# PHARMACOLOGY EXAM-READY ANSWERS
## MBBS 2nd Year | KD Tripathi / Rang & Dale Level
### Sections 4–5: Blood, Respiratory, TB, Hypolipidemic & CNS

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# SECTION 4: BLOOD, RESPIRATORY, TB, HYPOLIPIDEMIC

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## **Q1. Rationale of Low Dose Aspirin in Prophylaxis of MI (3 Marks)**

**Mechanism of Aspirin:**
- Aspirin irreversibly inhibits **cyclooxygenase (COX-1 and COX-2)** enzyme by acetylation of a serine residue.
- This blocks conversion of arachidonic acid → **Thromboxane A₂ (TXA₂)** in platelets and **Prostacyclin (PGI₂)** in endothelium.

**Why LOW dose (75–150 mg/day)?**
- **Platelets** lack nucleus → cannot synthesize new COX → irreversible inhibition throughout platelet lifespan (7–10 days).
- TXA₂ (platelet-derived): promotes **platelet aggregation + vasoconstriction** → pro-thrombotic.
- PGI₂ (endothelium-derived): **inhibits** platelet aggregation + vasodilates → anti-thrombotic.
- At **low doses**: COX-1 in platelets is selectively inhibited → ↓TXA₂ >> ↓PGI₂ → NET anti-platelet effect.
- At **high doses**: COX in endothelium also inhibited → ↓PGI₂ → anti-thrombotic benefit is reduced or negated.

**Clinical Rationale:**
- Low-dose aspirin reduces recurrent MI, unstable angina, TIA, and ischemic stroke.
- Used in **primary prophylaxis** (high-risk) and **secondary prophylaxis** (post-MI, post-stent).
- Dose: **75 mg/day** (UK), **81 mg/day** (USA).

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## **Q2. Name Any 3 Anti-platelet Drugs (3 Marks)**

1. **Aspirin** – irreversible COX inhibitor; ↓TXA₂ synthesis. Used in CAD, stroke prophylaxis.
2. **Clopidogrel** (P2Y₁₂ ADP receptor blocker) – irreversible inhibition of platelet ADP receptor → ↓platelet aggregation. Used in ACS, post-stent.
3. **Dipyridamole** – phosphodiesterase inhibitor → ↑cAMP in platelets → ↓aggregation; also ↑adenosine. Used in stroke prophylaxis (combined with aspirin).

**Others to know:** Ticlopidine, Prasugrel, Ticagrelor, Abciximab (GP IIb/IIIa inhibitor), Tirofiban, Eptifibatide.

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## **Q3. Name 3 Oral and 3 Parenteral Iron Preparations (3 Marks)**

**Oral Iron Preparations:**
1. **Ferrous sulphate** – most commonly used; cheap, effective; 200 mg tab (60 mg elemental Fe)
2. **Ferrous gluconate** – better tolerated; fewer GI side effects
3. **Ferrous fumarate** – high elemental iron content (33%); sustained-release forms available

**Parenteral Iron Preparations:**
1. **Iron dextran** – IM/IV; can give total dose infusion
2. **Iron sucrose (ferric sucrose)** – IV only; preferred in CKD on dialysis; safer profile
3. **Ferric carboxymaltose (Injectafer)** – IV; high single-dose possible; used in iron deficiency with intolerance to oral

**Others:** Sodium ferric gluconate complex, Low molecular weight iron dextran (LMWID)

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## **Q4. 3 Indications of Parenteral Iron Preparations (3 Marks)**

1. **Intolerance to oral iron** – severe GI side effects (nausea, vomiting, constipation, diarrhea) preventing adequate dosing.
2. **Malabsorption syndromes** – e.g., celiac disease, post-gastrectomy, Crohn's disease – oral iron not absorbed adequately.
3. **Chronic Kidney Disease (CKD) on dialysis** – rapid iron loss + impaired absorption; parenteral iron needed alongside erythropoietin therapy.

**Other indications:**
- Non-compliance with oral therapy
- Severe iron deficiency anemia where rapid repletion is needed (pre-operatively)
- Inflammatory bowel disease (oral iron worsens inflammation)

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## **Q5. Advantages of LMWH over Conventional (Unfractionated) Heparin (3 Marks)**

| Feature | LMWH (e.g., Enoxaparin) | UFH |
|---------|------------------------|-----|
| **Bioavailability (SC)** | ~90% | ~30% |
| **Half-life** | 4–6 hours | 1–2 hours |
| **Monitoring** | NOT required routinely | aPTT monitoring required |
| **Route** | SC once/twice daily | IV infusion or SC |
| **Anti-Xa:Anti-IIa ratio** | 4:1 (predictable) | 1:1 (variable) |
| **HIT risk** | Lower | Higher |
| **Osteoporosis risk** | Lower | Higher with long-term use |
| **Dose** | Weight-based, predictable | Variable, needs adjustment |
| **Renal elimination** | Yes (use caution in CRF) | Reticuloendothelial |

**Summary of Advantages of LMWH:**
- Greater bioavailability after SC injection
- Longer half-life → once or twice daily dosing (better compliance)
- No routine monitoring required (predictable kinetics)
- Lower incidence of HIT
- Lower risk of osteoporosis
- Can be used at home (outpatient DVT treatment)

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## **Q6. Treatment of Heparin Overdosage with Rationale (3 Marks)**

**Treatment: Protamine Sulfate**

**Dose:** 1 mg protamine neutralizes 100 units of heparin
- IV slow injection (max 50 mg in 10 minutes to avoid hypotension)
- Only half the dose if > 30 minutes since heparin given (due to heparin metabolism)

**Rationale:**
- Protamine is a **strongly basic (positively charged)** peptide derived from salmon sperm.
- Heparin is **strongly acidic (negatively charged)** – a sulfated mucopolysaccharide.
- They form a stable **ion-pair complex** which has NO anticoagulant activity → heparin effect is neutralized.
- Complex is then cleared by the reticuloendothelial system.

**Important notes:**
- Excess protamine itself has anticoagulant effect → avoid over-dosing.
- Protamine only **partially neutralizes LMWH** (neutralizes anti-IIa activity; anti-Xa activity not fully reversed).
- Protamine does **NOT reverse fondaparinux**.
- Also used after cardiopulmonary bypass to reverse heparin.

**Additional measures:**
- Stop heparin infusion
- Monitor aPTT
- Fresh frozen plasma if severe hemorrhage

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## **Q7. Treatment of Warfarin Overdosage with Rationale (3 Marks)**

**Treatment depends on severity:**

**A. Minor/Asymptomatic elevated INR (INR 3–5, no bleeding):**
- **Withhold warfarin** for 1–2 doses
- Repeat INR; restart at lower dose

**B. INR 5–9, no significant bleeding:**
- **Withhold warfarin**
- Give **oral Vitamin K₁ (phytomenadione) 1–2.5 mg** orally

**C. INR > 9 or any significant bleeding:**
- **Parenteral Vitamin K₁** (2.5–10 mg IV slow injection)
- **Fresh Frozen Plasma (FFP)** or **Prothrombin Complex Concentrate (PCC)** for immediate reversal

**D. Life-threatening bleeding:**
- **IV Vitamin K₁ + PCC** (or FFP) → rapid reversal
- **Recombinant Factor VIIa** in extreme cases

**Rationale:**
- Warfarin blocks **Vitamin K epoxide reductase** → prevents recycling of Vitamin K → ↓synthesis of factors II, VII, IX, X, protein C, S.
- Vitamin K₁ (exogenous) provides substrate for Vitamin K-dependent carboxylase via an alternative reductase pathway → restores factor synthesis.
- **Delay of 6–12 hours** for Vitamin K effect (time needed for new factor synthesis).
- PCC/FFP provides **immediate** preformed clotting factors → rapid hemostasis.

