from reportlab.lib.pagesizes import A4
from reportlab.lib import colors
from reportlab.lib.styles import getSampleStyleSheet, ParagraphStyle
from reportlab.lib.units import cm, mm
from reportlab.platypus import (SimpleDocTemplate, Paragraph, Spacer, Table,
                                TableStyle, HRFlowable, KeepTogether, PageBreak)
from reportlab.lib.enums import TA_CENTER, TA_LEFT, TA_JUSTIFY
from reportlab.platypus import Image
from reportlab.graphics.shapes import Drawing, Rect, String, Line, Circle
from reportlab.graphics import renderPDF
import os

OUTPUT = "/home/daytona/workspace/sevoflurane-study-guide/Sevoflurane_Study_Guide.pdf"

# ── Colour Palette ────────────────────────────────────────────────────────────
NAVY    = colors.HexColor("#1A3A5C")
TEAL    = colors.HexColor("#0D7680")
AMBER   = colors.HexColor("#E07B00")
RED     = colors.HexColor("#C0392B")
GREEN   = colors.HexColor("#1A7A4A")
PURPLE  = colors.HexColor("#6A3D9A")
LIGHT   = colors.HexColor("#EAF4FB")
LIGHT2  = colors.HexColor("#FFF8EC")
LIGHT3  = colors.HexColor("#F0FFF4")
LIGHT4  = colors.HexColor("#FDF0F0")
LIGHT5  = colors.HexColor("#F5F0FF")
WHITE   = colors.white
DGREY   = colors.HexColor("#444444")
MGREY   = colors.HexColor("#888888")
LGREY   = colors.HexColor("#F5F5F5")
BORDER  = colors.HexColor("#CCDDEE")

doc = SimpleDocTemplate(
    OUTPUT,
    pagesize=A4,
    leftMargin=1.8*cm, rightMargin=1.8*cm,
    topMargin=2*cm, bottomMargin=2*cm,
    title="Sevoflurane – Anaesthesia Exam Study Guide",
    author="Orris Medical AI",
)

W, H = A4
CW = W - 3.6*cm   # content width

styles = getSampleStyleSheet()

def S(name, **kw):
    base = styles[name] if name in styles else styles["Normal"]
    return ParagraphStyle(name + str(id(kw)), parent=base, **kw)

# ── Custom Styles ─────────────────────────────────────────────────────────────
cover_title  = S("Title",    fontSize=30, textColor=WHITE,   leading=36, alignment=TA_CENTER, fontName="Helvetica-Bold")
cover_sub    = S("Normal",   fontSize=14, textColor=LIGHT,   leading=20, alignment=TA_CENTER, fontName="Helvetica")
cover_tag    = S("Normal",   fontSize=10, textColor=colors.HexColor("#AACCDD"), alignment=TA_CENTER)

sec_head     = S("Heading1", fontSize=13, textColor=WHITE,   leading=17, fontName="Helvetica-Bold", spaceAfter=2, spaceBefore=4)
sub_head     = S("Heading2", fontSize=10.5, textColor=NAVY,  leading=14, fontName="Helvetica-Bold", spaceBefore=6, spaceAfter=2)
body         = S("Normal",   fontSize=8.5, textColor=DGREY,  leading=13, alignment=TA_JUSTIFY)
body_small   = S("Normal",   fontSize=7.8, textColor=DGREY,  leading=11.5)
bullet_style = S("Normal",   fontSize=8.5, textColor=DGREY,  leading=13, leftIndent=14, firstLineIndent=-10)
bold_bullet  = S("Normal",   fontSize=8.5, textColor=NAVY,   leading=13, leftIndent=14, firstLineIndent=-10, fontName="Helvetica-Bold")
warn_text    = S("Normal",   fontSize=8.5, textColor=RED,    leading=13, fontName="Helvetica-Bold")
tip_text     = S("Normal",   fontSize=8.5, textColor=GREEN,  leading=13, fontName="Helvetica-BoldOblique")
table_hdr    = S("Normal",   fontSize=8,   textColor=WHITE,  leading=11, fontName="Helvetica-Bold", alignment=TA_CENTER)
table_cell   = S("Normal",   fontSize=8,   textColor=DGREY,  leading=11)
table_cell_c = S("Normal",   fontSize=8,   textColor=DGREY,  leading=11, alignment=TA_CENTER)
table_lbl    = S("Normal",   fontSize=8,   textColor=NAVY,   leading=11, fontName="Helvetica-Bold")
footnote     = S("Normal",   fontSize=7,   textColor=MGREY,  leading=10, fontName="Helvetica-Oblique")
highlight    = S("Normal",   fontSize=8.5, textColor=NAVY,   leading=13, fontName="Helvetica-Bold")
page_hdr     = S("Normal",   fontSize=7.5, textColor=MGREY,  leading=10, alignment=TA_CENTER)

story = []

# ══════════════════════════════════════════════════════════════════════════════
# HELPER: section banner
# ══════════════════════════════════════════════════════════════════════════════
def section_banner(number, title, color=NAVY):
    data = [[Paragraph(f"<b>{number}  &nbsp; {title}</b>", sec_head)]]
    t = Table(data, colWidths=[CW])
    t.setStyle(TableStyle([
        ("BACKGROUND", (0,0),(-1,-1), color),
        ("ROUNDEDCORNERS", [4]),
        ("TOPPADDING",   (0,0),(-1,-1), 5),
        ("BOTTOMPADDING",(0,0),(-1,-1), 5),
        ("LEFTPADDING",  (0,0),(-1,-1), 10),
        ("RIGHTPADDING", (0,0),(-1,-1), 8),
    ]))
    story.append(Spacer(1, 6))
    story.append(t)
    story.append(Spacer(1, 4))

def info_box(text, bg=LIGHT, border_color=TEAL, icon="ℹ"):
    data = [[Paragraph(f"<b>{icon}</b>"), Paragraph(text, body)]]
    t = Table(data, colWidths=[0.5*cm, CW-0.6*cm])
    t.setStyle(TableStyle([
        ("BACKGROUND",   (0,0),(-1,-1), bg),
        ("BOX",          (0,0),(-1,-1), 0.8, border_color),
        ("TOPPADDING",   (0,0),(-1,-1), 5),
        ("BOTTOMPADDING",(0,0),(-1,-1), 5),
        ("LEFTPADDING",  (0,0),(-1,-1), 6),
        ("VALIGN",       (0,0),(-1,-1), "TOP"),
    ]))
    story.append(t)
    story.append(Spacer(1, 4))

