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SECTION A - Elaborate On (10 Marks Each)

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A1 - Classify Antihypertensive Drugs; MOA, ADRs, and Uses of ACE Inhibitors and Beta Blockers

Classification of Antihypertensive Drugs

• Thiazides: Hydrochlorothiazide, Chlorthalidone
• Loop diuretics: Furosemide
• Potassium-sparing: Spironolactone, Amiloride

• ACE Inhibitors: Enalapril, Ramipril, Lisinopril, Captopril
• Angiotensin Receptor Blockers (ARBs): Losartan, Valsartan
• Direct Renin Inhibitor: Aliskiren

• Dihydropyridines: Amlodipine, Nifedipine (vascular selective)
• Non-dihydropyridines: Verapamil (cardiac), Diltiazem

• Beta blockers: Atenolol, Propranolol, Metoprolol
• Alpha-1 blockers: Prazosin, Doxazosin
• Alpha + Beta blockers: Labetalol, Carvedilol
• Centrally acting: Clonidine (alpha-2 agonist), Methyldopa

• Arterial: Hydralazine, Minoxidil
• Arterial + Venous: Sodium nitroprusside

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ACE Inhibitors

• Block angiotensin-converting enzyme (ACE), which normally converts Angiotensin I → Angiotensin II
• Angiotensin II causes vasoconstriction and stimulates aldosterone secretion
• By blocking ACE: vasodilation occurs, aldosterone decreases (less Na+/water retention), blood pressure falls
• Also prevent breakdown of bradykinin → additional vasodilation (but also causes cough as a side effect)

• Hypertension (first-line, especially in diabetics)
• Congestive Heart Failure (reduce preload and afterload)
• Post-myocardial infarction (cardioprotective)
• Diabetic nephropathy (renoprotective - reduce proteinuria)
• Left ventricular dysfunction

• Dry, persistent cough (due to bradykinin accumulation - most common)
• Hyperkalemia (due to reduced aldosterone)
• First-dose hypotension
• Angioedema (serious - due to bradykinin; may be life-threatening)
• Renal impairment (avoid in bilateral renal artery stenosis)
• Teratogenic - contraindicated in pregnancy (causes fetal renal dysgenesis)

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Beta Blockers

• Competitively block beta-adrenergic receptors
  • Beta-1 (cardiac): reduce heart rate, contractility, and cardiac output → lower BP
  • Beta-2 (vascular/bronchial): non-selective beta blockers also block these
• Reduce renin release from juxtaglomerular cells → less Angiotensin II → lower BP
• Cardioselective beta-1 blockers: Atenolol, Metoprolol, Bisoprolol
• Non-selective (beta-1 + beta-2): Propranolol, Nadolol

• Hypertension
• Angina pectoris (reduce myocardial oxygen demand)
• Cardiac arrhythmias (atrial fibrillation, SVT)
• Post-myocardial infarction (cardioprotective)
• Heart failure (Carvedilol, Bisoprolol, Metoprolol - in stable HF)
• Hyperthyroidism (symptom control)
• Anxiety (tremor, palpitations)
• Migraine prophylaxis

• Bradycardia and heart block
• Bronchospasm (dangerous in asthmatics - avoid non-selective)
• Cold extremities (peripheral vasoconstriction)
• Fatigue, depression, sexual dysfunction
• Hypoglycemia masking in diabetics (mask tachycardia, the warning sign)
• Dyslipidemia (raise triglycerides, lower HDL)
• Rebound hypertension on abrupt withdrawal

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A2 - Define Congestive Cardiac Failure; Drugs Used; Mechanism of Cardiac Glycosides

Definition of Congestive Cardiac Failure (CCF)

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Drugs Used in Treatment of CCF

• Digoxin, Digitoxin

• Loop diuretics: Furosemide (most commonly used)
• Thiazides: Hydrochlorothiazide
• Potassium-sparing: Spironolactone (also has anti-remodeling effect)

• Enalapril, Ramipril, Lisinopril
• Reduce preload and afterload; improve survival

• Carvedilol, Bisoprolol, Metoprolol (in stable CCF)
• Reduce cardiac remodeling and improve survival

• Hydralazine + Isosorbide dinitrate (alternative if ACE inhibitors not tolerated)
• Sodium nitroprusside (acute/severe failure)