**Note:** Vitamin K given IV must be given slowly to avoid anaphylactoid reactions.

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## **Q8. Name 2 Anti-fibrinolytics and Their Uses (3 Marks)**

**1. Tranexamic Acid (TXA)**
- **MOA:** Competitive inhibitor of plasminogen activator; prevents binding of plasminogen to fibrin → inhibits fibrinolysis.
- **Uses:**
  - Trauma-associated hemorrhage (within 3 hours – CRASH-2 trial)
  - Post-partum hemorrhage
  - Menorrhagia (heavy menstrual bleeding)
  - Dental extraction in hemophiliacs
  - Surgery (cardiac, orthopedic) – reduces transfusion requirement
  - Hereditary angioedema (prophylaxis)

**2. Aminocaproic Acid (ε-aminocaproic acid)**
- **MOA:** Synthetic lysine analog; competitively inhibits plasminogen → ↓fibrinolysis.
- **Uses:**
  - Control of bleeding after fibrinolytic therapy overdose
  - Hemophilia (adjunct)
  - Subarachnoid hemorrhage (prevent re-bleeding)
  - Hematuria
  - Post-surgical bleeding

**3. Aprotinin** (also mentioned – serine protease inhibitor; withdrawn in many countries due to renal toxicity; used in cardiac surgery)

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## **Q9. 3 Contraindications to Thrombolytic Therapy (3 Marks)**

**Absolute Contraindications:**
1. **Prior intracranial hemorrhage (ICH)** at any time – risk of catastrophic re-bleeding
2. **Ischemic stroke within 3 months** – risk of hemorrhagic transformation
3. **Active internal bleeding** (excluding menstruation) – will exacerbate uncontrolled hemorrhage
4. **Structural cerebral vascular lesion** (e.g., AVM, aneurysm)
5. **Intracranial neoplasm** (primary or metastatic)
6. **Suspected aortic dissection**
7. **Significant closed-head trauma or facial trauma within 3 months**

**Relative Contraindications:**
- Severe uncontrolled hypertension (BP > 180/110 mmHg)
- History of chronic, severe, poorly controlled hypertension
- Recent major surgery (< 3 weeks)
- Active peptic ulcer disease
- Current anticoagulant use with elevated INR
- Traumatic or prolonged CPR (> 10 min)
- Pregnancy
- Non-compressible vascular punctures

*(For exam: state any 3 absolute contraindications with brief rationale)*

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## **Q10. Advantages of Inhalational Steroids over Systemic Steroids in Asthma (3 Marks)**

| Advantage | Inhalational Steroids | Systemic Steroids |
|-----------|----------------------|------------------|
| **Local action** | Direct delivery to airways → high local concentration | Systemic distribution required |
| **Systemic side effects** | Minimal (small amount absorbed) | Multiple, serious |
| **HPA axis suppression** | Minimal at normal doses | Significant |
| **Long-term safety** | Safe for long-term use | Not suitable for long-term |
| **Dose required** | Much lower (micrograms) | Much higher (mg) |
| **Onset** | Days–weeks for full effect | Hours |
| **Osteoporosis risk** | Low | High |
| **Immunosuppression** | Minimal | Significant |

**Drugs:** Beclomethasone, Budesonide, Fluticasone, Mometasone, Ciclesonide

**Specific Advantages:**
- No Cushingoid features at standard doses
- No significant growth retardation in children at low-moderate doses
- No adrenal suppression at low doses
- Local side effects only: **oral candidiasis** (prevented by spacer/rinsing mouth) and **dysphonia**
- **First-line controller** therapy in persistent asthma

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## **Q11. Rationale of Using Sodium Cromoglycate in Asthma (3 Marks)**

**Drug:** Sodium cromoglycate (Cromolyn sodium)

**Classification:** Mast cell stabilizer / Chromone derivative

**Mechanism of Action:**
- Stabilizes **mast cell membrane** by blocking calcium channels → prevents degranulation.
- Inhibits release of histamine, leukotrienes (LTC4, LTD4), prostaglandins, and other inflammatory mediators from mast cells.
- Also inhibits sensory nerve activation → blocks early AND late asthmatic responses.
- Inhibits eosinophil and neutrophil recruitment.

**Rationale of Use:**
- Acts **prophylactically** (not useful during acute attack).
- Prevents **allergen-induced** and **exercise-induced** bronchoconstriction.
- No direct bronchodilator effect → must be used regularly.
- Especially effective in **atopic (extrinsic/allergic) asthma** in children.
- Very **safe profile** – minimal systemic absorption, no systemic side effects.
- Used as **prophylactic/preventive** therapy in mild persistent asthma.
- Can be used before exercise to prevent exercise-induced bronchoconstriction.

**Limitations:**
- Must be inhaled regularly (4 times/day)
- Less effective than inhaled corticosteroids → now less commonly used
- Only preventive – has NO role in acute attack management

---

## **Q12. Name 3 Mucolytic Drugs (3 Marks)**

1. **Acetylcysteine (N-acetylcysteine, NAC)**
   - Breaks disulfide bonds in mucus glycoproteins → reduces viscosity
   - Inhaled or oral; also antidote for paracetamol poisoning
   - Used in COPD, cystic fibrosis, bronchiectasis

2. **Bromhexine**
   - Breaks down mucopolysaccharide fibers in sputum → liquefies mucus
   - Also stimulates surfactant production
   - Oral administration; used in productive cough

3. **Ambroxol**
   - Active metabolite of bromhexine
   - Stimulates surfactant secretion; reduces mucus viscosity
   - Used in COPD, asthma, neonatal respiratory distress

**Others:** Carbocisteine (S-carboxymethylcysteine), Dornase alfa (DNase for cystic fibrosis), Hypertonic saline

---

## **Q13. Name 3 Drugs Used in Dry Cough (3 Marks)**

*(Antitussives/Cough suppressants)*

1. **Codeine**
   - Opioid; acts centrally on cough center in medulla → raises threshold for cough reflex
   - Dose: 10–20 mg 4–6 hourly
   - Side effects: constipation, sedation, dependence (avoid in children)

2. **Dextromethorphan**
   - Non-opioid antitussive; NMDA receptor antagonist + sigma receptor agonist
   - Acts centrally; no analgesic or addictive properties
   - Preferred in children; available OTC

3. **Noscapine (Narcotine)**
   - Non-opioid antitussive; peripheral action; relaxes bronchial smooth muscle
   - No analgesic effect; safe in pregnancy
   - Used in mild-moderate dry cough

**Others:** Pholcodine, Benzonatate (peripheral – anesthetizes stretch receptors), Butamirate

---

## **Q14. Management of Acute Iron Intoxication (5 Marks)**

**Stages of Iron Toxicity:**
1. **0–6 hours:** Acute GI toxicity (nausea, vomiting, hematemesis, abdominal pain, diarrhea)
2. **6–12 hours:** Apparent clinical improvement ("latent phase") – deceptive
3. **12–24 hours:** Systemic toxicity – metabolic acidosis, hepatotoxicity, cardiovascular collapse, coagulopathy, hypoglycemia
4. **2–6 weeks:** Late – pyloric stenosis, GI scarring

**Lethal dose:** > 250 mg elemental iron/kg

**Management:**

**A. Initial Resuscitation:**
- IV fluids for dehydration/hypotension
- Correct acid-base and electrolyte disturbances
- Blood glucose monitoring
- Coagulation profile

**B. Decontamination:**
- **Gastric lavage** with sodium bicarbonate (forms insoluble ferrous carbonate) – if < 1 hour
- **Whole bowel irrigation** with polyethylene glycol – especially if X-ray shows iron tablets in GI tract
- Activated charcoal: **NOT effective** for iron (does not bind metals)

**C. Specific Antidote – Desferrioxamine (Deferoxamine):**
- **MOA:** Iron-specific chelating agent → binds free ferric iron (Fe³⁺) → forms ferrioxamine complex → excreted in urine (turns urine orange-red/"vin rosé")
- **Indication:** Serum iron > 300–350 μg/dL OR symptomatic toxicity (metabolic acidosis, altered consciousness, persistent vomiting)
- **Dose:** IV infusion 15 mg/kg/hour (max 6 g/day)
- Duration: Until urine clears or serum iron normalizes
- **Side effects:** Hypotension if given rapidly; pulmonary toxicity with prolonged use; Yersinia enterocolitica infections (iron provides growth medium for this organism)

**D. Supportive Treatment:**
- Treat metabolic acidosis with sodium bicarbonate
- Liver function support
- Monitor blood glucose (hypoglycemia common)
- Treat shock with fluids, vasopressors if needed
- Dialysis not effective for iron removal but may help uremia from renal failure