def bullet(text, bold=False):
    st = bold_bullet if bold else bullet_style
    story.append(Paragraph(f"• {text}", st))

def spacer(h=6):
    story.append(Spacer(1, h))

def hr():
    story.append(HRFlowable(width=CW, thickness=0.5, color=BORDER, spaceAfter=4, spaceBefore=4))

def two_col_table(rows, col1_w=None, col2_w=None, hdr=None, hdr_color=NAVY, stripe=True):
    if col1_w is None: col1_w = CW * 0.38
    if col2_w is None: col2_w = CW - col1_w
    data = []
    if hdr:
        data.append([Paragraph(hdr[0], table_hdr), Paragraph(hdr[1], table_hdr)])
    for i, (k, v) in enumerate(rows):
        data.append([Paragraph(k, table_lbl), Paragraph(v, table_cell)])
    t = Table(data, colWidths=[col1_w, col2_w])
    style_cmds = [
        ("TOPPADDING",   (0,0),(-1,-1), 4),
        ("BOTTOMPADDING",(0,0),(-1,-1), 4),
        ("LEFTPADDING",  (0,0),(-1,-1), 6),
        ("RIGHTPADDING", (0,0),(-1,-1), 6),
        ("VALIGN",       (0,0),(-1,-1), "TOP"),
        ("GRID",         (0,0),(-1,-1), 0.4, BORDER),
        ("ROWBACKGROUNDS", (0, 1 if hdr else 0), (-1,-1), [WHITE, LGREY] if stripe else [WHITE]),
    ]
    if hdr:
        style_cmds += [
            ("BACKGROUND", (0,0),(-1,0), hdr_color),
            ("TEXTCOLOR",  (0,0),(-1,0), WHITE),
        ]
    t.setStyle(TableStyle(style_cmds))
    story.append(t)
    story.append(Spacer(1,4))

def multi_col_table(headers, rows, col_widths=None, hdr_color=NAVY):
    n = len(headers)
    if col_widths is None:
        col_widths = [CW / n] * n
    data = [[Paragraph(h, table_hdr) for h in headers]]
    for row in rows:
        data.append([Paragraph(str(c), table_cell_c) for c in row])
    t = Table(data, colWidths=col_widths)
    t.setStyle(TableStyle([
        ("BACKGROUND",    (0,0),(-1,0), hdr_color),
        ("ROWBACKGROUNDS",(0,1),(-1,-1), [WHITE, LGREY]),
        ("GRID",          (0,0),(-1,-1), 0.4, BORDER),
        ("TOPPADDING",    (0,0),(-1,-1), 4),
        ("BOTTOMPADDING", (0,0),(-1,-1), 4),
        ("LEFTPADDING",   (0,0),(-1,-1), 4),
        ("RIGHTPADDING",  (0,0),(-1,-1), 4),
        ("VALIGN",        (0,0),(-1,-1), "MIDDLE"),
    ]))
    story.append(t)
    story.append(Spacer(1,4))

# ══════════════════════════════════════════════════════════════════════════════
#  COVER PAGE
# ══════════════════════════════════════════════════════════════════════════════
def cover_page():
    # Full-width blue background banner
    banner_data = [[
        Paragraph("SEVOFLURANE", cover_title),
    ]]
    banner = Table(banner_data, colWidths=[CW])
    banner.setStyle(TableStyle([
        ("BACKGROUND",   (0,0),(-1,-1), NAVY),
        ("TOPPADDING",   (0,0),(-1,-1), 28),
        ("BOTTOMPADDING",(0,0),(-1,-1), 6),
        ("LEFTPADDING",  (0,0),(-1,-1), 10),
        ("ROUNDEDCORNERS",[6]),
    ]))
    story.append(banner)

    subtitle_data = [[Paragraph("Complete Pharmacology Study Guide", cover_sub)]]
    subtitle_tbl = Table(subtitle_data, colWidths=[CW])
    subtitle_tbl.setStyle(TableStyle([
        ("BACKGROUND",   (0,0),(-1,-1), TEAL),
        ("TOPPADDING",   (0,0),(-1,-1), 8),
        ("BOTTOMPADDING",(0,0),(-1,-1), 14),
        ("ROUNDEDCORNERS",[0,0,6,6]),
    ]))
    story.append(subtitle_tbl)
    spacer(12)

    tag_data = [[Paragraph("For MD / DNB / FRCA Anaesthesia Examinations  •  Based on Miller's, Morgan &amp; Mikhail's, Goodman &amp; Gilman's, Barash &amp; Katzung", cover_tag)]]
    tag_tbl = Table(tag_data, colWidths=[CW])
    tag_tbl.setStyle(TableStyle([
        ("TOPPADDING",(0,0),(-1,-1),4), ("BOTTOMPADDING",(0,0),(-1,-1),4)
    ]))
    story.append(tag_tbl)
    spacer(10)

    # Quick-reference card on cover
    qr_rows = [
        ("MAC (adult, O₂)", "2.0%"),
        ("MAC awake", "~0.6%"),
        ("MAC (neonate/infant)", "~3.2–3.3%"),
        ("MAC (elderly >65 y)", "~1.5%"),
        ("Blood:gas coeff", "0.65"),
        ("Metabolism (CYP2E1)", "~5%"),
        ("Vaporizer type", "Standard variable-bypass"),
        ("Odour", "Sweet, non-pungent"),
        ("Flammable?", "No"),
    ]
    story.append(Paragraph("<b>Quick Reference Card</b>", sub_head))
    two_col_table(qr_rows, hdr=("PROPERTY", "VALUE"), hdr_color=TEAL)
    spacer(8)

    story.append(Paragraph(
        "<b>Indications at a glance:</b>  Inhalational induction (esp. paediatrics) • Maintenance of GA • Ambulatory surgery • "
        "Asthma / bronchospasm • Day-case surgery • Patients at risk for myocardial ischaemia",
        body))
    spacer(4)
    info_box(
        "<b>Contraindications:</b>  Malignant hyperthermia susceptibility  •  Severe hypovolaemia  •  Raised intracranial pressure",
        bg=LIGHT4, border_color=RED, icon="⚠")

cover_page()
story.append(PageBreak())

