SECTION B (40 Marks)

Q1. Parkinson's Disease - 60-year-old architect (2+3+3+2 = 10)

(a) Classify the drugs available to treat Parkinson's disease (2 marks)

• Benztropine, Trihexyphenidyl (biperiden)
• Useful mainly for tremor

(b) Treatment recommended (detail) (3 marks)

• Levodopa is the gold standard and most effective drug
• Carbidopa is a peripheral dopa decarboxylase inhibitor - it prevents peripheral conversion of levodopa to dopamine, thereby:
  • Reducing peripheral side effects (nausea, vomiting, hypotension)
  • Increasing the amount of levodopa reaching the brain by ~5x
  • Allowing a 75% reduction in levodopa dose
• Dose: Start with Levodopa 100 mg + Carbidopa 25 mg TDS, titrated upward
• Since the patient is 60 years old and working, levodopa is appropriate (preferred in older patients; dopamine agonists have more neuropsychiatric side effects)

• Pramipexole or Ropinirole (dopamine agonist) to reduce "off" periods
• Selegiline (MAO-B inhibitor) - neuroprotective, reduces motor fluctuations
• Entacapone - COMT inhibitor, extends levodopa half-life

(c) Side effects of the drugs given (3 marks)

• Nausea, vomiting, anorexia (most common early effect)
• Postural (orthostatic) hypotension
• Cardiac arrhythmias (rare)
• Flushing

• Motor fluctuations - "wearing-off" phenomenon (end-of-dose failure), "on-off" effect
• Dyskinesias - involuntary choreoathetotic movements (peak-dose effect; most common long-term problem)
• Hallucinations, paranoia, psychosis (dopamine excess in mesolimbic system)
• Confusion, insomnia, nightmares
• Hypersexuality, impulse control disorders

• Brownish discoloration of urine/sweat (melanin precursor)

(d) Why pyridoxine (Vitamin B6) should be avoided in patients on Levodopa therapy (2 marks)

• Pyridoxine (Vit B6) is a cofactor for DOPA decarboxylase (the enzyme that converts levodopa to dopamine)
• When given to patients on levodopa alone (without carbidopa), pyridoxine enhances peripheral decarboxylation of levodopa in the gut and blood
• This causes more dopamine to be formed peripherally - peripheral dopamine cannot cross the blood-brain barrier
• Result: less levodopa reaches the CNS, reducing therapeutic effectiveness dramatically
• Even small doses of pyridoxine (found in multivitamins, 5-10 mg) can abolish the effect of levodopa
• Exception: Pyridoxine is NOT a problem when levodopa is combined with carbidopa (a peripheral decarboxylase inhibitor already blocks this pathway)

Q2. Short Notes (4 x 5 = 20)

(a) Pre-anaesthetic agents (Premedication)

1. Sedatives/Anxiolytics - Benzodiazepines (midazolam is most popular)
2. Opioid analgesics - Morphine, Pethidine, Fentanyl
3. Anticholinergics - Atropine (dries secretions, prevents bradycardia)
4. H2 antagonists/PPIs - Ranitidine, Omeprazole (reduce aspiration pneumonitis risk)
5. Antiemetics - Ondansetron, Metoclopramide
6. Antacids - Sodium citrate, Magnesium trisilicate

(b) Atypical Antipsychotics

• Lower risk of extrapyramidal side effects (EPS)
• Better efficacy for negative symptoms of schizophrenia
• Mechanism: Block D2 receptors + 5-HT2A receptors (serotonin-dopamine antagonism)

• Schizophrenia (especially negative symptoms)
• Bipolar disorder (mania, depression)
• Treatment-resistant schizophrenia (clozapine)
• Agitation, delirium

• Metabolic syndrome: weight gain, hyperglycemia, dyslipidemia (especially olanzapine, clozapine)
• Agranulocytosis: clozapine (requires WBC monitoring weekly for 6 months)
• QT prolongation (ziprasidone, quetiapine)
• Sedation, postural hypotension
• Hyperprolactinemia (risperidone, amisulpride) - less than typicals

(c) Proton Pump Inhibitors (PPIs)