**E. Monitoring:**
- Serum iron levels every 4–6 hours
- ABG for metabolic acidosis
- LFT, coagulation, glucose

---

## **Q15. Parenteral Iron Preparations (5 Marks)**

**Indications for Parenteral Iron:**
- Intolerance/non-compliance with oral iron
- Malabsorption (gastrectomy, celiac, IBD)
- CKD on dialysis + EPO therapy
- Need for rapid iron repletion
- Active IBD (oral iron worsens inflammation)

**Preparations:**

### 1. Iron Dextran
- **Type:** High MW or Low MW complexes
- **Route:** IV or deep IM (Z-track technique)
- **Advantage:** Can give total-dose infusion (TDI)
- **Side effects:** Anaphylaxis (most common with this preparation); test dose mandatory; local staining (IM)
- **Monitoring:** Test dose required before full infusion

### 2. Iron Sucrose (Ferric Sucrose / Venofer)
- **Type:** Ferric hydroxide sucrose complex
- **Route:** IV only (infusion or slow bolus)
- **Advantage:** Very low anaphylaxis risk; widely used in CKD/dialysis
- **Side effects:** Hypotension, cramps, metallic taste; extravasation causes skin discoloration
- **Monitoring:** No test dose required in most guidelines

### 3. Ferric Carboxymaltose (Ferinject)
- **Route:** IV rapid infusion
- **Advantage:** Large single dose possible (up to 1000 mg/infusion); no test dose required
- **Side effects:** Hypophosphatemia (notable side effect), headache, nausea, hypertension
- **Use:** Post-partum iron deficiency anemia, CKD, pre-surgical optimization

### 4. Sodium Ferric Gluconate Complex (Ferrlecit)
- **Route:** IV
- **Use:** CKD/hemodialysis patients
- **Advantage:** Lower allergic reactions than iron dextran

### 5. Low Molecular Weight Iron Dextran (LMWID)
- Safer than HMW iron dextran
- Lower anaphylaxis risk
- Can give total dose infusion

**Calculation of Iron Dose (Ganzoni Formula):**
- Total iron deficit (mg) = Weight (kg) × (Target Hb – Actual Hb) × 2.4 + Iron stores (500 mg)

**Common Adverse Effects of All Parenteral Iron:**
- Anaphylaxis / anaphylactoid reactions (most serious)
- Hypotension
- Chest pain, dyspnea
- Arthralgia, myalgia
- Local: pain, phlebitis, skin discoloration
- Iron overload (hemosiderosis) if excessive dosing

---

## **Q16. Management of Megaloblastic Anemia (5 Marks)**

**Definition:** Anemia due to impaired DNA synthesis → large, immature RBCs (megaloblasts) in bone marrow.

**Causes:**
1. **Vitamin B₁₂ deficiency** – pernicious anemia, strict veganism, gastrectomy, malabsorption
2. **Folate deficiency** – poor diet (alcoholics, pregnancy), malabsorption, increased demand, drugs (methotrexate, phenytoin)
3. **Drug-induced** – methotrexate, hydroxyurea, azathioprine, trimethoprim

**Investigations:**
- CBC: Macrocytic anemia (MCV > 100 fL), pancytopenia in severe cases
- Peripheral smear: Oval macrocytes, hypersegmented neutrophils (> 5 lobes)
- Bone marrow: Megaloblasts
- Serum B₁₂ and folate levels
- Schilling test (if pernicious anemia suspected)
- Anti-intrinsic factor antibodies, anti-parietal cell antibodies

**Treatment:**

### A. Vitamin B₁₂ Deficiency:
- **Cyanocobalamin (Vitamin B₁₂):** 1000 μg IM daily × 7 days → weekly × 4 weeks → monthly for life (pernicious anemia)
- **Hydroxocobalamin:** preferred in UK (longer-acting)
- **Oral B₁₂ (1000–2000 μg/day):** effective even in pernicious anemia due to passive diffusion (1% absorbed without IF)
- **Sublingual/intranasal B₁₂:** available options

### B. Folate Deficiency:
- **Folic acid 5 mg/day orally × 4 months** (then identify/correct cause)
- Folic acid **supplementation in pregnancy** (400 μg/day preconception → prevents neural tube defects)
- Megaloblastic anemia of pregnancy: 5 mg/day

### C. Drug-induced (Methotrexate):
- **Folinic acid (Leucovorin/Citrovorum factor)** – bypasses DHF reductase block → rescues normal cells
- Used as "leucovorin rescue" after high-dose methotrexate

**CRITICAL POINT:** Never give folate alone in B₁₂ deficiency without replacing B₁₂:
- Will correct hematological picture but neurological damage (subacute combined degeneration of spinal cord) will progress → irreversible damage.
- Always ensure B₁₂ is adequate before or with folate supplementation.

**Supportive:**
- Treat underlying cause
- Blood transfusion if severely symptomatic (Hb < 7 g/dL)
- Iron supplementation if concurrent IDA (mixed deficiency)
- Folic acid for hemolytic anemias, dialysis patients (increased folate demand)

---

## **Q17. Oral Iron Preparations (5 Marks)**

**Principle:** Ferrous (Fe²⁺) salts are better absorbed than Ferric (Fe³⁺) salts. Absorption occurs in duodenum and upper jejunum.

**Preparations:**

### 1. Ferrous Sulphate (Most commonly used)
- **Elemental iron content:** 60 mg per 200 mg tablet (30%)
- **Dose:** 200 mg 2–3 times daily (→ 120–180 mg elemental iron/day)
- **Advantage:** Cheap, effective, widely available
- **Side effects:** Nausea, vomiting, constipation/diarrhea, black stools, epigastric pain
- Reduce with food (though absorption decreases by 30–50%)

### 2. Ferrous Gluconate
- **Elemental iron content:** 37 mg per 300 mg tablet (12%)
- Better GI tolerability than sulphate
- Dose: 300 mg 2–3 times daily

### 3. Ferrous Fumarate
- **Elemental iron content:** 65 mg per 200 mg tablet (33%) – highest
- Slow-release forms available
- Better tolerated; suitable for sustained-release formulation

### 4. Ferrous Succinate / Ferrous Glycine Sulphate
- Chelated forms with better tolerance
- Used when GI intolerance to other salts

### 5. Polysaccharide-Iron Complex (e.g., Ferronyl)
- Non-ionic form; absorbed via different pathway
- Fewer GI side effects; no black stools

**Factors INCREASING oral iron absorption:**
- Vitamin C (ascorbic acid) – keeps iron in ferrous form; forms soluble chelate
- Acidic gastric pH
- Iron deficiency state (increased mucosal uptake)
- Meat proteins (heme iron)
- Empty stomach

**Factors DECREASING oral iron absorption:**
- Antacids, PPIs (↑pH → impaired reduction)
- Tetracyclines, fluoroquinolones (chelation → impaired absorption and reduced antibiotic efficacy)
- Phytates (whole grains), tannins (tea, coffee)
- Calcium, phosphates
- High iron stores (hepcidin-mediated)

**Therapeutic Response:**
- Reticulocytosis: peaks 7–10 days
- Hb rises ~1 g/dL/week
- Hb normalizes in 6–8 weeks
- Continue treatment for 3–6 months after Hb normalizes to replenish iron stores

**Side effects:**
- GI: nausea, vomiting, constipation/diarrhea, cramping
- Black tarry stools (harmless – due to iron sulphide)
- Liquid preparations may stain teeth (dilute and use straw)
- Accidental overdose in children → serious toxicity

---

## **Q18. Direct Thrombin Inhibitors (5 Marks)**

**Classification:**

### A. Parenteral Direct Thrombin Inhibitors:
1. **Hirudin** (lepirudin) – natural (from leeches), recombinant available
2. **Bivalirudin** – synthetic analog of hirudin; short-acting
3. **Argatroban** – small synthetic molecule; hepatic metabolism

### B. Oral Direct Thrombin Inhibitors (NOACs):
1. **Dabigatran etexilate** (Pradaxa) – prodrug; most widely used oral DTI

**Mechanism of Action:**
- Directly inhibit **thrombin (Factor IIa)** without requiring antithrombin as cofactor.
- Block both **free thrombin** and **clot-bound thrombin** (unlike heparin which cannot inactivate clot-bound thrombin).
- Inhibit thrombin-mediated: fibrin formation, platelet activation, factors V, VIII activation, protein C activation.