• Dobutamine, Dopamine
• Phosphodiesterase inhibitors: Milrinone

• Reduces heart rate by blocking funny (If) channels in SA node; used in HFrEF

• Dapagliflozin, Empagliflozin - reduce hospitalizations and mortality in HF

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Mechanism of Action of Cardiac Glycosides (Digoxin)

1. Inhibition of Na+/K+ ATPase pump on myocardial cell membrane
   • This pump normally moves Na+ out and K+ in
   • Inhibition → intracellular Na+ accumulates
2. Increased intracellular Ca2+ (Positive Inotropy)
   • Elevated intracellular Na+ inhibits the Na+/Ca2+ exchanger
   • Ca2+ cannot be expelled → intracellular Ca2+ rises
   • More Ca2+ available for excitation-contraction coupling → stronger cardiac contraction (positive inotropy)
3. Negative Chronotropy (Slowed heart rate)
   • Vagomimetic effect: increases vagal tone → slows SA node firing and AV conduction
   • Useful for rate control in atrial fibrillation
4. Net Result: Increased force of contraction with decreased heart rate → improved cardiac output in CCF

• Nausea, vomiting, yellow-green visual disturbances (xanthopsia)
• Cardiac arrhythmias (premature ventricular contractions, AV block)
• Hypokalemia potentiates digoxin toxicity (K+ and digoxin compete for the same binding site on Na+/K+ ATPase)

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A3 - Classify Anti-Convulsant Drugs; MOA, ADRs, Uses

Classification of Anticonvulsant Drugs

• Phenytoin, Carbamazepine, Valproate, Lamotrigine, Oxcarbazepine

• Benzodiazepines (Diazepam, Clonazepam, Lorazepam)
• Barbiturates (Phenobarbitone)
• Valproate (also increases GABA synthesis)
• Vigabatrin (inhibits GABA transaminase)
• Gabapentin, Pregabalin (increase GABA release)

• Ethosuximide (used only in absence seizures)

• Topiramate (also Na+ channel blocker)
• Felbamate

• Levetiracetam (binds SV2A - synaptic vesicle protein)
• Lacosamide (slow inactivation of Na+ channels)
• Perampanel (AMPA receptor antagonist)

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Mechanism of Action

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Uses

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Adverse Drug Reactions

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A4 - Classify Anti-Anginal Drugs; Pharmacological Actions of Nitrates

Classification of Anti-Anginal Drugs

• Short-acting: Glyceryl trinitrate (GTN/Nitroglycerin) - sublingual
• Long-acting: Isosorbide dinitrate (ISDN), Isosorbide mononitrate (ISMN)

• Propranolol, Atenolol, Metoprolol

• Dihydropyridines: Amlodipine, Nifedipine (mainly vasospastic angina)
• Non-dihydropyridines: Verapamil, Diltiazem (also reduce HR)

• Nicorandil (also has nitrate component)

• Ivabradine (reduces heart rate, used when beta blockers not tolerated)

• Ranolazine (inhibits late Na+ current; reduces Ca2+ overload)

• Trimetazidine (metabolic: shifts myocardial metabolism from fatty acid to glucose oxidation)

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Pharmacological Actions of Nitrates

• Nitrates are prodrugs that release nitric oxide (NO) in vascular smooth muscle
• NO activates soluble guanylate cyclase → increases cGMP → activates protein kinase G → dephosphorylation of myosin light chain → smooth muscle relaxation → vasodilation

• Dilates capacitance veins → pooling of blood in periphery
• Reduces venous return (preload) → reduces cardiac filling pressure
• Decreased preload → reduced myocardial wall tension and oxygen demand

• Dilates arterioles → reduces systemic vascular resistance (afterload)
• Further reduces cardiac work

• Dilates large epicardial coronary arteries and collateral vessels
• Redistributes blood flow to ischemic subendocardial areas
• Relieves vasospasm in Prinzmetal's (variant) angina

• NO inhibits platelet aggregation

• Reduced O2 demand (less preload and afterload)
• Improved O2 supply (coronary vasodilation)
• Together relieve anginal pain

• Acute angina: sublingual GTN (onset 1-3 min)
• Prophylaxis: long-acting nitrates, transdermal patches
• Vasospastic/Prinzmetal angina: most effective here
• Acute heart failure and pulmonary edema (IV nitroglycerin)

