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PHARMACOLOGY - 2nd MBBS COMPLETE NOTES

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PART 1: PRE-ANAESTHETIC MEDICATION (PREMEDICATION)

Definition

Purposes / Goals of Premedication

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FOUR EXAMPLES FROM DIFFERENT CLASSES

1. Benzodiazepines - Midazolam / Diazepam

2. Opioid Analgesics - Morphine / Pethidine

3. Anticholinergics - Atropine / Glycopyrrolate

4. Antihistamines / Phenothiazines - Promethazine

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PHARMACOLOGICAL BASIS + MOA OF TWO AGENTS

Agent 1: MIDAZOLAM (Benzodiazepine)

• Water-soluble, short-acting, produces reliable anxiolysis, anterograde amnesia, and sedation
• Onset: 2-3 min IV; Duration: 30-60 min
• Most preferred premed in modern practice

┌─────────────────────────────────────────────────────────────┐
│           GABA-A RECEPTOR (Cl⁻ ion channel)                │
│                                                             │
│  BZD Binding Site                                           │
│       ↓ (Midazolam binds here)                             │
│  ┌────┴──────────────────────────────────────────────┐     │
│  │  α subunit ←— BZD Site   β subunit ←— GABA Site  │     │
│  │                                                    │     │
│  │        ↓ Allosteric potentiation                  │     │
│  │   GABA binding → ↑ frequency of Cl⁻               │     │
│  │   channel opening → Cl⁻ influx →                  │     │
│  │   HYPERPOLARIZATION of neuron                     │     │
│  └────────────────────────────────────────────────────┘     │
│                                                             │
│   Result: ↑ inhibitory neurotransmission → CNS depression  │
│   Anxiolysis, Sedation, Amnesia, Anticonvulsant            │
└─────────────────────────────────────────────────────────────┘

• Midazolam does NOT open Cl⁻ channels by itself - it requires GABA to be present
• It increases the frequency of Cl⁻ channel opening (barbiturates increase duration)
• Acts on α1 subunit (sedation, amnesia) and α2 subunit (anxiolysis)

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Agent 2: ATROPINE (Anticholinergic)

• Competitive antagonist of muscarinic receptors
• Used routinely in the past; now used selectively

     Normal:                    Atropine Effect:
   ACh + M receptor         Atropine blocks ACh binding
        ↓                              ↓
   ↑ Secretions                ↓ Salivary secretions (dry mouth)
   ↓ Heart rate                ↑ Heart rate (prevents bradycardia)
   Bronchoconstriction         Bronchodilation
   ↑ GI motility               ↓ GI motility

• Blocks M1, M2, M3 receptors (non-selective)
• M2 blockade → prevents reflex vagal bradycardia during laryngoscopy/intubation
• M3 blockade → reduces salivary, bronchial secretions (dry field for intubation)
• Also has mild CNS sedation at premedication doses

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PART 2: DRUG DEPENDENCE AND CHRONIC ALCOHOLISM MANAGEMENT

DRUG DEPENDENCE

Definition

Types

Terminology (WHO)

• Tolerance: Decreasing effect with same dose; need more drug for same effect
• Withdrawal syndrome: Symptoms on abrupt stoppage (opposite of drug effects)
• Cross-dependence: One drug suppresses withdrawal of another (e.g., methadone for heroin)
• Cross-tolerance: Tolerance to one drug confers tolerance to another in same class

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MANAGEMENT OF OPIOID DEPENDENCE

1. Detoxification

• Methadone substitution: Long-acting oral opioid; gradually tapered
  • Prevents withdrawal, suppresses craving
  • Dose: 20-80 mg/day, tapered over weeks to months
• Buprenorphine: Partial μ-agonist; safer (ceiling effect on respiratory depression)
  • Combined with naloxone (Suboxone) to prevent IV abuse
• Clonidine: α2-agonist; suppresses autonomic symptoms of withdrawal (sweating, piloerection, tachycardia, hypertension)