**Advantages over Heparin/Warfarin:**
- Work in the absence of antithrombin
- Can inhibit clot-bound thrombin
- No HIT (no platelet factor 4 interaction)
- Predictable pharmacokinetics → no routine monitoring
- Fixed dosing

**Dabigatran (Oral DTI) Details:**
- **Prodrug** → dabigatran etexilate → converted by esterase to active dabigatran
- **Bioavailability:** ~6% (low, but predictable)
- **Half-life:** 12–17 hours
- **Renal excretion:** 80% → CAUTION in renal impairment
- **Reversal agent:** **Idarucizumab (Praxbind)** – humanized antibody fragment; binds dabigatran with high affinity

**Clinical Uses of DTIs:**
- **Argatroban:** Treatment of **HIT** (Heparin-Induced Thrombocytopenia)
- **Bivalirudin:** Percutaneous coronary intervention (PCI); alternative to heparin in catheterization lab
- **Dabigatran:** 
  - Prevention of stroke/systemic embolism in **non-valvular atrial fibrillation** (RE-LY trial)
  - Treatment/prevention of DVT and PE
  - Prevention of VTE after hip/knee replacement surgery
- **Hirudin (lepirudin):** HIT; now largely replaced by argatroban

**Adverse Effects:**
- **Bleeding** (major risk)
- Dabigatran: dyspepsia, GI bleeding (higher than warfarin for GI bleeds); hepatotoxicity (ximelagatran – withdrawn)
- Argatroban: elevated LFTs (hepatic metabolism)

**Monitoring:**
- Ecarin clotting time (ECT) or dilute thrombin time – for dabigatran monitoring if needed
- aPTT: qualitative guide only

---

## **Q19. Heparin: Mechanism of Action, Therapeutic Uses & Adverse Effects (5 Marks)**

**Chemistry:**
- Heterogeneous mixture of sulfated mucopolysaccharides (glycosaminoglycans)
- MW: 5,000–30,000 Da
- Isolated from bovine lung or porcine intestinal mucosa

**Mechanism of Action:**
- Heparin binds to **antithrombin (AT-III)** via a specific pentasaccharide sequence.
- This conformational change in AT-III **accelerates the rate of inhibition** of activated clotting factors by 1000-fold.
- **Factors inhibited:** Thrombin (IIa), Xa, IXa, XIa, XIIa – especially IIa and Xa.
- For thrombin inhibition: both thrombin AND AT-III must bind heparin (requires longer chain, MW > 5000).
- For factor Xa inhibition: only AT-III needs to bind heparin (pentasaccharide sufficient).
- **Net effect:** ↓Thrombin → ↓Fibrin formation → ↓Clot formation.
- Acts within seconds (immediate anticoagulation).

**Pharmacokinetics:**
- NOT absorbed orally (large, charged molecule)
- Given IV or SC (never IM – risk of hematoma)
- Half-life: 30–90 minutes (dose-dependent)
- Metabolized by heparinase in liver/reticuloendothelial system
- Does NOT cross placenta (safe in pregnancy for anticoagulation)

**Therapeutic Uses:**
1. **DVT and PE** – treatment and prophylaxis
2. **Unstable angina / NSTEMI / STEMI** (with thrombolytics)
3. **Atrial fibrillation** – prevention of thrombus formation
4. **During cardiac surgery** (cardiopulmonary bypass) – high-dose heparin
5. **Acute peripheral arterial occlusion** – bridge therapy
6. **Hemodialysis** – prevent clotting in extracorporeal circuits
7. **Prevention of post-operative DVT** – low-dose SC heparin
8. **Disseminated intravascular coagulation (DIC)** – controversial
9. **Maintaining IV catheter patency** (heparin lock – low doses)

**Monitoring:**
- UFH: **aPTT** (target 1.5–2.5 × control = 60–100 seconds)
- Anti-Xa level: 0.3–0.7 units/mL (therapeutic)

**Adverse Effects:**
1. **Bleeding** (most common and serious) – hematuria, GI bleed, ICH; treated with protamine sulfate
2. **Heparin-Induced Thrombocytopenia (HIT)**
   - **Type I:** Non-immune, mild, transient (platelet count rarely < 100,000); self-limiting within 5 days; can continue heparin
   - **Type II:** Immune-mediated; IgG antibodies against heparin-PF4 complex → platelet activation → thrombocytopenia + paradoxical thrombosis; serious; discontinue heparin immediately; use argatroban or bivalirudin
3. **Osteoporosis** – with long-term use (> 3 months); activates osteoclasts
4. **Alopecia** – reversible
5. **Hypoaldosteronism** – ↓aldosterone synthesis → hyperkalemia
6. **Hypersensitivity** – urticaria, anaphylaxis (rare)
7. **Raised transaminases** (transient, benign)
8. **Hyperlipidemia** – releases lipoprotein lipase

**Contraindications:**
- Active bleeding, HIT, hemophilia, thrombocytopenia
- Severe hypertension, intracranial hemorrhage
- Recent brain/spinal surgery
- Infective endocarditis, active TB, ulcerative lesions of GI tract

---

## **Q20. Warfarin: Mechanism of Action, Therapeutic Uses & Adverse Effects (5 Marks)**

**Chemistry:**
- Synthetic coumarin derivative; oral anticoagulant
- Racemic mixture (S-warfarin 4× more potent than R-warfarin)
- Half-life: 36–42 hours

**Mechanism of Action:**
- Inhibits **Vitamin K epoxide reductase (VKOR/VKORC1)** → blocks recycling of Vitamin K epoxide back to active Vitamin K hydroquinone.
- Result: Vitamin K-dependent clotting factors cannot be γ-carboxylated (inactive proteins – PIVKA: Proteins Induced in Vitamin K Absence).
- **Factors affected:** II (prothrombin), VII, IX, X, Protein C, Protein S.
- **Onset of action:** 8–12 hours (time to deplete existing factors).
- **Full therapeutic effect:** 3–5 days.
- Factor VII has shortest half-life (6 hours) → PT increases first.
- Factor II has longest half-life (60–72 hours) → takes longest to deplete.

**Monitoring:**
- **Prothrombin Time (PT)** expressed as **INR (International Normalized Ratio)**
- Target INR: 2–3 for most indications
- Target INR: 2.5–3.5 for mechanical heart valves, recurrent PE

**Therapeutic Uses:**
1. **Prevention of stroke in non-valvular AF** (largely replaced by NOACs)
2. **Treatment of DVT and PE** (long-term)
3. **Mechanical prosthetic heart valves** (still preferred over NOACs)
4. **Rheumatic heart disease with AF** (mitral stenosis + AF)
5. **Recurrent VTE** (secondary prevention)
6. **Prevention of systemic embolism** in dilated cardiomyopathy
7. **Antiphospholipid syndrome**

**Adverse Effects:**
1. **Bleeding** – most common/serious: ecchymoses, hematuria, GI bleed, intracranial bleed, retroperitoneal bleed
2. **Warfarin embryopathy** (if used in 1st trimester 6–9 weeks): nasal hypoplasia, stippled epiphyses, growth restriction
3. **Fetal hemorrhage** (if used in 3rd trimester/around delivery)
4. **Skin necrosis** (days 3–10 of therapy) – due to Protein C depletion (short half-life) → hypercoagulable state → dermal venous thrombosis; occurs in Protein C/S deficiency patients
5. **Purple toe syndrome** – cholesterol microembolization (rare)
6. **Alopecia**
7. **Drug interactions** (very numerous – CYP2C9 metabolism):
   - **Enhance** warfarin effect (↑INR): Amiodarone, fluconazole, metronidazole, cimetidine, erythromycin, aspirin (additive bleeding risk)
   - **Reduce** warfarin effect (↓INR): Rifampicin, barbiturates, carbamazepine, phenytoin, vitamin K (dietary)

**Contraindications:**
- Pregnancy (teratogenic in 1st trimester; hemorrhagic in 3rd)
- Active bleeding
- Severe liver/kidney disease
- Uncontrolled hypertension
- Non-compliance issues

**Reversal:** See Q7 above.

---

## **Q21. Erythropoietin (5 Marks)**

**Definition:** Glycoprotein hormone produced primarily by peritubular cells of the renal cortex; regulates erythropoiesis.

**Physiology:**
- Hypoxia → ↑EPO production → binds EPO receptors on erythroid progenitor cells → ↑proliferation and differentiation → ↑RBC production.

