const pptxgen = require("pptxgenjs");
const { execSync } = require("child_process");

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pres.author = "Physiotherapy Pharmacology";
pres.title = "Irritants and Counterirritants";

// ─── COLOR PALETTE ──────────────────────────────────────────────
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// ─── HELPERS ────────────────────────────────────────────────────
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// ─── SLIDE 1: TITLE ─────────────────────────────────────────────
titleSlide(
  "Irritants & Counterirritants",
  "Mechanisms, Classifications & Clinical Use in Physiotherapy"
);

// ─── SLIDE 2: LEARNING OBJECTIVES ───────────────────────────────
contentSlide("Learning Objectives", [
  { text: "Define irritants and counterirritants", sub: ["Understand the distinction between primary irritants and sensitizers"] },
  { text: "Describe mechanisms of action", sub: ["Gate control theory, TRPV1, TRPM8 receptor pathways"] },
  { text: "Classify counterirritants", sub: ["Rubefacients, vesicants, escharotics"] },
  { text: "Identify key drug agents and their clinical indications", sub: [] },
  { text: "Recognize adverse effects and contraindications", sub: ["Safety in physiotherapy practice"] },
], { barColor: C.accent2 });

// ─── SLIDE 3: SECTION HEADER – IRRITANTS ────────────────────────
sectionHeader("SECTION 01", "Irritants", "Agents that cause direct tissue irritation at the site of contact");

// ─── SLIDE 4: DEFINITION & TYPES ────────────────────────────────
contentSlide("What Are Irritants?", [
  { text: "Definition", sub: ["Substances that cause reversible inflammatory changes on skin or mucous membranes at site of contact without involvement of immunological mechanisms"] },
  { text: "Primary (Non-immunological) Irritants", sub: [
    "Act directly — no prior sensitization required",
    "Effect is dose-dependent and universal",
    "Examples: strong acids, alkalis, soaps, detergents, turpentine",
  ]},
  { text: "Secondary Irritants (Sensitizers)", sub: [
    "Require prior sensitization (immunological mechanism)",
    "Produce allergic contact dermatitis on re-exposure",
    "Examples: nickel, formaldehyde, fragrances",
  ]},
  { text: "Relevance in physiotherapy: heat rubs, liniments, electro-conductive gels may act as irritants if misused" },
]);

// ─── SLIDE 5: MECHANISM OF IRRITANTS ────────────────────────────
contentSlide("Mechanism of Irritant Action", [
  { text: "Barrier Disruption", sub: [
    "Physical/chemical damage to stratum corneum",
    "Loss of lipid bilayer integrity → ↑ transepidermal water loss",
  ]},
  { text: "Innate Immune Activation", sub: [
    "Release of pro-inflammatory cytokines: IL-1α, IL-1β, TNF-α",
    "Keratinocyte activation → neutrophil & macrophage recruitment",
  ]},
  { text: "Neurogenic Inflammation", sub: [
    "Stimulation of nociceptors (C-fibers and Aδ-fibers)",
    "Release of Substance P, CGRP → vasodilation, erythema, pain",
  ]},
  { text: "Result: Redness, oedema, burning sensation, vesicle formation (high doses)" },
]);

// ─── SLIDE 6: OCCUPATIONAL IRRITANTS TABLE ──────────────────────
tableSlide(
  "Common Irritants: Classifications",
  ["Category", "Agent(s)", "Effect"],
  [
    ["Acids", "Hydrochloric, Sulphuric, Acetic", "Chemical burn, necrosis"],
    ["Alkalis", "NaOH, Ca(OH)₂, Cement", "Deep liquefaction necrosis"],
    ["Organic solvents", "Turpentine, Acetone, Alcohol", "De-fatting, barrier disruption"],
    ["Oxidizers", "Hydrogen peroxide, Bleach", "Tissue oxidation, irritation"],
    ["Soaps / Detergents", "Wet-work agents, SDS", "Cumulative barrier damage"],
    ["Plant-derived", "Capsaicin, Mustard oil, Cantharides", "Nociceptor activation / vesication"],
    ["Physical", "Heat, Friction, UV radiation", "Thermal/mechanical damage"],
  ],
  C.accent3
);

// ─── SLIDE 7: SECTION HEADER – COUNTERIRRITANTS ─────────────────
sectionHeader("SECTION 02", "Counterirritants", "Exploiting mild irritation to relieve deeper pain");

// ─── SLIDE 8: DEFINITION & RATIONALE ────────────────────────────
contentSlide("Counterirritants — Definition & Rationale", [
  { text: "Definition", sub: [
    "Agents that produce mild, controlled irritation/inflammation of superficial tissues",
    "Purpose: relieve pain/discomfort in underlying structures (muscles, joints)",
  ]},
  { text: "Theoretical Basis: Gate Control Theory (Melzack & Wall, 1965)", sub: [
    "Activation of Aβ large-diameter fibres (tactile/warm) inhibits Aδ/C fibre pain signals",
    "Spinal interneurons in dorsal horn 'close the gate' on pain transmission",
    "Counterirritants stimulate cutaneous sensory fibres → competing impulses → ↓ pain perception",
  ]},
  { text: "Additional Mechanisms", sub: [
    "Increased local blood flow → ↑ tissue metabolism, reduced ischaemic pain",
    "Endorphin release (central modulation)",
    "TRPV1 desensitization (capsaicin) → substance P depletion",
    "TRPM8 activation (menthol) → cool sensation overwhelms itch/pain",
  ]},
]);

// ─── SLIDE 9: CLASSIFICATION ────────────────────────────────────
contentSlide("Classification of Counterirritants", [
  { text: "Grade 1 — Rubefacients", sub: [
    "Produce redness (hyperaemia) without blister formation",
    "Examples: Methyl salicylate, Turpentine oil, Mustard, Camphor, Menthol",
  ]},
  { text: "Grade 2 — Vesicants (Pustulants)", sub: [
    "Produce blisters/vesicles by more intense irritation",
    "Example: Cantharides (Spanish fly — Cantharidin)",
    "Historically used in musculoskeletal pain; limited modern use",
  ]},
  { text: "Grade 3 — Escharotics (Caustics)", sub: [
    "Cause tissue destruction → eschar formation",
    "Used only for removal of warts/corns (salicylic acid >10%)",
  ]},
  { text: "Modern classification also includes: Coolants (menthol, camphor), Capsaicin-based agents" },
], { barColor: C.accent2 });

// ─── SLIDE 10: KEY COUNTERIRRITANT AGENTS ───────────────────────
tableSlide(
  "Key Counterirritant Agents",
  ["Drug", "Class", "Mechanism", "Clinical Use"],
  [
    ["Methyl Salicylate\n('Oil of Wintergreen')", "Rubefacient / NSAID", "Inhibits COX; topical hyperaemia; counterirritant", "Arthritis creams, sports rubs, liniments"],
    ["Camphor", "Rubefacient / Coolant", "TRPV1 activation at low conc; cooling sensation", "Analgesic liniments, antipruritic lotions"],
    ["Menthol", "Coolant / Counterirritant", "TRPM8 receptor agonist → cool sensation masks pain/itch", "Analgesic gels, cold sprays, antipruritic preparations"],
    ["Capsaicin", "Counterirritant / Analgesic", "TRPV1 agonist → Substance P depletion; receptor desensitization", "Neuropathic pain, osteoarthritis, CRPS"],
    ["Turpentine Oil", "Rubefacient", "Skin irritation → local hyperaemia; mild analgesic", "Embrocations, veterinary liniments"],
    ["Mustard Oil / Plaster", "Rubefacient", "Allyl isothiocyanate → TRPA1 activation → hyperaemia", "Traditional liniments, plasters"],
    ["Cantharidin (Cantharides)", "Vesicant", "Inhibits serine phosphatases → acantholysis and blistering", "Wart/molluscum treatment (dermatology)"],
  ],
  C.accent1
);

// ─── SLIDE 11: CAPSAICIN — DEEP DIVE ────────────────────────────
contentSlide("Capsaicin — Mechanism & Clinical Use", [
  { text: "Source: Capsicum frutescens (chilli pepper); active compound: capsaicin (8-methyl-N-vanillyl-6-nonenamide)" },
  { text: "Mechanism — TRPV1 Receptor", sub: [
    "Activates Transient Receptor Potential Vanilloid 1 (TRPV1) on C-fibers",
    "Initial activation → burning sensation, neurogenic inflammation (flare, oedema)",
    "Repeated application → TRPV1 desensitization → Substance P depletion",
    "Result: ↓ pain signal transmission — functional defunctionalization of nociceptors",
  ]},
  { text: "Formulations", sub: [
    "Low-dose cream (0.025–0.075%): OTC, multiple daily applications needed",
    "High-dose patch (8% — Qutenza™): single 30–60 min application, lasts ~3 months",
  ]},
  { text: "Clinical Indications", sub: [
    "Post-herpetic neuralgia, diabetic neuropathy, HIV neuropathy",
    "Osteoarthritis, CRPS, chemotherapy-induced neuropathy",
  ]},
], { barColor: C.accent1 });

// ─── SLIDE 12: MENTHOL & CAMPHOR ────────────────────────────────
twoColSlide(
  "Menthol & Camphor — Receptor-Based Coolants",
  "MENTHOL",
  [
    "Source: Peppermint oil (Mentha piperita) or synthetic",
    "Mechanism: TRPM8 receptor agonist",
    "TRPM8 = cold-sensitive TRP channel",
    "Cool sensation overwhelms pain/itch signals",
    "Lipid-soluble cyclic terpene alcohol",
    "Formulations: gels, sprays, creams, patches",
    "Uses: Analgesia, antipruritic, cold sprays",
    "Precaution: Avoid near face in infants (laryngospasm risk)",
  ],
  "CAMPHOR",
  [
    "Source: Cinnamomum camphora bark",
    "Mechanism: TRPV1 (low conc) + TRPM8 activation",
    "Produces both warm and cool sensations",
    "Mild analgesic + antipruritic",
    "Often combined with menthol (Sarna® lotion)",
    "FDA-approved: 3–11% for analgesic/antipruritic use",
    "Toxic in high doses — avoid ingestion",
    "Avoid in pregnancy (crosses placenta)",
  ],
  C.accent2
);

