aspirin irreversibly acetylates a serine residue on the active site of COX-1, permanently inactivating the enzyme
5. This shifts the balance from TXA2 (pro-aggregatory) toward Prostacyclin (PGI2) (anti-aggregatory), produced in endothelial cells
6. Since platelets have no nucleus, they cannot synthesize new COX; therefore the effect lasts the entire platelet lifespan (~7-10 days)
7. Endothelial cells DO have nuclei and can regenerate COX, so prostacyclin production recovers

Two Major Adverse Effects of Aspirin:

1. GI disturbances / Peptic ulcer / GI Bleeding
   • Aspirin inhibits COX-1 in gastric mucosa, reducing protective prostaglandin (PGE2) synthesis
   • Results in erosion of gastric mucosa, epigastric pain, nausea, and GI bleeding
   • Most common adverse effect; use of PPI or misoprostol reduces this risk
2. Bleeding tendency / Hemorrhage
   • Due to irreversible inhibition of platelet function for the entire platelet lifespan
   • Manifests as prolonged bleeding time, easy bruising, surgical bleeding
   • Contraindicated pre-operatively (stop 7-10 days before surgery)
   • Can cause Reye's syndrome in children with viral illness (hepatic failure + encephalopathy)

Q3. List Drugs Used in Cancer. Write Down the Common Adverse Effects of Anticancer Drugs. [2+3 = 5]

Classification of Anticancer Drugs (with examples)

Common Adverse Effects of Anticancer Drugs

1. Myelosuppression (Bone Marrow Suppression)
   • Leukopenia (infection risk), thrombocytopenia (bleeding), anemia
   • Most serious and dose-limiting toxicity for most agents
2. GI Toxicity
   • Nausea, vomiting (especially cisplatin - managed with ondansetron)
   • Mucositis (oral ulcers), diarrhea, anorexia
3. Alopecia (Hair Loss)
   • Due to destruction of rapidly dividing hair follicle cells
   • Usually reversible after stopping therapy
4. Reproductive Toxicity / Gonadal Suppression
   • Infertility, teratogenicity, amenorrhea
5. Immunosuppression
   • Increased susceptibility to opportunistic infections
6. Organ-specific toxicities:
   • Cardiotoxicity: Doxorubicin (dilated cardiomyopathy)
   • Nephrotoxicity: Cisplatin
   • Pulmonary fibrosis: Bleomycin
   • Peripheral neuropathy: Vincristine, Paclitaxel
   • Hemorrhagic cystitis: Cyclophosphamide (prevented by Mesna)
7. Secondary malignancies - risk of leukemia with long-term alkylating agents

Q4. Classify Antimalarial Drugs. Write the Uses and Adverse Effects of Chloroquine. Give the Mode of Action and Toxicities of Mefloquine. [1+1+2+1 = 5]

Classification of Antimalarial Drugs

• 4-Aminoquinolines: Chloroquine, Amodiaquine, Piperaquine
• Quinoline methanol: Mefloquine, Quinine
• Artemisinin derivatives: Artesunate, Artemether, Dihydroartemisinin
• Antifolates: Pyrimethamine, Proguanil

• 8-Aminoquinolines: Primaquine, Tafenoquine (radical cure of P. vivax)

• Primaquine (for P. falciparum gametocytes)
• Chloroquine (for P. vivax, P. ovale gametocytes)

• Primaquine, Proguanil

Chloroquine - Uses and Adverse Effects

1. Drug of choice for uncomplicated P. vivax and P. ovale malaria (given WITH primaquine for radical cure)
2. Treatment of sensitive P. falciparum malaria (resistance widespread)
3. Extra-intestinal amoebiasis (hepatic amoebiasis)
4. Rheumatoid arthritis and SLE (as disease-modifying agent)
5. Prophylaxis in chloroquine-sensitive regions

• GI: nausea, vomiting, abdominal pain (take with food)
• Retinopathy (cumulative dose-dependent) - most feared long-term toxicity; requires annual eye screening
• Pruritus (especially in African patients)
• CNS: headache, dizziness, insomnia
• Cardiotoxicity - QT prolongation at high doses
• Rare: agranulocytosis, bleaching of hair, exacerbation of psoriasis

Mefloquine - Mode of Action and Toxicities

• Mefloquine is a quinoline methanol compound
• Exact mechanism not fully established, but similar to chloroquine: believed to interfere with heme detoxification within the parasite food vacuole
• Mefloquine accumulates in parasite food vacuoles and is thought to form toxic complexes with free heme, disrupting parasite membrane integrity
• Active against blood schizonts of all four species
• Can be combined with artesunate (artemisinin-based combination therapy)

1. CNS toxicity - most important; the (-) enantiomer is particularly associated with CNS adverse effects
   • Dizziness, vertigo, ataxia
   • Vivid dreams, nightmares, insomnia
   • Neuropsychiatric effects - anxiety, depression, hallucinations, psychosis (rare but serious; black box warning)
2. GI disturbances - nausea, vomiting, diarrhea
3. Bradycardia and QT prolongation - avoid with other drugs prolonging QT
4. Contraindicated in: psychiatric disorders, seizure history, pilots/divers

Q5. Classify Drugs Used in Therapy of Thrombogenic/Thromboembolic Disorders with One Example Each. List Drugs Used in Therapy of Megaloblastic Anaemia with or without Neurological Involvement. [3+2 = 5]