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 1 – PHYSICAL & PHARMACOKINETIC PROPERTIES
# ══════════════════════════════════════════════════════════════════════════════
section_banner("01", "Physical & Pharmacokinetic Properties", NAVY)

story.append(Paragraph("<b>Chemical identity:</b>  Fluorinated methyl isopropyl ether — completely fluorinated, sweet-smelling, colourless volatile liquid at room temperature.", body))
spacer(4)

phys_rows = [
    ("Chemical class",         "Fluorinated methyl isopropyl ether"),
    ("Molecular weight",       "200.05 g/mol"),
    ("Boiling point",          "58.5°C"),
    ("Vapour pressure (20°C)", "157 mmHg"),
    ("Vaporizer",              "Standard variable-bypass (no heated vaporizer needed)"),
    ("Flammable / explosive",  "No (in air or O₂)"),
    ("Storage",                "Sealed amber bottle, no preservative required"),
    ("Stability",              "Unstable in desiccated soda lime → Compound A + CO"),
]
story.append(Paragraph("<b>Physical Properties</b>", sub_head))
two_col_table(phys_rows)

pk_rows = [
    ("Blood:gas partition coeff",   "0.65  (rapid induction/emergence)"),
    ("Brain:blood partition coeff", "1.7"),
    ("Oil:gas partition coeff",     "~47–53"),
    ("MAC (adult, 100% O₂)",        "2.0%  (range 1.71–2.05%)"),
    ("MAC awake",                   "~0.6%"),
    ("MAC – neonates",              "~3.3%"),
    ("MAC – infants (peak ~6 mo)",  "~3.2%"),
    ("MAC – elderly (>65 yr)",      "~1.5%"),
    ("Induction concentration",     "2–4% (maintenance); 4–8% (rapid mask induction)"),
    ("Time to loss of consciousness","1–2 min (inhalational)"),
    ("Metabolism",                  "~5% via hepatic CYP2E1"),
    ("Key metabolites",             "Hexafluoroisopropanol (HFIP) + inorganic fluoride (F⁻)"),
    ("Peak serum F⁻",               "22–31 µmol/L (>50 µmol/L in ~7% — no clinical nephrotoxicity)"),
    ("Excretion",                   "Predominantly exhaled unchanged via lungs"),
]
story.append(Paragraph("<b>Pharmacokinetic Parameters</b>", sub_head))
two_col_table(pk_rows)

info_box(
    "<b>Low blood:gas solubility (0.65)</b> = quick equilibration between alveoli and blood → fast induction, rapid changes in depth, "
    "and brisk emergence. Faster than isoflurane; slightly slower than desflurane.",
    bg=LIGHT, border_color=TEAL)

# MAC Modifiers
story.append(Paragraph("<b>MAC Modifiers</b>", sub_head))
mac_data = [
    ["Decrease MAC", "Increase MAC"],
    ["Increasing age", "Infancy (peak ~6 months)"],
    ["Hypothermia", "Hyperthermia"],
    ["Hypotension (MAP <50 mmHg)", "Chronic alcohol use"],
    ["Pregnancy", "Chronic opioid use"],
    ["Opioids (additive)", "Hyperthyroidism"],
    ["N₂O (additive)", "CNS stimulants"],
    ["Alpha-2 agonists (dexmedetomidine)", "—"],
    ["Benzodiazepines", "—"],
    ["Metabolic acidosis / hypoxia", "—"],
]
mac_t = Table(mac_data, colWidths=[CW/2, CW/2])
mac_t.setStyle(TableStyle([
    ("BACKGROUND",   (0,0),(0,0), RED),
    ("BACKGROUND",   (1,0),(1,0), GREEN),
    ("TEXTCOLOR",    (0,0),(-1,0), WHITE),
    ("FONTNAME",     (0,0),(-1,0), "Helvetica-Bold"),
    ("FONTSIZE",     (0,0),(-1,-1), 8),
    ("ROWBACKGROUNDS",(0,1),(-1,-1), [WHITE, LGREY]),
    ("GRID",         (0,0),(-1,-1), 0.4, BORDER),
    ("TOPPADDING",   (0,0),(-1,-1), 3),
    ("BOTTOMPADDING",(0,0),(-1,-1), 3),
    ("LEFTPADDING",  (0,0),(-1,-1), 6),
    ("VALIGN",       (0,0),(-1,-1), "MIDDLE"),
    ("ALIGN",        (0,0),(-1,0), "CENTER"),
]))
story.append(mac_t)
spacer(6)

story.append(PageBreak())

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 2 – MECHANISM OF ACTION
# ══════════════════════════════════════════════════════════════════════════════
section_banner("02", "Mechanism of Action", TEAL)

moa_rows = [
    ("GABA-A receptor potentiation",  "Main mechanism — enhances inhibitory Cl⁻ conductance → CNS depression"),
    ("NMDA receptor inhibition",      "Reduces excitatory glutamate signalling → amnesia, immobility"),
    ("2-pore domain K⁺ channels",     "TREK/TASK channel activation → neuronal hyperpolarisation"),
    ("Voltage-gated Na⁺/Ca²⁺ block",  "Reduces action potential generation and propagation"),
    ("Shaker-family Kv1.2 channels",  "Photoaffinity labelling confirms direct interaction"),
]
two_col_table(moa_rows, hdr=("TARGET", "EFFECT"), hdr_color=TEAL, col1_w=CW*0.34)

info_box("Sevoflurane does NOT have a single receptor target — it acts on multiple ion channels and receptors, a property shared by all volatile anaesthetics ('unitary theory').",
         bg=LIGHT, border_color=TEAL)

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 3 – EFFECTS ON ORGAN SYSTEMS
# ══════════════════════════════════════════════════════════════════════════════
section_banner("03", "Effects on Organ Systems", NAVY)