• Given as enteric-coated tablets (destroyed by gastric acid)
• Best taken 30 min before meals (pump must be active for drug to work)
• Inhibit both basal and stimulated acid secretion (unlike H2 blockers)
• Duration: 24-36 hours (new pumps must be synthesized)

• Peptic ulcer disease (gastric, duodenal)
• H. pylori eradication (part of triple/quadruple therapy)
• GERD (gastroesophageal reflux disease) - drug of choice
• Zollinger-Ellison syndrome
• NSAID-induced gastropathy (prevention and treatment)
• Stress ulcer prophylaxis in ICU

• Short-term: Headache, diarrhea, nausea (uncommon)
• Long-term: Hypomagnesemia, hyponatremia, vitamin B12 deficiency, osteoporosis (reduced calcium absorption), increased risk of C. difficile infection, community-acquired pneumonia (by raising gastric pH)
• Drug interaction: Reduce absorption of drugs needing acidic pH (e.g., ketoconazole, iron); clopidogrel interaction (omeprazole inhibits CYP2C19)

(d) Doctor-Patient Relationship: Principles for Delivering Bad News

• Truthfulness (Veracity): Patient has the right to know their diagnosis
• Autonomy: Respect patient's right to decide how much to know
• Non-maleficence: Avoid causing unnecessary psychological harm (pace information)
• Beneficence: The long-term benefit of knowing outweighs short-term distress
• Confidentiality: Discuss only with patient and those they authorize

• False reassurance
• Using jargon
• Giving all bad news at once without emotional support
• Breaking news in a corridor or public place

Q3. Very Short Answers (4 x 2.5 = 10)

(a) Why gastric lavage is performed in Morphine poisoning even if the drug has been taken intravenously?

(b) Why Barbiturates are contraindicated in Porphyria?

• Barbiturates are potent inducers of hepatic cytochrome P450 enzymes and δ-aminolevulinic acid (ALA) synthetase - the rate-limiting enzyme in heme/porphyrin synthesis
• In porphyric patients who already have a partial enzyme block downstream (e.g., deficiency of porphobilinogen deaminase), this induction massively increases accumulation of porphyrin precursors (ALA, porphobilinogen)
• This precipitates an acute attack of porphyria: severe abdominal pain, neuropsychiatric symptoms, autonomic instability, paralysis - which can be fatal
• Even a single dose can trigger a life-threatening attack

(c) Why Local Anaesthetics are less effective in infected/inflamed tissue?

• Tissue pH is low (acidic) due to metabolic acids produced by bacteria and inflammatory cells
• Acidic pH causes protonation of the local anaesthetic - it remains in the charged, ionized form (RNH+)
• The charged form cannot cross the lipid membrane of the nerve
• Less free-base drug enters the axon, so the block is incomplete and inadequate
• Additionally, increased vascularity in inflamed tissue causes faster absorption and washout of the drug

(d) Why Sulfasalazine and NOT its active component 5-ASA is given in Ulcerative Colitis?

• 5-ASA given orally is rapidly and almost completely absorbed in the small intestine (upper GI tract) before it reaches the colon where it is needed
• Very little reaches the colon intact, making it therapeutically ineffective as a plain oral preparation
• Sulfasalazine is an azo-bond prodrug: 5-ASA linked to sulfapyridine (carrier molecule) via an azo bond
• The intact sulfasalazine molecule is poorly absorbed in the small intestine (stays in the lumen)
• When it reaches the colon, bacterial azoreductases cleave the azo bond, releasing 5-ASA directly at the site of action in the colonic mucosa
• This targeted delivery ensures high local concentration of 5-ASA in the colon
• The sulfapyridine moiety is absorbed and is responsible for most of the systemic side effects (rash, oligospermia, hemolytic anemia)

SECTION C (40 Marks)

Q1. Beta-Adrenergic Receptor Blocking Agents - Classify, Pharmacological Actions, Therapeutic Uses, Adverse Effects (3+2+3+2 = 10)

Classification (3 marks)

• With ISA: Pindolol, Acebutolol, Oxprenolol (cause less resting bradycardia)
• Without ISA: Propranolol, Metoprolol, Atenolol, Bisoprolol