// ─── SLIDE 13: METHYL SALICYLATE ────────────────────────────────
contentSlide("Methyl Salicylate — 'Oil of Wintergreen'", [
  { text: "Chemistry: Ester of salicylic acid; naturally found in Gaultheria (wintergreen)" },
  { text: "Mechanism of Action", sub: [
    "Topical COX inhibition → ↓ prostaglandin synthesis (anti-inflammatory)",
    "Cutaneous hyperaemia → counterirritant effect (Gate control)",
    "Well absorbed through skin — systemic salicylate levels achievable",
  ]},
  { text: "Clinical Uses", sub: [
    "Musculoskeletal pain: arthritis, sprains, strains, backache",
    "Ingredient in: Deep Heat®, Tiger Balm®, Bengay®, Moov®",
    "Combined with menthol/camphor for enhanced effect",
  ]},
  { text: "Adverse Effects & Safety", sub: [
    "Skin irritation, contact dermatitis",
    "Systemic salicylate toxicity (especially in children — TOXIC if ingested)",
    "Avoid on broken skin; avoid with anticoagulants (warfarin interaction)",
    "Pregnancy: avoid during 3rd trimester",
  ]},
]);

// ─── SLIDE 14: ADVERSE EFFECTS COMPARISON ───────────────────────
tableSlide(
  "Adverse Effects & Precautions",
  ["Agent", "Common ADRs", "Contraindications"],
  [
    ["Capsaicin", "Burning, stinging (initial), erythema, cough (inhaled)", "Broken skin, hypersensitivity, near eyes/mucosa"],
    ["Menthol", "Skin irritation, allergic dermatitis, contact urticaria", "Infants (facial application), hypersensitivity"],
    ["Camphor", "Irritation, CNS toxicity if ingested, seizures", "Pregnancy, infants, G6PD deficiency"],
    ["Methyl Salicylate", "Contact dermatitis, salicylate toxicity", "Children <12 yrs, warfarin use, broken skin, pregnancy T3"],
    ["Turpentine Oil", "Blistering, renal toxicity (systemic absorption)", "Renal disease, large surface area application"],
    ["Cantharides", "Severe blistering, renal/urinary toxicity", "Never for systemic use; dermatology only (topical)"],
  ],
  C.accent3
);

// ─── SLIDE 15: PHYSIOTHERAPY CLINICAL APPLICATIONS ──────────────
contentSlide("Clinical Use in Physiotherapy Practice", [
  { text: "Pre-Treatment", sub: [
    "Counterirritant creams/gels applied before exercise or manual therapy",
    "Warmup liniments (methyl salicylate) → hyperaemia → tissue extensibility",
  ]},
  { text: "Pain Management", sub: [
    "Topical analgesics for musculoskeletal, arthritic and neuropathic pain",
    "Capsaicin cream for chronic pain syndromes (CRPS, post-herpetic neuralgia)",
    "Menthol-based cold sprays for acute sports injuries (cryotherapy substitute)",
  ]},
  { text: "Combined Modalities", sub: [
    "Ultrasound phonophoresis with topical NSAIDs / counterirritants",
    "Iontophoresis with salicylate preparations",
  ]},
  { text: "Patient Education", sub: [
    "Proper application technique — thin layer, avoid mucous membranes",
    "Handwashing after application (especially capsaicin)",
    "Report significant skin reactions; patch test if allergy history",
  ]},
], { barColor: C.accent2 });

// ─── SLIDE 16: GATE CONTROL THEORY DIAGRAM TEXT ─────────────────
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  s.addText("Aδ / C Fibres\n(Pain / Nociception)", { x: 0.2, y: 2.6, w: 1.8, h: 0.9, fontSize: 11, color: C.accent1, fontFace: "Calibri", align: "center", bold: true });

  // Arrows → gate
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  s.addShape(pres.ShapeType.rect, { x: 2.1, y: 2.96, w: 1.0, h: 0.08, fill: { color: C.accent1 } });

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  // Gate → transmission cell
  s.addShape(pres.ShapeType.rect, { x: 5.2, y: 2.26, w: 0.9, h: 0.08, fill: { color: C.white } });
  s.addShape(pres.ShapeType.rect, { x: 6.2, y: 1.5, w: 1.8, h: 1.5, fill: { color: C.midBg }, line: { color: C.white, width: 1.5 } });
  s.addText("Transmission\nCell (T Cell)", { x: 6.2, y: 1.5, w: 1.8, h: 1.5, fontSize: 12, color: C.white, fontFace: "Calibri", align: "center", valign: "middle" });

  // T cell → brain
  s.addShape(pres.ShapeType.rect, { x: 8.1, y: 2.26, w: 0.9, h: 0.08, fill: { color: C.white } });
  s.addShape(pres.ShapeType.rect, { x: 9.1, y: 1.8, w: 0.8, h: 0.9, fill: { color: C.midBg }, line: { color: C.accent2, width: 1.5 } });
  s.addText("Brain\n↑ Pain", { x: 9.1, y: 1.8, w: 0.8, h: 0.9, fontSize: 10, color: C.accent1, fontFace: "Calibri", align: "center", valign: "middle", bold: true });

  // Inhibitory pathway label
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// ─── SLIDE 17: COMPARISON TABLE ─────────────────────────────────
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  "IRRITANTS",
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    "Cause undesirable tissue damage",
    "Accidental or occupational exposure",
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    "No therapeutic benefit intended",
    "Mechanism: barrier disruption, cytokine release",
    "Treatment goal: avoidance, barrier repair",
    "Patch testing, occupational health management",
  ],
  "COUNTERIRRITANTS",
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    "Mild, controlled irritation = therapeutic goal",
    "Deliberate application for pain relief",
    "Lead to hyperaemia, sensory modulation",
    "Beneficial analgesic / antipruritic effect",
    "Mechanism: gate control, TRPV1/TRPM8 pathways",
    "Treatment goal: analgesia, improved function",
    "Applied in physiotherapy & sports medicine",
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// ─── SLIDE 18: KEY TAKE-AWAYS ───────────────────────────────────
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    ["03", C.accent3, "Menthol (TRPM8) provides cooling analgesia — safe, widely used in sports/clinical practice"],
    ["04", C.accent1, "Methyl salicylate combines COX inhibition + counterirritant hyperaemia — mainstay in PT liniments"],
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// ─── SLIDE 19: THANK YOU / END ───────────────────────────────────
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// ─── WRITE FILE ──────────────────────────────────────────────────
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// ─────────────────────────────────────────────────────────────────
// SLIDE 1 — TITLE
// ─────────────────────────────────────────────────────────────────
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// ─────────────────────────────────────────────────────────────────
// SLIDE 2 — LEARNING OBJECTIVES
// ─────────────────────────────────────────────────────────────────
contentSlide("Learning Objectives", [
  { text: "Define plasters, poultices, and pastes as topical pharmaceutical preparations", sub: [] },
  { text: "Describe composition and physical characteristics of each formulation", sub: [] },
  { text: "Explain mechanisms of drug delivery through skin", sub: ["Factors affecting percutaneous absorption"] },
  { text: "Classify and compare medicinal plasters", sub: ["Adhesive, medicated, and orthopaedic plasters"] },
  { text: "Identify clinical uses in physiotherapy", sub: ["Musculoskeletal pain, wound care, immobilisation"] },
  { text: "Recognize adverse effects, precautions and contraindications", sub: [] },
  { text: "Cite standard pharmacological references throughout", sub: [] },
], C.accent1);

// ─────────────────────────────────────────────────────────────────
// SLIDE 3 — OVERVIEW: TOPICAL FORMULATIONS
// ─────────────────────────────────────────────────────────────────
contentSlide("Topical Pharmaceutical Preparations — Overview", [
  { text: "Definition (British Pharmacopoeia / Fitzpatrick's)", sub: [
    "Topical preparations are designed for local or transdermal drug delivery on/through skin or mucous membranes",
    "May be: solutions, suspensions, emulsions, creams, ointments, gels, pastes, powders, plasters, or poultices",
  ]},
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    "Skin integrity: damaged/inflamed skin has ↑ permeability",
    "Molecular weight: lower MW drugs penetrate better",
    "Lipid solubility: lipophilic drugs cross stratum corneum more readily",
    "Vehicle: occlusive vehicles (ointments, plasters) greatly enhance absorption",
    "Concentration, contact time, surface area, body site",
  ]},
  { text: "Physiotherapy relevance: plasters, poultices & pastes are distinct preparation types that work locally and/or systemically" },
], C.accent1);

// ─────────────────────────────────────────────────────────────────
// SLIDE 4 — SECTION HEADER: PLASTERS
// ─────────────────────────────────────────────────────────────────
sectionHeader("SECTION 01", "Plasters", "Solid or semisolid preparations intended for external application to skin", C.accent2);

// ─────────────────────────────────────────────────────────────────
// SLIDE 5 — DEFINITION & COMPOSITION: PLASTERS
// ─────────────────────────────────────────────────────────────────
contentSlide("Plasters — Definition & Composition", [
  { text: "Definition (British Pharmacopoeia)", sub: [
    "Plasters are solid or semisolid preparations intended for external application",
    "Consist of a MASS (the plaster base) spread on a suitable BACKING (fabric, plastic, or paper)",
    "Designed to adhere firmly to skin; release active ingredient or provide physical support",
  ]},
  { text: "Composition of the Plaster Mass", sub: [
    "Base: resin, rubber (natural/synthetic), polyacrylate adhesive, or wax",
    "Active drug or medicament (in medicated plasters)",
    "Plasticisers (e.g., lanolin, paraffin) to improve flexibility",
    "Backing material: cotton fabric, polyester film, foam",
  ]},
  { text: "Plaster of Paris (Orthopaedic)", sub: [
    "Calcium sulfate hemihydrate (CaSO₄·½H₂O) — gypsum heated to ~128°C",
    "On wetting: recrystallises → hardens → immobilises fractures/joints",
    "Setting time: 3–8 min (fast); 5–15 min (medium); 10–20 min (slow) — Roberts & Hedges",
  ]},
], C.accent2);