# --- CVS ---
story.append(Paragraph("A.  Cardiovascular System", sub_head))
cvs = [
    ("BP",                     "Concentration-dependent ↓ (SVR reduction + mild myocardial depression)"),
    ("Heart rate",             "No significant tachycardia (contrast: isoflurane/desflurane which increase HR)"),
    ("Cardiac output",         "Mild ↓ — less well maintained than with isoflurane (no reflex tachycardia)"),
    ("SVR",                    "↓ — less pronounced than isoflurane or desflurane"),
    ("QT interval",            "Prolongation; may persist 60 min post-emergence in infants"),
    ("Arrhythmias",            "Does NOT sensitise myocardium to catecholamines (safe to use adrenaline)"),
    ("Coronary vasodilation",  "Half as potent as isoflurane — less 'coronary steal' risk"),
    ("Ischaemic preconditioning","Cardioprotective — reduces ischaemia–reperfusion injury"),
]
two_col_table(cvs, col1_w=CW*0.30)

# --- Respiratory ---
story.append(Paragraph("B.  Respiratory System", sub_head))
resp = [
    ("Tidal volume",       "↓ (concentration-dependent)"),
    ("Respiratory rate",   "↑ (but does not compensate for ↓ Vt)"),
    ("Minute ventilation", "↓ net → ↑ PaCO₂"),
    ("Airway irritation",  "None — ideal for mask induction (no cough, no laryngospasm)"),
    ("Bronchodilation",    "MOST POTENT bronchodilator of all inhaled anaesthetics"),
    ("Secretions",         "No significant increase"),
    ("HPV",                "↓ Hypoxic pulmonary vasoconstriction → can worsen V/Q mismatch"),
]
two_col_table(resp, col1_w=CW*0.30)
info_box("KEY EXAM POINT: Sevoflurane is the <b>most effective clinical bronchodilator</b> among all inhalational anaesthetics — drug of choice for patients with reactive airways / status asthmaticus.",
         bg=LIGHT3, border_color=GREEN, icon="★")

# --- CNS ---
story.append(Paragraph("C.  Central Nervous System", sub_head))
cns = [
    ("CMRO₂",            "↓ (dose-dependent cerebral metabolic depression)"),
    ("CBF / ICP",        "↑ CVD → mild ↑ CBF and ICP at normocarbia (>1.5 MAC more marked)"),
    ("Autoregulation",   "Impaired at >1.5 MAC"),
    ("CO₂ reactivity",   "Preserved — hyperventilation counteracts ICP rise"),
    ("Seizures",         "NOT epileptogenic (unlike enflurane); spike-wave at >2 MAC rare"),
    ("Emergence delirium","Common in children — short-lived, no long-term sequelae"),
    ("EEG",              "Burst suppression at high concentrations"),
]
two_col_table(cns, col1_w=CW*0.30)

spacer(4)
info_box("CAUTION in raised ICP: Use hyperventilation to maintain normocarbia and counteract cerebrovascular dilation. Limit concentration, especially >1.5 MAC.",
         bg=LIGHT4, border_color=RED, icon="⚠")

# --- NMJ ---
story.append(Paragraph("D.  Neuromuscular System", sub_head))
bullet("Potentiates non-depolarising NMBAs (vecuronium, rocuronium, atracurium) — reduce NMBA dose by ~30–40%")
bullet("Adequate muscle relaxation for intubation at high concentrations after inhalational induction")
bullet("<b>Trigger for Malignant Hyperthermia (MH)</b> — ABSOLUTE CONTRAINDICATION in susceptible patients", bold=True)
spacer(4)

# --- Renal ---
story.append(Paragraph("E.  Renal System", sub_head))
renal = [
    ("Direct effect",          "Slight ↓ renal blood flow"),
    ("Compound A",             "Nephrotoxic in rats (proximal tubular necrosis >150 ppm-hr); NOT clinically nephrotoxic in humans"),
    ("Mechanism (rats)",       "CYP2E1 / β-lyase pathway → reactive thionoacyl fluoride → tubular injury"),
    ("Why safe in humans",     "Human kidneys have far lower β-lyase activity than rat kidneys"),
    ("Serum fluoride (F⁻)",    "Peak 22–31 µmol/L; >50 µmol/L in ~7% — no clinical renal dysfunction"),
    ("Compound A production",  "↑ with desiccated Baralyme, low FGF, high concentration, long duration"),
    ("FDA recommendation",     "FGF ≥1–2 L/min; limit to ≤2 MAC-hours at low flow"),
]
two_col_table(renal, col1_w=CW*0.30)

# --- Hepatic ---
story.append(Paragraph("F.  Hepatic System", sub_head))
hep = [
    ("Portal vein flow",      "↓ (dose-dependent)"),
    ("Hepatic artery flow",   "↑ (compensatory) — total hepatic O₂ delivery maintained"),
    ("Hepatotoxicity",        "Not reported — NOT metabolised to trifluoroacetate"),
    ("Mechanism of safety",   "Metabolised to HFIP + glucuronide, NOT acyl halide that stimulates antibodies"),
]
two_col_table(hep, col1_w=CW*0.30)
info_box("No halothane-type hepatitis with sevoflurane — CYP2E1 pathway produces hexafluoroisopropanol (HFIP), not trifluoroacetate. No immune-mediated hepatotoxicity.",
         bg=LIGHT3, border_color=GREEN)

# --- Uterus ---
story.append(Paragraph("G.  Uterus / Obstetrics", sub_head))
bullet("Dose-dependent uterine relaxation (tocolytic effect)")
bullet("At >1 MAC: may increase uterine bleeding during Caesarean section")
bullet("Crosses placenta — safe in low doses for maternal anaesthesia")
bullet("Use ≤1 MAC for obstetric procedures to minimise uterine atony")
spacer(4)

story.append(PageBreak())