• α + β blockers: Labetalol, Carvedilol
• β blocker + NO donor: Nebivolol
• Lipid soluble (CNS penetration): Propranolol, Metoprolol
• Water soluble (less CNS effects): Atenolol, Nadolol

Pharmacological Actions (2 marks)

• Decreased heart rate (negative chronotropy) - bradycardia
• Decreased force of contraction (negative inotropy) - reduced cardiac output
• Decreased conduction velocity through AV node (negative dromotropy)
• Decreased automaticity - antiarrhythmic
• Reduced renin release from juxtaglomerular cells (antihypertensive mechanism)
• Decreased oxygen demand (antianginal)

• Bronchoconstriction (dangerous in asthmatics)
• Vasoconstriction in peripheral vessels (cold extremities)
• Inhibition of glycogenolysis (can mask hypoglycemia signs)
• Inhibition of tremor

Therapeutic Uses (3 marks)

1. Hypertension - First-line, especially with ischemic heart disease or heart failure
2. Angina pectoris - Reduce cardiac oxygen demand (drug of choice for stable angina)
3. Acute MI / Post-MI - Reduce infarct size, prevent reinfarction (metoprolol, atenolol)
4. Heart failure - Paradoxically beneficial; carvedilol, bisoprolol, metoprolol reduce mortality in chronic HF
5. Cardiac arrhythmias - SVT, atrial fibrillation (rate control), ventricular arrhythmias
6. Thyrotoxicosis - Control tachycardia and sympathetic symptoms (propranolol)
7. Migraine prophylaxis - Propranolol, metoprolol
8. Anxiety and tremor - Essential tremor, situational anxiety (propranolol)
9. Pheochromocytoma - After α-blockade is established (avoid using alone)
10. Glaucoma - Timolol eye drops (reduce aqueous humor production)
11. Portal hypertension - Propranolol (reduce variceal bleeding risk)

Adverse Effects (2 marks)

• Bradycardia, heart block, worsening of heart failure
• Bronchoconstriction (non-selective drugs; contraindicated in asthma/COPD)
• Cold extremities, peripheral vascular disease worsening (Raynaud's)
• Masking of hypoglycemia (sweating still present; tachycardia masked) - problem in diabetics on insulin
• Fatigue, lethargy (especially lipophilic drugs - propranolol)
• CNS effects: Nightmares, insomnia, depression (propranolol)
• Dyslipidemia: Increased TG, decreased HDL
• Rebound hypertension/angina on abrupt withdrawal (must taper)
• Sexual dysfunction (impotence)
• Hyperkalemia (β2 blockade reduces cellular K+ uptake)

Q2. Short Notes (4 x 5 = 20)

(a) Plasma Protein Binding and Clinical Significance

• Albumin: Most important; binds acidic drugs (warfarin, phenytoin, NSAIDs, furosemide) and some basic drugs
• α1-acid glycoprotein (AAG): Binds basic drugs (propranolol, lidocaine, quinidine)
• Lipoproteins: Bind lipophilic drugs (cyclosporine)
• Globulins: Bind hormones, vitamins, metals

1. Duration of action: Highly protein-bound drugs have longer t½ (reservoir effect) - e.g., warfarin (99% bound)
2. Drug-drug interactions (displacement): When two drugs compete for same binding site, one displaces the other, suddenly increasing free concentration of the displaced drug - toxicity risk. Classic example: Warfarin displaced by aspirin/phenylbutazone → hemorrhage.
3. Volume of distribution (Vd): Highly protein-bound drugs have smaller Vd (stay in plasma); drugs that bind extensively to tissues have large Vd.
4. Disease states:
   • Hypoalbuminemia (cirrhosis, nephrotic syndrome, malnutrition): Reduced binding → higher free drug → toxicity with usual doses (phenytoin, warfarin)
   • Renal failure: Uremic toxins displace drugs from albumin
   • Burns: Low albumin → unpredictable free drug levels
5. Drug extraction by kidney/liver: Only free drug is filtered glomerularly; only free drug is metabolized by enzymes
6. Dialysis: Highly protein-bound drugs are NOT removed by dialysis (e.g., warfarin)
7. Pregnancy: Albumin levels fall → increased free drug concentration

