"""
MBBS Pharmacology Quick Reference Sheet
Mechanism Diagrams - Drug Classes, Receptors, Pathways
Based on KD Tripathi Essentials of Medical Pharmacology
"""

from reportlab.lib.pagesizes import A4
from reportlab.lib import colors
from reportlab.lib.units import cm, mm
from reportlab.platypus import (
    SimpleDocTemplate, Paragraph, Spacer, Table, TableStyle,
    HRFlowable, KeepTogether
)
from reportlab.lib.styles import getSampleStyleSheet, ParagraphStyle
from reportlab.lib.enums import TA_CENTER, TA_LEFT, TA_RIGHT
from reportlab.graphics.shapes import (
    Drawing, Rect, String, Arrow, Line, Circle, Polygon,
    Group, ArcPath
)
from reportlab.graphics import renderPDF
from reportlab.graphics.shapes import Drawing, Rect, String, Line, Circle, Arrow, Polygon
from reportlab.platypus import Flowable
from reportlab.lib.colors import (
    HexColor, white, black, red, blue, green, orange, purple,
    lightblue, lightyellow, lightgreen, lightgrey, darkblue
)
import math

# ─── Color Palette ───────────────────────────────────────────────────────────
C_HEADER   = HexColor("#1a3a5c")   # dark navy
C_SUBHEAD  = HexColor("#2e6da4")   # medium blue
C_ACC1     = HexColor("#e8532b")   # orange-red (antagonist)
C_ACC2     = HexColor("#27ae60")   # green (agonist / activates)
C_ACC3     = HexColor("#8e44ad")   # purple (inhibits)
C_ACC4     = HexColor("#e67e22")   # orange
C_LIGHT    = HexColor("#eaf4fb")   # very light blue
C_LIGHT2   = HexColor("#fef9e7")   # very light yellow
C_LIGHT3   = HexColor("#f0fff0")   # very light green
C_LIGHT4   = HexColor("#fdf2f8")   # very light pink
C_BORDER   = HexColor("#aed6f1")
C_TEXT     = HexColor("#1a1a1a")
C_GRAY     = HexColor("#7f8c8d")
C_RECEPTOR = HexColor("#2980b9")
C_DRUG     = HexColor("#c0392b")
C_EFFECT   = HexColor("#16a085")
C_BOX_BG   = HexColor("#f7fbff")

W, H = A4  # 595.27 x 841.89

# ─── Custom Flowable: Pathway Diagram ────────────────────────────────────────
class PathwayDiagram(Flowable):
    """Generic pathway box - renders a multi-step arrow diagram."""
    def __init__(self, steps, width=500, height=80, title="", colors_list=None):
        Flowable.__init__(self)
        self.steps = steps          # list of (label, sublabel)
        self.width = width
        self.height = height
        self.title = title
        self.colors_list = colors_list or [C_SUBHEAD] * len(steps)
        self.hAlign = 'CENTER'

    def wrap(self, availW, availH):
        return self.width, self.height + 20

    def draw(self):
        canvas = self.canv
        n = len(self.steps)
        box_w = (self.width - 20 * (n - 1)) / n
        box_h = 50
        y0 = 0

        if self.title:
            canvas.setFont("Helvetica-Bold", 8)
            canvas.setFillColor(C_HEADER)
            canvas.drawString(0, box_h + 10, self.title)

        for i, (label, sub) in enumerate(self.steps):
            x = i * (box_w + 20)
            col = self.colors_list[i % len(self.colors_list)]

            # Box
            canvas.setFillColor(col)
            canvas.setStrokeColor(col)
            canvas.roundRect(x, y0, box_w, box_h, 5, fill=1, stroke=0)

            # Label
            canvas.setFillColor(white)
            canvas.setFont("Helvetica-Bold", 8)
            canvas.drawCentredString(x + box_w / 2, y0 + box_h - 15, label)
            if sub:
                canvas.setFont("Helvetica", 6.5)
                canvas.drawCentredString(x + box_w / 2, y0 + box_h - 28, sub)