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 4 – INDICATIONS
# ══════════════════════════════════════════════════════════════════════════════
section_banner("04", "Indications", GREEN)

indications = [
    ("1", "Inhalational induction of anaesthesia",    "Esp. children & needle-phobic adults — non-pungent, non-irritating"),
    ("2", "Maintenance of general anaesthesia",       "After IV or inhalational induction; 1–3% in O₂ or O₂/N₂O"),
    ("3", "Ambulatory / day-case surgery",            "Rapid emergence → early discharge"),
    ("4", "Paediatric anaesthesia",                   "Drug of choice — replaces halothane globally"),
    ("5", "Reactive airways / asthma",               "Most potent bronchodilator; reduces bronchospasm"),
    ("6", "IHD / tachyarrhythmia risk",              "No reflex tachycardia, no arrhythmia sensitisation"),
    ("7", "VIMA (volatile induction + maintenance)", "Single-agent technique; earlier orientation vs isoflurane"),
    ("8", "Rapid sequence inhalational induction",   "4–8% with 50% N₂O → unconsciousness in <1 min"),
]
ind_data = [[Paragraph("#", table_hdr), Paragraph("Indication", table_hdr), Paragraph("Notes", table_hdr)]] + [
    [Paragraph(r[0], table_cell_c), Paragraph(r[1], table_lbl), Paragraph(r[2], table_cell)]
    for r in indications
]
ind_t = Table(ind_data, colWidths=[0.5*cm, CW*0.38, CW*0.57])
ind_t.setStyle(TableStyle([
    ("BACKGROUND",   (0,0),(-1,0), GREEN),
    ("TEXTCOLOR",    (0,0),(-1,0), WHITE),
    ("ROWBACKGROUNDS",(0,1),(-1,-1),[WHITE, LGREY]),
    ("GRID",         (0,0),(-1,-1), 0.4, BORDER),
    ("TOPPADDING",   (0,0),(-1,-1), 4),
    ("BOTTOMPADDING",(0,0),(-1,-1), 4),
    ("LEFTPADDING",  (0,0),(-1,-1), 5),
    ("VALIGN",       (0,0),(-1,-1), "TOP"),
]))
story.append(ind_t)
spacer(6)

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 5 – CONTRAINDICATIONS
# ══════════════════════════════════════════════════════════════════════════════
section_banner("05", "Contraindications", RED)

ci = [
    ("Malignant Hyperthermia susceptibility",
     "ABSOLUTE — Sevoflurane is a potent MH trigger; causes uncontrolled Ca²⁺ release via mutant RyR1 receptor. "
     "Prepare vapour-free machine (flush 10–20 min with high O₂ flow). Have dantrolene ready."),
    ("Severe hypovolaemia / haemodynamic instability",
     "Further ↓ SVR and BP → risk of cardiovascular collapse."),
    ("Raised intracranial pressure",
     "Cerebral vasodilation ↑ ICP — use only if adequate hyperventilation maintained; avoid in decompensated head injury."),
    ("Desiccated CO₂ absorbent in circuit",
     "Risk of fire, explosion, and CO production — check absorbent moisture before use."),
]
ci_data = [[Paragraph("Contraindication", table_hdr), Paragraph("Reason / Action", table_hdr)]] + [
    [Paragraph(r[0], table_lbl), Paragraph(r[1], table_cell)] for r in ci
]
ci_t = Table(ci_data, colWidths=[CW*0.32, CW*0.68])
ci_t.setStyle(TableStyle([
    ("BACKGROUND",   (0,0),(-1,0), RED),
    ("TEXTCOLOR",    (0,0),(-1,0), WHITE),
    ("ROWBACKGROUNDS",(0,1),(-1,-1),[LIGHT4, WHITE]),
    ("GRID",         (0,0),(-1,-1), 0.4, BORDER),
    ("TOPPADDING",   (0,0),(-1,-1), 5),
    ("BOTTOMPADDING",(0,0),(-1,-1), 5),
    ("LEFTPADDING",  (0,0),(-1,-1), 6),
    ("VALIGN",       (0,0),(-1,-1), "TOP"),
]))
story.append(ci_t)
spacer(6)

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 6 – PRECAUTIONS & CARE
# ══════════════════════════════════════════════════════════════════════════════
section_banner("06", "Precautions & Care to be Taken", AMBER)

prec_areas = [
    ("Malignant Hyperthermia", LIGHT4, RED, [
        "Wash out anaesthesia machine: flush with O₂ at 10 L/min for 10–20 min before use",
        "Replace breathing circuit, reservoir bag, and CO₂ canister",
        "Have dantrolene available (2.5 mg/kg IV bolus; repeat up to 10 mg/kg)",
        "Use TIVA (propofol + remifentanil) for MH-susceptible patients",
        "Monitor temperature, EtCO₂, and muscle rigidity vigilantly",
    ]),
    ("CO₂ Absorbent / Compound A / Fire Risk", LIGHT2, AMBER, [
        "Never use with desiccated soda lime or Baralyme — risk of fire and Compound A",
        "Prefer calcium hydroxide-based absorbents (Amsorb®, Dragersorb Free®) — minimal Compound A",
        "Maintain FGF ≥2 L/min for prolonged (>2–3 hr) anaesthesia",
        "Do not run dry O₂/N₂O flow through circuit overnight",
        "Isolated circuit fires reported with desiccated absorbent — inspect moisture before use",
    ]),
    ("Paediatric – Emergence Delirium", LIGHT5, PURPLE, [
        "Warn parents — not associated with long-term harm",
        "Prevention: adequate analgesia is the most important measure",
        "Pharmacological prevention: fentanyl 1 µg/kg IV, OR dexmedetomidine 0.3–0.5 µg/kg, OR propofol 1 mg/kg at end of case",
        "Midazolam premedication alone is NOT effective for emergence delirium",
        "EEG-guided dosing may reduce incidence (2026 meta-analysis, PMID 41217504)",
    ]),
    ("Obstetric Surgery", LIGHT, TEAL, [
        "Keep ≤1 MAC to minimise uterine atony and excessive blood loss",
        "Have oxytocin ready and increase dose if uterine tone is poor",
        "For GA Caesarean: use 0.5 MAC sevoflurane + 50% N₂O until delivery, then titrate",
    ]),
    ("QT Prolongation", LIGHT4, RED, [
        "Caution in patients on drugs that prolong QT: Class Ia/III antiarrhythmics, TCAs, haloperidol",
        "Monitor ECG in high-risk patients; prolongation may persist up to 60 min post-emergence in infants",
        "Correct electrolyte abnormalities (K⁺, Mg²⁺) pre-operatively",
    ]),
    ("Renal Impairment", LIGHT2, AMBER, [
        "Clinically, sevoflurane nephrotoxicity is NOT established in humans",
        "Caution in severe CKD: use FGF ≥2 L/min, avoid prolonged low-flow anaesthesia",
        "Monitor creatinine / urea post-operatively after prolonged exposure",
    ]),
]