2. Maintenance (relapse prevention)

• Naltrexone: Opioid antagonist; blocks euphoria if opioid is taken
  • Oral 50 mg/day or monthly IM injection (Vivitrol)
• Methadone maintenance therapy (MMT): For chronic heroin addicts

3. Psychosocial support

• Counseling, cognitive behavioral therapy, support groups (NA)

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MANAGEMENT OF CHRONIC ALCOHOLISM

Stages of Management

A. Acute Withdrawal (Alcohol Withdrawal Syndrome)

  0-6 hrs: Tremors, anxiety, insomnia, tachycardia, hypertension
  6-24 hrs: Seizures ("rum fits")
  24-72 hrs: Delirium Tremens (DTs) — hallucinations, agitation, fever, autonomic instability

• Benzodiazepines (FIRST LINE):
  • Diazepam: 10-20 mg PO Q1-2h (symptom-triggered) or fixed schedule
  • Chlordiazepoxide: Preferred in liver disease
  • Lorazepam: Safe in severe liver disease (no active metabolites)
  • Cross-tolerant with alcohol (both work on GABA-A receptor)
• Thiamine (B1) 100-200 mg IV/IM BEFORE glucose (prevents Wernicke's)
• Propranolol/Atenolol: Adjunct for autonomic symptoms
• Haloperidol: For hallucinations (not for seizures)
• Magnesium sulfate: Correct hypomagnesemia (lowers seizure threshold)

B. Long-Term Abstinence (Anti-craving Drugs)

C. DISULFIRAM REACTION (Important Exam Topic)

Alcohol ingestion + Disulfiram
         ↓
Alcohol → Acetaldehyde (by ADH)
         ↓
Disulfiram inhibits ALDH
         ↓
Acetaldehyde ACCUMULATES (10x normal)
         ↓
Flushing, Throbbing headache,
Nausea/Vomiting, Hypotension,
Tachycardia, Respiratory distress
(Severe reaction may be fatal)

D. Nutritional Support

• Thiamine (B1): Prevent Wernicke-Korsakoff syndrome
• Folate, B12: Correct deficiencies
• Multivitamins

E. Treatment of Complications

• Liver cirrhosis, peripheral neuropathy, cardiomyopathy management

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PART 3: SEDATIVE AND HYPNOTIC DRUGS

Classification

SEDATIVE-HYPNOTIC DRUGS
│
├── Benzodiazepines
│   ├── Long-acting: Diazepam, Chlordiazepoxide, Flurazepam
│   ├── Intermediate: Oxazepam, Lorazepam, Temazepam
│   └── Short-acting: Triazolam, Midazolam, Alprazolam
│
├── Barbiturates
│   ├── Ultra-short: Thiopentone, Methohexitone
│   ├── Short: Secobarbital, Pentobarbital
│   ├── Intermediate: Amobarbital, Butabarbital
│   └── Long-acting: Phenobarbital, Mephobarbital
│
├── Z-drugs (Non-BZD BZD-receptor agonists)
│   ├── Zopiclone, Zolpidem, Zaleplon
│
├── Melatonin receptor agonists: Ramelteon, Melatonin
├── Orexin antagonists: Suvorexant, Lemborexant
├── Older sedatives: Chloral hydrate, Paraldehyde, Bromides
└── Antihistamines: Diphenhydramine, Promethazine

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PART 4: BENZODIAZEPINES

Classification of Benzodiazepines

Based on Duration of Action

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MECHANISM OF ACTION OF BENZODIAZEPINES

