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prs.author = "Orris Medical";

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// ── SLIDE 1: TITLE ──────────────────────────────────────────────────────────
{
  const s = prs.addSlide();
  titleSlide(s, "PROPOFOL", "Complete Clinical Reference — Pharmacology, Doses & Clinical Use");
}

// ── SLIDE 2: OVERVIEW ───────────────────────────────────────────────────────
addSlide("Overview", [
  "Generic name: Propofol  |  Brand name: Diprivan",
  "Class: Alkylphenol — IV sedative-hypnotic (non-barbiturate)",
  "First studied in 1970s; reformulated emulsion released 1986 (ICI 35868)",
  "Most widely used IV induction agent worldwide",
  "Formulation: 1% propofol, 10% soybean oil, 1.2% egg phospholipid, 2.25% glycerol",
  "Appearance: Milky white, slightly viscous emulsion — pH 7",
  "EDTA added as bacteriostatic agent in US formulation",
  "2% formulation & MCT/LCT variants available in Europe",
]);

// ── SLIDE 3: MECHANISM OF ACTION ────────────────────────────────────────────
addSlide("Mechanism of Action", [
  { type: "heading", text: "Primary Target: GABA-A Receptor" },
  "Positive allosteric modulator of GABA-A receptor",
  "Increases chloride conductance → membrane hyperpolarisation → CNS depression",
  "Reduces rate of GABA dissociation from receptor",
  { type: "heading", text: "Secondary Targets" },
  "Inhibits NMDA glutamate receptors",
  "Modulates voltage-gated sodium channels",
  "Modulates slow calcium ion channels",
  "Glycine antagonism (may contribute to excitatory side effects)",
]);

// ── SLIDE 4: PHARMACOKINETICS ────────────────────────────────────────────────
addSlide("Pharmacokinetics", [
  "Highly lipid-soluble — rapidly crosses blood-brain barrier",
  "Protein binding: ~98% (albumin, alpha-1 acid glycoprotein)",
  "Volume of distribution: very large (>2000 L, due to high lipophilicity)",
  "Initial distribution half-life: ~2–4 minutes",
  "Elimination half-life: 4–7 hours (context-sensitive half-time: shorter)",
  "Clearance: >1.5 L/min — exceeds hepatic blood flow",
  "Extrahepatic metabolism: kidney (up to 30%), lung (20–30%)",
  "Metabolites: conjugated glucuronides — pharmacologically inactive",
  "<1% excreted unchanged in urine; <2% in feces",
  "Metabolites excreted in urine for >60 hours after 2.5-hr anesthetic",
]);

// ── SLIDE 5: PK MODEL ───────────────────────────────────────────────────────
addSlide("Pharmacokinetic Model & Drug Interactions", [
  "Three-compartment model describes propofol distribution",
  "Rapid decline after bolus = redistribution + elimination",
  "CYP3A4 inhibitor — reduces clearance of co-administered drugs",
  { type: "heading", text: "Key Drug Interactions" },
  "Midazolam: raises blood propofol ~25%; reduces propofol clearance 1.94 → 1.61 L/min",
  "Alfentanil: reduces elimination clearance 2.1 → 1.9 L/min",
  "Opioids: synergistic — reduce propofol infusion rate & concentrations needed",
  "Propofol may reduce hepatic blood flow → reduces clearance of high-extraction drugs",
  "3 mcg/mL propofol reduces CYP3A4 activity by ~37%",
]);

// ── SLIDE 6: DOSES TABLE ─────────────────────────────────────────────────────
tableSlide(
  "Doses — Quick Reference",
  ["Indication", "Population", "Dose", "Route"],
  [
    ["Induction", "Adults (healthy)", "1.5–2.5 mg/kg IV (over 30–60 s)", "IV bolus"],
    ["Induction", "Elderly / ASA III–IV", "1–1.75 mg/kg IV (with premedication: 1 mg/kg)", "IV bolus"],
    ["Induction", "Children 3–16 yr", "2–3 mg/kg IV (ED95)", "IV bolus"],
    ["Maintenance (TIVA)", "Adults", "100–200 mcg/kg/min (6–12 mg/kg/h)", "IV infusion"],
    ["Maintenance + N₂O/opioid", "Adults", "50–100 mcg/kg/min", "IV infusion"],
    ["Sedation (ICU/MAC)", "Adults", "5–50 mcg/kg/min — titrate to effect", "IV infusion"],
    ["Antiemetic", "Adults", "10–20 mg IV bolus (subanesthetic)", "IV bolus"],
    ["Status epilepticus", "Adults", "1–2 mg/kg IV then 2–10 mg/kg/h infusion", "IV"],
    ["ICP reduction (TBI)", "Adults", "25–75 mcg/kg/min (blood conc. ~2 mcg/mL)", "IV infusion"],
  ]
);