            # Arrow
            if i < n - 1:
                ax = x + box_w + 2
                ay = y0 + box_h / 2
                canvas.setFillColor(C_ACC4)
                canvas.setStrokeColor(C_ACC4)
                canvas.setLineWidth(1.5)
                canvas.line(ax, ay, ax + 14, ay)
                # arrowhead
                canvas.setFillColor(C_ACC4)
                p = canvas.beginPath()
                p.moveTo(ax + 14, ay - 4)
                p.lineTo(ax + 20, ay)
                p.lineTo(ax + 14, ay + 4)
                p.close()
                canvas.drawPath(p, fill=1, stroke=0)


class ReceptorDiagram(Flowable):
    """Draws a receptor-drug-effect schematic."""
    def __init__(self, drug, receptor, effect, drug_action="AGONIST",
                 width=500, height=100):
        Flowable.__init__(self)
        self.drug = drug
        self.receptor = receptor
        self.effect = effect
        self.drug_action = drug_action
        self.width = width
        self.height = height
        self.hAlign = 'CENTER'

    def wrap(self, availW, availH):
        return self.width, self.height

    def draw(self):
        c = self.canv
        w, h = self.width, self.height
        box_h = 44
        y0 = (h - box_h) / 2

        # Drug box
        col_d = C_ACC2 if "AGONIST" in self.drug_action else C_ACC1
        c.setFillColor(col_d)
        c.roundRect(0, y0, 130, box_h, 6, fill=1, stroke=0)
        c.setFillColor(white)
        c.setFont("Helvetica-Bold", 8)
        c.drawCentredString(65, y0 + box_h - 16, "DRUG")
        c.setFont("Helvetica", 7)
        for j, line in enumerate(self.drug.split("\n")):
            c.drawCentredString(65, y0 + box_h - 27 - j * 10, line)

        # Action label
        c.setFillColor(col_d)
        c.setFont("Helvetica-Bold", 7)
        c.drawCentredString(200, y0 + box_h / 2 + 14, self.drug_action)

        # Arrow drug -> receptor
        c.setStrokeColor(col_d)
        c.setLineWidth(2)
        c.line(130, y0 + box_h / 2, 268, y0 + box_h / 2)
        p = c.beginPath()
        p.moveTo(268, y0 + box_h / 2 - 5)
        p.lineTo(276, y0 + box_h / 2)
        p.lineTo(268, y0 + box_h / 2 + 5)
        p.close()
        c.setFillColor(col_d)
        c.drawPath(p, fill=1, stroke=0)

        # Receptor box
        c.setFillColor(C_RECEPTOR)
        c.roundRect(276, y0, 130, box_h, 6, fill=1, stroke=0)
        c.setFillColor(white)
        c.setFont("Helvetica-Bold", 8)
        c.drawCentredString(341, y0 + box_h - 16, "RECEPTOR")
        c.setFont("Helvetica", 7)
        for j, line in enumerate(self.receptor.split("\n")):
            c.drawCentredString(341, y0 + box_h - 27 - j * 10, line)

        # Arrow receptor -> effect
        c.setStrokeColor(C_EFFECT)
        c.setLineWidth(2)
        c.line(406, y0 + box_h / 2, 496, y0 + box_h / 2)
        p = c.beginPath()
        p.moveTo(496, y0 + box_h / 2 - 5)
        p.lineTo(504, y0 + box_h / 2)
        p.lineTo(496, y0 + box_h / 2 + 5)
        p.close()
        c.setFillColor(C_EFFECT)
        c.drawPath(p, fill=1, stroke=0)

