Q1. Classify Beta-Blockers: Pharmacological Actions, Therapeutic Uses, and Adverse Effects

Classification

1. Non-selective (β1 + β2 blockers)

• Without ISA: Propranolol, Timolol, Nadolol, Sotalol
• With ISA: Pindolol, Oxprenolol

2. Cardioselective (β1-selective blockers)

• Without ISA: Metoprolol, Atenolol, Bisoprolol, Esmolol, Nebivolol
• With ISA: Acebutolol, Celiprolol

3. Alpha + Beta blockers (mixed blockers)

• Carvedilol (α1, β1, β2 blockade)
• Labetalol (α1, β1, β2 blockade)

4. Beta-blockers with vasodilatory action

• Nebivolol (releases NO causing vasodilation)
• Carvedilol, Labetalol

Pharmacological Actions

Therapeutic Uses

1. Hypertension - reduce cardiac output and renin secretion
2. Angina pectoris - reduce myocardial oxygen demand by lowering HR and contractility
3. Acute MI - reduce infarct size, prevent arrhythmias, improve survival
4. Heart failure (HFrEF) - bisoprolol, carvedilol, metoprolol succinate (Class I indication, EF <40%)
5. Cardiac arrhythmias - AF, SVT, ventricular arrhythmias (sotalol)
6. Hyperthyroidism - control tachycardia and tremor (propranolol)
7. Glaucoma - topical timolol, betaxolol
8. Migraine prophylaxis - propranolol, atenolol
9. Anxiety / performance anxiety - propranolol (blocks peripheral symptoms)
10. Pheochromocytoma - after alpha-blockade (never alone - risk of hypertensive crisis)
11. Portal hypertension / variceal bleeding prophylaxis - propranolol, nadolol

Adverse Effects

1. Cardiovascular: Bradycardia, heart block, hypotension, worsening acute decompensated HF
2. Respiratory: Bronchoconstriction (especially non-selective) - contraindicated in asthma/COPD
3. CNS: Fatigue, sleep disturbances, nightmares, depression (propranolol > cardioselective)
4. Metabolic:
   • Masking hypoglycemia symptoms in diabetics (tachycardia blunted, not sweating)
   • Hyperglycemia, hypertriglyceridemia, reduced HDL
5. Peripheral vascular disease: Cold extremities, worsening claudication, Raynaud's phenomenon
6. Sexual dysfunction: Impotence
7. Abrupt withdrawal: Rebound angina, tachycardia, MI (must taper gradually)
8. Hyperkalemia (particularly with non-selective agents)

Q2. Management of Opioid Poisoning

Clinical Features ("Opioid Toxidrome")

1. Coma / CNS depression
2. Pinpoint (miotic) pupils
3. Respiratory depression (slow, shallow breathing or apnea)

Management

Step 1: Immediate Resuscitation (ABC)

• Airway: Clear the airway; jaw-lift, head-tilt; intubate if necessary
• Breathing: Bag-mask ventilation or mechanical ventilation if apneic
• Circulation: IV access, monitor BP, HR, SpO2, ECG

Step 2: Antidote - NALOXONE (Narcan)

• Route: IV (preferred), IM, SC, or intranasal (Narcan® nasal spray 4 mg)
• Dose:
  • IV: 0.4-2 mg; repeat every 2-3 minutes if no response
  • Total dose up to 10 mg may be required (especially for fentanyl derivatives)
  • Continuous IV infusion if recurrent coma (because naloxone t½ ~1 hour is shorter than most opioids)
• Note: The duration of naloxone is shorter than most opioids → patients can slip back into coma; close monitoring and repeated dosing/infusion is essential

Step 3: Supportive Measures

• IV fluids for hypotension
• Maintain body temperature (hypothermia is common)
• Treat pulmonary edema if present
• Urinary catheterization to monitor output
• Seizure management (especially in children, meperidine/normeperidine toxicity)

