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pres.title = "Sedatives, Sleeping Pills & Alcohol Pharmacology";
pres.author = "Clinical Pharmacology";

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// ═══════════════════════════════════════════════════════════════════════════
// SLIDE 1 – TITLE
// ═══════════════════════════════════════════════════════════════════════════
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  s.addText("Benzodiazepines  ·  Barbiturates  ·  New Sleeping Pills\nAlcohol Pharmacology  ·  Antagonists", {
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// ═══════════════════════════════════════════════════════════════════════════
// SLIDE 2 – OVERVIEW / AGENDA
// ═══════════════════════════════════════════════════════════════════════════
contentSlide(
  "Overview of CNS Depressants",
  [
    { text: "Two Main Classes of Sedative-Hypnotics", sub: [
      "Group 1 (Older): Barbiturates, meprobamate, chloral hydrate — dose-dependent CNS depression up to coma and death",
      "Group 2 (Modern): Benzodiazepines and Z-drugs (zolpidem, zaleplon) — safer, targeted GABA-A modulation"
    ]},
    { text: "Key Pharmacological Distinction", sub: [
      "Benzodiazepines do NOT produce surgical anesthesia or fatal intoxication alone (unlike barbiturates)",
      "Exception: midazolam can reduce tidal volume and respiratory rate",
      "Specific antagonist exists for benzodiazepines: flumazenil"
    ]},
    { text: "Alcohol (Ethanol) — a CNS Depressant", sub: [
      "Shares pharmacological properties with barbiturates and volatile anesthetics",
      "Produces dose-dependent sedation, incoordination, stupor, and death"
    ]},
    { text: "Topics Covered", sub: [
      "Benzodiazepines: mechanism, pharmacokinetics, uses, toxicity, withdrawal",
      "Barbiturates: mechanism, classification, toxicity",
      "New Sleeping Pills: Z-drugs, melatonin agonists, orexin antagonists",
      "Alcohol: pharmacokinetics, mechanisms, effects, clinical management",
      "Alcohol Antagonists: disulfiram, naltrexone, acamprosate"
    ]}
  ],
  C.accent1
);

// ═══════════════════════════════════════════════════════════════════════════
// SECTION A – BENZODIAZEPINES
// ═══════════════════════════════════════════════════════════════════════════
sectionSlide("BENZODIAZEPINES", "Mechanism · Pharmacokinetics · Clinical Uses · Adverse Effects", C.accent1);

// ─── A1 Mechanism of Action ───────────────────────────────────────────────
contentSlide(
  "Benzodiazepines — Mechanism of Action",
  [
    { text: "Target: GABA-A Receptor (Ionotropic Cl⁻ Channel)", sub: [
      "Benzodiazepines bind to a specific allosteric site at the interface of α and γ subunits",
      "They INCREASE the frequency of Cl⁻ channel opening in response to GABA",
      "They do NOT open the channel in the absence of GABA (partial allosteric modulators)"
    ]},
    { text: "Subunit Selectivity and Function", sub: [
      "Anxiolytic & sedative effects: α1 subunit (widely expressed, dominant)",
      "Anxiolytic effects: α2 subunit (limbic system)",
      "Anticonvulsant effects: α1, α2, α5 subunits",
      "Muscle relaxation: spinal cord α2/α3 subunits"
    ]},
    { text: "Result of Binding", sub: [
      "Enhanced inhibitory neurotransmission throughout the CNS",
      "Reduction of neuronal excitability → sedation, anxiolysis, muscle relaxation, anticonvulsion",
      "Contrast with barbiturates: BZDs increase FREQUENCY of Cl⁻ opening; barbiturates increase DURATION"
    ]},
    { text: "Receptor Differences from Barbiturates", sub: [
      "BZDs are allosteric modulators — require GABA to work (ceiling effect = safer)",
      "Barbiturates can directly activate GABA-A at high doses AND block AMPA/kainate receptors"
    ]}
  ],
  C.accent1
);

// ─── A2 Pharmacokinetics ─────────────────────────────────────────────────
contentSlide(
  "Benzodiazepines — Pharmacokinetics",
  [
    { text: "Absorption & Distribution", sub: [
      "Well absorbed orally; highly lipophilic → rapid CNS penetration",
      "Highly protein bound (85–99%); volume of distribution is large",
      "IV/IM routes available for urgent use (lorazepam, midazolam, diazepam)"
    ]},
    { text: "Metabolism — Hepatic (CYP3A4, CYP2C19)", sub: [
      "Most metabolised to active metabolites (e.g. diazepam → desmethyldiazepam → oxazepam)",
      "Exceptions — LOT: Lorazepam, Oxazepam, Temazepam undergo direct glucuronidation (safer in liver disease)"
    ]},
    { text: "Half-Life Classification", sub: [
      "Ultra-short: triazolam (2–5 h) — rebound insomnia common",
      "Short: oxazepam, lorazepam (8–15 h) — preferred in elderly",
      "Intermediate: temazepam, alprazolam (10–20 h)",
      "Long-acting: diazepam, chlordiazepoxide, clonazepam (20–100 h) — accumulate with repeated dosing"
    ]},
    { text: "Special Populations", sub: [
      "Elderly: reduced hepatic metabolism → increased half-life → toxicity risk",
      "Pregnancy: cross placenta → neonatal sedation; Category D for most",
      "Liver disease: use LOT drugs (glucuronidation unaffected)"
    ]}
  ],
  C.accent1
);