// ─────────────────────────────────────────────────────────────────
// SLIDE 6 — CLASSIFICATION OF PLASTERS
// ─────────────────────────────────────────────────────────────────
tableSlide(
  "Classification of Plasters",
  ["Type", "Examples", "Active Ingredient / Base", "Clinical Use"],
  [
    ["Adhesive / Protective", "Elastoplast®, Bandage plaster", "Zinc oxide, rubber/resin adhesive", "Wound cover, skin protection, securing dressings"],
    ["Medicated Analgesic", "Salonpas®, Voltaren Patch®", "Methyl salicylate, diclofenac, lidocaine", "Musculoskeletal pain, arthritis, sports injuries"],
    ["Counterirritant", "Capsicum plaster, Mustard plaster", "Capsicum oleoresin / mustard oil", "Deep tissue hyperaemia, pain relief (rubefacient)"],
    ["Hormone / Systemic", "Fentanyl patch, Estradiol patch, Testosterone", "Lipophilic drugs in rate-controlling membrane", "Systemic drug delivery via transdermal route"],
    ["Orthopaedic (POP)", "Plaster of Paris cast/splint", "Calcium sulfate hemihydrate (CaSO₄·½H₂O)", "Fracture immobilisation, joint splinting"],
    ["Salicylic Acid", "Corn/wart plasters (Bazuka®)", "Salicylic acid 10–40%", "Keratolytic — corns, calluses, warts"],
    ["Hydrocolloid", "DuoDERM®, Comfeel®", "Gelatin, pectin, carboxymethylcellulose", "Wound healing, pressure ulcer management"],
  ],
  C.accent2,
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);

// ─────────────────────────────────────────────────────────────────
// SLIDE 7 — MEDICATED PLASTERS: MECHANISM
// ─────────────────────────────────────────────────────────────────
contentSlide("Medicated Plasters — Mechanism of Drug Delivery", [
  { text: "Transdermal Drug Delivery (Goodman & Gilman's; Dermatology 2-Vol Set)", sub: [
    "Drug in adhesive mass creates concentration gradient → diffuses into stratum corneum",
    "Rate-limiting step: stratum corneum (especially for polar/high MW drugs)",
    "Lipophilic drugs (e.g., fentanyl, methyl salicylate) penetrate well; absorbed through skin",
    "Dermis forms secondary reservoir → slow release continues after patch removal",
  ]},
  { text: "Occlusion Effect", sub: [
    "Plaster backing prevents evaporation → ↑ skin hydration → ↑ stratum corneum permeability",
    "Temperature ↑ under plaster → vasodilation → ↑ drug absorption into systemic circulation",
    "Occlusion can ↑ drug potency by 10-fold compared to non-occluded application",
  ]},
  { text: "Advantages over oral route", sub: [
    "Avoids first-pass hepatic metabolism",
    "Steady plasma levels — improved compliance",
    "Localised effect limits systemic side effects",
  ]},
], C.accent2);

// ─────────────────────────────────────────────────────────────────
// SLIDE 8 — PLASTER OF PARIS: CLINICAL USE IN PT
// ─────────────────────────────────────────────────────────────────
contentSlide("Plaster of Paris (POP) — Clinical Application in Physiotherapy", [
  { text: "Chemistry (Roberts & Hedges' Clinical Procedures)", sub: [
    "CaSO₄·2H₂O (gypsum) → heat to 128°C → CaSO₄·½H₂O (plaster of Paris)",
    "Rehydration reaction: CaSO₄·½H₂O + 1.5H₂O → CaSO₄·2H₂O + heat",
    "Sets by recrystallisation; generates heat during hardening — burn risk if excessive",
  ]},
  { text: "Preparation & Application", sub: [
    "Submerge plaster slab in water (room temp) → squeeze out excess → apply in layers",
    "Mold with flat of palm — avoid fingertip ridges (pressure necrosis risk)",
    "Complete moulding before 'critical period' — movement after sets incorrectly",
  ]},
  { text: "Physiotherapy Role", sub: [
    "Immobilisation of fractures, dislocations, sprains",
    "Serial casting for spasticity, contractures (e.g., cerebral palsy, stroke)",
    "Removable POP splints for rest + controlled mobilisation",
  ]},
  { text: "Complications to Monitor", sub: [
    "Pressure sores, compartment syndrome, thermal burns, skin maceration",
    "Restrict movement → muscle atrophy, joint stiffness → PT rehabilitation post-cast",
  ]},
], C.accent2);

// ─────────────────────────────────────────────────────────────────
// SLIDE 9 — SECTION HEADER: POULTICES
// ─────────────────────────────────────────────────────────────────
sectionHeader("SECTION 02", "Poultices", "Moist, soft masses applied to skin for therapeutic local effects", C.accent1);

// ─────────────────────────────────────────────────────────────────
// SLIDE 10 — DEFINITION & HISTORY
// ─────────────────────────────────────────────────────────────────
contentSlide("Poultices — Definition, History & Composition", [
  { text: "Definition (Fitzpatrick's Dermatology; RxList Medical Dictionary)", sub: [
    "Also called a CATAPLASM — from Latin pulta / Greek poltos (porridge)",
    "A wet, soft mass of particles, sometimes heated, applied to diseased or inflamed skin",
    "Used for moist local heat, pain relief, or wound cleansing",
  ]},
  { text: "Historical Background (Schwartz's Surgery)", sub: [
    "One of the oldest therapeutic interventions — Egyptian Edwin Smith Papyrus (1650 BC)",
    "Originally: meal, herbs, seeds, plant material, linseed, bread, mustard",
    "Modern poultice: sterile dextranomer beads or polymer hydrogel material",
  ]},
  { text: "Modern Composition (Fitzpatrick's Dermatology)", sub: [
    "Dextranomer beads (porous, absorptive) — draws wound exudate",
    "Clay (kaolin), bran, starch — traditional moist heat vehicles",
    "Active agents: turmeric/curcumin (anti-inflammatory), mustard, herbal extracts",
  ]},
  { text: "Key characteristic: MOIST preparation — distinguishes from dry plasters and pastes" },
], C.accent1);

// ─────────────────────────────────────────────────────────────────
// SLIDE 11 — MECHANISM OF ACTION: POULTICES
// ─────────────────────────────────────────────────────────────────
contentSlide("Poultices — Mechanisms of Action", [
  { text: "1. Moist Local Heat", sub: [
    "Warm poultice raises local tissue temperature → vasodilation → ↑ blood flow",
    "↑ metabolic rate, oedema reabsorption, pain relief",
    "Gate control: thermal stimulation of Aβ fibres → ↓ pain signal via dorsal horn",
  ]},
  { text: "2. Absorptive / Drawing Action (Dextranomer)", sub: [
    "Porous beads absorb exudate, bacteria, and wound debris by capillary action",
    "Debriding effect: removes necrotic material from chronic wounds",
    "Creates optimal moist wound environment for healing",
  ]},
  { text: "3. Counterirritant Effect (Mustard / Kaolin Poultices)", sub: [
    "Mustard: allyl isothiocyanate activates TRPA1 → local hyperaemia (rubefacient)",
    "Heat promotes skin penetration of active agents",
    "Reduces deeper pain via competing cutaneous sensory input (Gate Control Theory)",
  ]},
  { text: "4. Anti-inflammatory (Curcumin/Turmeric Poultice)", sub: [
    "Curcumin → suppression of NF-κB → ↓ IL-1β, IL-6, TNF-α (Fitzpatrick's)",
    "Topical application to joints/active inflammatory sites",
  ]},
], C.accent1);

// ─────────────────────────────────────────────────────────────────
// SLIDE 12 — TYPES OF POULTICES
// ─────────────────────────────────────────────────────────────────
tableSlide(
  "Types of Poultices — Classification & Uses",
  ["Type", "Composition", "Mechanism", "Clinical Use"],
  [
    ["Kaolin Poultice", "Hydrated aluminium silicate (clay) + glycerine + peppermint oil", "Moist heat; counterirritant; absorbent", "Chest (bronchitis, pleurisy), musculoskeletal pain, boils/abscesses"],
    ["Mustard Plaster/Poultice", "Mustard flour + wheat flour + warm water", "TRPA1 activation → hyperaemia; counterirritant", "Chest congestion, backache, joint pain (traditional)"],
    ["Linseed (Flaxseed) Poultice", "Linseed meal + boiling water → paste", "Moist heat; softens tissues; anti-inflammatory omega-3", "Abscesses, suppuration, drawing ulcers, skin softening"],
    ["Dextranomer Poultice", "Porous dextranomer beads (Debrisan®)", "Absorbs exudate and bacteria by capillary action", "Exudative wounds, decubitus ulcers, leg ulcers"],
    ["Charcoal Poultice", "Activated charcoal + linseed", "Adsorbs toxins, bacteria; odour control", "Infected/malodorous wounds, ulcers"],
    ["Herbal (Turmeric/Comfrey)", "Curcumin / allantoin in moist base", "Anti-inflammatory; cell proliferation (allantoin)", "Arthritis, sprains, bruising, wound healing"],
    ["Epsom Salt Poultice", "Magnesium sulfate paste in glycerine", "Osmotic draw; reduces oedema; bacteriostatic", "Abscesses, splinters, boils, foot soaks"],
  ],
  C.accent1,
  [2.0, 2.3, 2.3, 2.8]
);

// ─────────────────────────────────────────────────────────────────
// SLIDE 13 — SECTION HEADER: PASTES
// ─────────────────────────────────────────────────────────────────
sectionHeader("SECTION 03", "Pastes", "Stiff, thick semisolid preparations with ≥20% powder in an ointment base", C.accent3);

// ─────────────────────────────────────────────────────────────────
// SLIDE 14 — DEFINITION & COMPOSITION: PASTES
// ─────────────────────────────────────────────────────────────────
contentSlide("Pastes — Definition & Composition", [
  { text: "Definition (Fitzpatrick's Dermatology; British Pharmacopoeia)", sub: [
    "Pastes are thick, stiff semisolid preparations containing a HIGH proportion of finely powdered solids",
    "Typically 20–50% powder suspended in an ointment base",
    "Stiffer than ointments → do NOT spread easily → remain localised at application site",
  ]},
  { text: "Composition", sub: [
    "Powder component (20–50%): zinc oxide, starch, titanium dioxide, talc, calcium carbonate",
    "Ointment base: petrolatum, soft white paraffin, or lanolin",
    "May contain active drugs: coal tar, salicylic acid, ichthammol, antifungals",
  ]},
  { text: "Physical Properties", sub: [
    "High viscosity → acts as a physical barrier and protective film",
    "Less occlusive than pure ointments → allows some moisture exchange",
    "Stiffness reduces spreading → ideal for inflamed/weeping skin lesions",
    "Difficult to remove → often needs paraffin oil or mineral oil for removal",
  ]},
], C.accent3);

