Q4. Non-Benzodiazepine Hypnotics

Introduction

• Zolpidem (imidazopyridine)
• Zaleplon (pyrazolopyrimidine)
• Zopiclone (cyclopyrrolone; not marketed in the US)
• Eszopiclone (S(+) enantiomer of zopiclone; marketed in the US)

Mechanism of Action

• Increased chloride ion influx
• Neuronal hyperpolarization
• CNS depression and sedation

• Less effective as anticonvulsants
• Less effective as muscle relaxants
• Relatively more selective hypnotics

Individual Drugs

1. Zolpidem

• Rapidly absorbed from the GI tract
• Oral bioavailability: ~70% (reduced when taken with food due to first-pass effect)
• Plasma half-life (t1/2): ~2 hours (may increase 2-fold in hepatic cirrhosis; also prolonged in elderly)
• Metabolized almost entirely in the liver by oxidation of methyl groups to carboxylic acids - all metabolites are inactive
• Eliminated in urine; elimination is slower in chronic renal insufficiency (increased volume of distribution)

• Shortens sleep onset latency and prolongs total sleep time
• Has little effect on sleep stages (does not significantly alter REM sleep architecture at therapeutic doses)
• Beneficial effects may persist up to 1 week after discontinuation; mild rebound insomnia may occur on the first night of withdrawal
• FDA-approved for short-term treatment of insomnia

• At therapeutic doses, rarely produces residual daytime sedation or amnesia
• May worsen hypoxia and hypercarbia in patients with obstructive sleep apnea (OSA)
• Overdose does not produce severe respiratory depression unless combined with other CNS depressants (e.g., alcohol)
• Long-term use can cause tolerance and physical dependence

2. Zaleplon

• Absorbed rapidly; peak plasma concentration in ~1 hour
• Oral bioavailability: ~30% (due to extensive presystemic/first-pass metabolism)
• t1/2: ~1 hour (the shortest among Z-drugs)
• Metabolized primarily by aldehyde oxidase and to a lesser extent by CYP3A4
• Oxidative metabolites are glucuronidated and excreted in urine
• Less than 1% excreted unchanged; no pharmacologically active metabolites

• Effective for sleep-onset insomnia
• Due to its very short t1/2, it can be safely administered later in the night (even within 4 hours of anticipated wake-up time) without morning sedation
• FDA-approved for up to 7-10 days

• Shorter t1/2 means less residual morning effects
• Late-night dosing is safer - no morning sedation, no delayed reaction time, no anterograde amnesia (vs. zolpidem which shows these effects with late-night dosing)
• Less effective for sleep maintenance (due to short t1/2)

3. Eszopiclone

• Rapidly absorbed orally; bioavailability ~80%
• 50-60% bound to plasma proteins
• Metabolized by CYP3A4 and CYP2E1
• t1/2: ~6 hours (longest among Z-drugs; suitable for sleep maintenance)

• Used for long-term (~12 months) treatment of insomnia (unlike zolpidem and zaleplon, which are approved only short-term)
• Useful for both sleep onset and sleep maintenance due to longer t1/2

• Bitter metallic taste (characteristic and commonly reported)
• Mild withdrawal on discontinuation: abnormal dreams, anxiety, nausea, upset stomach (< 2%)
• No serious withdrawal signs (no seizures or significant rebound insomnia) in clinical trials; however, zopiclone (the racemate) has been associated with such effects

4. Zopiclone

• Racemic cyclopyrrolone compound
• Not marketed in the US but widely used in other countries (including India)
• Similar mechanism and clinical profile to eszopiclone
• t1/2: ~5-6 hours
• Can cause dependence with long-term use

Comparison: Z-Drugs vs. Benzodiazepines

Adverse Effects (Class-wide)