        # Effect box
        c.setFillColor(C_EFFECT)
        c.roundRect(504, y0, 130, box_h, 6, fill=1, stroke=0)
        c.setFillColor(white)
        c.setFont("Helvetica-Bold", 8)
        c.drawCentredString(569, y0 + box_h - 16, "CLINICAL EFFECT")
        c.setFont("Helvetica", 7)
        for j, line in enumerate(self.effect.split("\n")):
            c.drawCentredString(569, y0 + box_h - 27 - j * 10, line)


class MiniTable(Flowable):
    """Small info table: Drug | Receptor | Mechanism | Use"""
    def __init__(self, rows, col_headers, col_widths, bg_color=C_LIGHT, width=500):
        Flowable.__init__(self)
        self.rows = rows
        self.col_headers = col_headers
        self.col_widths = col_widths
        self.bg_color = bg_color
        self.width = width

    def wrap(self, availW, availH):
        self.table = self._build()
        return self.table.wrap(availW, availH)

    def _build(self):
        data = [self.col_headers] + self.rows
        t = Table(data, colWidths=self.col_widths)
        style = TableStyle([
            ('BACKGROUND', (0, 0), (-1, 0), C_SUBHEAD),
            ('TEXTCOLOR', (0, 0), (-1, 0), white),
            ('FONTNAME', (0, 0), (-1, 0), 'Helvetica-Bold'),
            ('FONTSIZE', (0, 0), (-1, 0), 7.5),
            ('BACKGROUND', (0, 1), (-1, -1), self.bg_color),
            ('FONTNAME', (0, 1), (-1, -1), 'Helvetica'),
            ('FONTSIZE', (0, 1), (-1, -1), 7),
            ('ROWBACKGROUNDS', (0, 1), (-1, -1), [self.bg_color, white]),
            ('GRID', (0, 0), (-1, -1), 0.4, C_BORDER),
            ('ALIGN', (0, 0), (-1, -1), 'LEFT'),
            ('VALIGN', (0, 0), (-1, -1), 'MIDDLE'),
            ('LEFTPADDING', (0, 0), (-1, -1), 4),
            ('RIGHTPADDING', (0, 0), (-1, -1), 4),
            ('TOPPADDING', (0, 0), (-1, -1), 3),
            ('BOTTOMPADDING', (0, 0), (-1, -1), 3),
            ('WORDWRAP', (0, 0), (-1, -1), True),
        ])
        t.setStyle(style)
        return t

    def draw(self):
        self.table.drawOn(self.canv, 0, 0)


# ─── Build Document ──────────────────────────────────────────────────────────
def build_pdf(out_path):
    doc = SimpleDocTemplate(
        out_path,
        pagesize=A4,
        leftMargin=1.5 * cm, rightMargin=1.5 * cm,
        topMargin=1.8 * cm, bottomMargin=1.8 * cm,
        title="MBBS Pharmacology Quick Reference",
        author="KD Tripathi Framework"
    )

    styles = getSampleStyleSheet()
    USABLE_W = W - 3 * cm

    # Custom styles
    s_title = ParagraphStyle("Title2", parent=styles["Normal"],
        fontSize=18, fontName="Helvetica-Bold", textColor=white,
        alignment=TA_CENTER, spaceAfter=2)
    s_sub_title = ParagraphStyle("SubTitle", parent=styles["Normal"],
        fontSize=9, fontName="Helvetica", textColor=HexColor("#cce0f0"),
        alignment=TA_CENTER, spaceAfter=4)
    s_h1 = ParagraphStyle("H1", parent=styles["Normal"],
        fontSize=11, fontName="Helvetica-Bold", textColor=white,
        backColor=C_HEADER, borderPad=5, leading=16,
        spaceBefore=10, spaceAfter=4, leftIndent=6)
    s_h2 = ParagraphStyle("H2", parent=styles["Normal"],
        fontSize=9.5, fontName="Helvetica-Bold", textColor=C_SUBHEAD,
        spaceBefore=8, spaceAfter=3, borderWidth=0,
        borderColor=C_SUBHEAD, leftIndent=0)
    s_body = ParagraphStyle("Body", parent=styles["Normal"],
        fontSize=7.5, fontName="Helvetica", textColor=C_TEXT,
        leading=11, spaceBefore=1, spaceAfter=1)
    s_bullet = ParagraphStyle("Bullet", parent=styles["Normal"],
        fontSize=7, fontName="Helvetica", textColor=C_TEXT,
        leading=10, leftIndent=12, bulletIndent=4, spaceBefore=1)
    s_note = ParagraphStyle("Note", parent=styles["Normal"],
        fontSize=6.5, fontName="Helvetica-Oblique", textColor=C_GRAY,
        leading=9, spaceBefore=2)
    s_tag_g = ParagraphStyle("TagG", parent=styles["Normal"],
        fontSize=7, fontName="Helvetica-Bold", textColor=white,
        backColor=C_ACC2, borderPad=2, alignment=TA_CENTER)
    s_tag_r = ParagraphStyle("TagR", parent=styles["Normal"],
        fontSize=7, fontName="Helvetica-Bold", textColor=white,
        backColor=C_ACC1, borderPad=2, alignment=TA_CENTER)