// ─────────────────────────────────────────────────────────────────
// SLIDE 15 — MECHANISMS OF ACTION: PASTES
// ─────────────────────────────────────────────────────────────────
contentSlide("Pastes — Mechanisms of Action", [
  { text: "1. Physical Barrier & Skin Protection", sub: [
    "Thick powder-in-oil matrix → mechanical barrier against moisture, irritants, friction",
    "Prevents maceration in moist/intertriginous areas",
    "Absorbent powders (starch, zinc oxide) reduce wetness",
  ]},
  { text: "2. Astringent & Anti-inflammatory (Zinc Oxide)", sub: [
    "Zinc oxide: precipitates proteins → mild astringent action",
    "Anti-inflammatory: ↓ pro-inflammatory cytokines, antimicrobial properties",
    "Used in Lassar's paste (zinc + starch + salicylic acid + white soft paraffin)",
  ]},
  { text: "3. Drug Delivery — Localised & Concentrated (Fitzpatrick's)", sub: [
    "High powder content slows drug diffusion → prolonged local drug contact",
    "Ideal for localising drugs that may stain or irritate (e.g., coal tar, anthralin)",
    "Less drug absorption than ointments or creams due to reduced skin contact",
  ]},
  { text: "4. Protective Dressing Role in PT", sub: [
    "Applied under compression bandaging in chronic leg ulcers (zinc paste bandage)",
    "Ichthammol paste for chronic inflammatory skin conditions",
  ]},
], C.accent3);

// ─────────────────────────────────────────────────────────────────
// SLIDE 16 — KEY PASTES TABLE
// ─────────────────────────────────────────────────────────────────
tableSlide(
  "Important Medicinal Pastes — Classification & Clinical Use",
  ["Paste / Preparation", "Composition", "Mechanism / Properties", "Clinical Use in PT / Dermatology"],
  [
    ["Zinc Oxide Paste\n(Lassar's Paste)", "Zinc oxide 25%, starch 25%, salicylic acid 2%, white soft paraffin", "Astringent, barrier, mild antiseptic, keratolytic", "Eczema, psoriasis, nappy rash, skin protection under bandages"],
    ["Zinc & Ichthammol\nPaste", "Zinc oxide + ichthammol (ammonium bituminosulfonate)", "Anti-inflammatory, antiseptic, antipruritic", "Chronic eczema, lichenification, compression bandage base"],
    ["Coal Tar Paste\n(Compound Coal Tar)", "Coal tar 4–12% + zinc oxide + starch", "Antiproliferative, anti-inflammatory, antipruritic", "Psoriasis, chronic eczema — often in dermatology + PT rehab units"],
    ["Titanium Dioxide Paste", "Titanium dioxide in paraffin base", "Physical UV barrier; astringent", "Sun protection, radiation-associated skin protection"],
    ["Calamine Paste", "Calamine (98% ZnO + 1% Fe₂O₃) + starch + glycerine", "Astringent, antipruritic, soothing", "Pruritic skin conditions, chickenpox, insect bites"],
    ["Salicylic Acid Paste", "Salicylic acid 10–40% in vaseline/paraffin", "Keratolytic: softens and breaks down keratin", "Verrucae, hyperkeratosis, psoriatic plaques"],
    ["Antifungal Paste", "Miconazole / clotrimazole in paste base", "Azole antifungal; disrupts ergosterol synthesis", "Fungal skin infections in immobilised/PT patients"],
  ],
  C.accent3,
  [2.0, 2.2, 2.4, 2.8]
);

// ─────────────────────────────────────────────────────────────────
// SLIDE 17 — COMPARATIVE TABLE: PLASTER vs POULTICE vs PASTE
// ─────────────────────────────────────────────────────────────────
tableSlide(
  "Comparison: Plasters vs Poultices vs Pastes",
  ["Feature", "Plasters", "Poultices", "Pastes"],
  [
    ["Consistency", "Solid / semisolid on backing", "Moist, soft mass (wet)", "Thick, stiff semisolid"],
    ["Moisture Content", "Dry (most types)", "HIGH — defining feature", "Low (ointment-based, dry powder)"],
    ["Backing Material", "Fabric, plastic film, foam", "Cloth, gauze", "No backing (applied directly)"],
    ["Main Effect", "Adhesion + local/systemic drug", "Moist heat + draw + absorb", "Protective barrier + local drug"],
    ["Occlusion", "High (enhances absorption)", "Moderate", "Moderate (less than ointments)"],
    ["Key Drugs", "Diclofenac, methyl salicylate, fentanyl", "Dextranomer, kaolin, mustard", "Zinc oxide, coal tar, ichthammol"],
    ["PT Application", "Pain patches, casting, wound cover", "Wound care, moist heat therapy", "Compression bandage base, wound protection"],
    ["Source", "BP, Goodman & Gilman's", "Fitzpatrick's, BP", "Fitzpatrick's, BP"],
  ],
  C.accent1,
  [1.8, 2.5, 2.5, 2.6]
);

// ─────────────────────────────────────────────────────────────────
// SLIDE 18 — SKIN ABSORPTION FACTORS DIAGRAM
// ─────────────────────────────────────────────────────────────────
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    { label: "Vehicle / Formulation", detail: "Plasters > Ointments > Pastes > Creams > Gels", color: C.accent2 },
    { label: "Skin Integrity", detail: "Damaged skin ↑↑ absorption; inflamed skin permeable", color: C.accent1 },
    { label: "Drug Properties", detail: "Low MW, high lipophilicity = better penetration", color: C.accent3 },
    { label: "Occlusion", detail: "Occlusive vehicle ↑ hydration → ↑ penetration ~10×", color: C.green },
    { label: "Body Site", detail: "Scrotum > face > chest > forearm > palm/sole", color: C.accent2 },
    { label: "Concentration & Time", detail: "↑ concentration gradient & contact time = ↑ absorption", color: C.accent1 },
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// ─────────────────────────────────────────────────────────────────
// SLIDE 19 — PHYSIOTHERAPY CLINICAL APPLICATIONS
// ─────────────────────────────────────────────────────────────────
contentSlide("Clinical Applications in Physiotherapy Practice", [
  { text: "Plasters in Physiotherapy", color: C.accent2, sub: [
    "POP casts/splints: fracture management, serial casting for spasticity/contractures",
    "TENS/counterirritant patches (methyl salicylate, diclofenac) for MSK pain",
    "Hydrocolloid plasters for wound/pressure area management",
    "Kinesio / adhesive plasters: support, lymphatic drainage, proprioception",
  ]},
  { text: "Poultices in Physiotherapy", color: C.accent1, sub: [
    "Moist heat therapy using kaolin/flaxseed poultices — superficial heat modality",
    "Dextranomer/hydrocolloid for wound debridement in chronic patients",
    "Mustard poultice (traditional): chest physiotherapy, backache",
  ]},
  { text: "Pastes in Physiotherapy", color: C.accent3, sub: [
    "Zinc paste bandages (Viscopaste®) under compression in venous leg ulcer therapy",
    "Ichthammol paste for anti-inflammatory effect in chronic soft-tissue conditions",
    "Protective pastes over bony prominences / pressure areas",
  ]},
], C.accent1);

// ─────────────────────────────────────────────────────────────────
// SLIDE 20 — ADVERSE EFFECTS & PRECAUTIONS
// ─────────────────────────────────────────────────────────────────
tableSlide(
  "Adverse Effects & Precautions",
  ["Preparation", "Common Adverse Effects", "Precautions / Contraindications"],
  [
    ["Medicated Plasters\n(Analgesic Patches)", "Local erythema, contact dermatitis, skin irritation, blistering", "Broken/infected skin, allergy to adhesive, avoid over mucous membranes"],
    ["POP Plaster", "Pressure necrosis, thermal burn, compartment syndrome, skin maceration", "Proper padding essential; monitor circulation (capillary refill, sensation)"],
    ["Salicylic Acid Plaster", "Skin erosion, chemical burn (if overused), perilesional irritation", "Avoid normal skin; diabetics/peripheral neuropathy (↑ ulcer risk)"],
    ["Kaolin Poultice", "Burns if too hot, skin irritation with prolonged use", "Test temperature before applying; avoid on open wounds"],
    ["Mustard Poultice", "Vesication (blistering), irritant dermatitis, skin burns", "Apply only 10–15 min; do NOT leave unattended; avoid in children"],
    ["Zinc Oxide Paste", "Rare: contact allergy; skin dryness", "Avoid in known zinc allergy; difficult removal without oil"],
    ["Coal Tar Paste", "Skin irritation, folliculitis, photosensitivity, staining", "Avoid UV exposure; not near face; teratogenic potential — avoid in pregnancy"],
    ["Ichthammol Paste", "Skin sensitisation, folliculitis (rare)", "Avoid on acutely inflamed/infected skin"],
  ],
  C.accent2,
  [2.2, 3.2, 4.0]
);

// ─────────────────────────────────────────────────────────────────
// SLIDE 21 — SOURCES & REFERENCES
// ─────────────────────────────────────────────────────────────────
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  titleBar(s, "Standard References & Sources");

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    ["01", C.accent2, "Fitzpatrick's Dermatology (9th Ed)", "Chapters on Topical Formulations (Poultices, Pastes, Powders, Ointments) — Wolff K et al., McGraw-Hill"],
    ["02", C.accent1, "Goodman & Gilman's Pharmacological Basis of Therapeutics (14th Ed)", "Drug Absorption, ADME, Transdermal Delivery — Brunton L et al., McGraw-Hill"],
    ["03", C.accent3, "Roberts & Hedges' Clinical Procedures in Emergency Medicine (7th Ed)", "Plaster of Paris — Splint Application, Heat Injury Sections"],
    ["04", C.accent2, "British Pharmacopoeia (BP 2024)", "Monographs: Plasters, Pastes, Topical Preparations — MHRA, London"],
    ["05", C.accent1, "Dermatology 2-Volume Set (5th Ed)", "Transdermal Drug Delivery, Topicals — Elsevier Dermatology"],
    ["06", C.accent3, "Lippincott Illustrated Reviews: Pharmacology (7th Ed)", "Topical NSAIDs, Methyl Salicylate — Wolters Kluwer"],
  ];