**Recombinant Human EPO (rHuEPO) Preparations:**
- **Epoetin alfa** (Epogen, Procrit) – IV or SC; half-life 8 hours (IV), 24 hours (SC)
- **Epoetin beta** – similar to alfa
- **Darbepoetin alfa** (Aranesp) – hyperglycosylated; half-life 25 hours → less frequent dosing
- **Methoxy PEG-epoetin beta (CERA)** – pegylated; half-life 130 hours → once monthly dosing

**Mechanism of Action:**
- Binds EPO receptor (homodimer JAK2/STAT5 pathway) on erythroid progenitors.
- ↑Proliferation + differentiation of BFU-E and CFU-E → ↑reticulocyte production → ↑mature RBCs.
- Also inhibits apoptosis of erythroid progenitors.

**Therapeutic Uses:**
1. **Anemia of Chronic Kidney Disease (CKD)** – most important indication; on or off dialysis
2. **Chemotherapy-induced anemia** in cancer patients
3. **Anemia in HIV patients** on zidovudine
4. **Pre-operative blood donation augmentation** (autologous blood banking)
5. **Reduction of allogeneic blood transfusions** in elective surgery (orthopedic, cardiac)
6. **Anemia of prematurity**
7. **Myelodysplastic syndrome** (some cases)

**Dose:**
- CKD: 50–300 units/kg SC 3 times/week (target Hb 10–12 g/dL)
- Darbepoetin: once weekly or once every 2 weeks

**Requirements for EPO to work:**
- Adequate **iron stores** (serum ferritin > 100 ng/mL, TSAT > 20%)
- Adequate B₁₂ and folate
- Absence of infection/inflammation (CRP elevation reduces EPO response)

**Adverse Effects:**
1. **Hypertension** – most common; occurs in 25–35%; mechanism: ↑blood viscosity, ↑peripheral resistance
2. **Thrombotic events** – increased risk; higher if Hb overcorrected (> 12 g/dL in CKD)
3. **Flu-like symptoms** – especially with IV administration
4. **Seizures** – risk in CKD (related to hypertension)
5. **Pure Red Cell Aplasia (PRCA)** – rare but serious; anti-EPO antibodies (mainly with subcutaneous epoetin alfa); aplastic crisis
6. **Iron deficiency** – iron is rapidly used up; must supplement iron
7. **Tumor growth** – EPO receptors on some tumor cells; concern in cancer patients
8. **Misuse in sports** (doping) – increases RBC mass → enhanced oxygen carrying capacity

---

## **Q22. Urokinase: Mechanism of Action, Therapeutic Uses and Adverse Effects (5 Marks)**

**Classification:** Thrombolytic agent (second generation); direct plasminogen activator

**Chemistry:**
- Serine protease; originally isolated from urine/kidney cells; now produced by recombinant technology
- MW: 54,000 Da; two-chain form (high and low MW forms)

**Mechanism of Action:**
- **Directly converts plasminogen → plasmin** (does NOT require fibrin for activation – non-fibrin-selective).
- Plasmin: broad-spectrum serine protease that degrades fibrin, fibrinogen, factors V, VIII, and other proteins.
- Activates both fibrin-bound and circulating plasminogen → systemic fibrinogenolysis (lytic state).
- Since it's not fibrin-specific, it causes a **systemic lytic state** → higher bleeding risk compared to fibrin-specific agents (tPA, tenecteplase).

**Pharmacokinetics:**
- Given **IV only** (not oral)
- Half-life: ~20 minutes
- Cleared by liver

**Therapeutic Uses:**
1. **Acute massive PE** – IV infusion (4400 IU/kg loading dose, then 4400 IU/kg/hour for 12 hours)
2. **DVT** – catheter-directed thrombolysis for extensive iliofemoral DVT
3. **Arterial thrombosis** – acute peripheral arterial occlusion
4. **Catheter-directed thrombolysis** – clearing blocked IV catheters (lower doses)
5. **Central venous catheter occlusion** – instillation of urokinase to restore patency
6. **Acute MI** – historically used; largely replaced by streptokinase, tPA

**Advantages over Streptokinase:**
- Not antigenic (no antibodies formed → can repeat use)
- Does not cause allergic reactions
- Higher fibrinolytic activity per unit

**Adverse Effects:**
1. **Bleeding** – major risk; intracranial hemorrhage (most serious ~1%), GI bleed, retroperitoneal bleed
2. **Fever, chills** (less than streptokinase)
3. **Reperfusion arrhythmias** (after coronary reperfusion)
4. **Hypotension** (mild)
5. No **allergic reactions** (unlike streptokinase)
6. **Nausea, vomiting**

**Contraindications:** See Q9 above.

---

## **Q23. Antiplatelet Drugs (5 Marks)**

**Classification by Mechanism:**

### 1. COX Inhibitors:
- **Aspirin** – irreversible COX-1/2 inhibitor → ↓TXA₂
- **Indobufen** – reversible; used post-bypass

### 2. ADP (P2Y₁₂) Receptor Blockers:
- **Thienopyridines** (prodrugs requiring hepatic activation):
  - **Ticlopidine** (1st generation – withdrawn due to TTP risk)
  - **Clopidogrel** (2nd generation – most widely used; active metabolite formed via CYP2C19)
  - **Prasugrel** (3rd generation – more potent, faster onset; not for prior TIA/stroke)
- **Non-thienopyridines** (direct-acting, reversible):
  - **Ticagrelor** – reversible P2Y₁₂ blocker; no hepatic activation needed; fastest onset; causes dyspnea (unique side effect)
  - **Cangrelor** – IV formulation; ultra-short acting (half-life 3–5 min); used in PCI

### 3. Phosphodiesterase Inhibitors:
- **Dipyridamole** – inhibits PDE → ↑cAMP in platelets + ↑adenosine (blocks adenosine reuptake) → ↓platelet aggregation + vasodilation
  - Uses: Stroke prevention (with aspirin – Aggrenox), cardiac stress testing
- **Cilostazol** – PDE3 inhibitor; also vasodilator; used in peripheral arterial disease (intermittent claudication)

### 4. Glycoprotein IIb/IIIa (αIIbβ3) Inhibitors – most potent antiplatelet agents:
- **Abciximab (ReoPro)** – chimeric monoclonal antibody fragment; irreversible; long platelet effect (days)
- **Tirofiban (Aggrastat)** – non-peptide; reversible; short-acting
- **Eptifibatide (Integrilin)** – cyclic peptide; reversible
- Uses: ACS with PCI; high-risk PCI; refractory unstable angina
- Side effects: Thrombocytopenia, bleeding

### 5. Protease-Activated Receptor-1 (PAR-1) Antagonists (Thrombin receptor blockers):
- **Vorapaxar** – PAR-1 antagonist; reduces platelet activation by thrombin; used as add-on in stable CAD; contraindicated in prior stroke/TIA

### 6. Other:
- **Prostacyclin (PGI₂) analogs:** Epoprostenol, Iloprost – used in PAH, critical limb ischemia

**Clinical Uses Summary:**
| Indication | Drug(s) |
|------------|---------|
| Stable CAD | Aspirin |
| ACS (STEMI/NSTEMI) | Aspirin + Clopidogrel/Ticagrelor (DAPT) |
| Post-coronary stent | Aspirin + Clopidogrel/Prasugrel/Ticagrelor (DAPT × 12 months) |
| Ischemic stroke/TIA | Aspirin ± Clopidogrel; or Aspirin + Dipyridamole |
| Peripheral arterial disease | Aspirin or Clopidogrel |
| PCI | GP IIb/IIIa inhibitors |
| Intermittent claudication | Cilostazol |

---

## **Q24. Atorvastatin: Mechanism of Action, Therapeutic Uses and Adverse Effects (5 Marks)**

**Class:** Statin / HMG-CoA Reductase Inhibitor

**Mechanism of Action:**
- **Competitive inhibitor of HMG-CoA reductase** – the rate-limiting enzyme in cholesterol biosynthesis (converts HMG-CoA → mevalonate).
- ↓Intracellular cholesterol synthesis in hepatocytes.
- ↑LDL receptor expression on hepatocytes (upregulation) → ↑LDL clearance from blood.
- **Net effect:**
  - ↓Total cholesterol (20–60%)
  - ↓LDL-C (major effect – 35–60%)
  - ↓VLDL and triglycerides (moderate)
  - ↑HDL (modest: 5–15%)