Step 4: Monitoring and Disposition

• Observation period depends on the opioid involved:
  • Heroin (short-acting): minimum 4-6 hours after naloxone
  • Long-acting opioids (methadone, morphine extended-release): 24 hours minimum
  • Sustained-release preparations: longer observation warranted
• Consider naltrexone (oral, longer-acting) for maintenance in opioid use disorder

Step 5: Prevent Re-exposure

• Social and addiction medicine consultation
• Prescribe take-home naloxone to family/contacts

Q3. Classify Anti-hypertensive Drugs + Pharmacology of ACE Inhibitors

Classification of Anti-hypertensive Drugs

1. Diuretics

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

2. Renin-Angiotensin-Aldosterone System (RAAS) Inhibitors

• ACE Inhibitors: Enalapril, Ramipril, Lisinopril, Captopril, Perindopril
• ARBs: Losartan, Valsartan, Olmesartan, Telmisartan
• Direct Renin Inhibitors: Aliskiren
• Aldosterone antagonists: Spironolactone, Eplerenone

3. Calcium Channel Blockers (CCBs)

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

4. Adrenergic Blockers

• Beta-blockers: Atenolol, Metoprolol, Bisoprolol, Carvedilol
• Alpha-1 blockers: Prazosin, Doxazosin, Terazosin
• Central alpha-2 agonists: Clonidine, Methyldopa
• Alpha + Beta blockers: Labetalol, Carvedilol

5. Vasodilators

• Direct: Hydralazine, Minoxidil
• Nitrates: Sodium nitroprusside (hypertensive emergency)

Pharmacology of ACE Inhibitors

Mechanism of Action

• Decreased Angiotensin II → decreased vasoconstriction → vasodilation
• Decreased Angiotensin II → decreased aldosterone → decreased Na+/water retention → decreased blood volume
• Increased bradykinin → vasodilation (also causes cough and angioedema)
• Decreased afterload and preload → improved cardiac output in HF
• Decreased stimulation of sympathetic NS (less epinephrine release)

Pharmacological Actions

1. Reduce vascular resistance (afterload) and venous tone (preload)
2. Reduce sodium and water retention (via decreased aldosterone)
3. Improve cardiac output in HFrEF
4. Renal protection: reduce intraglomerular pressure → slow progression of diabetic nephropathy and CKD
5. Prevent/reverse LV hypertrophy and remodeling

Therapeutic Uses

1. Hypertension (first-line, especially with diabetes or CKD)
2. Heart failure (HFrEF) - Class I, cornerstone therapy
3. Post-MI - reduce mortality and prevent LV remodeling
4. Diabetic nephropathy - reduce proteinuria and slow CKD progression
5. CKD with proteinuria (non-diabetic)
6. Left ventricular dysfunction (even asymptomatic)

Adverse Effects

1. Dry cough - most common (5-20%), due to bradykinin accumulation; switch to ARB if intolerable
2. Angioedema - rare but serious (head/neck/intestinal); caused by excess bradykinin
3. Hyperkalemia - due to decreased aldosterone
4. First-dose hypotension - especially in volume-depleted patients
5. Acute kidney injury - in bilateral renal artery stenosis (reduce GFR)
6. Teratogenicity - contraindicated in pregnancy (2nd and 3rd trimester - fetal renal toxicity)
7. Rash, dysgeusia (especially captopril - sulfhydryl group)

Q4. Classification of Oral Anti-diabetic Drugs

1. Insulin Secretagogues (increase insulin release)

a) Sulfonylureas

• 1st generation: Tolbutamide, Chlorpropamide
• 2nd generation: Glibenclamide (Glyburide), Glipizide, Gliclazide, Glimepiride
• Mechanism: Close ATP-sensitive K+ channels on beta cells → depolarization → insulin release
• Risk: Hypoglycemia, weight gain

b) Meglitinides (Glinides)