// ─── A3 Clinical Uses ─────────────────────────────────────────────────────
twoColSlide(
  "Benzodiazepines — Clinical Uses",
  "Indications",
  [
    "Anxiety disorders (GAD, panic, social phobia)",
    "Insomnia (short-term use only)",
    "Alcohol withdrawal (first-line: diazepam/lorazepam CIWA protocol)",
    "Status epilepticus (IV lorazepam — first-line)",
    "Acute seizures (rectal/buccal diazepam, IM midazolam)",
    "Muscle spasms / spasticity (diazepam)",
    "Pre-operative sedation & anaesthetic induction (midazolam)",
    "Procedural sedation (midazolam — anterograde amnesia)",
    "Acute agitation in psychosis (IM lorazepam)",
    "Vertigo / inner ear disorders"
  ],
  "Key Drug Examples",
  [
    "Diazepam (Valium): long-acting, muscle relaxant, alcohol WD",
    "Lorazepam (Ativan): status epilepticus, procedural, anxiety",
    "Alprazolam (Xanax): panic disorder, short-term anxiety",
    "Clonazepam (Klonopin): seizures, panic, restless legs",
    "Midazolam (Versed): induction anaesthesia, procedural sedation",
    "Temazepam: insomnia (intermediate half-life)",
    "Triazolam: insomnia (ultra-short — caution rebound)",
    "Chlordiazepoxide (Librium): alcohol withdrawal",
    "Oxazepam: alcohol WD in elderly/liver disease"
  ],
  C.accent1
);

// ─── A4 Adverse Effects ───────────────────────────────────────────────────
contentSlide(
  "Benzodiazepines — Adverse Effects & Toxicity",
  [
    { text: "CNS Effects (Dose-Dependent)", sub: [
      "Sedation, drowsiness, anterograde amnesia",
      "Psychomotor impairment — major cause of falls in elderly",
      "Paradoxical disinhibition (agitation, aggression) — especially in children and elderly",
      "Respiratory depression: significant only in overdose or when combined with other CNS depressants"
    ]},
    { text: "Tolerance and Dependence", sub: [
      "Tolerance develops to sedative and anticonvulsant effects (but less to anxiolytic effects)",
      "Physical dependence occurs with regular use for >2–4 weeks",
      "Psychological dependence — craving and compulsive use"
    ]},
    { text: "Withdrawal Syndrome", sub: [
      "Short-acting BZDs: rapid, intense withdrawal (anxiety, insomnia, tremors, sweating)",
      "Long-acting BZDs: delayed but milder withdrawal",
      "Severe withdrawal: seizures (life-threatening), delirium — similar to alcohol withdrawal",
      "Management: slow taper with long-acting BZD; cross-tolerance permits substitution"
    ]},
    { text: "Overdose", sub: [
      "Relatively safe alone: drowsiness → ataxia → sedation; rarely fatal in isolation",
      "Dangerous combined with alcohol, opioids, or other CNS depressants → respiratory failure",
      "Antidote: Flumazenil IV (competitive GABA-A antagonist) — short-acting, resedation risk"
    ]}
  ],
  C.accent1
);

// ─── A5 Flumazenil ────────────────────────────────────────────────────────
contentSlide(
  "Flumazenil — Benzodiazepine Antagonist",
  [
    { text: "Mechanism", sub: [
      "Competitive antagonist at the benzodiazepine binding site on GABA-A receptor",
      "Rapidly displaces BZDs — does NOT itself activate or significantly inhibit the receptor"
    ]},
    { text: "Pharmacokinetics", sub: [
      "IV administration; rapid onset (1–2 min), peak effect ~6–10 min",
      "Short half-life (~1 h) — much shorter than most BZDs → RESEDATION is the major risk",
      "Repeated doses or infusion may be needed"
    ]},
    { text: "Clinical Uses", sub: [
      "Reversal of BZD-induced sedation after procedures",
      "Management of BZD overdose (diagnostic and therapeutic)",
      "Note: does NOT reverse effects of barbiturates, alcohol, or Z-drugs"
    ]},
    { text: "Cautions & Contraindications", sub: [
      "Can precipitate acute withdrawal seizures in BZD-dependent patients",
      "Do NOT use in mixed overdose with TCA (can unmask TCA cardiotoxicity)",
      "Use cautiously in patients with head trauma or raised ICP",
      "Not effective for non-BZD CNS depressant overdose"
    ]}
  ],
  C.accent1
);

// ═══════════════════════════════════════════════════════════════════════════
// SECTION B – BARBITURATES
// ═══════════════════════════════════════════════════════════════════════════
sectionSlide("BARBITURATES", "Mechanism · Classification · Toxicity · Withdrawal", C.accent2);