Classification - Drugs for Thrombogenic/Thromboembolic Disorders

• Parenteral: Heparin (UFH), Enoxaparin (LMWH)
• Oral: Warfarin; Direct oral: Dabigatran, Rivaroxaban

• COX inhibitors: Aspirin
• P2Y12 inhibitors: Clopidogrel, Ticagrelor
• PDE inhibitors: Dipyridamole
• GP IIb/IIIa inhibitors: Abciximab

• Streptokinase, Alteplase (tPA), Urokinase, Tenecteplase

• Tranexamic acid, Aminocaproic acid

Drugs for Megaloblastic Anaemia

• Folic acid (folate) - oral supplementation
  • Given orally, rapidly absorbed in jejunum
  • Causes: inadequate intake, increased demand (pregnancy), alcoholism, methotrexate use, malabsorption
  • Dose: 5 mg/day orally

• Cyanocobalamin or Hydroxocobalamin (Vitamin B12)
  • Given IM (preferred in pernicious anaemia due to lack of intrinsic factor)
  • Hydroxocobalamin IM is preferred - highly protein bound, maintains longer plasma levels
  • In dietary deficiency: oral cyanocobalamin
  • In pernicious anaemia: IM therapy must be continued FOR LIFE

CRITICAL POINT for exams: Empiric treatment of megaloblastic anaemia must NEVER use folic acid alone. Always use BOTH folic acid + vitamin B12 unless confirmed by investigations. Giving folic acid alone will correct the anaemia but MASK the B12 deficiency, allowing neurological damage (subacute combined degeneration of spinal cord) to progress irreversibly.

Q6. Classify Antihistamines. Write Down the Pharmacological Management of Chronic Obstructive Pulmonary Disease (COPD). Write Down Their Uses and Adverse Effects. [3+3 = 6]

Classification of Antihistamines

• Cetirizine, Loratadine, Fexofenadine, Desloratadine, Levocetirizine, Bilastine

• Ranitidine, Famotidine, Cimetidine (used for peptic ulcer, GERD)

• Thioperamide (CNS research)

Pharmacological Management of COPD

• Short-acting Beta-2 agonists (SABA): Salbutamol (albuterol), Terbutaline - for rescue/PRN use
• Long-acting Beta-2 agonists (LABA): Salmeterol, Formoterol, Indacaterol - for maintenance
• Short-acting muscarinic antagonists (SAMA): Ipratropium bromide
• Long-acting muscarinic antagonists (LAMA): Tiotropium, Umeclidinium (preferred maintenance bronchodilator in COPD)
• Methylxanthines: Theophylline (bronchodilator + anti-inflammatory; narrow therapeutic index)

• Budesonide, Fluticasone, Beclomethasone
• Used in combination with LABA (e.g., Salmeterol/Fluticasone)
• Reserved for patients with frequent exacerbations or concurrent asthma

• LABA + LAMA (dual bronchodilation) - e.g., Indacaterol/Glycopyrronium
• LABA + ICS - e.g., Formoterol/Budesonide
• Triple therapy: LABA + LAMA + ICS for severe disease

• Roflumilast - reduces exacerbation frequency; used as add-on therapy in severe COPD with chronic bronchitis

• N-acetylcysteine, Carbocisteine - reduce mucus viscosity

Uses of Antihistamines

1. Allergic conditions - allergic rhinitis, urticaria, angioedema, atopic dermatitis
2. Anaphylaxis (adjunct to epinephrine)
3. Motion sickness - Promethazine, Cyclizine, Meclizine
4. Nausea and vomiting - Promethazine (antiemetic)
5. Pruritus - Chlorpheniramine, Cetirizine
6. Sedation/premedication - 1st generation (e.g., Promethazine)
7. Common cold - 1st generation for symptomatic relief
8. Antitussive (cough suppression) - Diphenhydramine

1. Peptic ulcer disease
2. GERD
3. Zollinger-Ellison syndrome

Adverse Effects of Antihistamines

1. Sedation and drowsiness - most common (due to H1 blockade in CNS)
2. Impaired psychomotor performance - avoid driving, operating machinery
3. Anticholinergic effects:
   • Dry mouth, blurred vision, urinary retention, constipation
   • Tachycardia
4. Paradoxical CNS excitation in children - restlessness, insomnia
5. Appetite stimulation and weight gain (Cyproheptadine)
6. GI: nausea, epigastric discomfort
7. Potentiates CNS depressants (alcohol, sedatives)

1. Minimal sedation (do not cross BBB well)
2. Rare cardiotoxicity - QT prolongation (mostly with old agents like terfenadine - now withdrawn)
3. Headache, dry mouth (mild)

1. Gynecomastia, impotence (anti-androgenic effect)
2. Drug interactions (inhibits CYP450)

Summary of Short Notes (from the list on paper):

• Chloroquine kills erythrocytic (blood) stage schizonts - eliminates the acute attack
• But it has NO activity against hypnozoites (dormant liver stage of P. vivax)
• Primaquine is the only drug that kills hepatic hypnozoites (radical cure) and gametocytes
• Together: Chloroquine (blood stage) + Primaquine (liver stage + gametocytes) = COMPLETE cure and prevention of relapse
• Always check for G6PD deficiency before giving primaquine (can cause hemolytic anaemia)