**Pleiotropic Effects (beyond lipid lowering):**
- Anti-inflammatory (↓CRP, ↓cytokines)
- Plaque stabilization (↓lipid core, ↑fibrous cap)
- Anti-thrombotic (↓platelet aggregation, ↑tPA, ↓PAI-1)
- Endothelial function improvement (↑NO production)
- Antioxidant

**Pharmacokinetics:**
- Oral; active HMG-CoA reductase inhibitor (unlike lovastatin/simvastatin which are prodrugs)
- Hepatic metabolism via CYP3A4
- Half-life: 14 hours (longest half-life among statins → effective even with non-daily dosing, but given once daily)
- Can be given at any time (unlike other statins which are best given at night)

**Therapeutic Uses:**
1. **Primary hypercholesterolemia / Mixed dyslipidemia** (Type IIa, IIb)
2. **Prevention of cardiovascular events** – primary and secondary prevention of MI, stroke, unstable angina
3. **Coronary artery disease** – reduces mortality and morbidity (ASCOT, CARDS, 4S, HPS trials)
4. **Diabetes mellitus + dyslipidemia** (reduces CV risk independent of baseline LDL)
5. **Post-ACS** – high-intensity statin started immediately (atorvastatin 80 mg/day)
6. **Hypertriglyceridemia** (moderate effect)
7. **Metabolic syndrome / Obesity with dyslipidemia**

**Dosing:** 10–80 mg once daily

**Adverse Effects:**
1. **Myopathy** – most important; ranges from:
   - Asymptomatic ↑CK to myalgia, myositis → **Rhabdomyolysis** (rare but serious: myoglobinuria, acute renal failure)
   - Risk factors: High dose, CYP3A4 inhibitors (clarithromycin, itraconazole, cyclosporine), hypothyroidism, renal failure
   - Fibrates + statins → ↑myopathy risk
2. **Hepatotoxicity** – transaminase elevation (↑LFT) in 1–3%; dose-related; reversible on stopping; monitor LFTs
3. **New-onset diabetes mellitus** – all statins associated with modest increase (~10%) in diabetes risk; risk-benefit still overwhelmingly favors statin use
4. **GI disturbances** – nausea, constipation, dyspepsia (mild)
5. **Headache, insomnia** (mild CNS effects)
6. **Cognitive effects** – transient memory impairment (rare, reversible)

**Drug Interactions:**
- CYP3A4 inhibitors → ↑atorvastatin levels → ↑myopathy risk: Azole antifungals, macrolides, HIV protease inhibitors, grapefruit juice
- Fibrates (gemfibrozil) → ↑myopathy risk
- Cholestyramine → ↓atorvastatin absorption (give 2 hours apart)

**Contraindications:**
- Active liver disease
- Pregnancy and lactation (inhibits cholesterol synthesis needed for fetal development – Category X)
- Myopathy/rhabdomyolysis history

---

## **Q25. Salbutamol: Mechanism of Action, Therapeutic Uses & Adverse Effects (5 Marks)**

**Class:** Selective β₂-adrenoceptor agonist (Short-acting β₂ agonist – SABA)

**Mechanism of Action:**
- Selectively stimulates **β₂ adrenergic receptors** (Gs-coupled) in bronchial smooth muscle.
- ↑cAMP via adenylyl cyclase activation → activates PKA → phosphorylation of myosin light chain kinase (MLCK) → smooth muscle relaxation → **bronchodilation**.
- Also:
  - ↓Mast cell degranulation (reduces mediator release)
  - ↑Mucociliary clearance
  - ↑Surfactant production
  - Uterine relaxation (tocolysis)
  - Skeletal muscle tremor (β₂ in muscle)

**Pharmacokinetics:**
- Inhalation: onset 5 minutes, duration 4–6 hours
- Oral: longer onset, more systemic effects
- MDI, DPI, nebulization, oral, IV

**Therapeutic Uses:**
1. **Acute bronchospasm/Asthma attack** – drug of choice for immediate bronchodilation ("rescue inhaler")
2. **COPD** – bronchodilation (less responsive than asthma)
3. **Status asthmaticus** – nebulized salbutamol (repeated doses or continuous)
4. **Exercise-induced bronchoconstriction** (prophylaxis: 2 puffs 15 min before exercise)
5. **Hyperkalemia** – IV salbutamol shifts K⁺ into cells (β₂ → Na/K ATPase stimulation)
6. **Premature labor (Tocolysis)** – IV salbutamol to delay preterm delivery (off-label in many countries)
7. **Nocturnal asthma** – not first-line (LABA preferred for nocturnal symptoms)

**Adverse Effects:**
1. **Tremor** (most common) – fine tremor of hands and fingers (β₂ in skeletal muscle)
2. **Tachycardia, palpitations** – direct β₁ (minor) + reflex tachycardia from peripheral vasodilation (β₂)
3. **Hypokalemia** – β₂ stimulation → K⁺ entry into cells; clinically significant with high doses/IV use
4. **Restlessness, anxiety, headache** (CNS effects)
5. **Paradoxical bronchospasm** – rare; inhaled cold propellant/aerosol can trigger
6. **Hyperglycemia** – glycogenolysis (especially in diabetics)
7. **Decreased arterial pO₂** – pulmonary vasodilation → ↑V/Q mismatch in asthma (transient)
8. **Tolerance/down-regulation** of β₂ receptors with overuse → reduced bronchodilator response

**Drug Interactions:**
- β-blockers (especially non-selective): antagonize bronchodilator effect; contraindicated in asthma
- Theophylline + salbutamol: additive effect; ↑tachycardia risk
- MAOIs, TCAs: ↑cardiovascular effects

**Long-acting β₂ Agonists (LABAs):** Salmeterol, Formoterol, Indacaterol – used for maintenance, NOT rescue therapy. Never use LABA without ICS in asthma.

---

## **Q26. Inhalational Corticosteroids (5 Marks)**

**Drugs:** Beclomethasone dipropionate (BDP), Budesonide, Fluticasone propionate, Mometasone furoate, Ciclesonide, Flunisolide

**Mechanism of Action:**
- Enter cells → bind cytoplasmic **glucocorticoid receptors (GR)**.
- GR-steroid complex translocates to nucleus → binds glucocorticoid response elements (GRE).
- **Genomic effects (anti-inflammatory):**
  - ↓Transcription of pro-inflammatory cytokines (IL-1, IL-2, IL-4, IL-5, TNF-α)
  - ↓Arachidonic acid release (↓PLA₂ via lipocortin)
  - ↓Synthesis of prostaglandins, leukotrienes
  - ↓Inflammatory cell recruitment (eosinophils, mast cells, macrophages)
  - ↓Bronchial hyperreactivity
  - ↑β₂ receptor expression (sensitization to bronchodilators)
- **Non-genomic effects:** Rapid membrane effects (minutes)

**Therapeutic Uses:**
1. **Persistent asthma (mild, moderate, severe)** – first-line controller therapy
2. **COPD** with frequent exacerbations (combined with LABA – ICS+LABA inhalers: Seretide, Symbicort)
3. **Allergic rhinitis** (intranasal formulations)
4. **Nasal polyps** – topical intranasal steroids reduce polyp size
5. **Eosinophilic bronchitis**

**Dose Equivalences (approximate):**
- Low dose: BDP 100–200 μg/day
- Medium dose: BDP 200–500 μg/day
- High dose: BDP > 500 μg/day

**Advantages over Systemic Steroids** (see Q10):
- Minimal systemic absorption at standard doses
- High local bioavailability
- Rapid local effects
- Safe for long-term use

**Adverse Effects:**

*Local (most common):*
1. **Oral candidiasis (thrush)** – Candida albicans overgrowth in oropharynx; prevented by:
   - Rinsing mouth after each use
   - Using spacer device with MDI
2. **Dysphonia (hoarseness)** – adductor muscle myopathy; dose-related; usually reversible
3. **Reflex cough, bronchospasm** (paradoxical) with some propellants

*Systemic (at high doses):*
4. **HPA axis suppression** – significant at high doses (> 800 μg BDP equivalent/day)
5. **Growth retardation** in children – at high doses; use lowest effective dose
6. **Osteoporosis** – with very high doses; ↓bone mineral density
7. **Skin thinning, bruising** – at very high doses
8. **Cataract, glaucoma** – rare

**Ciclesonide:**
- Prodrug activated in airway (by airway esterases)
- Reduced oral bioavailability → fewer local side effects
- Less systemic effect

---

## **Q27. Theophylline: Mechanism of Action, Therapeutic Uses & Adverse Effects (5 Marks)**

**Class:** Methylxanthine bronchodilator / xanthine derivative

**Mechanism of Action (Multiple mechanisms):**
1. **Phosphodiesterase (PDE) inhibition** – inhibits PDE III and IV → ↓cAMP/cGMP breakdown → ↑intracellular cAMP → bronchodilation, anti-inflammatory effects, ↑diaphragmatic contractility.
2. **Adenosine receptor antagonism** – blocks A₁ and A₂ receptors → bronchodilation (adenosine causes bronchoconstriction); also explains CNS stimulation, diuresis.
3. **↑Catecholamine release** (adrenal medulla) → indirect bronchodilation.
4. **Histone deacetylase (HDAC) activation** at low doses → anti-inflammatory; ↑corticosteroid sensitivity.
5. **Inhibition of Ca²⁺ influx** into smooth muscle.
6. **↑Diaphragm contractility** → useful in respiratory failure.