    def sp(h=4): return Spacer(1, h)
    def hr(): return HRFlowable(width="100%", thickness=0.5, color=C_BORDER,
                                spaceAfter=4, spaceBefore=2)
    def h1(t): return Paragraph(f"&nbsp; {t}", s_h1)
    def h2(t): return Paragraph(t, s_h2)
    def body(t): return Paragraph(t, s_body)
    def note(t): return Paragraph(t, s_note)
    def bul(t): return Paragraph(f"• {t}", s_bullet)

    story = []

    # ── COVER BANNER ──────────────────────────────────────────────────────────
    banner_data = [[Paragraph(
        "<font color='white'><b>MBBS PHARMACOLOGY</b></font><br/>"
        "<font color='#cce0f0' size=10>Quick Reference Sheet - Mechanisms, Receptors &amp; Pathways</font><br/>"
        "<font color='#aed6f1' size=8>Based on KD Tripathi Essentials of Medical Pharmacology | 2nd MBBS Prof Exams</font>",
        ParagraphStyle("ban", alignment=TA_CENTER, fontSize=16,
                       fontName="Helvetica-Bold", textColor=white, leading=22))]]
    banner = Table(banner_data, colWidths=[USABLE_W])
    banner.setStyle(TableStyle([
        ('BACKGROUND', (0, 0), (-1, -1), C_HEADER),
        ('TOPPADDING', (0, 0), (-1, -1), 14),
        ('BOTTOMPADDING', (0, 0), (-1, -1), 14),
        ('LEFTPADDING', (0, 0), (-1, -1), 10),
        ('RIGHTPADDING', (0, 0), (-1, -1), 10),
        ('ROUNDEDCORNERS', [6, 6, 6, 6]),
    ]))
    story.append(banner)
    story.append(sp(10))

    # Legend
    leg_data = [[
        Paragraph("<font color='white'><b> AGONIST / ACTIVATES </b></font>",
                  ParagraphStyle("l1", backColor=C_ACC2, fontSize=7,
                                 fontName="Helvetica-Bold", textColor=white,
                                 alignment=TA_CENTER, borderPad=3)),
        Paragraph("<font color='white'><b> ANTAGONIST / BLOCKS </b></font>",
                  ParagraphStyle("l2", backColor=C_ACC1, fontSize=7,
                                 fontName="Helvetica-Bold", textColor=white,
                                 alignment=TA_CENTER, borderPad=3)),
        Paragraph("<font color='white'><b> INHIBITS ENZYME </b></font>",
                  ParagraphStyle("l3", backColor=C_ACC3, fontSize=7,
                                 fontName="Helvetica-Bold", textColor=white,
                                 alignment=TA_CENTER, borderPad=3)),
        Paragraph("<font color='white'><b> CLINICAL EFFECT </b></font>",
                  ParagraphStyle("l4", backColor=C_EFFECT, fontSize=7,
                                 fontName="Helvetica-Bold", textColor=white,
                                 alignment=TA_CENTER, borderPad=3)),
    ]]
    leg = Table(leg_data, colWidths=[USABLE_W / 4] * 4)
    leg.setStyle(TableStyle([
        ('TOPPADDING', (0, 0), (-1, -1), 4),
        ('BOTTOMPADDING', (0, 0), (-1, -1), 4),
        ('LEFTPADDING', (0, 0), (-1, -1), 2),
        ('RIGHTPADDING', (0, 0), (-1, -1), 2),
    ]))
    story.append(leg)
    story.append(sp(10))