// ── SLIDE 7: INDUCTION DETAILS ───────────────────────────────────────────────
addSlide("Induction — Detailed Dosing", [
  { type: "heading", text: "Standard Adult Induction" },
  "1.5–2.5 mg/kg IV; inject over 30–60 seconds to reduce pain and apnea",
  "Onset: 30–60 seconds; duration: 5–10 minutes (single bolus)",
  { type: "heading", text: "Dose Reduction Scenarios" },
  "Elderly patients (>60 yr): reduce to 1–1.75 mg/kg",
  "Elderly (>80 yr): require approximately half the dose of young (<20 yr) patients",
  "With opioid/benzodiazepine premedication: dose can be reduced by 20–30%",
  "ASA III–IV: titrate carefully; hypotension risk is pronounced",
  { type: "heading", text: "Children (3–16 years)" },
  "2–3 mg/kg IV (ED95 higher due to larger Vd, increased clearance, smaller central compartment)",
]);

// ── SLIDE 8: MAINTENANCE DETAILS ─────────────────────────────────────────────
addSlide("Maintenance — TIVA & Sedation Dosing", [
  { type: "heading", text: "Total IV Anesthesia (TIVA)" },
  "Start: 100–200 mcg/kg/min after induction dose",
  "Titrate to BIS 40–60 or clinical signs; reduce with adjuncts (opioids, midazolam)",
  "With N₂O + opioid: typically 50–100 mcg/kg/min sufficient",
  { type: "heading", text: "ICU Sedation" },
  "5–50 mcg/kg/min — titrate to target sedation score (e.g. RASS)",
  "Monitor for propofol infusion syndrome (PRIS) if >4 mg/kg/h for >48 h",
  { type: "heading", text: "Procedural Sedation (MAC)" },
  "Load: 100–150 mcg/kg/min × 3–5 min, then reduce to 25–75 mcg/kg/min",
  "Target: BIS 70–80 for conscious sedation; titrate by clinical response",
]);

// ── SLIDE 9: CNS EFFECTS ─────────────────────────────────────────────────────
addSlide("CNS Effects", [
  "Dose-dependent CNS depression: sedation → hypnosis → burst suppression",
  "Sub-hypnotic doses: sedation and amnesia (≥2 mg/kg/h for reliable amnesia)",
  "BIS 50% non-response to verbal command: 63 | 95%: BIS 51",
  "Concentration for 50% verbal non-response: 2.35 mcg/mL",
  "95% lack of recall at BIS 77",
  "Reduces ICP by 30–50% (associated with ↓ CPP — caution in head injury)",
  "Reduces cerebral metabolic rate (CMRO₂) and cerebral blood flow (CBF)",
  "Reduces intraocular pressure by ~30%",
  "Anticonvulsant properties — used in refractory status epilepticus",
  "Can paradoxically cause excitatory phenomena: myoclonus, opisthotonos",
]);

// ── SLIDE 10: CVS EFFECTS ────────────────────────────────────────────────────
twoCol(
  "Cardiovascular Effects",
  [
    { type: "heading", text: "Haemodynamic Changes" },
    "↓ Systolic BP by 15–40%",
    "↓ Systemic vascular resistance",
    "↓ Cardiac contractility (negative inotrope)",
    "↓ Preload (venodilation)",
    "Heart rate usually unchanged or slight ↑",
    { type: "heading", text: "Mechanism" },
    "Direct myocardial depression",
    "Inhibits Ca²⁺ influx into vascular smooth muscle",
    "Sympatholysis at vasomotor centres",
  ],
  [
    { type: "heading", text: "Clinical Considerations" },
    "Significant hypotension in elderly, hypovolaemic, or high ASA patients",
    "Pre-load IV fluids in high-risk patients",
    "Slower injection rate reduces cardiovascular depression",
    { type: "heading", text: "Cardiac Surgery / Ischaemia" },
    "Evidence for cardioprotection via ischaemic preconditioning",
    "Desflurane vs. propofol off-pump CABG: similar outcomes",
    "High-dose propofol (120 mcg/kg/min) studied in cardiac surgery",
    "Use with caution in cardiogenic shock",
  ]
);

// ── SLIDE 11: RESPIRATORY EFFECTS ────────────────────────────────────────────
addSlide("Respiratory Effects", [
  "Dose-dependent respiratory depression — most significant side effect",
  "Apnea occurs in 25–35% of patients with induction doses",
  "Reduces tidal volume and respiratory rate",
  "Blunts hypoxic and hypercapnic ventilatory drive",
  "Upper airway reflexes are depressed — facilitates LMA insertion",
  "Does NOT trigger bronchospasm — can be used in asthma/COPD",
  "Bronchodilator properties reported (useful in reactive airways)",
  "No analgesic effect — always combine with opioids for painful procedures",
  "Always have airway equipment and resuscitation ready",
]);