• Throbbing headache (meningeal vessel dilation - most common)
• Flushing, dizziness, postural hypotension
• Reflex tachycardia (overcome by combining with beta blockers)
• Methemoglobinemia (large doses)
• Tolerance: develops with continuous use; requires nitrate-free interval of 8-10 hours daily

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SECTION B - Write Notes On (5 Marks Each)

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B1 - Classify Antihyperlipidemics; Note on HMG-CoA Reductase Inhibitors (Statins)

Classification of Antihyperlipidemics

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HMG-CoA Reductase Inhibitors (Statins)

• Competitively inhibit HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis in the liver
• Reduced hepatic cholesterol → upregulation of LDL receptors on hepatocytes
• More LDL cleared from blood → LDL levels fall significantly

• Decrease LDL by 30-60% (primary benefit)
• Modest decrease in triglycerides
• Modest increase in HDL
• Pleiotropic effects: anti-inflammatory, plaque stabilization, endothelial function improvement

• Primary and secondary prevention of cardiovascular disease
• Hypercholesterolemia (all types - Type IIa most responsive)
• Post-myocardial infarction (irrespective of baseline cholesterol)

• Myopathy/Rhabdomyolysis (muscle pain, weakness - most serious; monitor CK levels)
• Elevated liver enzymes (hepatotoxicity - monitor LFTs)
• GI disturbances (nausea, diarrhea)
• Headache, sleep disturbances
• Risk of new-onset diabetes (slightly increased)

• Risk of myopathy increases with fibrates (especially gemfibrozil), cyclosporine, macrolide antibiotics, azole antifungals (CYP3A4 inhibitors)

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B2 - Stages of General Anaesthesia

Stage I - Analgesia (Induction)

• Patient conscious but drowsy
• Pain sensation reduced, other senses mostly intact
• Able to respond to verbal commands
• Amnesia may begin

Stage II - Excitement (Delirium)

• Loss of consciousness
• Irregular breathing, breath-holding, vomiting risk
• Increased muscle tone, involuntary movements, coughing
• Dangerous stage - induction should pass through this quickly
• Modern IV induction agents (Propofol, Thiopentone) minimize this stage

Stage III - Surgical Anaesthesia (4 Planes)

• Plane 1: Regular breathing, eyelid reflex lost, eye movement present
• Plane 2: Eye movements cease, lacrimation stops, muscle relaxation begins
• Plane 3: Intercostal paralysis, abdominal muscles relax, pupil dilates - ideal surgical plane
• Plane 4: Full intercostal paralysis, diaphragmatic breathing only, pupil maximally dilated

Stage IV - Medullary Depression (Overdose)

• Respiratory and vasomotor center depression
• Cessation of breathing, circulatory collapse
• Death if not immediately reversed
• This stage must be AVOIDED

1. Unconsciousness/Hypnosis (propofol, isoflurane)
2. Analgesia (opioids - fentanyl)
3. Muscle Relaxation (vecuronium, succinylcholine)

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B3 - Classify Sedatives & Hypnotics; Mechanism of Barbiturates

Classification of Sedatives and Hypnotics

• Short-acting: Triazolam, Midazolam
• Intermediate: Oxazepam, Lorazepam, Temazepam
• Long-acting: Diazepam, Chlordiazepoxide, Flurazepam

• Ultra-short: Thiopentone (IV anaesthesia)
• Short: Secobarbital
• Intermediate: Amobarbital
• Long-acting: Phenobarbitone (mainly antiepileptic)

• Zolpidem, Zopiclone, Zaleplon

• Ramelteon, Melatonin

• Diphenhydramine, Promethazine

• Chloral hydrate
• Buspirone (anxiolytic, non-sedating)

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Mechanism of Barbiturates

1. Barbiturates bind to a specific site on the GABA-A receptor complex (distinct from the benzodiazepine site and GABA binding site)
2. They potentiate GABA-mediated Cl- influx by increasing the duration of Cl- channel opening (benzodiazepines increase the frequency)
3. At higher doses, barbiturates can directly open Cl- channels even without GABA - this accounts for their narrow safety margin and lethality in overdose
4. Cl- influx → hyperpolarization of the neuron → CNS depression

• Low dose: Sedation, anxiolysis
• Moderate dose: Hypnosis (sleep induction)
• High dose: Anaesthesia (thiopentone IV)
• Toxic dose: Coma, respiratory depression, death