• Repaglinide, Nateglinide
• Mechanism: Same as sulfonylureas but faster onset, shorter duration
• Taken before each meal; lower hypoglycemia risk

2. Insulin Sensitizers (reduce insulin resistance)

a) Biguanides

• Metformin (drug of choice in T2DM)
• Mechanism: Activates AMPK → decreases hepatic gluconeogenesis, increases peripheral glucose uptake
• No hypoglycemia, weight neutral/loss; may reduce CV events
• Contraindicated: Renal failure (eGFR <30), risk of lactic acidosis

b) Thiazolidinediones (TZDs / Glitazones)

• Pioglitazone, Rosiglitazone
• Mechanism: Activate PPAR-γ nuclear receptors → improve insulin sensitivity in fat and muscle
• Side effects: Weight gain, fluid retention, heart failure, bone fractures, bladder cancer (pioglitazone)

3. Alpha-Glucosidase Inhibitors

• Acarbose, Miglitol, Voglibose
• Mechanism: Inhibit intestinal alpha-glucosidase → delay carbohydrate absorption → reduce postprandial hyperglycemia
• Side effects: Flatulence, bloating, diarrhea

4. DPP-4 Inhibitors (Gliptins)

• Sitagliptin, Vildagliptin, Saxagliptin, Alogliptin, Teneligliptin
• Mechanism: Inhibit DPP-4 enzyme → prevent GLP-1 inactivation → increased insulin, decreased glucagon
• Weight neutral; no hypoglycemia; well tolerated
• Risk: Pancreatitis (rare), heart failure (saxagliptin)

5. GLP-1 Receptor Agonists (injectable, but some oral)

• Oral semaglutide (Rybelsus) - oral formulation
• Mechanism: Mimic GLP-1 → stimulate glucose-dependent insulin secretion, suppress glucagon, slow gastric emptying, reduce appetite
• Cardiovascular and renal benefits

6. SGLT-2 Inhibitors (Gliflozins)

• Dapagliflozin, Empagliflozin, Canagliflozin, Ertugliflozin
• Mechanism: Inhibit sodium-glucose cotransporter 2 in proximal tubule → glycosuria (excrete glucose in urine)
• Benefits: Weight loss, BP reduction, heart failure benefit, renal protection
• Side effects: Genital mycotic infections, UTI, DKA (euglycemic), Fournier's gangrene

7. Bile Acid Sequestrants

• Colesevelam - modestly lowers glucose; mechanism unclear

8. Dopamine Agonists

• Bromocriptine (Cycloset) - resets circadian rhythm of glucose metabolism

Q5. Management of DKA (Diabetic Ketoacidosis)

Diagnosis

• Hyperglycemia (blood glucose >250 mg/dL, though may be lower in euglycemic DKA)
• Metabolic acidosis (pH <7.3, bicarbonate <18 mEq/L)
• Ketonemia/ketonuria

Goals of Treatment

1. Correct dehydration
2. Correct hyperglycemia
3. Correct electrolyte abnormalities (especially potassium)
4. Correct ketoacidosis
5. Identify and treat precipitating cause (infections, missed insulin, MI)

Step-by-Step Management (Barash's Clinical Anesthesia + Creasy & Resnik)

1. IV Fluids (most important initial step)

• DKA patients are severely dehydrated - anticipate 4-10 L fluid deficit
• Start: 0.9% Normal Saline (isotonic) at 1 L/hr for first 1-2 hours (or 15-20 mL/kg/hr)
• Then: 0.45% NaCl at 250-500 mL/hr (once hemodynamically stable)
• When blood glucose falls to 250 mg/dL, switch to Dextrose 5% in 0.45% NaCl at 100-250 mL/hr (to prevent hypoglycemia while continuing insulin)