// ── SLIDE 12: OTHER EFFECTS ───────────────────────────────────────────────────
twoCol(
  "Other Clinical Effects",
  [
    { type: "heading", text: "Anti-Emetic" },
    "Sub-hypnotic doses: 10–20 mg IV reduces PONV",
    "Mechanism: antagonism of dopamine D₂ receptors, 5-HT₃",
    { type: "heading", text: "Neuromuscular" },
    "No significant effect on NMJ or twitch",
    "Does NOT trigger malignant hyperthermia (safe in MH-susceptible)",
    { type: "heading", text: "Euphoriant Effect" },
    "Sense of well-being, hallucinations reported",
    "Potential for abuse and addiction (healthcare worker risk)",
  ],
  [
    { type: "heading", text: "Infection Risk" },
    "Inhibits phagocytosis of S. aureus and E. coli",
    "Soybean emulsion is growth medium for bacteria",
    "Strict aseptic technique — discard opened vials within 6 hours",
    { type: "heading", text: "Pain on Injection" },
    "Occurs in 28–90% — especially antecubital vein",
    "Mitigation: lidocaine 40 mg IV prior, or use dorsum of hand",
    "Mix lidocaine 20–40 mg with propofol, or inject into antecubital vein",
    "MCT/LCT formulation reduces pain on injection",
  ]
);

// ── SLIDE 13: SIDE EFFECTS & SAFETY ──────────────────────────────────────────
addSlide("Side Effects & Safety Considerations", [
  { type: "heading", text: "Propofol Infusion Syndrome (PRIS)" },
  "Life-threatening: metabolic acidosis, rhabdomyolysis, cardiac failure, renal failure",
  "Risk factors: dose >4 mg/kg/h, duration >48 h, low carbohydrate intake, catecholamines",
  "Avoid prolonged high-dose infusions in ICU — consider alternative sedatives",
  { type: "heading", text: "Egg / Soy Allergy" },
  "Egg phosphatide used as emulsifier — caution (not absolute CI in egg allergy)",
  "Soybean allergy: discuss risk-benefit carefully",
  { type: "heading", text: "FDA Warnings" },
  "Dec 2016: potential neurotoxicity to developing fetal/neonatal brain",
  "Animal data: prolonged/repetitive exposure linked to neurodevelopmental harm",
  "Pregnancy: use only if clearly necessary; fetal exposure should be minimised",
]);

// ── SLIDE 14: CONTRAINDICATIONS ──────────────────────────────────────────────
addSlide("Contraindications & Precautions", [
  { type: "heading", text: "Absolute Contraindications" },
  "Known allergy to propofol or its components",
  "Allergy to eggs, soya, or peanuts (relative; weigh risk-benefit)",
  { type: "heading", text: "Relative Contraindications / Use with Caution" },
  "Severe haemodynamic instability / cardiogenic shock",
  "Hypovolaemia (pre-load with fluids first)",
  "Severe hepatic impairment (reduced extrahepatic metabolism)",
  "Pancreatitis (triglyceride-raising potential)",
  "Mitochondrial disease (PRIS risk)",
  "Pregnancy / breastfeeding (FDA warning re: neurotoxicity)",
  "ICU sedation >48 h at high doses (PRIS risk)",
]);

// ── SLIDE 15: SPECIAL POPULATIONS ────────────────────────────────────────────
tableSlide(
  "Dosing in Special Populations",
  ["Population", "Induction Dose", "Maintenance / Sedation", "Notes"],
  [
    ["Elderly (>60 yr)", "1–1.75 mg/kg IV", "Reduce infusion by 30–50%", "↑ Hypotension risk; slow injection"],
    ["Elderly (>80 yr)", "~0.5–1 mg/kg IV", "30–70 mcg/kg/min", "Require ~50% of young adult dose"],
    ["Children (3–16 yr)", "2–3 mg/kg IV", "125–300 mcg/kg/min", "↑ Clearance & Vd; not approved <3yr"],
    ["Pregnancy", "Reduce per clinical", "Limit duration", "FDA neurotoxicity warning; Category B"],
    ["Obese patients", "Dose on LBW for induction", "Titrate to effect (TCI/BIS)", "Avoid excessive lipid load"],
    ["Renal impairment", "Standard dose", "Standard / monitor", "Renal metabolism up to 30%"],
    ["Hepatic impairment", "Reduce with caution", "Monitor carefully", "Extrahepatic sites compensate"],
    ["ICU (prolonged)", "N/A", "<4 mg/kg/h; max 48 h", "PRIS risk with prolonged high dose"],
  ]
);