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// ─────────────────────────────────────────────────────────────────
// SLIDE 22 — KEY TAKE-AWAYS
// ─────────────────────────────────────────────────────────────────
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  bgBase(s);
  topBar(s, C.green);
  titleBar(s, "Key Take-Aways");

  const pts = [
    [C.accent2, "Plasters = solid/semisolid on backing; includes POP (orthopaedic), medicated (analgesic patches) and protective types"],
    [C.accent1, "Poultices (cataplasms) = moist preparations; mechanism: heat → vasodilation, TRPA1 activation, absorbent debridement"],
    [C.accent3, "Pastes = ≥20% powder in ointment base; stiff, localised, ideal for skin protection + drug delivery in inflamed skin"],
    [C.accent2, "Occlusion under plasters/pastes ↑ skin hydration → ↑ drug penetration by up to 10× (Goodman & Gilman's)"],
    [C.accent1, "POP serial casting: key physiotherapy tool for spasticity management — monitor neurovascular status always"],
    [C.accent3, "Zinc paste bandages + compression = first-line in venous leg ulcer physiotherapy protocols"],
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// ─────────────────────────────────────────────────────────────────
// SLIDE 23 — THANK YOU
// ─────────────────────────────────────────────────────────────────
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  // ── COVER ──────────────────────────────────────────────────────
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    children: [new TextRun({ text: "DRUG DISCOVERY", font: "Calibri", size: 72, bold: true, color: DARK_BLUE })],
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  new Paragraph({
    children: [new TextRun({ text: "Lecture Notes for Postgraduate Students", font: "Calibri", size: 32, color: TEAL, italics: true })],
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    spacing: { before: 0, after: 80 },
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    children: [new TextRun({ text: "• Goodman & Gilman's The Pharmacological Basis of Therapeutics (14th Ed., 2023) — Chapter 1", font: "Calibri", size: 20, color: GRAY_TEXT })],
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    children: [new TextRun({ text: "• Lippincott Illustrated Reviews: Pharmacology (7th Ed., 2023)", font: "Calibri", size: 20, color: GRAY_TEXT })],
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    children: [new TextRun({ text: "• Rang & Dale's Pharmacology (9th Ed., 2020)", font: "Calibri", size: 20, color: GRAY_TEXT })],
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    children: [new TextRun({ text: "• FDA Drug Approval Process (2024) | British Pharmacopoeia (2024)", font: "Calibri", size: 20, color: GRAY_TEXT })],
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  sectionBreak(),

  // ── 1. INTRODUCTION ────────────────────────────────────────────
  h1("1. Introduction to Drug Discovery"),

  body("Drug discovery is the multidisciplinary process by which new candidate medicines are identified and developed. Historically, therapeutic agents were discovered through empirical observation — notably from plants, fungi, and other natural organisms. Today, the field is driven by target-based rational design, high-throughput screening, computational methods, and increasingly by artificial intelligence (AI). The modern drug discovery pipeline is a highly structured, resource-intensive continuum spanning from early target identification to FDA/EMA regulatory approval and post-marketing surveillance."),

  noteBox("Goodman & Gilman (14th Ed., 2023): 'Drug discovery in the past often resulted from serendipitous observations… Drugs were selected based on effect, with no understanding of mechanism as we use the term today.' — Chapter 1, p. 22"),

  spacer(),

  h2("1.1  Drug Discovery or Drug Invention?"),

  body("The term 'drug discovery' is historically appropriate for compounds obtained from nature. However, most modern therapeutics are deliberately designed ('invented') through systematic chemical modification of known pharmacophores, computational modelling, and biological testing. Goodman & Gilman distinguish: serendipitous discovery (natural products, accidental observations) vs. rational drug design (target-based, structure-guided synthesis)."),

  bullet1("Classic examples of discovery (Goodman & Gilman Ch. 1):"),
  bullet2("Morphine (opium) — pain; observed in poppy (Papaver somniferum)"),
  bullet2("Penicillin — antibiotic; Fleming's accidental observation (Penicillium mould, 1928)"),
  bullet2("Aspirin — anti-inflammatory; willow bark (salicin) → synthetic acetylsalicylic acid"),
  bullet2("Digitalis — cardiac glycoside; Foxglove plant (Digitalis purpurea)"),
  bullet2("Atropine — anticholinergic; Atropa belladonna (pupil dilation)"),
  bullet2("Ephedrine — sympathomimetic; Chinese herb ma huang"),

  spacer(),

  keyBox("Key Term: Pharmacophore — the minimal structural framework of a drug molecule that is responsible for its biological activity."),

  spacer(),

  h2("1.2  Scope and Scale of Modern Drug Discovery"),

  body("Modern drug development is extraordinarily expensive and time-consuming. Estimates suggest that bringing a new molecular entity (NME) to market takes on average 10–15 years and costs USD 1–3 billion (Conti et al., JAMA Health Forum 2021; Congressional Budget Office 2021). The vast majority of candidate molecules fail — approximately 90% of compounds entering Phase I clinical trials never receive approval."),

  makeTable(
    ["Parameter", "Approximate Figure"],
    [
      ["Average time to market", "10–15 years"],
      ["Estimated cost per approved drug", "USD 1–3 billion"],
      ["Compounds screened per approved drug", "~10,000 – 1,000,000"],
      ["Success rate (Phase I → Approval)", "~10%"],
      ["Annual global pharmaceutical R&D spend", ">USD 240 billion (2024)"],
    ],
    [4600, 4600]
  ),

  spacer(2),

  sectionBreak(),

  // ── 2. THE DRUG DISCOVERY PIPELINE ────────────────────────────
  h1("2. The Drug Discovery & Development Pipeline"),

  body("The process from idea to approved medicine is divided into sequential but iterative stages. Each stage has defined objectives, methodologies, and criteria to proceed ('go') or terminate ('no-go') the programme."),

  spacer(),

  makeTable(
    ["Stage", "Key Activities", "Duration (approx.)"],
    [
      ["Target Identification", "Genomics, proteomics, phenotypic screening, disease biology", "1–3 years"],
      ["Target Validation", "Genetic knockouts, RNAi, biomarker studies, disease relevance confirmation", "1–2 years"],
      ["Hit Discovery", "HTS, FBDD, natural product screening, DEL", "1–2 years"],
      ["Lead Identification", "SAR analysis, selectivity, preliminary ADME", "1–2 years"],
      ["Lead Optimisation", "Medicinal chemistry, PK/PD optimisation, in vitro/in vivo models", "2–3 years"],
      ["Preclinical Development", "Toxicology (GLP), pharmacology, formulation, IND filing", "1–2 years"],
      ["Phase I Clinical Trial", "Safety, tolerability, PK in healthy volunteers (20–100)", "1–2 years"],
      ["Phase II Clinical Trial", "Efficacy + safety in patients with disease (100–500)", "2–3 years"],
      ["Phase III Clinical Trial", "Large RCT; efficacy, safety, dose confirmation (1,000–5,000)", "3–5 years"],
      ["NDA/BLA Submission & Approval", "Regulatory review by FDA/EMA; advisory committee", "1–2 years"],
      ["Phase IV (Post-marketing)", "Pharmacovigilance, real-world evidence, rare ADRs", "Ongoing"],
    ],
    [2200, 4000, 2000]
  ),

  spacer(2),
  noteBox("Goodman & Gilman (Fig. 1-6, p. 34): Funnel diagram showing progressive attrition from target to approved drug. Only ~1 in 10,000 compounds screened ultimately reaches approval."),

  spacer(),

  h2("2.1  Investigational New Drug (IND) Application"),

  body("Before a drug can enter clinical trials in the US, the sponsor must file an IND application with the FDA. The IND includes: (i) all preclinical animal data; (ii) manufacturing and quality information; (iii) proposed clinical study protocols; and (iv) investigator qualifications. The FDA has 30 days to review the IND before trials may commence."),

  bullet1("Key IND Components (FDA 21 CFR §312):"),
  bullet2("Pharmacology and toxicology data (animal studies)"),
  bullet2("Chemistry, Manufacturing, and Controls (CMC)"),
  bullet2("Clinical protocol with study design, endpoints, statistical plan"),
  bullet2("Investigator brochure"),

  spacer(),

  sectionBreak(),

  // ── 3. TARGET IDENTIFICATION & VALIDATION ─────────────────────
  h1("3. Target Identification and Validation"),

  body("A drug target is a molecule (usually a protein, but also nucleic acids, lipids, or carbohydrates) whose activity can be modulated by a drug to produce a therapeutic effect. The process of finding and confirming the right target is one of the most critical steps in drug discovery, as ~50% of late-stage failures are attributed to lack of efficacy — frequently the result of poorly validated targets."),

  h2("3.1  Target Identification Strategies"),

  h3("3.1.1  Genomics and Transcriptomics"),
  body("Comparison of gene expression profiles (microarray, RNA-seq) between diseased and healthy tissue reveals upregulated/downregulated genes as candidate targets. Genome-wide association studies (GWAS) link single nucleotide polymorphisms (SNPs) to disease susceptibility, nominating causal genes."),
  noteBox("Van de Sande et al. (Nat Rev Drug Discov, 2023; PMID 37117846): Single-cell RNA sequencing (scRNA-seq) now enables cell-type-specific target identification, revealing previously inaccessible disease biology at single-cell resolution."),

  h3("3.1.2  Proteomics and Structural Biology"),
  body("Mass spectrometry-based proteomics identifies differentially expressed or post-translationally modified proteins. X-ray crystallography and cryo-electron microscopy (cryo-EM) resolve 3D protein structures, enabling structure-based drug design (SBDD)."),

  h3("3.1.3  Phenotypic Screening"),
  body("Rather than starting with a molecular target, phenotypic screening identifies compounds that produce a desired cellular or whole-organism effect. The mechanism of action is elucidated post-hoc using chemical proteomics (activity-based protein profiling, ABPP) or genetic methods."),
  noteBox("Walker & Clardy (Biochemistry, 2024; PMID 39497571): Natural product-derived leads frequently identified via phenotypic screens — the target is often unknown at initial discovery."),

  h3("3.1.4  Multi-Omics Integration"),
  body("Integration of genomics, transcriptomics, proteomics, metabolomics, and epigenomics (multi-omics) provides a systems-level view of disease. Causal inference methods (e.g., Mendelian randomisation) distinguish causally linked targets from mere bystanders."),
  noteBox("Du et al. (Biomolecules, 2024; PMID 38927095): Multi-omics integration substantially improves target prioritisation by filtering out non-causal disease associations."),

  spacer(),

  h2("3.2  Target Validation"),

  body("Target validation confirms that modulating the identified target will produce the desired therapeutic effect without unacceptable harm. Methods include:"),

  bullet1("Genetic validation:"),
  bullet2("Gene knockout (KO) / knockin models in mice (CRISPR-Cas9)"),
  bullet2("RNA interference (RNAi) — siRNA, shRNA to silence gene expression"),
  bullet2("Patient genetic data — loss-of-function variants confirming target link to disease"),

  bullet1("Pharmacological validation:"),
  bullet2("Use of tool compounds (selective inhibitors/activators) to probe target function"),
  bullet2("Phenotype rescue: re-expression of target in KO model reverses phenotype"),

  bullet1("Biomarker validation:"),
  bullet2("Target engagement biomarkers confirm drug binds its target in vivo (PET imaging, target occupancy assays)"),