// ─── B1 Intro & Mechanism ─────────────────────────────────────────────────
contentSlide(
  "Barbiturates — Introduction & Mechanism",
  [
    { text: "Historical & Current Context", sub: [
      "~50 barbiturates once marketed; now few remain in clinical use",
      "Largely replaced by benzodiazepines due to narrow therapeutic index and high abuse potential",
      "Still used: phenobarbital (seizures), thiopental/pentobarbital (anaesthesia, raised ICP)"
    ]},
    { text: "Chemical Basis", sub: [
      "All derived from barbituric acid; pharmacological potency depends on lipid solubility and pKa",
      "Higher lipid solubility → greater CNS potency, faster onset, shorter duration (e.g. thiopental)"
    ]},
    { text: "Mechanism of Action at GABA-A Receptor", sub: [
      "Enhance GABA-A inhibition at pre- and postsynaptic sites",
      "Increase DURATION of Cl⁻ channel opening (vs. BZDs which increase FREQUENCY)",
      "At high doses: directly activate GABA-A (independent of GABA) AND block AMPA/kainate receptors",
      "This direct activation explains the steep dose-response and ability to cause coma/death"
    ]},
    { text: "Additional CNS Targets", sub: [
      "Depress reticular activating system (RAS) → impaired consciousness",
      "Reduce excitatory postsynaptic potentials",
      "Overlap with sites of action of alcohol and volatile anaesthetics"
    ]}
  ],
  C.accent2
);

// ─── B2 Classification ────────────────────────────────────────────────────
tableSlide(
  "Barbiturates — Classification by Duration of Action",
  [
    // Header row
    [
      { text: "Class / Drug", options: { bold: true, fontSize: 12.5, color: C.darkBg, fill: { color: C.accent2 }, align: "center" } },
      { text: "Duration / Half-Life", options: { bold: true, fontSize: 12.5, color: C.darkBg, fill: { color: C.accent2 }, align: "center" } },
      { text: "Clinical Uses", options: { bold: true, fontSize: 12.5, color: C.darkBg, fill: { color: C.accent2 }, align: "center" } }
    ],
    [
      { text: "Ultra-short acting\nThiopental, methohexital", options: { fontSize: 11, color: C.white, fill: { color: C.cardBg }, bold: true } },
      { text: "Onset seconds; duration 5–30 min (IV)", options: { fontSize: 11, color: C.lightGrey, fill: { color: C.cardBg } } },
      { text: "IV induction of general anaesthesia; raised ICP management", options: { fontSize: 11, color: C.lightGrey, fill: { color: C.cardBg } } }
    ],
    [
      { text: "Short-acting\nPentobarbital (Nembutal)\nSecobarbital (Seconal)", options: { fontSize: 11, color: C.white, fill: { color: C.midBg }, bold: true } },
      { text: "< 3 h", options: { fontSize: 11, color: C.lightGrey, fill: { color: C.midBg } } },
      { text: "Pre-operative sedation; formerly: insomnia; substance abuse", options: { fontSize: 11, color: C.lightGrey, fill: { color: C.midBg } } }
    ],
    [
      { text: "Intermediate-acting\nAmobarbital (Amytal)\nButalbital", options: { fontSize: 11, color: C.white, fill: { color: C.cardBg }, bold: true } },
      { text: "3–6 h", options: { fontSize: 11, color: C.lightGrey, fill: { color: C.cardBg } } },
      { text: "Formerly: insomnia, anxiety; Butalbital: migraine (Fiorinal)", options: { fontSize: 11, color: C.lightGrey, fill: { color: C.cardBg } } }
    ],
    [
      { text: "Long-acting\nPhenobarbital", options: { fontSize: 11, color: C.white, fill: { color: C.midBg }, bold: true } },
      { text: "6+ h (half-life 80–120 h)", options: { fontSize: 11, color: C.lightGrey, fill: { color: C.midBg } } },
      { text: "Epilepsy (grand mal, status), neonatal seizures, sedation", options: { fontSize: 11, color: C.lightGrey, fill: { color: C.midBg } } }
    ]
  ],
  C.accent2
);

// ─── B3 Pharmacokinetics & Drug Interactions ─────────────────────────────
contentSlide(
  "Barbiturates — Pharmacokinetics & Drug Interactions",
  [
    { text: "Absorption & Distribution", sub: [
      "Well absorbed orally; IV form for anaesthesia and acute seizures",
      "Highly lipophilic barbiturates (thiopental) rapidly redistribute to muscle and fat after IV bolus"
    ]},
    { text: "Metabolism & Elimination", sub: [
      "Primary metabolism: hepatic (CYP1A2, CYP2C9, CYP2C19, CYP3A4) → glucuronidation → renal excretion",
      "Phenobarbital: ~25% excreted unchanged in urine (alkaline diuresis enhances elimination in overdose)"
    ]},
    { text: "ENZYME INDUCTION — Critical Drug Interactions", sub: [
      "Chronic barbiturates markedly induce CYP1A2, CYP2C9, CYP2C19, CYP3A4 + glucuronyl transferase",
      "Reduces efficacy of: warfarin, oral contraceptives, corticosteroids, vitamin D, phenytoin, theophylline",
      "Increases metabolism of endogenous: steroid hormones, cholesterol, bile salts, vitamins K and D",
      "Self-induction accounts for some pharmacological tolerance",
      "Also induces ALA synthase → may precipitate acute porphyria (CONTRAINDICATED in porphyria)"
    ]},
    { text: "Tolerance & Dependence", sub: [
      "Both pharmacodynamic (receptor downregulation) and pharmacokinetic (enzyme induction) tolerance",
      "High dependence liability; physical withdrawal can be life-threatening"
    ]}
  ],
  C.accent2
);