**Pharmacokinetics:**
- Oral well absorbed; IV formulation (aminophylline = theophylline + ethylenediamine, 85% theophylline)
- **Therapeutic window very narrow: 10–20 mg/L**
- Toxic at > 20 mg/L
- Half-life: 8–9 hours (wide individual variation)
- Metabolized by CYP1A2
- **Drug interactions alter clearance significantly:**
  - ↑Theophylline levels: Cimetidine, erythromycin, ciprofloxacin, zileuton, oral contraceptives
  - ↓Theophylline levels: Rifampicin, phenytoin, carbamazepine, smoking, high-protein diet

**Therapeutic Uses:**
1. **Asthma** – add-on therapy in moderate-severe asthma (3rd line after ICS+LABA); useful for nocturnal asthma
2. **COPD** – bronchodilation + ↑diaphragmatic contractility; add-on therapy
3. **Status asthmaticus** – IV aminophylline (loading dose 6 mg/kg IV over 20 min, then infusion 0.5–0.9 mg/kg/hour)
4. **Apnea of prematurity** (caffeine preferred now) – stimulates respiratory center
5. **Cheyne-Stokes respiration** – stimulates respiratory center
6. **Cor pulmonale** (with COPD) – mild diuretic effect

**Adverse Effects:**

*Dose-related (increase with serum levels):*
1. **GI effects** – nausea, vomiting, diarrhea, gastric irritation (common even at therapeutic levels)
2. **CNS stimulation** – restlessness, anxiety, insomnia, headache (at therapeutic levels)
3. **Tachycardia, palpitations** – cardiac stimulation
4. **Diuresis** – xanthine diuresis

*Toxic (serum levels > 20 mg/L):*
5. **Convulsions** (refractory, life-threatening) – can occur without prior GI/cardiac symptoms
6. **Severe tachyarrhythmias** – ventricular tachycardia, AF
7. **Hypotension**
8. **Hypokalaemia** (↓K⁺)
9. **Death** in severe toxicity

**Management of Theophylline Toxicity:**
- Stop theophylline
- Activated charcoal (multiple doses) for oral overdose
- Treat seizures with IV benzodiazepines
- Treat arrhythmias
- Hemoperfusion/hemodialysis for severe toxicity

---

## **Q28. Management of Status Asthmaticus (5 Marks)**

**Definition:** Severe acute asthma unresponsive to standard bronchodilator therapy (β₂ agonists); life-threatening if untreated.

**Assessment (ABCDE):**
- Respiratory rate > 30/min, pulse > 120/min
- SpO₂ < 92%, PaO₂ < 60 mmHg
- Pulsus paradoxus > 15 mmHg
- Silent chest, cyanosis, altered consciousness → **immediately life-threatening**
- ABG: Initially ↓CO₂ (respiratory alkalosis), then **normal/rising CO₂ = danger sign** (respiratory fatigue)

**Management:**

### A. Immediate (First-line):
1. **High-flow Oxygen** (40–60%) via face mask → maintain SpO₂ ≥ 93%
2. **Nebulized Salbutamol** – 2.5–5 mg every 20 minutes (3 doses), then hourly or continuous
   - Or: IV salbutamol (if severe, not responding to inhaled)
3. **Ipratropium bromide** (anticholinergic) – 0.5 mg nebulized every 4–6 hours; additive bronchodilation; especially useful in first 24 hours
4. **Systemic Corticosteroids** – Hydrocortisone 100–200 mg IV every 6 hours **OR** Prednisolone 40–50 mg orally (if can swallow); anti-inflammatory; takes 4–6 hours to act
5. **IV Fluids** – for dehydration and electrolyte correction

### B. Second-line (if inadequate response):
6. **IV Aminophylline** – loading dose 250 mg (6 mg/kg) IV over 20 minutes (if NOT on theophylline), then infusion 0.5–0.9 mg/kg/hour; monitor levels
7. **IV Magnesium Sulphate** – 1.2–2 g IV over 20 minutes; bronchodilator via Ca²⁺ channel block and smooth muscle relaxation; safe and effective
8. **Heliox** (80% helium + 20% O₂) – reduces airway resistance; used as bridge while other therapies take effect

### C. Severe/Life-threatening (ICU level):
9. **IV Ketamine** – dissociative anesthetic with bronchodilator properties; used during intubation
10. **IV Adrenaline (Epinephrine)** – 0.5 mg IM or SC; used in near-fatal asthma
11. **Non-invasive ventilation (NIV/BiPAP)** – may avoid intubation in selected patients
12. **Mechanical ventilation** – if respiratory arrest imminent; use strategies to avoid air-trapping:
    - Low respiratory rate
    - Long expiratory time (I:E ratio 1:4 or more)
    - Allow permissive hypercapnia

### D. Other measures:
- Avoid sedatives/opioids (respiratory depression)
- Antibiotics only if bacterial infection confirmed
- IV fluids + K⁺ replacement (hypokalemia from β₂ agonists)
- Monitor ECG, electrolytes, ABG regularly
- Stepwise escalation with monitoring

**Discharge criteria:**
- SpO₂ > 94% on room air
- PEFR > 75% predicted
- No nocturnal symptoms
- Adequate supply of medications and inhaler technique checked

---

## **Q29. First Line Anti-TB Drugs with Their MOA and Adverse Effects (5 Marks)**

**Mnemonic: RIPES (Rifampicin, Isoniazid, Pyrazinamide, Ethambutol, Streptomycin)**

### Standard Regimen: 2HRZE / 4HR
*(2 months intensive: INH + Rifampicin + Pyrazinamide + Ethambutol, then 4 months continuation: INH + Rifampicin)*

---

### 1. ISONIAZID (INH) – H
**MOA:**
- Prodrug; activated by mycobacterial **catalase-peroxidase (KatG)** → reactive intermediates.
- Inhibits **InhA (enoyl-ACP reductase)** → blocks mycolic acid synthesis (essential component of mycobacterial cell wall).
- Also inhibits **KasA (β-ketoacyl-ACP synthase)**.
- **Bactericidal** against actively dividing bacilli; **bacteriostatic** against dormant.
- Unique activity: kills intracellular bacilli effectively.

**Adverse Effects:**
- **Peripheral neuropathy** (most common) – due to pyridoxine (B₆) antagonism; prevented by pyridoxine 10 mg/day supplementation; *risk highest in slow acetylators, alcoholics, malnutrition, pregnancy, DM*
- **Hepatotoxicity** – most serious; hepatitis (monitor LFTs); may be fatal if continued
- CNS effects: psychosis, seizures (rare; give B₆)
- Lupus-like syndrome (SLE)
- Drug interactions: inhibits CYP2C9, CYP3A4 → ↑phenytoin, carbamazepine, warfarin levels
- Slow vs. fast acetylators (NAT2 gene) – slow acetylators: ↑drug levels → ↑toxicity

---

### 2. RIFAMPICIN (Rifampin) – R
**MOA:**
- Inhibits **bacterial DNA-dependent RNA polymerase** (binds β-subunit, encoded by *rpoB* gene) → blocks initiation of mRNA synthesis → bactericidal.
- Does NOT inhibit mammalian RNA polymerase (selectivity).
- **Most potent bactericidal** first-line drug; active against intra- and extracellular bacilli; "sterilizing agent".