// ── SLIDE 16: PROPOFOL INFUSION SYNDROME ─────────────────────────────────────
addSlide("Propofol Infusion Syndrome (PRIS)", [
  { type: "heading", text: "Definition" },
  "Rare but life-threatening complication of high-dose, prolonged propofol infusion",
  { type: "heading", text: "Clinical Features (PRIS)" },
  "Metabolic acidosis (anion gap) | ↑ Lactate | Rhabdomyolysis",
  "Acute kidney injury | Cardiac arrhythmias | Cardiac failure",
  "↑ Triglycerides | Hepatomegaly | Green/pink urine",
  { type: "heading", text: "Risk Factors" },
  "Dose >4 mg/kg/h for >48 hours | Low carbohydrate / high fat diet",
  "Concurrent catecholamines or glucocorticoids | Mitochondrial disease",
  { type: "heading", text: "Management" },
  "STOP propofol immediately | Switch to alternative sedative",
  "Supportive: treat acidosis, arrhythmias, renal replacement if needed",
]);

// ── SLIDE 17: CLINICAL USES ───────────────────────────────────────────────────
addSlide("Clinical Uses of Propofol", [
  { type: "heading", text: "Operating Room" },
  "Induction of general anaesthesia (most common use worldwide)",
  "Maintenance anaesthesia — TIVA technique",
  "Adjunct to regional anaesthesia for procedural sedation",
  { type: "heading", text: "Outside OR" },
  "ICU sedation (short-term)",
  "Procedural sedation in ED, endoscopy, radiology, dentistry",
  "Electroconvulsive therapy (ECT) — rapid recovery profile ideal",
  { type: "heading", text: "Other Uses" },
  "Refractory status epilepticus (second-line)",
  "Post-operative nausea & vomiting (sub-anaesthetic doses)",
  "Refractory pruritus (opioid-induced) — low-dose propofol 10 mg",
]);

// ── SLIDE 18: TCI ─────────────────────────────────────────────────────────────
addSlide("Target-Controlled Infusion (TCI)", [
  "TCI uses pharmacokinetic models to target plasma or effect-site concentration",
  { type: "heading", text: "Commonly Used Models" },
  "Marsh model: targets plasma concentration; weight-based",
  "Schnider model: targets effect-site concentration; uses age, weight, height, lean BW",
  { type: "heading", text: "Target Concentrations (Adults)" },
  "Sedation: 1–2 mcg/mL (effect-site)",
  "Anaesthesia induction: 4–8 mcg/mL (effect-site)",
  "Anaesthesia maintenance: 3–6 mcg/mL (effect-site; adjust for adjuncts)",
  "Awareness prevention may require >10 mcg/mL if used as sole agent",
  { type: "heading", text: "Notes" },
  "Adjust target down by 20–50% when combined with opioids or midazolam",
  "TCI systems not approved for paediatric or some elderly populations in all countries",
]);

// ── SLIDE 19: FOSPROPOFOL ─────────────────────────────────────────────────────
addSlide("Fospropofol (Lusedra)", [
  "Water-soluble prodrug of propofol; FDA approved Dec 2008",
  "Indication: Monitored Anaesthesia Care (MAC) in adults",
  "Hydrolysed by alkaline phosphatases in liver → releases active propofol",
  "1.86 mg fospropofol = 1 mg propofol (molar equivalent)",
  { type: "heading", text: "Advantages vs. Propofol" },
  "No pain on injection (unlike propofol emulsion)",
  "No lipid vehicle — lower triglyceride concern",
  { type: "heading", text: "Disadvantages" },
  "Perineal paresthesia and pruritus (phosphate metabolite) — mild to moderate",
  "Slower onset than propofol due to prodrug conversion",
  "Limited pharmacokinetic data (six early studies retracted — assay error)",
  "Classified as DEA Schedule IV controlled substance (unlike propofol)",
]);

// ── SLIDE 20: SUMMARY / KEY POINTS ────────────────────────────────────────────
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  const keyPoints = [
    "Induction dose: 1.5–2.5 mg/kg IV adults; reduce 30–50% in elderly",
    "Maintenance: 100–200 mcg/kg/min TIVA; 50–100 with N₂O/opioid",
    "ICU sedation: 5–50 mcg/kg/min — watch for PRIS if >4 mg/kg/h × 48 h",
    "TCI targets: sedation 1–2 mcg/mL; anaesthesia 3–8 mcg/mL (effect-site)",
    "Antiemetic: 10–20 mg IV (subanesthetic)",
    "Mechanism: GABA-A potentiation + NMDA inhibition",
    "No MH risk; reduces ICP; bronchodilator — NOT analgesic",
    "Major risks: hypotension, apnea, PRIS, pain on injection",
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  s.addText("Sources: Miller's Anesthesia 10e (Ch. 21) • Morgan & Mikhail's Clinical Anesthesiology 7e • Harriet Lane Handbook 23e", {
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