// ─── B4 Toxicity & Overdose ───────────────────────────────────────────────
contentSlide(
  "Barbiturate Toxicity & Overdose",
  [
    { text: "Acute Overdose Presentation", sub: [
      "Dose-response: sedation → ataxia → slurred speech → stupor → coma",
      "Fatal dose: >3 g for short-acting agents; phenobarbital >6–10 g",
      "Lethal plasma levels: pentobarbital/amobarbital ≈ 10 mg/mL; phenobarbital ≈ 60 mg/mL"
    ]},
    { text: "Respiratory Depression (Primary Cause of Death)", sub: [
      "Suppress neurogenic respiratory drive AND rhythmic respiratory centres",
      "3× hypnotic dose eliminates neurogenic drive; 10× can cause apnoea",
      "Abolishes hypoxic drive at high doses",
      "Hazardous combination with alcohol → synergistic respiratory depression"
    ]},
    { text: "Cardiovascular Effects in Overdose", sub: [
      "Hypotension from vasodilation + myocardial depression at anaesthetic doses",
      "Partial inhibition of ganglionic transmission → impaired cardiovascular reflexes",
      "Cardiac arrhythmias with IV thiobarbiturates (especially with epinephrine/halothane)"
    ]},
    { text: "Management of Acute Overdose", sub: [
      "No specific antidote (unlike BZDs with flumazenil)",
      "Supportive: airway management, mechanical ventilation, IV fluids, vasopressors",
      "Activated charcoal (if within 1 h of ingestion)",
      "Urine alkalinisation (sodium bicarbonate) to enhance phenobarbital excretion",
      "Haemodialysis for severe long-acting barbiturate poisoning"
    ]}
  ],
  C.accent2
);

// ─── B5 Withdrawal ────────────────────────────────────────────────────────
contentSlide(
  "Barbiturate Withdrawal Syndrome",
  [
    { text: "Onset & Severity", sub: [
      "More dangerous than opioid withdrawal; potentially life-threatening (like alcohol withdrawal)",
      "Short-acting barbiturates: withdrawal begins 12–24 h after last dose, peak at 2–3 days",
      "Long-acting (phenobarbital): delayed onset, milder course"
    ]},
    { text: "Clinical Features — Progressive", sub: [
      "Mild (12–24 h): anxiety, tremors, weakness, sweating, insomnia, GI upset",
      "Moderate (24–72 h): pronounced tremors, hyperreflexia, postural hypotension, fever",
      "Severe (2–8 days): grand mal seizures, hyperthermia, delirium, cardiovascular collapse"
    ]},
    { text: "Mechanism", sub: [
      "Upregulation of excitatory NMDA receptors + downregulation of inhibitory GABA-A during chronic use",
      "Abrupt cessation → NMDA hyperactivity = hyperexcitability state"
    ]},
    { text: "Management", sub: [
      "Gradual taper using long-acting phenobarbital or BZDs (cross-tolerance)",
      "Phenobarbital dose titration using CIWA-like principles",
      "Supportive care: IV fluids, electrolytes, temperature management",
      "IV BZD or pentobarbital for refractory seizures"
    ]}
  ],
  C.accent2
);

// ═══════════════════════════════════════════════════════════════════════════
// SECTION C – NEW SLEEPING PILLS
// ═══════════════════════════════════════════════════════════════════════════
sectionSlide("NEW SLEEPING PILLS", "Z-Drugs · Melatonin Agonists · Orexin Antagonists", C.accent3);

// ─── C1 Z-Drugs ───────────────────────────────────────────────────────────
contentSlide(
  "Z-Drugs — Non-Benzodiazepine Hypnotics",
  [
    { text: "Overview", sub: [
      "Also called 'benzodiazepine receptor agonists' — bind to BZD site on GABA-A but are chemically distinct",
      "Primary agents: Zolpidem (Ambien), Zaleplon (Sonata), Eszopiclone (Lunesta), Zopiclone",
      "Developed to provide safer, more selective hypnosis with reduced dependence vs. classic BZDs"
    ]},
    { text: "Mechanism", sub: [
      "Selective for GABA-A receptors containing α1 subunit (sedation/hypnosis) > α2/α3 (anxiolysis)",
      "Result: hypnotic effect without significant anxiolytic, anticonvulsant, or muscle relaxant action at therapeutic doses"
    ]},
    { text: "Pharmacokinetics", sub: [
      "Zolpidem: t½ ~2.5 h (short), rapid onset — good for sleep initiation",
      "Zaleplon: t½ ~1 h (ultra-short) — can be taken even if only 4 h until waking",
      "Eszopiclone: t½ ~6 h — better for sleep maintenance",
      "All metabolised by CYP3A4 (significant drug interactions)"
    ]},
    { text: "Adverse Effects & Cautions", sub: [
      "Residual sedation, rebound insomnia (less than BZDs but still occurs with triazolam class)",
      "Anterograde amnesia — complex behaviours: sleep-walking, sleep-driving, sleep-eating",
      "Tolerance and dependence: lower than BZDs but not absent — not for long-term use",
      "Interactions: alcohol, CYP3A4 inhibitors/inducers; caution in elderly (falls)"
    ]}
  ],
  C.accent3
);