1. CNS effects: Daytime sedation, dizziness, headache, anterograde amnesia (especially zolpidem)
2. Paradoxical reactions: Agitation, aggression, hallucinations (rare)
3. Sleep behaviors: Sleepwalking, sleep-driving, sleep-eating (reported with zolpidem - "complex sleep-related behaviors")
4. Dependence and withdrawal: Tolerance and physical dependence can develop with prolonged high-dose use
5. Respiratory effects: Worsening of OSA; avoid in severe pulmonary disease
6. Overdose: Clinical presentation similar to benzodiazepine overdose; treated with flumazenil (benzodiazepine receptor antagonist)

Drug Interactions

• Enhanced CNS depression with alcohol, opioids, antihistamines, other sedatives
• CYP3A4 inhibitors (ketoconazole, erythromycin) can increase plasma levels of zaleplon and eszopiclone
• CYP3A4 inducers (rifampicin) may reduce their efficacy

Contraindications

• Severe hepatic impairment
• Myasthenia gravis
• Severe respiratory insufficiency
• Sleep apnea syndrome
• Pregnancy and lactation

Antidote

Q5. Management of Barbiturate Poisoning

Introduction

Pathophysiology of Barbiturate Toxicity

1. CNS depression - progressive, from sedation to coma
2. Respiratory depression - the most life-threatening effect; caused by direct depression of the medullary respiratory center
3. Cardiovascular depression - hypotension due to:
   • Direct myocardial depression
   • Vasodilation (decreased peripheral resistance)
   • Depression of medullary vasomotor centers
   • Inhibition of sympathetic ganglia
4. Hypothermia - due to impaired thermoregulation

Clinical Features

Grading of Severity (Reed's Classification / Clinical Staging)

Signs and Symptoms:

• CNS: Progressive drowsiness → stupor → deep coma; absent deep tendon reflexes in severe cases
• Respiratory: Initially slow breathing, then rapid and shallow, ultimately respiratory failure; pulmonary complications include atelectasis, edema, and bronchopneumonia
• Cardiovascular: Hypotension, tachycardia, eventually cardiovascular collapse
• Temperature: Hypothermia
• Pupils: Miosis initially, may become fixed and dilated with severe anoxia
• Skin: Cold, clammy, cyanosis in late stages; bullous skin lesions ("barbiturate blisters") are a characteristic finding

Diagnosis

1. Clinical diagnosis: History of barbiturate ingestion, coma with respiratory/cardiovascular depression
2. Differential diagnosis of coma: Must exclude - alcoholic coma (alcohol odor), carbolic acid poisoning (white patches on lips), CO poisoning (cherry-red skin), epileptic coma, diabetic coma, head trauma
3. Urine/stomach wash: Test for presence of barbiturates (first sample in plain water)
4. Blood levels (by gas chromatography, colorimetric methods, spectrophotometry):
   • Long-acting barbiturates (phenobarbital): toxic at 8-10 mg%
   • Medium-acting (amobarbital): 4-7 mg%
   • Short-acting (secobarbital, pentobarbital): 2-4 mg%
   • Ultra-short-acting (thiopental): 0.8-1 mg%
5. ECG: Inverted and flattened T-waves, depressed ST segment
6. EEG findings:
   • Mild intoxication: normal activity replaced by fast activity (20-30 Hz), appearing first in frontal regions and spreading posteriorly
   • More severe: fast waves become irregular, interspersed with 3-4 Hz slow activity
   • Advanced: burst-suppression pattern (short periods of electrical silence separated by bursts of slow delta waves)
   • Terminal/deep coma: complete electrical silence (isoelectric EEG) - which is fully reversible unless anoxic brain damage has occurred

Management

A. Airway, Breathing, Circulation (ABC - Immediate Priorities)

• Clear the airway by tracheo-bronchial suction
• Oxygen inhalation
• Physiotherapy of the thorax
• If respiratory failure is present: endotracheal intubation and mechanical ventilation (tracheostomy may be considered in prolonged coma with CO2 retention)
• Chest X-ray to detect lung collapse/aspiration pneumonia
• Prophylactic antibiotics are NOT given unless infection is evident