╔══════════════════════════════════════════════════════════════════════╗
║              GABA-A RECEPTOR COMPLEX                                ║
║                                                                      ║
║    Pentameric structure: 2α + 2β + 1γ subunits                     ║
║                                                                      ║
║         BZD site (α-γ interface)                                    ║
║              ↓                                                       ║
║  ┌──────────────────────────────────────────────────────────┐       ║
║  │  α1 → Sedation, amnesia, anticonvulsant                 │       ║
║  │  α2 → Anxiolysis, muscle relaxation                     │       ║
║  │  α3 → Anxiolysis                                        │       ║
║  │  α5 → Cognitive/memory effects                          │       ║
║  └──────────────────────────────────────────────────────────┘       ║
║                                                                      ║
║  BZD binds → ALLOSTERIC MODULATION                                  ║
║           ↓                                                          ║
║  GABA affinity ↑ → MORE Cl⁻ channel openings                       ║
║           ↓                                                          ║
║  ↑ FREQUENCY of Cl⁻ channel opening (NOT duration)                 ║
║           ↓                                                          ║
║  Cl⁻ influx → Membrane HYPERPOLARIZATION                           ║
║           ↓                                                          ║
║  ↓ Neuronal excitability → CNS DEPRESSION                          ║
║                                                                      ║
║  KEY: BZDs REQUIRE GABA to be present - they are allosteric        ║
║  modulators, NOT direct channel openers (→ safer ceiling)          ║
╚══════════════════════════════════════════════════════════════════════╝

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THERAPEUTIC USES OF BENZODIAZEPINES

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ADVERSE EFFECTS OF BENZODIAZEPINES

CNS Effects

• Sedation, drowsiness, hangover effect (long-acting)
• Anterograde amnesia (especially midazolam)
• Impaired psychomotor performance - dangerous for driving
• Paradoxical excitement (especially in elderly/children)
• Cognitive impairment with prolonged use

Respiratory

• Respiratory depression (especially IV; less than barbiturates)
• Dangerous in COPD, sleep apnea, obesity hypoventilation

Cardiovascular

• Mild hypotension (IV)
• Generally cardiovascularly safe

Tolerance and Dependence

• Tolerance develops to sedative/hypnotic effects (less to anxiolytic)
• Physical dependence with prolonged use
• Withdrawal syndrome: Rebound anxiety, insomnia, tremors, seizures (severe)
• Cross-dependence with alcohol and other CNS depressants

Teratogenicity

• Category D in pregnancy
• Neonatal withdrawal syndrome
• Floppy infant syndrome

Drug Interactions

• Potentiated by alcohol, opioids, antihistamines (CNS depression)
• Reduced by enzyme inducers (rifampicin, carbamazepine)

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PART 5: BARBITURATES

Classification of Barbiturates

By Duration of Action

BARBITURATES (Based on Duration of Action)
│
├── ULTRA-SHORT ACTING (IV Anaesthesia)
│   ├── Thiopentone sodium (t½: 5-10 min)
│   ├── Methohexitone
│   └── (Mechanism: Rapid redistribution to fat/muscle)
│
├── SHORT ACTING (Hypnotic)
│   ├── Secobarbital (Seconal)
│   └── Pentobarbital (Nembutal)
│   (t½: 3-8 hrs)
│
├── INTERMEDIATE ACTING
│   ├── Amobarbital (Amytal)
│   └── Butabarbital
│   (t½: 8-20 hrs)
│
└── LONG ACTING (Anticonvulsant)
    ├── Phenobarbital (t½: 40-140 hrs)
    └── Mephobarbital
    (Primarily hepatic metabolism + renal excretion)

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MECHANISM OF ACTION OF BARBITURATES

╔══════════════════════════════════════════════════════════════════╗
║           BARBITURATE MOA AT GABA-A RECEPTOR                    ║
║                                                                  ║
║  Barbiturate binding site: β subunit (separate from BZD site)  ║
║                                                                  ║
║  LOW doses:                                                      ║
║    Barbiturate binds β subunit                                  ║
║         ↓                                                        ║
║    Potentiates GABA action                                       ║
║    ↑ DURATION of Cl⁻ channel opening                           ║
║         ↓                                                        ║
║    Cl⁻ influx → Hyperpolarization → CNS depression             ║
║                                                                  ║
║  HIGH doses:                                                     ║
║    Direct activation of Cl⁻ channel (GABA-INDEPENDENT)         ║
║         ↓                                                        ║
║    Also block AMPA/kainate (glutamate) receptors               ║
║         ↓                                                        ║
║    NO CEILING EFFECT → Respiratory depression, DEATH           ║
║                                                                  ║
║  KEY DIFFERENCE FROM BZD:                                       ║
║  Barbiturates can directly open Cl⁻ channels without GABA     ║
║  → Explains narrow therapeutic index + lethality in overdose   ║
╚══════════════════════════════════════════════════════════════════╝