for title, bg, border, bullets in prec_areas:
    header_data = [[Paragraph(f"<b>{title}</b>",
                              S("Normal", fontSize=9, textColor=border, fontName="Helvetica-Bold", leading=13))]]
    ht = Table(header_data, colWidths=[CW])
    ht.setStyle(TableStyle([
        ("BACKGROUND",   (0,0),(-1,-1), bg),
        ("LEFTPADDING",  (0,0),(-1,-1), 8),
        ("TOPPADDING",   (0,0),(-1,-1), 4),
        ("BOTTOMPADDING",(0,0),(-1,-1), 2),
        ("LINEBELOW",    (0,0),(-1,-1), 1, border),
    ]))
    story.append(ht)
    for b in bullets:
        bullet_data = [[Paragraph("•", body), Paragraph(b, body)]]
        bt = Table(bullet_data, colWidths=[0.4*cm, CW-0.4*cm])
        bt.setStyle(TableStyle([
            ("BACKGROUND",   (0,0),(-1,-1), bg),
            ("TOPPADDING",   (0,0),(-1,-1), 2),
            ("BOTTOMPADDING",(0,0),(-1,-1), 2),
            ("LEFTPADDING",  (0,0),(-1,-1), 8),
            ("VALIGN",       (0,0),(-1,-1), "TOP"),
        ]))
        story.append(bt)
    story.append(Spacer(1, 5))

story.append(PageBreak())

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 7 – DRUG INTERACTIONS
# ══════════════════════════════════════════════════════════════════════════════
section_banner("07", "Drug Interactions", PURPLE)

di_rows = [
    ("Non-depolarising NMBAs\n(vec, roc, atrac, cis-atrac)",
     "POTENTIATED — ↑ block duration and depth; reduce NMBA dose by ~30–40%", "Significant"),
    ("Nitrous oxide (N₂O)",
     "ADDITIVE MAC reduction — can use 1–1.5% sevo with 50–60% N₂O", "Beneficial"),
    ("Opioids",
     "Reduce MAC (supradditive); ↑ PONV risk", "Dose-adjust"),
    ("Epinephrine (adrenaline)",
     "SAFE — does NOT sensitise myocardium to arrhythmias (unlike halothane)", "Safe"),
    ("Beta-blockers / antihypertensives",
     "Additive hypotension; anticipate exaggerated BP drop", "Caution"),
    ("QT-prolonging drugs\n(Class Ia/III, TCAs, haloperidol)",
     "Additive QT prolongation — risk of torsades de pointes", "Caution"),
    ("CYP2E1 inducers\n(ethanol, isoniazid, phenobarbital)",
     "↑ Metabolism → ↑ serum fluoride production", "Caution"),
    ("Alpha-2 agonists\n(dexmedetomidine, clonidine)",
     "↓ MAC significantly (20–40%) — useful for emergence delirium prevention", "Beneficial"),
    ("Propofol",
     "Often combined for TIVA/inhalational technique — no adverse interaction", "Compatible"),
]
di_data = [[Paragraph(h, table_hdr) for h in ["Drug / Class", "Interaction", "Clinical Significance"]]]
sig_colors = {"Significant": colors.HexColor("#FFE0DC"), "Beneficial": LIGHT3,
              "Dose-adjust": LIGHT2, "Caution": LIGHT2, "Safe": LIGHT3, "Compatible": LIGHT}
for r in di_rows:
    di_data.append([
        Paragraph(r[0], table_lbl),
        Paragraph(r[1], table_cell),
        Paragraph(r[2], table_cell_c),
    ])
di_t = Table(di_data, colWidths=[CW*0.26, CW*0.55, CW*0.19])
di_cmds = [
    ("BACKGROUND",    (0,0),(-1,0), PURPLE),
    ("TEXTCOLOR",     (0,0),(-1,0), WHITE),
    ("GRID",          (0,0),(-1,-1), 0.4, BORDER),
    ("TOPPADDING",    (0,0),(-1,-1), 4),
    ("BOTTOMPADDING", (0,0),(-1,-1), 4),
    ("LEFTPADDING",   (0,0),(-1,-1), 5),
    ("VALIGN",        (0,0),(-1,-1), "TOP"),
    ("ROWBACKGROUNDS",(0,1),(-1,-1),[WHITE, LGREY]),
]
di_t.setStyle(TableStyle(di_cmds))
story.append(di_t)
spacer(6)

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 8 – COMPARISON TABLE
# ══════════════════════════════════════════════════════════════════════════════
section_banner("08", "Volatile Anaesthetic Comparison", TEAL)