(b) Desferrioxamine (Deferoxamine) and its Uses

• Poorly absorbed orally - given IM, SC, or IV
• Continuous SC infusion (8-12 hours, 5-7 days/week) is most common for chronic iron overload
• Ferrioxamine excreted in urine and feces

1. Acute iron poisoning - IV/IM infusion in severe poisoning (serum Fe > 350 mcg/dL or symptomatic); test: "vin rosé" urine confirms chelation
2. Chronic iron overload (iron toxicity):
   • Transfusion-dependent anemias: Beta-thalassemia major, sickle cell disease (multiple transfusions cause hemosiderosis)
   • Each unit of blood contains ~200-250 mg iron; body cannot excrete excess → accumulates in heart, liver, endocrine organs
3. Hemochromatosis - though phlebotomy is preferred; DFO used when phlebotomy not possible
4. Aluminum overload in chronic renal failure (dialysis patients) - DFO chelates aluminum; risk of mucormycosis with this use

• Ocular toxicity (cataract, retinal degeneration) - requires regular eye monitoring
• Auditory toxicity (sensorineural hearing loss)
• Growth retardation in children
• Local reactions at injection site
• Increased risk of mucormycosis (Mucor species use desferrioxamine as a siderophore)
• Hypotension with rapid IV infusion
• ARDS (with large doses)

(c) Selective COX-2 Inhibitors

• COX-1: Constitutive; present in stomach, platelets, kidney. Produces "protective" prostaglandins (gastric mucosal protection, platelet aggregation via TXA2, renal perfusion)
• COX-2: Inducible; expressed at sites of inflammation, pain, fever. Also constitutively expressed in kidney, brain, vascular endothelium

• Significantly reduced GI ulceration and bleeding (COX-1 spared, gastric mucosa protected)
• No effect on platelet aggregation (platelets only have COX-1; COX-2 inhibitors don't affect platelet TXA2)
• Equivalent anti-inflammatory and analgesic efficacy

• Osteoarthritis and rheumatoid arthritis (especially in patients with GI risk)
• Acute pain, dysmenorrhea
• Familial adenomatous polyposis (celecoxib approved as adjunct)
• Prevention of colorectal cancer (under research)

• Increased cardiovascular risk - by blocking vascular COX-2-derived prostacyclin (PGI2 - vasodilatory, anti-aggregatory) while TXA2 (COX-1-derived) remains unopposed → prothrombotic state → increased MI and stroke risk
• Hypertension, fluid retention (still inhibit renal COX-2)
• Contraindicated in patients with established cardiovascular disease
• Still cause renal side effects like non-selective NSAIDs

(d) Prostaglandin Analogues and their Uses

Q3. Pharmacological Basis (5 x 2 = 10)

(a) Why Atropine is preferred for refraction testing in Children?

1. Longest duration of cycloplegia: Atropine produces cycloplegia lasting 7-14 days vs cyclopentolate (24-48 hrs) or tropicamide (4-6 hrs)
2. Children have a very strong accommodation reflex (high accommodative amplitude); short-acting agents cannot fully overcome it in young children
3. Children with strabismus or high hypermetropia need complete, prolonged cycloplegia for accurate refraction
4. As a 1% eye drop or ointment given for 3 days before testing, it ensures complete paralysis of accommodation on the day of testing
5. Also produces prolonged mydriasis (pupil dilation) for adequate fundoscopic examination

• Systemic absorption via nasolacrimal duct can cause tachycardia, fever, flushing, dryness (atropine toxicity - "hot as a hare, dry as a bone, red as a beet, blind as a bat, mad as a hatter")
• Must press on inner canthus after instillation to minimize systemic absorption

(b) Partial agonist antagonizes the action of a Full agonist - Give one suitable example

• It competes with the full agonist for receptor binding
• It displaces the full agonist (competitive displacement)
• The partial agonist occupies receptors but generates a weaker response than the full agonist it displaced
• Net effect: Response is reduced compared to full agonist alone = functional antagonism