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ADVERSE EFFECTS OF BARBITURATES

Acute Effects

• Sedation, hangover, impaired cognition
• Respiratory depression (dose-dependent, NO ceiling)
• Cardiovascular depression (hypotension, myocardial depression)
• Laryngospasm (thiopentone)
• Nausea, vomiting

Chronic/Long-term Effects

• Enzyme induction (CYP450): Accelerates metabolism of many drugs
  • Warfarin, OCP, phenytoin, corticosteroids - all have reduced effect
  • Also induces its own metabolism (pharmacokinetic tolerance)
• Tolerance develops rapidly
• Dependence - both physical and psychological
• Severe withdrawal (seizures, hyperthermia, death - worse than opioid withdrawal)

Idiosyncratic/Special Effects

• Acute intermittent porphyria: Barbiturates induce ALA synthase → precipitate porphyric crisis (ABSOLUTE CONTRAINDICATION)
• Hyperalgesia: Paradoxical increase in pain sensitivity at subanaesthetic doses
• Antianalgesia: Barbiturates worsen pain - NOT analgesics
• Hypersensitivity reactions (skin rashes, Stevens-Johnson syndrome - rare)

Teratogenicity

• Neonatal drug withdrawal
• Fetal effects with chronic use

Overdose

• Coma, respiratory arrest, cardiovascular collapse
• No specific antidote (unlike BZD which has flumazenil)
• Treatment: supportive, alkalinize urine (for phenobarbital)

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PART 6: BENZODIAZEPINES vs. BARBITURATES - WHY BZDs ARE PREFERRED

BZDs Preferred Over Barbiturates - Reasons

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COMPARE AND CONTRAST: BENZODIAZEPINES vs. BARBITURATES

┌──────────────────────┬────────────────────────────┬──────────────────────────────┐
│ FEATURE              │ BENZODIAZEPINES             │ BARBITURATES                 │
├──────────────────────┼────────────────────────────┼──────────────────────────────┤
│ Prototype            │ Diazepam                   │ Phenobarbital / Thiopentone  │
│ Year introduced      │ 1961 (Chlordiazepoxide)    │ 1903 (Barbital)              │
├──────────────────────┼────────────────────────────┼──────────────────────────────┤
│ Receptor site        │ BZD site (α-γ junction)    │ β subunit of GABA-A          │
│                      │ GABA-A receptor             │ GABA-A + AMPA receptors      │
├──────────────────────┼────────────────────────────┼──────────────────────────────┤
│ MOA (Channel)        │ ↑ FREQUENCY of Cl⁻ opening │ ↑ DURATION of Cl⁻ opening   │
│ GABA dependence      │ YES - requires GABA         │ NO - can activate directly   │
├──────────────────────┼────────────────────────────┼──────────────────────────────┤
│ Ceiling effect       │ YES                         │ NO                           │
│ Therapeutic index    │ Wide                        │ Narrow                       │
├──────────────────────┼────────────────────────────┼──────────────────────────────┤
│ CNS selectivity      │ More selective              │ General CNS depressant       │
│ Analgesia            │ Minimal                     │ Anti-analgesic               │
├──────────────────────┼────────────────────────────┼──────────────────────────────┤
│ Enzyme induction     │ None                        │ Potent (CYP2C9, CYP3A4)     │
│ Drug interactions    │ Less                        │ Many (reduces drug levels)   │
├──────────────────────┼────────────────────────────┼──────────────────────────────┤
│ Antidote             │ Flumazenil                  │ None                         │
│ Overdose             │ Rarely fatal alone          │ Often fatal                  │
├──────────────────────┼────────────────────────────┼──────────────────────────────┤
│ Dependence           │ Yes (less severe withdrawal)│ Yes (severe, fatal withdrawal│
│ Withdrawal           │ Rebound anxiety, seizures   │ Seizures, hyperthermia,death │
├──────────────────────┼────────────────────────────┼──────────────────────────────┤
│ Sleep architecture   │ Mild REM suppression        │ Marked REM suppression       │
│ Hangover             │ Less                        │ More                         │
├──────────────────────┼────────────────────────────┼──────────────────────────────┤
│ Porphyria            │ Safe                        │ Contraindicated              │
│ Abuse potential      │ Moderate                    │ High                         │
├──────────────────────┼────────────────────────────┼──────────────────────────────┤
│ Uses                 │ Anxiety, insomnia, epilepsy │ Epilepsy, IV anaesthesia     │
│                      │ Alcohol withdrawal, premed  │ (limited modern use)         │
└──────────────────────┴────────────────────────────┴──────────────────────────────┘