  spacer(),

  h2("3.3  Target Druggability"),

  body("Druggability refers to the ability of a target to bind a small molecule drug with sufficient affinity and selectivity. Druggable targets typically have a well-defined binding pocket (e.g., active site of an enzyme, orthosteric site of a receptor). Traditionally ~10–15% of the human proteome is considered druggable by small molecules."),

  bullet1("Druggable target classes (Goodman & Gilman, Ch. 1):"),
  bullet2("Enzymes (kinases, proteases, phosphodiesterases): ~47% of all drug targets"),
  bullet2("G-protein coupled receptors (GPCRs): ~33%"),
  bullet2("Ion channels: ~18%"),
  bullet2("Nuclear receptors, transporters, others: remainder"),

  noteBox("'Undruggable' targets — e.g., Ras, Myc, p53 — have historically been resistant to small molecule inhibition due to lack of defined binding pockets. Recent advances in covalent drugs and PROTACs are beginning to address this challenge. (Boike et al., Nat Rev Drug Discov, 2022; PMID 36008483)"),

  spacer(),

  h2("3.4  Beyond Single-Protein Targets"),

  body("Complex diseases (cancer, neurodegeneration) often involve networks of dysregulated proteins rather than single targets. Emerging strategies include:"),

  bullet1("Polypharmacology: deliberate design of drugs hitting multiple targets simultaneously"),
  bullet1("PROTACs (Proteolysis Targeting Chimeras): bifunctional molecules that recruit E3 ubiquitin ligases to degrade the target protein rather than simply inhibit it"),
  bullet1("Allosteric modulators: bind outside the active site, modulating protein function with greater selectivity"),
  bullet1("Protein–protein interaction (PPI) inhibitors: disrupt disease-relevant protein complexes"),

  spacer(),

  sectionBreak(),

  // ── 4. EXPERIMENTAL APPROACHES ────────────────────────────────
  h1("4. Experimental Approaches to Drug Discovery"),

  h2("4.1  Medicinal Chemistry and Structure-Activity Relationships (SAR)"),

  body("Medicinal chemistry is the discipline that bridges chemistry and pharmacology, focused on designing and synthesising compounds with optimised biological activity, selectivity, pharmacokinetic properties, and safety."),

  h3("4.1.1  Structure-Activity Relationships (SAR)"),
  body("SAR systematically examines how chemical structural modifications affect biological activity. A lead compound is structurally modified (e.g., by varying substituents, ring systems, functional groups) and each analogue is tested. Patterns in the data guide further synthesis. (Figure 1-1, Goodman & Gilman Ch. 1: ALDH inhibitor example)"),

  bullet1("Key objectives of SAR/lead optimisation:"),
  bullet2("Potency: Maximise affinity for target (↓ IC50/EC50/Kd)"),
  bullet2("Selectivity: Minimise off-target activity (avoid toxicity)"),
  bullet2("ADME: Optimise absorption, distribution, metabolism, excretion"),
  bullet2("Lipinski's Rule of Five: MW ≤ 500, LogP ≤ 5, H-bond donors ≤ 5, H-bond acceptors ≤ 10 (for oral bioavailability)"),
  bullet2("Metabolic stability: Avoid rapid hepatic CYP-mediated degradation"),
  bullet2("Toxicity flags: Avoid reactive metabolites, hERG inhibition, mutagenic groups"),

  spacer(),

  h2("4.2  High-Throughput Screening (HTS)"),

  body("HTS involves automated, rapid screening of large chemical libraries (10^4 to 10^6+ compounds) against a purified biological target or cell-based assay. Robotic liquid handling enables screening thousands of compounds per day."),

  bullet1("Types of HTS assays:"),
  bullet2("Biochemical assays: enzyme inhibition (fluorescence, luminescence, radiometric)"),
  bullet2("Cell-based assays: receptor binding, reporter gene (luciferase), cell viability"),
  bullet2("DNA-Encoded Libraries (DEL): each compound tagged with a unique DNA barcode; enables screening of >10^9 compounds simultaneously (Hafford, 2017; Goodman & Gilman)"),

  bullet1("Hit criteria:"),
  bullet2("Typically >50% inhibition/activation at single fixed concentration"),
  bullet2("Confirmed in dose-response (IC50/EC50 determination)"),
  bullet2("Orthogonal counter-screens to exclude assay artefacts (fluorescent, aggregating compounds)"),

  spacer(),

  h2("4.3  Fragment-Based Drug Discovery (FBDD)"),

  body("FBDD uses very small molecules (fragments, MW ~100–300 Da) as starting points. Fragments bind weakly but efficiently to target binding sites. They are detected by sensitive biophysical methods and then grown, merged, or linked to improve affinity. FBDD addresses the limitation that even large HTS libraries sample a tiny fraction of drug-like chemical space (~10^60 possible organic molecules; Reymond et al., 2010)."),

  bullet1("Key detection methods in FBDD:"),
  bullet2("X-ray crystallography — gold standard; reveals binding mode"),
  bullet2("Surface Plasmon Resonance (SPR) — measures binding kinetics"),
  bullet2("NMR spectroscopy (especially ¹H and ¹⁹F) — detects weak binding"),
  bullet2("Differential Scanning Fluorimetry (DSF) / thermal shift assay"),

  bullet1("Fragment → Lead strategies:"),
  bullet2("Fragment growing: add chemical groups to improve affinity"),
  bullet2("Fragment linking: connect two fragments binding adjacent sites"),
  bullet2("Fragment merging: combine pharmacophoric elements of two fragments"),

  noteBox("Example: Venetoclax (BCL-2 inhibitor, FDA-approved 2016 for CLL) originated from FBDD. Starting fragments were grown and optimised over many iterations into a potent clinical candidate."),

  spacer(),

  h2("4.4  Natural Product Drug Discovery"),

  body("Natural products (NPs) — compounds produced by plants, fungi, bacteria, and marine organisms — represent the historical foundation of drug discovery and continue to be a prolific source of molecular scaffolds and bioactive leads. Approximately 50% of all approved drugs are derived from or inspired by natural products (Newman & Cragg, 2020)."),

  bullet1("Examples of natural product-derived drugs:"),
  bullet2("Penicillin (Penicillium notatum) → antibiotics"),
  bullet2("Taxol/paclitaxel (Taxus brevifolia bark) → antineoplastic"),
  bullet2("Artemisinin (Artemisia annua) → antimalarial"),
  bullet2("Lovastatin (Aspergillus terreus) → statin platform → atorvastatin"),
  bullet2("Cyclosporin (Tolypocladium inflatum) → immunosuppressant"),

  noteBox("Mullowney et al. (Nat Rev Drug Discov, 2023; PMID 37697042): AI-powered genome mining of biosynthetic gene clusters is accelerating natural product discovery, enabling identification of novel scaffolds without cultivation."),

  spacer(),

  sectionBreak(),

  // ── 5. COMPUTER-AIDED DRUG DISCOVERY ─────────────────────────
  h1("5. Computer-Aided Drug Discovery (CADD)"),

  body("CADD encompasses all computational methods used to facilitate the drug discovery process. It is now an indispensable component of every major pharmaceutical R&D programme, significantly reducing the cost and time of lead identification and optimisation."),

  h2("5.1  Structure-Based Drug Design (SBDD)"),

  body("SBDD uses the experimentally determined or computationally predicted 3D structure of the target protein (usually its ligand-binding site) to guide the design of new drug molecules."),

  h3("5.1.1  Molecular Docking"),
  body("Molecular docking computationally predicts the preferred orientation (binding pose) of a small molecule within the target's binding site and estimates binding affinity. Widely used in virtual screening to rank and filter large compound libraries."),

  h3("5.1.2  Molecular Dynamics (MD) Simulations"),
  body("MD simulations model the motion of atoms in a molecular system over time, revealing conformational flexibility, allosteric mechanisms, and the stability of protein-ligand complexes. Key for understanding 'induced fit' and cryptic binding sites."),

  h3("5.1.3  AlphaFold and Protein Structure Prediction"),
  body("DeepMind's AlphaFold2 (2021) revolutionised structural biology by predicting protein structures with near-experimental accuracy. The AlphaFold Protein Structure Database now covers >200 million protein structures, dramatically expanding the range of druggable targets accessible for SBDD."),

  noteBox("Key impact of AlphaFold: Previously 'undruggable' proteins lacking experimental structures can now be modelled with high confidence, enabling virtual screening and SBDD for previously inaccessible targets."),

  h2("5.2  Ligand-Based Drug Design (LBDD)"),

  body("When the target structure is unavailable, LBDD exploits known active compounds to predict activity. Methods include:"),
  bullet1("Pharmacophore modelling: defines spatial arrangement of features required for activity"),
  bullet1("Quantitative Structure-Activity Relationships (QSAR): builds mathematical models relating chemical descriptors to biological activity"),
  bullet1("Similarity searching: finds compounds structurally similar to known actives in large databases (PubChem, ChEMBL)"),

  spacer(),

  h2("5.3  Artificial Intelligence in Drug Discovery"),

  body("AI — particularly deep learning (DL) and generative AI — is transforming drug discovery by enabling the analysis of vast, high-dimensional datasets and the de novo design of drug candidates. A landmark 2025 review in Nature Medicine (Zhang et al.; PMID 39833407) defines AI's role across the full development pipeline."),

  bullet1("Key AI applications (Zhang et al., Nat Med, 2025; Pun et al., Trends Pharmacol Sci, 2023):"),

  bullet2("Target identification: Natural Language Processing (NLP) mines literature; graph neural networks model protein interaction networks"),
  bullet2("Virtual screening: Deep learning models (e.g., convolutional neural nets) predict binding affinity with higher speed and accuracy than classical docking"),
  bullet2("De novo molecular generation: Generative AI (VAEs, GANs, diffusion models) designs entirely new drug-like molecules with desired properties — no longer restricted to screening existing libraries"),
  bullet2("ADMET prediction: ML models predict absorption, distribution, metabolism, excretion, and toxicity from structure alone (Bai et al., Adv Sci, 2025; PMID 39899688)"),
  bullet2("Clinical trial optimisation: AI identifies patient subgroups, predicts trial outcomes, enables adaptive trial designs (Bordukova et al., Expert Opin Drug Discov, 2024; PMID 37887266)"),

  bullet1("Notable AI-discovered drugs entering clinical trials (as of 2025):"),
  bullet2("INX-315 (CDK2 inhibitor) — Insilico Medicine (first AI-designed drug in Phase II)"),
  bullet2("SYN023 (COVID-19 antibody) — AI-designed in 46 days"),
  bullet2("DSP-1181 (OCD candidate) — Sumitomo/Exscientia; designed in 12 months vs. usual 4.5 years"),