// ─── C2 Melatonin Agonists & Orexin Antagonists ───────────────────────────
twoColSlide(
  "New Sleeping Pills — Other Agents",
  "Melatonin Receptor Agonists",
  [
    "Ramelteon (Rozerem): MT1/MT2 receptor agonist",
    "Tasimelteon: MT1/MT2 agonist (non-24 sleep-wake disorder)",
    "Mechanism: mimic melatonin action in suprachiasmatic nucleus → circadian rhythm regulation",
    "Use: sleep-onset insomnia; safe in elderly and those with substance abuse history",
    "No abuse potential — not a controlled substance",
    "Adverse effects: dizziness, somnolence, elevated prolactin",
    "Caution: CYP1A2 inhibitors (fluvoxamine markedly increases ramelteon levels)",
    "NOT effective for sleep-maintenance insomnia"
  ],
  "Orexin (Hypocretin) Receptor Antagonists",
  [
    "Suvorexant (Belsomra): dual orexin receptor antagonist (OX1R + OX2R)",
    "Lemborexant (Dayvigo): similar mechanism to suvorexant",
    "Mechanism: block wakefulness-promoting orexin/hypocretin signalling in lateral hypothalamus",
    "Use: sleep-onset AND sleep-maintenance insomnia",
    "Advantages: novel mechanism, low abuse potential vs. BZDs",
    "Adverse effects: somnolence, complex sleep behaviours, sleep paralysis",
    "Caution: CNS depressants (additive), CYP3A4 substrates",
    "Doxepin (low-dose 3–6 mg): histamine H1 antagonist — sleep maintenance"
  ],
  C.accent3
);

// ─── C3 Comparison Table ──────────────────────────────────────────────────
tableSlide(
  "Comparison of Hypnotic Drug Classes",
  [
    [
      { text: "Drug Class", options: { bold: true, fontSize: 11.5, color: C.darkBg, fill: { color: C.accent3 }, align: "center" } },
      { text: "Receptor Target & Mechanism", options: { bold: true, fontSize: 11.5, color: C.darkBg, fill: { color: C.accent3 }, align: "center" } },
      { text: "Key Clinical Notes", options: { bold: true, fontSize: 11.5, color: C.darkBg, fill: { color: C.accent3 }, align: "center" } }
    ],
    [
      { text: "Barbiturates", options: { fontSize: 11, color: C.white, fill: { color: C.cardBg } } },
      { text: "GABA-A: increase Cl⁻ channel DURATION; direct activation at high doses", options: { fontSize: 11, color: C.lightGrey, fill: { color: C.cardBg } } },
      { text: "Narrow TI; enzyme inducer; abuse potential; no antidote", options: { fontSize: 11, color: C.lightGrey, fill: { color: C.cardBg } } }
    ],
    [
      { text: "Benzodiazepines", options: { fontSize: 11, color: C.white, fill: { color: C.midBg } } },
      { text: "GABA-A (α/γ site): increase Cl⁻ channel FREQUENCY; GABA-dependent", options: { fontSize: 11, color: C.lightGrey, fill: { color: C.midBg } } },
      { text: "Wide TI; antidote (flumazenil); tolerance/dependence; safe in overdose alone", options: { fontSize: 11, color: C.lightGrey, fill: { color: C.midBg } } }
    ],
    [
      { text: "Z-Drugs\n(Zolpidem, Zaleplon)", options: { fontSize: 11, color: C.white, fill: { color: C.cardBg } } },
      { text: "GABA-A α1 selective; less anxiolytic/muscle relaxant effect", options: { fontSize: 11, color: C.lightGrey, fill: { color: C.cardBg } } },
      { text: "Short-acting; complex sleep behaviours; lower (not absent) dependence", options: { fontSize: 11, color: C.lightGrey, fill: { color: C.cardBg } } }
    ],
    [
      { text: "Melatonin Agonists\n(Ramelteon)", options: { fontSize: 11, color: C.white, fill: { color: C.midBg } } },
      { text: "MT1/MT2 in SCN; circadian regulation", options: { fontSize: 11, color: C.lightGrey, fill: { color: C.midBg } } },
      { text: "No abuse; sleep onset only; safe in elderly/SUD patients", options: { fontSize: 11, color: C.lightGrey, fill: { color: C.midBg } } }
    ],
    [
      { text: "Orexin Antagonists\n(Suvorexant)", options: { fontSize: 11, color: C.white, fill: { color: C.cardBg } } },
      { text: "OX1R+OX2R block; reduces wakefulness drive", options: { fontSize: 11, color: C.lightGrey, fill: { color: C.cardBg } } },
      { text: "Both onset + maintenance insomnia; low abuse; novel mechanism", options: { fontSize: 11, color: C.lightGrey, fill: { color: C.cardBg } } }
    ]
  ],
  C.accent3
);

// ═══════════════════════════════════════════════════════════════════════════
// SECTION D – ALCOHOL
// ═══════════════════════════════════════════════════════════════════════════
sectionSlide("CLINICAL PHARMACOLOGY OF ALCOHOL", "Pharmacokinetics · CNS Effects · Chronic Toxicity", C.accent4);

// ─── D1 Pharmacokinetics ─────────────────────────────────────────────────
contentSlide(
  "Ethanol — Pharmacokinetics",
  [
    { text: "Absorption & Distribution", sub: [
      "Rapidly absorbed from GI tract (stomach and small intestine); peak blood levels in 30–90 min",
      "Highly water-soluble; distributes to all tissues proportional to water content",
      "First-pass metabolism in gastric wall by alcohol dehydrogenase (ADH) — greater in men"
    ]},
    { text: "Metabolism — 3 Pathways (Hepatic)", sub: [
      "1. Alcohol dehydrogenase (ADH) + isoenzymes — accounts for 80–90% of oxidation → acetaldehyde + NADH",
      "2. Catalase (peroxisomes/mitochondria) — minor role",
      "3. Microsomal ethanol oxidising system (MEOS/CYP2E1) — induced by chronic alcohol use"
    ]},
    { text: "Acetaldehyde Metabolism", sub: [
      "Acetaldehyde → acetate via aldehyde dehydrogenase (ALDH)",
      "Acetaldehyde accumulation → flushing reaction (vasodilation, nausea, tachycardia)",
      "ALDH deficiency in East Asians explains alcohol flush syndrome"
    ]},
    { text: "Elimination Kinetics", sub: [
      "Zero-order kinetics: metabolised at constant rate ~150 mg/kg/h (≈ 1 standard drink/h)",
      "Does NOT depend on blood concentration (unlike most drugs which follow first-order kinetics)",
      "Exception: very high concentrations slightly increase rate; chronic use induces MEOS → tolerance"
    ]}
  ],
  C.accent4
);