• Morphine is a full μ-opioid receptor agonist (produces maximal analgesia and euphoria)
• Buprenorphine is a partial μ-opioid receptor agonist with very high receptor affinity
• When buprenorphine is given, it displaces morphine from μ-receptors (due to higher affinity)
• But it produces only partial activation - net effect is reduced opioid effect (antagonism of morphine's full agonist activity)
• This is why buprenorphine is used in opioid dependence treatment (replaces heroin/morphine while producing less euphoria)

• Nalorphine (partial agonist) antagonizes morphine
• Pentazocine (κ agonist, partial μ agonist) - can precipitate withdrawal in morphine-dependent patients

(c) Folinic Acid (Leucovorin) and NOT Folic Acid is used to reverse Methotrexate Toxicity

• Dihydrofolate (DHF) → Tetrahydrofolate (THF)
• Folic acid → DHF → THF (same enzyme in both steps)

• Folic acid needs to be converted to THF by DHFR (folic acid → DHF → THF)
• Methotrexate is a competitive inhibitor of DHFR with extremely high affinity (Ki ~1 nmol/L)
• DHFR is blocked by MTX, so folic acid cannot be processed - it cannot be converted to active THF
• Giving folic acid is useless; it accumulates but cannot be utilized

• Folinic acid (5-formyl-THF) is already in the active, reduced tetrahydrofolate form
• It bypasses DHFR entirely - no need for the blocked enzyme
• It directly enters the folate pool as THF, replenishing active folate cofactors needed for:
  • DNA synthesis (thymidylate)
  • Purine synthesis
  • Amino acid metabolism
• This is called "leucovorin rescue" - rapidly reverses bone marrow and GI toxicity of MTX

(d) Why Antihistamines are NOT used for Bronchial Asthma?

1. Asthma is a multi-mediator disease: Many other mediators contribute besides histamine:
   • Leukotrienes (LTC4, LTD4, LTE4) - far more potent bronchoconstrictors than histamine (100-1000x)
   • Prostaglandins (PGD2)
   • Platelet-activating factor (PAF)
   • Bradykinin
   • Cytokines (IL-4, IL-5, IL-13)
   • Blocking only histamine has negligible impact on the overall bronchoconstriction
2. Histamine's role is minor: In asthma, the late-phase bronchoconstriction is dominated by leukotrienes and eosinophilic inflammation; antihistamines only block the early, minor histamine component
3. Older antihistamines are anticholinergic (dry secretions → thick mucus plugs → worsen obstruction)
4. Antihistamines may actually worsen asthma: By thickening bronchial secretions (anticholinergic effect), particularly the first-generation drugs
5. H1 antihistamines are effective for allergic rhinitis (where histamine is the dominant mediator) but not asthma

(e) Pralidoxime is used in Organophosphorus Poisoning but NOT in Carbamate Poisoning

• OP compounds bind to and inhibit acetylcholinesterase (AChE) at its esteratic site by phosphorylating it
• Initially, this binding is reversible
• Over time (hours), the phosphoryl-enzyme complex undergoes "aging" - loses an alkyl group, becomes irreversibly inactivated
• Pralidoxime (2-PAM) is an AChE reactivator: its oxime group has a strong affinity for the phosphorus atom; it cleaves the phosphoryl-enzyme bond before aging occurs, regenerating active AChE
• Must be given early (within 24-48 hours, before aging)

1. Carbamates also bind to AChE (carbamylation of esteratic site), but this bond is spontaneously and rapidly reversible - the carbamate-enzyme complex hydrolyzes on its own within 30-40 minutes to a few hours
2. Aging does NOT occur with carbamate-AChE complexes (unlike OP compounds)
3. Pralidoxime is therefore unnecessary - the enzyme spontaneously regenerates
4. Some evidence suggests pralidoxime may actually increase toxicity in carbamate poisoning by:
   • Releasing more carbamate after the complex has already partially hydrolyzed
   • Inhibiting plasma cholinesterase
5. CNS penetration of some carbamates is limited, and carbamate poisoning is generally milder and shorter-lived