  noteBox("'The integration of AI-driven methodologies into the drug development pipeline has already heralded subtle yet meaningful enhancements in both efficiency and effectiveness of this process.' — Zhang et al., Nature Medicine 2025 (PMID 39833407)"),

  spacer(),

  sectionBreak(),

  // ── 6. PRECLINICAL DEVELOPMENT ────────────────────────────────
  h1("6. Preclinical Development"),

  body("Before a compound can enter human trials, a comprehensive preclinical package must be assembled demonstrating the drug's pharmacological profile, safety in animals, and manufacturability. These studies are performed under Good Laboratory Practice (GLP) regulations."),

  h2("6.1  Pharmacology Studies"),

  bullet1("Primary pharmacodynamics: demonstrate target engagement and efficacy in disease-relevant models"),
  bullet1("Secondary pharmacodynamics: identify off-target effects on major receptor/enzyme panels (safety pharmacology panel)"),
  bullet1("Safety pharmacology: cardiovascular (hERG, QTc); CNS (Irwin test); respiratory (plethysmography)"),
  bullet1("PK/PD modelling: establish dose–response relationships for translation to human dosing"),

  spacer(),

  h2("6.2  ADME (Drug Metabolism and Pharmacokinetics — DMPK)"),

  makeTable(
    ["Parameter", "Key Assay / Method", "Relevance"],
    [
      ["Absorption", "Caco-2 cell permeability, solubility assays", "Predicts oral bioavailability"],
      ["Distribution", "Plasma protein binding, tissue distribution, P-gp efflux", "Volume of distribution, CNS penetration"],
      ["Metabolism", "Liver microsomal stability, CYP inhibition, metabolite ID", "Half-life, drug interactions, reactive metabolites"],
      ["Excretion", "Renal/biliary excretion in rodent models", "Route and rate of elimination"],
      ["Bioavailability (F%)", "IV vs oral PK study in rodent/dog", "Overall exposure from oral dose"],
    ],
    [2200, 3200, 3800]
  ),

  spacer(2),

  h2("6.3  Toxicology"),

  body("GLP toxicology studies are conducted in at least two species (typically rodent + non-rodent). Required studies include:"),

  bullet1("Single-dose (acute) toxicity — LD50, maximum tolerated dose"),
  bullet1("Repeat-dose (subchronic/chronic) toxicity — 28-day, 90-day, 6-month studies; establishes NOAEL (No Observed Adverse Effect Level)"),
  bullet1("Genotoxicity — Ames test (bacterial mutagenicity), in vitro chromosomal aberration, in vivo micronucleus test"),
  bullet1("Reproductive toxicology — embryo-fetal development, fertility studies"),
  bullet1("Carcinogenicity — 2-year rodent bioassay (required for chronic use drugs)"),
  bullet1("Local tolerance — injection site, ophthalmic, dermal tolerance"),

  noteBox("The therapeutic index (TI = TD50/ED50) derived from preclinical data guides selection of the starting human dose (typically 1/10th of the NOAEL in the most sensitive species, converted using body surface area)."),

  spacer(),

  sectionBreak(),

  // ── 7. CLINICAL TRIALS ────────────────────────────────────────
  h1("7. Clinical Trials"),

  body("Clinical trials are prospective, controlled studies in human subjects that evaluate the safety, efficacy, and dosing of drug candidates. They are conducted under International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines and require ethics committee (IRB/IEC) approval at each site. Participants must provide written informed consent."),

  makeTable(
    ["Phase", "Population", "Primary Goal", "Typical N", "Duration"],
    [
      ["Phase 0", "Healthy volunteers (microdosing)", "PK/PD, target engagement; <pharmacological dose", "~10", "Weeks"],
      ["Phase I", "Healthy volunteers (occasionally patients)", "Safety, tolerability, PK; dose escalation (SAD/MAD)", "20–100", "1–2 years"],
      ["Phase II a/b", "Patients with target disease", "Proof of concept (IIa); dose finding, preliminary efficacy (IIb)", "100–500", "2–3 years"],
      ["Phase III", "Patients; multi-centre RCT", "Confirm efficacy vs. placebo/SOC; define safety profile", "1,000–10,000", "3–5 years"],
      ["Phase IV", "Post-marketing; general population", "Long-term safety; rare ADRs; new indications; pharmacovigilance", "Thousands", "Ongoing"],
    ],
    [900, 1700, 3100, 800, 700]
  ),

  spacer(2),

  h2("7.1  Randomised Controlled Trial (RCT) Design"),

  body("Phase III trials are typically double-blind, randomised, placebo-controlled (or active-comparator-controlled) to eliminate bias. Key design considerations include:"),

  bullet1("Randomisation: eliminates selection bias; can be simple, block, or stratified"),
  bullet1("Blinding: single-blind (patient unaware), double-blind (patient + investigator unaware), triple-blind (+ statistician)"),
  bullet1("Primary endpoint: must be pre-specified; clinically meaningful (e.g., OS, PFS, HbA1c, LVEF)"),
  bullet1("Surrogate endpoints: biomarkers assumed to predict clinical outcomes (e.g., LDL→ MI; HbA1c→ complications) — require careful validation"),
  bullet1("Adaptive designs: pre-planned modifications to dose, sample size, or arms based on interim data (increasingly common; Boxer & Sperling, Cell 2023)"),
  bullet1("Biomarker-driven enrichment: select patients most likely to respond (precision medicine strategy)"),

  noteBox("Goodman & Gilman (Box 1-2, p. 34): The torcetrapib example illustrates surrogate endpoint failure — raising HDL cholesterol did NOT reduce cardiovascular mortality; instead caused significant excess deaths. An $800 million, 15-year programme was terminated. This underlines the danger of unvalidated surrogate endpoints."),

  spacer(),

  h2("7.2  FDA Drug Approval Process"),

  body("Once Phase III trials are complete, the sponsor submits a New Drug Application (NDA) or Biologics License Application (BLA) to the FDA. The FDA has a user-fee funded review target of 10–12 months (standard review) or 6 months (priority review, breakthrough therapy)."),

  bullet1("FDA review components:"),
  bullet2("Clinical efficacy review"),
  bullet2("Clinical pharmacology and biopharmaceutics"),
  bullet2("CMC (manufacturing quality and controls)"),
  bullet2("Non-clinical (preclinical) safety"),
  bullet2("Statistics review"),
  bullet2("Advisory committee (ADCOM) meeting (for complex or controversial applications)"),

  bullet1("Special designations (FDA) that expedite approval:"),
  bullet2("Fast Track: facilitates development/review of drugs for serious conditions"),
  bullet2("Breakthrough Therapy: preliminary clinical evidence shows substantial improvement"),
  bullet2("Accelerated Approval: approval based on surrogate/intermediate endpoint"),
  bullet2("Priority Review: reduces standard 10-month review to 6 months"),

  spacer(),

  sectionBreak(),

  // ── 8. BIOPHARMACEUTICALS ─────────────────────────────────────
  h1("8. Biopharmaceuticals and Large-Molecule Drug Discovery"),

  body("Biopharmaceuticals (biologics) are therapeutic agents derived from biological sources, including proteins, antibodies, nucleic acids, and cell-based therapies. They represent the fastest-growing segment of modern therapeutics, accounting for >35% of new FDA approvals annually."),

  h2("8.1  Categories of Biopharmaceuticals"),

  makeTable(
    ["Type", "Examples", "Mechanism"],
    [
      ["Monoclonal antibodies (mAbs)", "Adalimumab (anti-TNF), trastuzumab (anti-HER2), pembrolizumab (anti-PD-1)", "Target-specific binding → blockade, ADCC, CDC"],
      ["Antibody-drug conjugates (ADCs)", "Ado-trastuzumab emtansine (T-DM1), brentuximab vedotin", "Antibody delivers cytotoxin directly to tumour cell"],
      ["Recombinant proteins", "Insulin (rHumulin), erythropoietin, G-CSF", "Replace deficient endogenous protein"],
      ["mRNA therapeutics", "mRNA-1273 (Moderna COVID vaccine), mResvia (RSV)", "In vivo protein expression from mRNA"],
      ["Gene therapy / siRNA", "Patisiran (siRNA, TTR amyloidosis), Zolgensma (AAV-SMN1)", "Silence or correct disease-causing gene"],
      ["CAR-T cell therapy", "Tisagenlecleucel (CD19-CAR-T), axicabtagene", "Engineered T cells targeting tumour antigens"],
      ["Bispecific antibodies", "Blinatumomab (CD3×CD19)", "Redirect immune cells to tumour targets"],
    ],
    [1900, 2800, 4500]
  ),

  spacer(2),

  h2("8.2  Biosimilars"),

  body("A biosimilar is a biological product that is highly similar to an already-approved reference biologic, with no clinically meaningful differences in safety, purity, or potency. Biosimilars are approved under an abbreviated pathway (Section 351(k) of the PHS Act in US; EMA Guideline in EU). They represent a major health-economic opportunity as original biologics lose patent protection."),

  noteBox("Goodman & Gilman (Ch. 1): 'Unlike generic drugs, biosimilars are not 'identical' to the reference product because of the complexity and variability inherent in biological manufacturing processes.'"),

  spacer(),

  sectionBreak(),

  // ── 9. PRECISION MEDICINE ─────────────────────────────────────
  h1("9. Precision Medicine and Pharmacogenomics in Drug Discovery"),

  body("Precision (personalised) medicine aims to tailor drug therapy to individual patient characteristics — particularly genetic, genomic, and biomarker data. It is increasingly integrated into drug discovery from the earliest stages."),

  h2("9.1  Pharmacogenomics"),

  body("Pharmacogenomics studies how genetic variation (polymorphisms in drug-metabolising enzymes, transporters, targets) influences drug response. Key enzymes include CYP2D6, CYP2C19, CYP2C9, and TPMT."),

  bullet1("Clinical examples:"),
  bullet2("CYP2D6 poor metabolisers: codeine → morphine conversion impaired → reduced analgesia; ultrarapid metabolisers → toxicity"),
  bullet2("HER2 amplification → trastuzumab benefit in breast cancer"),
  bullet2("EGFR mutation → erlotinib/gefitinib benefit in NSCLC"),
  bullet2("BRCA1/2 mutation → PARP inhibitor (olaparib) sensitivity"),
  bullet2("BCR-ABL translocation → imatinib (Gleevec) as paradigm case of precision oncology"),