// ─── D2 CNS Effects & BAC Correlations ───────────────────────────────────
contentSlide(
  "Ethanol — CNS Effects & Blood Alcohol Concentration (BAC)",
  [
    { text: "BAC Correlations (mg/dL) — Non-Tolerant Individuals", sub: [
      "30 mg/dL: mild euphoria, reduced inhibition",
      "50 mg/dL: mild incoordination, impaired judgment",
      "100 mg/dL: ataxia (legal limit in most countries is 80 mg/dL)",
      "200 mg/dL: confusion, reduced mental activity",
      "300 mg/dL: stupor, severe CNS depression",
      "400 mg/dL: deep anaesthesia, potentially fatal (respiratory failure)"
    ]},
    { text: "Mechanism of CNS Depression", sub: [
      "Potentiates GABA-A receptors (similar to BZDs and barbiturates) → inhibitory CNS effects",
      "Inhibits NMDA glutamate receptors → further CNS depression and amnestic effects",
      "Increases dopamine in nucleus accumbens → reward/euphoria (mesolimbic pathway)",
      "Activates opioid peptide systems — endorphin release (blocked by naltrexone)"
    ]},
    { text: "Acute Intoxication — Clinical Features", sub: [
      "Disinhibition, euphoria → slurred speech, ataxia, nystagmus → respiratory depression, coma",
      "Hypoglycaemia (inhibits gluconeogenesis) — particularly dangerous in fasted state",
      "Aspiration risk (vomiting + impaired airway reflexes) — major cause of alcohol-related death"
    ]}
  ],
  C.accent4
);

// ─── D3 Chronic Alcohol Effects ──────────────────────────────────────────
contentSlide(
  "Chronic Alcohol Use — Systemic Toxicity",
  [
    { text: "Neurological", sub: [
      "Wernicke-Korsakoff syndrome: thiamine (B1) deficiency → encephalopathy → amnesia",
      "Peripheral neuropathy, cerebellar degeneration, central pontine myelinolysis",
      "Alcohol-related dementia; fetal alcohol syndrome (prenatal exposure)"
    ]},
    { text: "Hepatic (Most Common Cause of Alcohol Mortality)", sub: [
      "Alcoholic fatty liver (steatosis) → alcoholic hepatitis → cirrhosis",
      "Mechanism: increased NADH from ADH → impaired beta-oxidation, increased lipid synthesis",
      "CYP2E1 induction → increased reactive oxygen species → oxidative liver damage"
    ]},
    { text: "Cardiovascular", sub: [
      "Alcoholic cardiomyopathy (dilated), arrhythmias (holiday heart syndrome — AF after binge)",
      "Moderate use: possibly protective (J-curve relationship for coronary artery disease)",
      "Hypertension with heavy chronic use"
    ]},
    { text: "Gastrointestinal & Metabolic", sub: [
      "Gastritis, pancreatitis (acute and chronic), GI bleeding (oesophageal varices in cirrhosis)",
      "Hypoglycaemia, hyperuricaemia (gout), hyperlipidaemia",
      "Malnutrition: empty calories (7 kcal/g) — no proteins or vitamins"
    ]}
  ],
  C.accent4
);

// ─── D4 Alcohol Withdrawal ────────────────────────────────────────────────
contentSlide(
  "Alcohol Withdrawal Syndrome",
  [
    { text: "Pathophysiology", sub: [
      "Chronic alcohol → GABA-A downregulation + NMDA upregulation",
      "Abrupt cessation → neuronal hyperexcitability (NMDA dominance) = withdrawal syndrome",
      "Life-threatening — untreated mortality ~5–15%"
    ]},
    { text: "Clinical Timeline (CIWA-Ar Scale Used to Quantify)", sub: [
      "6–12 h: tremor, anxiety, sweating, nausea, tachycardia, hypertension",
      "12–24 h: alcohol hallucinosis (visual/auditory hallucinations with clear sensorium)",
      "24–48 h: Grand mal seizures (major risk — prophylactic BZDs essential)",
      "48–72 h (peak): Delirium Tremens (DTs) — confusion, hyperthermia, autonomic storm, 5% mortality"
    ]},
    { text: "Treatment of Alcohol Withdrawal", sub: [
      "First-line: Benzodiazepines (diazepam or lorazepam/oxazepam in liver disease)",
      "Thiamine 100 mg IV BEFORE any glucose (prevent Wernicke precipitation)",
      "Electrolyte replacement (Mg²⁺, K⁺, PO₄³⁻)",
      "Supportive: IV fluids, nutrition, calm environment",
      "Refractory DTs: IV phenobarbital or propofol"
    ]}
  ],
  C.accent4
);