2. Insulin

• Do NOT start insulin until K+ ≥ 3.5 mEq/L (insulin drives K+ into cells → fatal hypokalemia)
• Regular insulin:
  • IV bolus: 0.1 units/kg, then
  • IV infusion: 0.1 units/kg/hr (or use glucose/150 formula)
• Target: blood glucose reduction of 50-75 mg/dL/hr
• Continue insulin infusion until pH >7.3, bicarb >15, anion gap closed
• Transition to subcutaneous insulin 1-2 hours before stopping infusion

3. Potassium Replacement (critical)

• DKA patients have total body K+ depletion (despite initially normal/high serum K+ due to acidosis shifting K+ out of cells)
• Replace K+ when:
  • K+ < 3.5 mEq/L: Replace before starting insulin (20-40 mEq/hr)
  • K+ 3.5-5.5 mEq/L: Replace 20-30 mEq/hr alongside insulin
  • K+ > 5.5 mEq/L: Hold K+, recheck every 2 hours
• Monitor K+ every 1-2 hours with continuous ECG monitoring when replacing >10 mEq/hr

4. Bicarbonate

• Only consider if pH < 6.9 (severe acidosis)
• Not routinely recommended as it may worsen hypokalemia, paradoxical CNS acidosis, and delay resolution of ketosis

5. Phosphate

• Routine replacement not recommended; replace if severe symptomatic hypophosphatemia (<1 mg/dL) or respiratory compromise

6. Treat Precipitating Cause

• Most common: Infection (pneumonia, UTI) - cultures, antibiotics if infected
• Missed insulin doses, new-onset T1DM, MI, stroke, pancreatitis

7. Monitoring

• Blood glucose every 1 hour
• Electrolytes, BUN, creatinine, ABG every 2-4 hours
• Urine output >0.5 mL/kg/hr
• Vital signs continuously

Q6. Decomposition (Composition) and Uses of ORS

Composition of ORS (WHO/UNICEF Oral Rehydration Salts)

WHO 2003 Revised Low-Osmolarity ORS Formula:

Electrolyte content per litre:

Home-made ORS (simple recipe)

• 1 litre clean water
• 6 level teaspoons of sugar
• 0.5 teaspoon of salt

Mechanism of Action

Uses of ORS

1. Acute diarrheal illness (gastroenteritis, cholera, traveler's diarrhea) - primary indication; WHO-recommended first-line treatment in mild-to-moderate dehydration
2. Cholera - ORS is the cornerstone; reduces mortality dramatically
3. Prevention of dehydration in early diarrhea before dehydration sets in
4. Replacement of ongoing losses during diarrhea (in addition to IV fluids in severe cases)
5. Rehydration in children with acute diarrhea - reduces hospitalization rates and mortality
6. Heat exhaustion / heat stroke with fluid and electrolyte loss
7. Supplementation after IV rehydration in severe cases (oral maintenance after correction)
8. Sports rehydration (commercial versions like electrolyte drinks)

Advantages of ORS over Plain Water

• Replaces both fluid AND electrolytes (Na+, K+, bicarbonate/citrate)
• Corrects metabolic acidosis (citrate/bicarbonate)
• Restores potassium (prevents hypokalemia)
• Cheaper and accessible compared to IV fluids
• Can be administered by family caregivers at home

Management of Organophosphate (OP) Poisoning

Background and Mechanism

• Muscarinic receptors (smooth muscle, secretory glands, heart)
• Nicotinic receptors (skeletal muscle, autonomic ganglia)
• CNS receptors (brain, spinal cord)

Clinical Features

Muscarinic Effects (mnemonic: DUMBELS or SLUDGE)

Nicotinic Effects (NMJ and autonomic ganglia)

• Muscle fasciculations and twitching
• Muscle weakness → paralysis (including respiratory muscles)
• Tachycardia (nicotinic ganglionic stimulation)
• Hypertension

CNS Effects

• Anxiety, restlessness, headache
• Seizures
• Coma
• Central respiratory depression → apnea

Death in OP poisoning is primarily due to respiratory failure - from bronchospasm + bronchorrhea + respiratory muscle paralysis + central apnea.