  h2("9.2  Companion Diagnostics"),

  body("Companion diagnostics (CDx) are in vitro diagnostic tests that identify patients likely to benefit from (or be harmed by) a specific drug. FDA requires co-development and co-approval of drug + CDx when the test is essential for safe/effective use."),

  bullet1("Examples: FISH/IHC for HER2 (trastuzumab), EGFR mutation PCR (erlotinib), PD-L1 IHC (pembrolizumab), BRCA testing (olaparib)"),

  spacer(),

  sectionBreak(),

  // ── 10. PUBLIC POLICY & ETHICS ───────────────────────────────
  h1("10. Public Policy, Intellectual Property, and Ethics"),

  h2("10.1  Intellectual Property and Patents"),

  body("Drug patents provide exclusive market rights for 20 years from filing date, incentivising the massive investment required for drug development. However, since significant development time occurs during the patent period, the effective market exclusivity is typically 7–12 years post-approval. The Hatch-Waxman Act (1984) balanced generic drug competition with research incentives."),

  bullet1("Data exclusivity: 5 years (small molecules) / 12 years (biologics) in the US — prevents FDA from relying on originator's data for generic/biosimilar approval"),
  bullet1("Orphan Drug Act: provides 7 years market exclusivity for drugs targeting diseases affecting <200,000 patients in US"),

  h2("10.2  Bayh-Dole Act"),

  body("The 1980 Bayh-Dole Act allowed universities and non-profit research institutions receiving federal funding to own patents on resulting inventions and license them to industry. This catalysed academic–industry partnerships and significantly accelerated drug discovery translation."),

  h2("10.3  The 'Me Too' Drug Problem"),

  body("'Me too' drugs are structurally similar analogues of already-approved drugs that offer little therapeutic advantage over existing treatments. While commercially rational, they divert R&D resources from genuinely innovative medicines. Regulatory agencies have been criticised for approving such drugs without head-to-head comparator trials."),

  h2("10.4  Ethical Considerations"),

  bullet1("Informed consent: voluntary participation; full disclosure of risks/benefits"),
  bullet1("Declaration of Helsinki (WMA): placebo use acceptable only when no effective alternative exists"),
  bullet1("Equitable access: global health equity — approved drugs are often unaffordable in low-income countries"),
  bullet1("Data transparency: publication of negative trial results; registration on ClinicalTrials.gov"),
  bullet1("AI ethics in drug discovery: algorithmic bias, data privacy (patient genomic data), IP ownership of AI-generated compounds"),

  spacer(),

  sectionBreak(),

  // ── 11. EMERGING TECHNOLOGIES ────────────────────────────────
  h1("11. Emerging Technologies and Future Directions"),

  makeTable(
    ["Technology", "Description", "Current Status / Impact"],
    [
      ["CRISPR-Cas9 screening", "Genome-wide loss-of-function screens identify essential disease genes as targets", "Widely deployed in target ID; CRISPR therapeutics in trials (2023–2025)"],
      ["Organ-on-a-chip / Microphysiological systems", "Microfluidic devices mimicking organ function for preclinical testing", "Reducing animal use; improving human translatability"],
      ["3D organoids", "Patient-derived 3D tissue models (tumour, intestinal, brain) for drug testing", "Personalised drug sensitivity testing in oncology"],
      ["Proteolysis Targeting Chimeras (PROTACs)", "Bifunctional molecules degrade target proteins via ubiquitin-proteasome", "Multiple PROTACs in Phase I/II (2024–2025)"],
      ["Molecular Glues", "Small molecules that induce target protein–E3 ligase proximity → degradation", "CDK12 degraders; CC-92480 (iberdomide) in myeloma"],
      ["DNA-Encoded Libraries (DEL)", "Libraries of >10⁹ compounds each tagged with unique DNA barcode", "Standard in pharma HTS; massive chemical space coverage"],
      ["Single-cell multi-omics", "scRNA-seq + ATAC-seq identifies cell-type-specific disease mechanisms and targets", "Transforming target ID in heterogeneous diseases"],
      ["Generative AI / LLMs", "Large language models (GPT-based) and graph neural networks for de novo drug design", "INX-315, DSP-1181 in clinical trials; AlphaFold3 (2024)"],
      ["mRNA therapeutics", "Encode therapeutic proteins in lipid nanoparticle-delivered mRNA", "Vaccines (COVID), cancer neoantigen vaccines (mRNA-4157 + pembrolizumab, Phase III)"],
      ["Cell & gene therapy", "CAR-T, TCR-T, base editing, prime editing for genetic diseases", "Casgevy (CRISPR, sickle cell disease) — first CRISPR therapy approved (2023)"],
    ],
    [1800, 3500, 3900]
  ),

  spacer(2),

  sectionBreak(),

  // ── 12. SUMMARY ───────────────────────────────────────────────
  h1("12. Summary"),

  body("Drug discovery is a long, expensive, and high-attrition process, but one of the most impactful endeavours in biomedical science. Modern drug discovery integrates:"),

  bullet1("Biology (genomics, proteomics, cell biology, disease pathology) to identify and validate targets"),
  bullet1("Chemistry (medicinal chemistry, SAR, FBDD, natural products) to develop drug-like molecules"),
  bullet1("Computation (SBDD, molecular docking, AI/ML, generative modelling) to accelerate design and optimisation"),
  bullet1("Clinical science (trial design, biomarkers, precision medicine) to translate molecules into medicines"),
  bullet1("Regulatory science (IND, NDA, GLP/GCP) to ensure safety, efficacy, and quality"),

  spacer(),

  keyBox("The paradigm is shifting from 'one target, one drug, one disease' toward systems pharmacology, polypharmacology, and precision medicine — where the right drug reaches the right patient at the right dose."),

  spacer(),

  makeTable(
    ["Stage", "Duration", "Key Output", "Success Rate"],
    [
      ["Target ID & Validation", "2–4 years", "Validated target with tool compounds", "~60%"],
      ["Hit → Lead", "1–2 years", "Lead series with SAR data", "~40%"],
      ["Lead Optimisation", "2–3 years", "Clinical candidate (IND-enabling)", "~30%"],
      ["Preclinical Development", "1–2 years", "IND filing", "~70%"],
      ["Phase I", "1–2 years", "MTD, PK, safety profile", "~63%"],
      ["Phase II", "2–3 years", "Proof of concept, dose selection", "~35%"],
      ["Phase III", "3–5 years", "NDA/BLA-supporting efficacy + safety", "~58%"],
      ["Regulatory Approval", "1–2 years", "Approved drug", "~85%"],
      ["Overall (target → approval)", "10–15 years", "1 approved drug per ~10,000 starts", "~10%"],
    ],
    [2000, 1400, 3200, 1400]
  ),

  spacer(2),

  sectionBreak(),

  // ── 13. REFERENCES ────────────────────────────────────────────
  h1("13. References"),

  body("The following standard and updated sources were used in the preparation of these notes:"),

  spacer(),

  ...([
    ["1.", "Brunton LL, Knollmann BC (Eds). Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th Edition. McGraw-Hill, 2023. Chapter 1: Drug Discovery: From Medicinal Plants to Computer-Aided Drug Design (Gilson MK, Brunton LL)."],
    ["2.", "Whalen K (Ed). Lippincott Illustrated Reviews: Pharmacology, 7th Edition. Wolters Kluwer, 2023."],
    ["3.", "Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology, 9th Edition. Elsevier, 2020. Chapter 8: Drug discovery and development."],
    ["4.", "FDA. Drug Development and Review Definitions. US Food and Drug Administration, 2024. Available at: www.fda.gov"],
    ["5.", "FDA. New Drug Application (NDA) Process. CDER, 2024. Available at: www.fda.gov/drugs/development-approval-process-drugs"],
    ["6.", "British Pharmacopoeia Commission. British Pharmacopoeia 2024. MHRA, London."],
    ["7.", "Zhang K, Yang X, Wang Y, et al. Artificial intelligence in drug development. Nature Medicine. 2025;31:105–120. doi:10.1038/s41591-024-03434-4 [PMID: 39833407]"],
    ["8.", "Pun FW, Ozerov IV, Zhavoronkov A. AI-powered therapeutic target discovery. Trends in Pharmacological Sciences. 2023;44(9):561–572. [PMID: 37479540]"],
    ["9.", "Mullowney MW, Duncan KR, Elsayed SS, et al. Artificial intelligence for natural product drug discovery. Nature Reviews Drug Discovery. 2023;22(11):895–916. [PMID: 37697042]"],
    ["10.", "Boike L, Henning NJ, Nomura DK. Advances in covalent drug discovery. Nature Reviews Drug Discovery. 2022;21(12):881–898. [PMID: 36008483]"],
    ["11.", "Van de Sande B, Lee JS, Mutasa-Gottgens E, et al. Applications of single-cell RNA sequencing in drug discovery and development. Nature Reviews Drug Discovery. 2023;22(6):496–520. [PMID: 37117846]"],
    ["12.", "Du P, Fan R, Zhang N, et al. Advances in integrated multi-omics analysis for drug-target identification. Biomolecules. 2024;14(6):711. [PMID: 38927095]"],
    ["13.", "Bordukova M, Makarov N, Rodriguez-Esteban R, et al. Generative AI empowers digital twins in drug discovery and clinical trials. Expert Opinion on Drug Discovery. 2024;19(1):33–43. [PMID: 37887266]"],
    ["14.", "Bai C, Wu L, Li R, et al. Machine Learning-Enabled Drug-Induced Toxicity Prediction. Advanced Science. 2025;12(15):e2412234. [PMID: 39899688]"],
    ["15.", "Walker AS, Clardy J. Primed for Discovery. Biochemistry. 2024;63(21):2687–2700. [PMID: 39497571]"],
    ["16.", "Singh S, Kumar R, Payra S, et al. Artificial Intelligence and Machine Learning in Pharmacological Research. Cureus. 2023;15(8):e44359. [PMID: 37779744]"],
    ["17.", "Congressional Budget Office. Research and Development in the Pharmaceutical and Biotech Industries. CBO, 2021. Available at: www.cbo.gov/publication/57025"],
    ["18.", "World Medical Association. Declaration of Helsinki — Ethical Principles for Medical Research Involving Human Subjects. WMA, 2013 (amended 2024)."],
    ["19.", "ICH E6(R3). Good Clinical Practice. International Council for Harmonisation, 2023."],
    ["20.", "Casgevy (exagamglogene autotemcel). FDA Approval. December 2023. First CRISPR gene therapy approved."],
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