// ═══════════════════════════════════════════════════════════════════════════
// SECTION E – ALCOHOL ANTAGONISTS
// ═══════════════════════════════════════════════════════════════════════════
sectionSlide("ALCOHOL ANTAGONISTS", "Disulfiram · Naltrexone · Acamprosate · Other Agents", C.accent1);

// ─── E1 Disulfiram ────────────────────────────────────────────────────────
contentSlide(
  "Disulfiram (Antabuse) — Aversion Therapy",
  [
    { text: "Mechanism", sub: [
      "Irreversibly inhibits aldehyde dehydrogenase (ALDH) — both cytosolic and mitochondrial forms",
      "Active metabolite: diethylthiomethylcarbamate acts as suicide-substrate inhibitor of ALDH",
      "Result: acetaldehyde accumulates 5–10× above normal after any alcohol ingestion",
      "Sensitisation persists for 14 days after last dose (slow ALDH regeneration)"
    ]},
    { text: "Disulfiram-Ethanol Reaction (DER)", sub: [
      "Onset: within 5–10 min of alcohol ingestion",
      "Mild (BAC 5–10 mg%): facial flushing, throbbing headache, nausea, tachycardia",
      "Moderate (BAC up to 50 mg%): vomiting, sweating, hypotension, dyspnoea",
      "Severe (BAC > 125 mg%): loss of consciousness, cardiovascular collapse — potentially fatal",
      "Same reaction with hidden alcohol: sauces, vinegar, cough syrups, mouthwash, aftershave"
    ]},
    { text: "Clinical Use & Dosing", sub: [
      "Second-line; patient must be alcohol-free for ≥12 h before starting",
      "FDA dose: 250–500 mg/day; effectiveness based on fear of DER, not craving reduction",
      "Contraindicated: cardiovascular disease, liver failure, psychosis",
      "Drug interactions: inhibits CYPs → ↑ phenytoin, warfarin, chlordiazepoxide, barbiturate levels"
    ]}
  ],
  C.accent1
);

// ─── E2 Naltrexone & Acamprosate ─────────────────────────────────────────
twoColSlide(
  "Naltrexone & Acamprosate — First-Line AUD Treatments",
  "Naltrexone (ReVia, Vivitrol)",
  [
    "CLASS: Opioid receptor antagonist (mu, kappa, delta)",
    "MECHANISM: Blocks endogenous opioid activity in mesolimbic reward pathway → reduces alcohol-induced dopamine release → reduces reinforcing effects",
    "DOSING: Oral 50 mg/day OR extended-release IM 380 mg/month (Vivitrol)",
    "EFFICACY: Reduces relapse to drinking and binge drinking (meta-analyses); APA first-line drug",
    "ADVERSE EFFECTS: Nausea (most common), headache, dizziness, insomnia, hepatotoxicity (>300 mg oral)",
    "CONTRAINDICATIONS: Current opioid use/dependence (precipitates withdrawal), liver failure",
    "NOTE: Start only after 7–10 days opioid-free; opioid analgesia still possible but higher doses needed"
  ],
  "Acamprosate (Campral)",
  [
    "CLASS: Amino acid analogue (N-acetylhomotaurine)",
    "MECHANISM: Not fully elucidated; likely modulates NMDA glutamate and GABA-B receptors → reduces post-withdrawal neuronal hyperexcitability and craving",
    "DOSING: 1998 mg/day in 3 divided doses (666 mg TID) — can limit compliance",
    "EFFICACY: Reduces risk of relapse in abstinent patients; does NOT reduce binge drinking",
    "Best outcome: patients already abstinent at treatment initiation",
    "ADVERSE EFFECTS: Diarrhea (main), abdominal discomfort — generally well tolerated",
    "CONTRAINDICATIONS: Renal failure (renally excreted unchanged)",
    "ADVANTAGE: No hepatotoxicity risk; safe in liver disease"
  ],
  C.accent1
);

// ─── E3 Other Agents & Comparison ────────────────────────────────────────
contentSlide(
  "Other Pharmacological Agents for Alcohol Use Disorder",
  [
    { text: "Baclofen (GABA-B Agonist)", sub: [
      "Skeletal muscle relaxant; approved for AUD in France (off-label elsewhere)",
      "Mechanism: GABA-B agonism → reduced mesolimbic dopamine activity",
      "Evidence: reduces return to drinking and increases abstinence, esp. in heavy drinkers",
      "Caution: Increased sedation with alcohol; unclear as first-line treatment"
    ]},
    { text: "Nalmefene (Opioid Antagonist)", sub: [
      "Mu opioid antagonist + kappa partial agonist; analogue of naltrexone",
      "Approved in EU for reduction of alcohol consumption (not abstinence-based)",
      "As-needed dosing before anticipated drinking — unique approach vs. daily naltrexone"
    ]},
    { text: "Gabapentin & Pregabalin", sub: [
      "Alpha-2-delta subunit voltage-gated calcium channel modulators",
      "Used off-label for alcohol withdrawal and maintenance treatment",
      "Reduces withdrawal severity; some evidence for craving reduction"
    ]},
    { text: "Pharmacotherapy Strategy Summary", sub: [
      "Naltrexone: First-line — reduce drinking quantity/frequency; any patient",
      "Acamprosate: First-line — maintain abstinence; better in abstinent-at-start patients",
      "Disulfiram: Second-line — aversion; motivated patients, close supervision required",
      "Baclofen/Nalmefene: Emerging/specialist-use alternatives"
    ]}
  ],
  C.accent1
);