Diagnosis

• Clinical - exposure history + cholinergic toxidrome
• Lab: Serum and RBC cholinesterase levels (reduced) - obtain before giving pralidoxime
• ABG (hypoxemia, respiratory acidosis)
• ECG (bradycardia, prolonged QTc)
• Blood glucose (may be elevated)

Management

Step 1: Decontamination (very important, done simultaneously with resuscitation)

• Remove clothing immediately (OP compounds are absorbed through skin)
• Wash skin thoroughly with soap and water
• Eye exposure: Irrigate with copious water/saline
• Ingestion: Gastric lavage if within 1 hour of ingestion and airway is protected
• Healthcare workers must wear gloves and protective gear - secondary contamination is a real risk

Step 2: Resuscitation (ABC)

• Airway: Suction secretions; early endotracheal intubation in severe poisoning
  • Avoid succinylcholine (suxamethonium) - AChE inhibition prolongs its action → prolonged neuromuscular blockade; prefer rocuronium
• Breathing: Mechanical ventilation if respiratory failure
• Circulation: IV access, fluids for hypotension, cardiac monitoring
• Avoid beta-blockers and ester-type anesthetics (potentiate OP poisoning)

Step 3: ANTIDOTES

A. ATROPINE - First-line antidote

• Adults: 1-3 mg IV initially (0.05 mg/kg in children)
• Double the dose every 5 minutes until adequate atropinization is achieved
• Severely poisoned patients may need 200-500 mg in the first hour (and hundreds of mg total)
• Once stabilized: maintenance IV infusion at 10-20% of the total loading dose per hour

• Drying of respiratory secretions (most important)
• Clear chest on auscultation (no wheeze/crackles)
• Heart rate > 80 bpm
• Systolic BP > 80 mmHg
• Easing of respiratory effort, normal respiratory rate

• Tachycardia is NOT a contraindication to atropine (it may be from hypoxia due to bronchospasm - which atropine treats)
• Pupillary dilation is NOT the endpoint
• Atropine does NOT reverse muscle weakness/paralysis - respiratory support is still needed
• Large quantities of atropine may be needed; contact pharmacy/blood bank early for supply

B. PRALIDOXIME (2-PAM) - Oxime / Cholinesterase Reactivator

• Adults: 1-2 g IV bolus over 30 minutes (25-50 mg/kg in children)
• Can repeat every 1 hour as needed based on response
• Alternative: 2 g bolus over 20 min → infusion of 500 mg/hr for up to 7 days
• WHO recommended: 30 mg/kg IV bolus → infusion of 8 mg/kg/hr

• Respiratory depression or failure
• Muscle fasciculations
• Seizures
• Dysrhythmias
• Hemodynamic instability
• Need for large/repeated atropine doses

Step 4: Seizure Management

• Benzodiazepines (diazepam, lorazepam) - first-line
• Atropine may also help abort early seizures from cholinergic overstimulation
• Phenytoin is less effective
• Airway protection, oxygen, and atropine must accompany antiepileptic treatment

Step 5: Monitoring

Phases and Complications

Drugs to AVOID in OP Poisoning

Summary Algorithm

Exposure to OP
     ↓
Decontaminate (remove clothes, wash skin) + PPE for staff
     ↓
Resuscitate: Airway (intubate if needed) + Breathing + IV access
     ↓
ATROPINE 1-3 mg IV → double every 5 min → until secretions dry
     ↓
PRALIDOXIME 1-2 g IV over 30 min → infusion 500 mg/hr
     ↓
BENZODIAZEPINES for seizures
     ↓
ICU monitoring: AChE levels, ABG, ECG, respiratory function
     ↓
Watch for Intermediate Syndrome (24-96 h) → Ventilate
     ↓
Delayed neuropathy (2-5 wk) → Supportive