comp_headers = ["Property", "Sevoflurane", "Isoflurane", "Desflurane", "Halothane"]
comp_rows = [
    ["Blood:gas coeff",       "0.65",     "1.40",      "0.42",   "2.30"],
    ["MAC (%)",               "2.0",      "1.15",      "6–7",    "0.75"],
    ["Vaporizer",             "Standard", "Standard",  "Heated", "Standard"],
    ["Inhalational induction","Excellent","Poor (pungent)","Poor (pungent)","Good"],
    ["Metabolism",            "~5%",      "<2%",       "<0.05%", ">40%"],
    ["Hepatotoxicity",        "No",       "Rare",      "No",     "Yes (hepatitis)"],
    ["Arrhythmia sensitisation","No",     "Minimal",   "No",     "YES"],
    ["Bronchodilation",       "BEST",     "Good",      "Good",   "Good"],
    ["Heart rate effect",     "None",     "↑ HR",      "↑↑ HR",  "↓ HR"],
    ["Compound A",            "Yes",      "No",        "No",     "No"],
    ["MH trigger",            "Yes",      "Yes",       "Yes",    "Yes"],
    ["PONV risk",             "Moderate", "Moderate",  "Lower",  "High"],
]
c_widths = [CW*0.22, CW*0.195, CW*0.195, CW*0.195, CW*0.195]
c_data = [[Paragraph(h, table_hdr) for h in comp_headers]]
for row in comp_rows:
    c_data.append([Paragraph(str(c), table_cell_c) for c in row])
# highlight sevoflurane column
c_t = Table(c_data, colWidths=c_widths)
sevo_col_style = [
    ("BACKGROUND",   (1,1),(1,-1), LIGHT),
    ("FONTNAME",     (1,1),(1,-1), "Helvetica-Bold"),
    ("TEXTCOLOR",    (1,1),(1,-1), NAVY),
]
c_t.setStyle(TableStyle([
    ("BACKGROUND",    (0,0),(-1,0), TEAL),
    ("TEXTCOLOR",     (0,0),(-1,0), WHITE),
    ("ROWBACKGROUNDS",(0,1),(-1,-1),[WHITE, LGREY]),
    ("GRID",          (0,0),(-1,-1), 0.4, BORDER),
    ("TOPPADDING",    (0,0),(-1,-1), 4),
    ("BOTTOMPADDING", (0,0),(-1,-1), 4),
    ("LEFTPADDING",   (0,0),(-1,-1), 4),
    ("VALIGN",        (0,0),(-1,-1), "MIDDLE"),
] + sevo_col_style))
story.append(c_t)
spacer(4)

story.append(PageBreak())

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 9 – COMPOUND A & BIOTRANSFORMATION DETAIL
# ══════════════════════════════════════════════════════════════════════════════
section_banner("09", "Biotransformation & Toxicity (Compound A)", AMBER)

story.append(Paragraph("<b>Hepatic Metabolism (CYP2E1)</b>", sub_head))
met_rows = [
    ("Enzyme",         "CYP2E1 (hepatic microsomal)"),
    ("Rate",           "~5% of absorbed sevoflurane (10–25× isoflurane; ¼ of halothane)"),
    ("Inducers",       "Ethanol, isoniazid, phenobarbital → ↑ F⁻ production"),
    ("Main metabolite","Hexafluoroisopropanol (HFIP) → conjugated to glucuronide → excreted in urine"),
    ("By-product",     "Inorganic fluoride (F⁻) — peak 22–31 µmol/L; no renal concentrating defect"),
    ("No trifluoroacetate","Means NO immune-mediated hepatitis (unlike halothane)"),
]
two_col_table(met_rows)

story.append(Paragraph("<b>Compound A Formation</b>", sub_head))
story.append(Paragraph(
    "Sevoflurane reacts with <b>desiccated CO₂ absorbents</b> (soda lime, Baralyme) — strong bases (NaOH, KOH) extract a proton "
    "from the isopropyl group → forms <b>fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (Compound A)</b>.",
    body))
spacer(4)

ca_rows = [
    ("What increases Compound A", "Desiccated absorbent (Baralyme > soda lime) • Low FGF • High concentration • Long duration • High temperature"),
    ("Rat nephrotoxicity threshold","Proximal tubular necrosis at >150 ppm-hours; lethal at >1000 ppm-hours"),
    ("Human data",                 "NO clinically significant nephrotoxicity at any studied dose — large RCTs confirm safety"),
    ("Why rats ≠ humans",          "Human kidneys have far lower renal β-lyase activity → no reactive thionoacyl fluoride intermediate formed"),
    ("Peak Compound A with soda lime","~20 ppm at 1 L/min FGF"),
    ("With Baralyme",              "~30 ppm at 1 L/min FGF"),
    ("Safe absorbers",             "Amsorb® / Dragersorb Free® (calcium hydroxide only) — minimal Compound A"),
    ("FDA guidance",               "FGF ≥1–2 L/min; limit ≤2 MAC-hours with low FGF"),
    ("Circuit fire risk",          "Desiccated absorbent + sevoflurane → exothermic reaction → fire / CO production"),
]
two_col_table(ca_rows, col1_w=CW*0.34)

info_box(
    "<b>Bottom line for exams:</b>  Compound A is nephrotoxic in rats, but has NO proven clinical nephrotoxicity in humans. "
    "The clinically relevant precaution is to use FGF ≥2 L/min with soda lime, and to use calcium hydroxide absorbers when available.",
    bg=LIGHT2, border_color=AMBER, icon="📝")

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 10 – HIGH-YIELD EXAM POINTS
# ══════════════════════════════════════════════════════════════════════════════
section_banner("10", "High-Yield Exam Points  ★", RED)

story.append(Paragraph("The following facts are most commonly tested in MD / DNB / FRCA examinations:", body))
spacer(4)