// ═══════════════════════════════════════════════════════════════════════════
// SLIDE — PHARMACOLOGY SUMMARY TABLE
// ═══════════════════════════════════════════════════════════════════════════
tableSlide(
  "Alcohol Use Disorder — Drug Treatment Comparison",
  [
    [
      { text: "Drug", options: { bold: true, fontSize: 11.5, color: C.darkBg, fill: { color: C.accent1 }, align: "center" } },
      { text: "Mechanism", options: { bold: true, fontSize: 11.5, color: C.darkBg, fill: { color: C.accent1 }, align: "center" } },
      { text: "Key Clinical Points", options: { bold: true, fontSize: 11.5, color: C.darkBg, fill: { color: C.accent1 }, align: "center" } }
    ],
    [
      { text: "Disulfiram\n250–500 mg/day", options: { fontSize: 11, color: C.white, fill: { color: C.cardBg }, bold: true } },
      { text: "Irreversible ALDH inhibitor → acetaldehyde accumulation → aversion", options: { fontSize: 11, color: C.lightGrey, fill: { color: C.cardBg } } },
      { text: "Second-line; requires supervision; CIs: CV disease, psychosis, liver failure", options: { fontSize: 11, color: C.lightGrey, fill: { color: C.cardBg } } }
    ],
    [
      { text: "Naltrexone\n50 mg/day PO\n380 mg/month IM", options: { fontSize: 11, color: C.white, fill: { color: C.midBg }, bold: true } },
      { text: "Opioid receptor antagonist → blocks mesolimbic reward pathway", options: { fontSize: 11, color: C.lightGrey, fill: { color: C.midBg } } },
      { text: "First-line; reduces relapse; CI: opioid dependence, liver failure", options: { fontSize: 11, color: C.lightGrey, fill: { color: C.midBg } } }
    ],
    [
      { text: "Acamprosate\n1998 mg/day (TID)", options: { fontSize: 11, color: C.white, fill: { color: C.cardBg }, bold: true } },
      { text: "NMDA/GABA-B modulation → reduces neuronal hyperexcitability", options: { fontSize: 11, color: C.lightGrey, fill: { color: C.cardBg } } },
      { text: "First-line for abstinence; best when already abstinent; CI: renal failure", options: { fontSize: 11, color: C.lightGrey, fill: { color: C.cardBg } } }
    ],
    [
      { text: "Baclofen", options: { fontSize: 11, color: C.white, fill: { color: C.midBg }, bold: true } },
      { text: "GABA-B agonist → reduces reward signalling", options: { fontSize: 11, color: C.lightGrey, fill: { color: C.midBg } } },
      { text: "Approved France; off-label elsewhere; heavy drinkers; caution: sedation", options: { fontSize: 11, color: C.lightGrey, fill: { color: C.midBg } } }
    ]
  ],
  C.accent1
);

// ═══════════════════════════════════════════════════════════════════════════
// FINAL SUMMARY SLIDE
// ═══════════════════════════════════════════════════════════════════════════
contentSlide(
  "Key Takeaways",
  [
    { text: "Benzodiazepines", sub: [
      "Allosteric GABA-A modulators (↑ Cl⁻ frequency); require GABA → ceiling effect → safer than barbiturates",
      "Flumazenil reverses overdose; withdrawal can cause seizures; LOT drugs safe in liver disease"
    ]},
    { text: "Barbiturates", sub: [
      "GABA-A (↑ Cl⁻ duration + direct activation at high doses) → narrow TI, high lethality in overdose",
      "Major CYP inducers; no antidote; phenobarbital still used for epilepsy"
    ]},
    { text: "New Sleeping Pills", sub: [
      "Z-drugs (α1-selective GABA-A): short-acting, complex sleep behaviours possible",
      "Melatonin agonists: no abuse potential; circadian; sleep onset only",
      "Orexin antagonists: block wakefulness drive; both onset + maintenance insomnia"
    ]},
    { text: "Alcohol Pharmacology", sub: [
      "Zero-order kinetics; potentiates GABA-A + inhibits NMDA + activates opioid/dopamine pathways",
      "Withdrawal: NMDA hyperactivity → seizures + DTs; treat with BZDs + thiamine"
    ]},
    { text: "Alcohol Antagonists", sub: [
      "Disulfiram: ALDH inhibitor → aversion (second-line); Naltrexone: opioid blockade → first-line",
      "Acamprosate: NMDA/GABA-B → abstinence maintenance; first-line"
    ]}
  ],
  C.accent3
);

// ═══════════════════════════════════════════════════════════════════════════
// THANK YOU / REFERENCES SLIDE
// ═══════════════════════════════════════════════════════════════════════════
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    "1. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th Ed. McGraw-Hill.",
    "2. Katzung BG. Basic and Clinical Pharmacology, 16th Ed. McGraw-Hill.",
    "3. Ropper AH, Samuels MA, Klein JP. Adams and Victor's Principles of Neurology, 12th Ed. McGraw-Hill.",
    "4. Lippincott Illustrated Reviews: Pharmacology, 8th Ed. Wolters Kluwer.",
    "5. Kaplan HI, Sadock BJ. Comprehensive Textbook of Psychiatry. Lippincott Williams & Wilkins.",
    "6. Tintinalli JE. Tintinalli's Emergency Medicine: A Comprehensive Study Guide. McGraw-Hill.",
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