**Adverse Effects:**
- **Enzyme induction** (CYP1A2, 2C9, 2C19, 3A4, P-gp) – ↓levels of: warfarin, OCP, phenytoin, protease inhibitors, methadone, corticosteroids → **many drug interactions**; reduces OCP efficacy (use barrier contraception)
- **Hepatotoxicity** – dose-dependent; monitor LFTs
- **Orange-red discoloration** of urine, tears, saliva, sweat – harmless; warn patients (stains contact lenses)
- Flu-like syndrome (intermittent therapy) – fever, chills, bone pain
- **Thrombocytopenia** (intermittent regimens)
- Cholestatic jaundice (rare)
- **Rifampicin-resistant TB** correlates with **MDR-TB** (rpoB mutation)

---

### 3. PYRAZINAMIDE (PZA) – Z
**MOA:**
- Prodrug → converted by **pyrazinamidase (PncA)** → pyrazinoic acid (active) → acidifies mycobacterial cytoplasm → disrupts membrane potential + inhibits **fatty acid synthase I (FAS-I)**.
- **Active only in acidic environment (intracellular/inflammatory sites)** where pH is low.
- **Bactericidal for dormant/persister bacilli** in acidic macrophage phagolysosomes.
- Essential for shortening treatment duration from 9 to 6 months.

**Adverse Effects:**
- **Hyperuricemia** (most common) – inhibits renal tubular secretion of urate → gout-like arthralgia (treat with allopurinol if symptomatic)
- **Hepatotoxicity** – dose-related; most hepatotoxic first-line drug
- Arthralgia (non-gouty)
- Photosensitivity, skin rash
- Nausea, vomiting

---

### 4. ETHAMBUTOL – E
**MOA:**
- Inhibits **arabinosyl transferases (EmbB gene product)** → blocks polymerization of arabinogalactan → disrupts mycobacterial cell wall synthesis.
- **Bacteriostatic** (mainly); at high doses bactericidal.
- Used to prevent resistance; particularly useful in the intensive phase.

**Adverse Effects:**
- **Optic neuritis (retrobulbar neuritis)** – most important; dose-related; ↓visual acuity, ↓color discrimination (especially red-green), ↓visual fields; usually reversible on stopping early; **baseline and monthly visual acuity testing required** (Ishihara charts)
- Peripheral neuropathy (rare)
- Hyperuricemia (mild)
- GI upset (nausea)
- **Avoid in children** (cannot report early visual changes reliably) – use with caution

---

### 5. STREPTOMYCIN – S (injectable; used when resistant to ethambutol or in special circumstances)
**MOA:**
- **Aminoglycoside**; binds **30S ribosomal subunit** (16S rRNA) → misreading of mRNA → aberrant protein synthesis → bactericidal.
- Only active on **extracellular** (well-oxygenated) bacilli.

**Adverse Effects:**
- **Ototoxicity** – vestibular > cochlear (compare: gentamicin = vestibular; amikacin = cochlear); irreversible damage
- **Nephrotoxicity** – acute tubular necrosis; monitor renal function
- Hypersensitivity reactions
- Neuromuscular blockade
- **Contraindicated in pregnancy** (causes irreversible deafness in neonate)

---

## **Q30. Management of MDR-Tuberculosis (5 Marks)**

**Definition:**
- **MDR-TB:** Resistant to at least **INH + Rifampicin** (two most important first-line drugs).
- Global burden: ~500,000 new cases/year.

**WHO Treatment Guidelines (2022):**
- Standard MDR/RR-TB regimen: **BPaLM** (Bedaquiline + Pretomanid + Linezolid + Moxifloxacin) – newer shorter regimen (6 months)
- **Longer regimen:** 18–20 months (individualized)

**Drug Categories for MDR-TB:**

**Group A (Priority – use all three if possible):**
1. **Levofloxacin or Moxifloxacin** (fluoroquinolones) – inhibit DNA gyrase/topoisomerase IV; bactericidal
2. **Bedaquiline** – novel diarylquinoline; inhibits mycobacterial **ATP synthase** (subunit c) → depletes ATP → bactericidal; **remarkable sterilizing activity**; may prolong QTc
3. **Linezolid** – oxazolidinone; inhibits 50S ribosome (23S rRNA) → blocks protein synthesis; bactericidal; adverse effects: peripheral neuropathy, myelosuppression, optic neuritis

**Group B (Add if needed):**
4. **Clofazimine** – anti-leprosy drug; also active against TB; membrane disruption + ROS generation; red/brown skin discoloration
5. **Cycloserine or Terizidone** – inhibits cell wall D-alanine synthesis; bacteriostatic; CNS toxicity (psychosis, seizures)

**Group C (Use when Groups A and B insufficient):**
6. **Ethambutol**
7. **Delamanid** – nitroimidazo-oxazole; inhibits mycolic acid synthesis; used when bedaquiline not available; may prolong QT
8. **Pyrazinamide** (if susceptible)
9. **Imipenem-cilastatin** or **Meropenem** (with clavulanic acid)
10. **Amikacin/Streptomycin** (injectable; only Group A/B not available)
11. **Ethionamide/Prothionamide**
12. **p-aminosalicylic acid (PAS)**

**Shorter MDR-TB Regimen (WHO 2022):**
- **BPaL** regimen: Bedaquiline + Pretomanid + Linezolid × 6 months (ZeNix trial)
- **BPaLM:** Adds Moxifloxacin for non-XDR MDR-TB

**Key Principles:**
- Never add a single drug to a failing regimen
- Use at least 4 effective drugs
- Drug susceptibility testing (DST) mandatory
- Monitor for QT prolongation (bedaquiline + delamanid + fluoroquinolones)
- Address malnutrition, HIV co-infection
- Directly observed therapy (DOT)
- Surgery (lung resection) in localized disease with drug resistance

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## **Q31. Management of XDR-Tuberculosis (5 Marks)**

**Definition:**
- **XDR-TB (Extensively Drug-Resistant TB):** MDR-TB + resistance to at least one fluoroquinolone + at least one Group B agent (bedaquiline or linezolid).
- *(Updated WHO 2021 definition)*
- Previously: MDR-TB + resistance to fluoroquinolone + any injectable.

**Epidemiology:**
- Accounts for ~6.2% of MDR-TB cases globally.
- Higher mortality, very limited treatment options.

**Treatment Options:**

**Newer Drugs:**
1. **Bedaquiline** – ATP synthase inhibitor; essential backbone; duration up to 24 months now approved
2. **Delamanid** – nitroimidazo-oxazole; inhibits mycolic acid synthesis; QT prolongation
3. **Pretomanid** – nitroimidazo-oxazine; inhibits mycolic acid synthesis; bactericidal
4. **Linezolid** – 50S ribosomal inhibitor; bactericidal against XDR-TB

**BPaL Regimen (Nix-TB and ZeNix trials):**
- **Bedaquiline + Pretomanid + Linezolid (BPaL)** × 6–9 months
- Showed >90% favorable outcomes in XDR-TB
- **FDA breakthrough therapy designation**
- **ZeNix trial:** Different linezolid doses studied to optimize efficacy/toxicity balance

**Other drugs used:**
5. **Meropenem + Clavulanate (co-amoxiclav)** – carbapenem; β-lactamase inhibitor
6. **Imipenem-cilastatin + clavulanic acid**
7. **Chlorofazimine** (clofazimine)
8. **High-dose INH** (if only low-level INH resistance)

**Principles of XDR-TB Management:**
- **Multidisciplinary team** (TB specialist, microbiologist, pharmacist)
- **Drug susceptibility testing** – molecular (Xpert MTB/RIF, whole genome sequencing) and phenotypic
- Duration: Minimum **18–24 months** after culture conversion (shorter with BPaL regimen)
- Manage comorbidities (HIV, diabetes, malnutrition)
- HIV co-infection: Start ART early; drug interactions with rifabutin-based regimens
- **Surgical resection** of cavitary disease can improve outcomes in localized XDR-TB
- Adverse effects monitoring: QTc (bedaquiline + delamanid), peripheral neuropathy (linezolid), myelosuppression
- **Infection control** – negative pressure isolation rooms
- Nutritional support

**Prognosis:**
- Treatment success rate: ~40–60% with XDR-TB (improved to >90% with BPaL)
- BPaL regimen represents a revolution in XDR-TB treatment

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