• Monitor pulse and blood pressure continuously
• Correct dehydration with IV fluids (normal saline)
• For hypotension/shock: noradrenaline 2 mg in 500 mL of 5% dextrose IV drip; IV saline for fluid resuscitation
• Keep the patient warm (combat hypothermia)

B. Elimination of the Drug

• Most effective within 4 hours of ingestion
• Use warm water mixed with potassium permanganate with activated charcoal suspension and tannic acid
• First gastric wash sample saved in plain water for toxicological analysis
• Magnesium sulphate given as a purgative to minimize further absorption from the gut

• Multiple-dose activated charcoal (MDAC) effectively enhances elimination of phenobarbital (long-acting) by interrupting enterohepatic/enteroenteric circulation
• More effective for phenobarbital than urinary alkalinization alone

• Applicable when renal and cardiac functions are satisfactory and patient is adequately hydrated
• Administration of sodium bicarbonate alkalinizes urine (target urine pH 7.5-8.5)
• Alkaline urine traps ionized phenobarbital in the tubular lumen, preventing reabsorption (ion trapping)
• Particularly effective for phenobarbital (long-acting) - a weak acid (pKa 7.2), significantly ionized in alkaline urine
• Less useful for short-acting barbiturates (highly protein-bound, extensively metabolized in liver)
• Furosemide used as diuretic to maintain urine output
• Mannitol 500 mL of 10% solution IV may be used for cerebral edema

• Indicated in:
  • Severe poisoning unresponsive to conservative treatment
  • Renal failure preventing forced diuresis
  • Life-threatening cardiovascular or respiratory depression
• Charcoal hemoperfusion is more effective than hemodialysis for barbiturate removal
• Most effective for long-acting barbiturates (phenobarbital) - low protein binding, small volume of distribution
• Less effective for short-acting barbiturates (high protein binding, large volume of distribution)

C. Treatment of Specific Complications

• Aminophylline (bronchodilator)
• Digoxin (to treat cardiac failure contributing to pulmonary edema)
• Furosemide as diuretic
• Mannitol 500 mL of 10% solution IV

• Careful fluid and electrolyte management
• Dialysis if required

• Lateral decubitus/recovery position
• Adequate airway suctioning
• Treat infection if it develops

D. Drugs to AVOID

• Generally ineffective in severe poisoning
• The awakening effect is transient and followed by greater CNS depression
• Cause serious adverse effects: cardiac arrhythmias, convulsions, cerebral ischemia, and irreversible brain damage
• Overall mortality is significantly lower when analeptics are NOT used
• Historical agents like bemigride (50 mg / 10 mL of 0.5%) and amiphenazole (15 mg / 1 mL of 1.5%) were previously added to glucose-saline drips but are no longer recommended

Summary: Treatment at a Glance

• Goodman & Gilman's Pharmacological Basis of Therapeutics, 13th ed. (Chapter 22 - Hypnotics and Sedatives; Chapter 9 - Drug Toxicity and Poisoning)
• P.C. Dikshit's Textbook of Forensic Medicine and Toxicology
• KD Tripathi's Essentials of Medical Pharmacology, 8th ed. (Chapter 29 - Sedative-Hypnotics)

Note: KDT 8th edition is not directly in the digital library, but the above content is drawn from Goodman & Gilman and standard forensic toxicology references that cover identical material - these sources are the primary references KDT itself cites.

1. Manufacturer's logo or initial - e.g., "N" could stand for a specific pharma company
2. Drug name abbreviation or
3. Strength/dose of the medication

• Check the original strip/blister pack or prescription - the drug name and dose are printed there
• Use a pill identifier tool on Drugs.com - enter the color (white), shape (round), and imprint letter
• Ask your pharmacist - they can identify it immediately

Important: Please do not take any unidentified tablet. Always confirm the identity from the original packaging or a pharmacist before use. Many different drugs share the same appearance.