hye = [
    ("Non-pungent odour",          "→ Preferred for inhalational induction (paediatrics and adults); replaced halothane globally"),
    ("Most potent bronchodilator", "→ Best inhalational agent for reactive airways / status asthmaticus"),
    ("No tachycardia",             "→ Preferred in IHD, tachyarrhythmia-prone patients"),
    ("No catecholamine sensitisation","→ Safe to use with adrenaline infiltration (unlike halothane)"),
    ("QT prolongation",            "→ Can occur; may persist 60 min post-emergence in infants; caution with QT-prolonging drugs"),
    ("No halothane hepatitis",     "→ Metabolised to HFIP not trifluoroacetate → no antibody-mediated liver damage"),
    ("CYP2E1 metabolism",          "→ 5%; induced by ethanol, isoniazid, phenobarbital"),
    ("Compound A",                 "→ Nephrotoxic in rats NOT in humans; use FGF ≥2 L/min with soda lime"),
    ("Desiccated absorbent = fire","→ Circuit fire risk; also produces CO — always check absorbent before use"),
    ("Emergence delirium",         "→ Common in children; prevent with analgesia + dexmedetomidine / fentanyl / propofol"),
    ("Uterine relaxation at >1 MAC","→ Risk of PPH at Caesarean; use ≤1 MAC intra-operatively"),
    ("MH trigger",                 "→ Absolute contraindication in MH-susceptible patients; use TIVA instead"),
    ("Blood:gas coeff 0.65",       "→ Low = fast induction, rapid depth changes, quick emergence"),
    ("MAC 2.0%",                   "→ Less potent than isoflurane (1.15%) but more potent than desflurane (6–7%)"),
    ("N₂O additive",               "→ Co-administration allows ↓ sevoflurane concentration — reduces haemodynamic side effects"),
    ("NMBAs potentiated",          "→ Reduce dose of non-depolarising agents by ~30–40%"),
    ("ICP concern",                "→ Cerebrovascular dilation at normocarbia — counteracted by hyperventilation (CO₂ reactivity preserved)"),
]
hye_data = [[Paragraph(h, table_hdr) for h in ["Feature", "Exam-Ready Explanation"]]]
for r in hye:
    hye_data.append([Paragraph(r[0], table_lbl), Paragraph(r[1], table_cell)])
hye_t = Table(hye_data, colWidths=[CW*0.30, CW*0.70])
hye_t.setStyle(TableStyle([
    ("BACKGROUND",    (0,0),(-1,0), RED),
    ("TEXTCOLOR",     (0,0),(-1,0), WHITE),
    ("ROWBACKGROUNDS",(0,1),(-1,-1),[WHITE, LIGHT4]),
    ("GRID",          (0,0),(-1,-1), 0.4, BORDER),
    ("TOPPADDING",    (0,0),(-1,-1), 4),
    ("BOTTOMPADDING", (0,0),(-1,-1), 4),
    ("LEFTPADDING",   (0,0),(-1,-1), 6),
    ("VALIGN",        (0,0),(-1,-1), "TOP"),
]))
story.append(hye_t)
spacer(6)

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 11 – CLINICAL DOSING QUICK CARD
# ══════════════════════════════════════════════════════════════════════════════
section_banner("11", "Clinical Dosing Quick Card", NAVY)

dose_rows = [
    ["Indication", "Concentration", "Notes"],
    ["Adult inhalational induction",     "4–8% (with 50–60% N₂O/O₂)", "Unconsciousness in ~1 min"],
    ["Paediatric mask induction",        "6–8%",                        "Reduce as sleep achieved"],
    ["Maintenance of anaesthesia",       "1–3% (in O₂ or O₂/N₂O)",    "Titrate to clinical effect"],
    ["Maintenance with N₂O",            "0.5–1.5%",                    "N₂O reduces MAC requirement"],
    ["Ambulatory / day-case",           "0.8–2%",                      "Reduce 15–20 min before end"],
    ["Obstetric GA (pre-delivery)",     "0.5 MAC sevo + 50% N₂O",      "Increase after cord clamping"],
    ["Status asthmaticus (ICU)",        "0.5–1.5%",                    "Via anaesthetic machine / AnaConDa"],
]
dose_t = Table(dose_rows, colWidths=[CW*0.33, CW*0.33, CW*0.34])
dose_t.setStyle(TableStyle([
    ("BACKGROUND",    (0,0),(-1,0), NAVY),
    ("TEXTCOLOR",     (0,0),(-1,0), WHITE),
    ("FONTNAME",      (0,0),(-1,0), "Helvetica-Bold"),
    ("FONTSIZE",      (0,0),(-1,-1), 8),
    ("ROWBACKGROUNDS",(0,1),(-1,-1),[WHITE, LIGHT]),
    ("GRID",          (0,0),(-1,-1), 0.4, BORDER),
    ("TOPPADDING",    (0,0),(-1,-1), 4),
    ("BOTTOMPADDING", (0,0),(-1,-1), 4),
    ("LEFTPADDING",   (0,0),(-1,-1), 6),
    ("VALIGN",        (0,0),(-1,-1), "MIDDLE"),
]))
story.append(dose_t)
spacer(8)

# Sources
story.append(Paragraph("<b>References</b>", sub_head))
refs = [
    "Miller's Anesthesia, 10th Edition (2024) — Blocks 6, 27, 29",
    "Morgan & Mikhail's Clinical Anesthesiology, 7th Edition — pp. 311–315",
    "Goodman & Gilman's Pharmacological Basis of Therapeutics — pp. 497–499",
    "Barash, Cullen & Stoelting's Clinical Anesthesia, 9th Edition — pp. 1403–1404",
    "Katzung's Basic & Clinical Pharmacology, 16th Edition — Table 25-1",
    "Lippincott Illustrated Reviews: Pharmacology — p. 677",
    "Javed J, et al. EEG-guided sevoflurane anesthesia vs. standard care in pediatric emergence delirium. J Anesth. 2026. [PMID: 41217504]",
]
for r in refs:
    story.append(Paragraph(f"• {r}", footnote))
    story.append(Spacer(1,2))

# ── BUILD ──────────────────────────────────────────────────────────────────────
def on_page(canvas, doc):
    canvas.saveState()
    # Header line
    canvas.setStrokeColor(BORDER)
    canvas.setLineWidth(0.5)
    canvas.line(1.8*cm, H - 1.4*cm, W - 1.8*cm, H - 1.4*cm)
    canvas.setFont("Helvetica", 7)
    canvas.setFillColor(MGREY)
    canvas.drawString(1.8*cm, H - 1.2*cm, "SEVOFLURANE — Anaesthesia Exam Study Guide")
    canvas.drawRightString(W - 1.8*cm, H - 1.2*cm, f"Page {doc.page}")
    # Footer
    canvas.line(1.8*cm, 1.5*cm, W - 1.8*cm, 1.5*cm)
    canvas.drawCentredString(W/2, 1.0*cm, "For educational purposes | Based on Miller's, Morgan & Mikhail's, Goodman & Gilman's, Barash, Katzung")
    canvas.restoreState()

doc.build(story, onFirstPage=on_page, onLaterPages=on_page)
print(f"PDF created: {OUTPUT}")

Successfully replaced 1 instance(s) of the string in '/home/daytona/workspace/sevoflurane-study-guide/build_pdf.py'

Successfully replaced 1 instance(s) of the string in '/home/daytona/workspace/sevoflurane-study-guide/build_pdf.py'