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GABA-A RECEPTOR - COMBINED DIAGRAM (BZD vs. Barbiturate Sites)

                    GABA-A RECEPTOR CHLORIDE CHANNEL
                         (Pentameric Structure)

                    ┌──────────────────────┐
                    │    Extracellular      │
                    │                       │
          GABA ─────┤→ β subunit site       │
                    │                       │
     Benzodiazepines┤→ α-γ interface site   │
                    │   (BZD binding site)  │
    Barbiturates ───┤→ β subunit site       │
                    │   (inside channel)    │
      Neurosteroids ┤→ α-δ / α-β interface │
                    │                       │
                    │    Cl⁻ Channel ←──── │
                    │      ↓↑               │
                    │   Cl⁻ flux            │
                    └──────────────────────┘
                         Intracellular

  BZD effect: ↑ FREQUENCY of channel opening (GABA-dependent)
  BAR effect: ↑ DURATION of channel opening + direct activation (at high doses)

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SUMMARY MNEMONICS

• Benzodiazepines - anxiolysis/amnesia
• Opioids - analgesia
• Anticholinergics - dry secretions, prevent bradycardia
• Steroids/antiemetics/antacids - prevent aspiration/PONV

• Safe in overdose (wide TI)
• Antidote exists (flumazenil)
• Frequency of Cl⁻ channel opening (selective MOA)
• Enzyme induction - absent
• Sleep architecture - less disturbed
• Therapeutic selectivity - better

• Disulfiram - aversion
• Naltrexone - anti-craving
• Acamprosate - reduces glutamate-mediated craving

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• Tripathi KD. Essentials of Medical Pharmacology, 8th ed. - Chapters 21, 22, 26, 27
• Goodman & Gilman's Pharmacological Basis of Therapeutics, 13th ed.
• Katzung's Basic and Clinical Pharmacology, 16th ed.

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Quick Navigation Guide

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1. BZD MOA = ↑ FREQUENCY of Cl⁻ channel opening (GABA-dependent, allosteric)
2. Barbiturate MOA = ↑ DURATION of Cl⁻ channel opening + direct activation at high doses
3. BZD antidote = Flumazenil (competitive antagonist); Barbiturate antidote = None
4. Midazolam = preferred premed (water-soluble, anterograde amnesia, short-acting)
5. Atropine in premed = prevents vagal bradycardia + dries secretions (M2/M3 blockade)
6. Disulfiram = inhibits aldehyde dehydrogenase → acetaldehyde accumulation
7. Naltrexone = μ-opioid antagonist used in both opioid dependence and alcoholism
8. Acamprosate = NMDA antagonist; reduces craving in abstinent alcoholics
9. Alcohol withdrawal = treat with benzodiazepines (cross-tolerance with alcohol on GABA-A)
10. Phenobarbital = long-acting barbiturate used for epilepsy; potent CYP450 inducer
11. Barbiturates are CONTRAINDICATED in acute intermittent porphyria