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B4 - Note on Bronchodilators

Classification

• Short-acting (SABAs): Salbutamol (albuterol), Terbutaline - onset minutes, used as rescue therapy
• Long-acting (LABAs): Salmeterol, Formoterol - duration 12+ hours, maintenance therapy

• Short-acting (SAMAs): Ipratropium bromide
• Long-acting (LAMAs): Tiotropium bromide - especially useful in COPD

• Theophylline, Aminophylline (IV for acute attacks)

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Mechanism of Action

• Activate beta-2 receptors on bronchial smooth muscle → activate adenylate cyclase → increase cAMP → activate protein kinase A → phosphorylate myosin light chain kinase (MLCK) → muscle relaxation → bronchodilation
• Also inhibit mast cell mediator release

• Block muscarinic M3 receptors in bronchial smooth muscle and glands
• Reduce vagal tone → prevent bronchoconstriction and reduce mucus secretion

• Inhibits phosphodiesterase (PDE) → prevents cAMP breakdown → bronchodilation
• Also blocks adenosine receptors (adenosine causes bronchoconstriction)
• Narrow therapeutic index; requires blood level monitoring

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B5 - Pharmacology of Morphine

Mechanism of Action

• Acts on opioid receptors (mu, kappa, delta) - G-protein coupled receptors (GPCRs)
• Mu (μ) receptors are primarily responsible for analgesia and euphoria
• Activation → inhibition of adenylate cyclase (↓cAMP), opening of K+ channels (hyperpolarization), closure of Ca2+ channels
• Net effect: decreased neuronal excitability and reduced neurotransmitter (substance P) release → analgesia

Pharmacological Actions

Uses

• Severe pain (post-operative, cancer pain, myocardial infarction)
• Acute pulmonary edema (reduces preload by venodilation)
• Pre-anesthetic medication
• Severe diarrhea (loperamide - peripheral opioid)
• Palliative care

ADRs

• Respiratory depression (most dangerous)
• Constipation (most common, does not develop tolerance)
• Nausea and vomiting
• Physical dependence and addiction
• Miosis
• Histamine release → pruritus, bronchoconstriction, hypotension

Tolerance and Dependence

• Tolerance develops to analgesia, euphoria, respiratory depression, but NOT to constipation and miosis
• Physical dependence: withdrawal symptoms (yawning, lacrimation, rhinorrhea, piloerection, diarrhea, muscle cramps)

Antidote

• Naloxone (opioid receptor antagonist) - reverses all effects including respiratory depression; short duration, may need repeat dosing

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B6 - Classify and Explain Pharmacology of Antitussives

Classification

1. Opioid antitussives
   • Codeine (most commonly used - gold standard)
   • Hydrocodone
   • Pholcodine
2. Non-opioid central antitussives
   • Dextromethorphan (NMDA receptor antagonist; most widely used OTC)
   • Noscapine (isoquinoline alkaloid from opium)

1. Demulcents - soothe respiratory mucosa
   • Honey, glycerol, linctus preparations
2. Local Anesthetics (inhalation)
   • Lignocaine (lidocaine) nebulized - suppresses laryngeal and bronchial receptors
3. Expectorants - liquefy secretions (help productive cough)
   • Guaifenesin, Ammonium chloride, Bromhexine, Ambroxol
4. Mucolytics
   • Acetylcysteine (breaks disulfide bonds in mucus)

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Mechanism of Action of Key Antitussives

• Acts on opioid (mu) receptors in the cough center in the medulla oblongata
• Raises the threshold for cough reflex
• Less potent analgesic effect than morphine; good antitussive dose is lower than analgesic dose
• Can cause constipation, mild sedation, dependence (with long-term use)

• Acts on sigma receptors and NMDA receptors centrally
• Suppresses cough center without opioid-like analgesic or addictive properties
• Widely used in OTC cough preparations
• Overdose can cause hallucinations ("robotripping")

• Acts on opioid receptors centrally
• No analgesic, sedative, or addictive properties
• May cause mild bronchospasm

Uses of Antitussives

Important Notes:

• Antitussives are NOT used for productive cough (cough serves to clear secretions)
• Codeine is contraindicated in children under 12 years (risk of respiratory depression)
• Dextromethorphan is preferred OTC antitussive in children and pregnancy

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Summary Table - All Drug Classes at a Glance