    # ═══════════════════════════════════════════════════════════════
    # SECTION 1 - GENERAL PHARMACOLOGY
    # ═══════════════════════════════════════════════════════════════
    story.append(h1("SECTION 1 — GENERAL PHARMACOLOGY"))
    story.append(sp(4))

    story.append(h2("1.1  Routes of Drug Administration — Summary"))
    routes_data = [
        ["Route", "Absorption", "Bioavailability", "Key Feature", "Example"],
        ["Oral (PO)", "GI tract", "Variable (10-100%)", "First-pass effect", "Most drugs"],
        ["Sublingual (SL)", "Oral mucosa", "High (~90%)", "Avoids first-pass", "GTN, buprenorphine"],
        ["Rectal (PR)", "Rectal mucosa", "Partial first-pass", "Useful if vomiting", "Diazepam"],
        ["Intravenous (IV)", "Direct", "100%", "No absorption step", "Emergencies"],
        ["Intramuscular (IM)", "Muscle capillaries", "~75-100%", "Depot possible", "Vaccines, penicillin"],
        ["Subcutaneous (SC)", "Slow", "~75-100%", "Depot for proteins", "Insulin, heparin"],
        ["Inhalation", "Pulmonary alveoli", "High (for gases)", "Rapid CNS entry", "General anaesthetics"],
        ["Transdermal", "Skin", "Slow, sustained", "Avoids first-pass", "GTN patch, fentanyl"],
    ]
    routes_t = Table(routes_data,
        colWidths=[70, 90, 90, 110, 100])
    routes_t.setStyle(TableStyle([
        ('BACKGROUND', (0, 0), (-1, 0), C_SUBHEAD),
        ('TEXTCOLOR', (0, 0), (-1, 0), white),
        ('FONTNAME', (0, 0), (-1, 0), 'Helvetica-Bold'),
        ('FONTSIZE', (0, 0), (-1, 0), 7.5),
        ('ROWBACKGROUNDS', (0, 1), (-1, -1), [C_LIGHT, white]),
        ('FONTNAME', (0, 1), (-1, -1), 'Helvetica'),
        ('FONTSIZE', (0, 1), (-1, -1), 7),
        ('GRID', (0, 0), (-1, -1), 0.4, C_BORDER),
        ('ALIGN', (0, 0), (-1, -1), 'LEFT'),
        ('VALIGN', (0, 0), (-1, -1), 'MIDDLE'),
        ('LEFTPADDING', (0, 0), (-1, -1), 4),
        ('TOPPADDING', (0, 0), (-1, -1), 3),
        ('BOTTOMPADDING', (0, 0), (-1, -1), 3),
    ]))
    story.append(routes_t)
    story.append(sp(6))

    story.append(h2("1.2  Pharmacokinetics Pathway"))
    story.append(PathwayDiagram(
        steps=[
            ("ABSORPTION", "GI/skin/lung"),
            ("DISTRIBUTION", "Plasma protein\nbinding + Vd"),
            ("METABOLISM", "Liver CYP450\nPhase I & II"),
            ("EXCRETION", "Kidney, bile,\nlungs"),
        ],
        width=USABLE_W, height=60,
        colors_list=[C_SUBHEAD, C_ACC4, C_ACC3, C_ACC1]
    ))
    story.append(sp(4))
    story.append(note("Key equation: Steady state achieved after 4-5 half-lives (t½). Loading dose = Vd × target conc. Maintenance dose = Cl × target conc."))
    story.append(sp(6))

    story.append(h2("1.3  Receptor Types and Signal Transduction"))
    rec_data = [
        ["Receptor Type", "Mechanism", "Speed", "Examples", "Drug Class"],
        ["Ionotropic (Ligand-gated ion channel)", "Opens ion channel directly", "Milliseconds", "nAChR, GABA-A, NMDA", "BZDs, neuromuscular blockers"],
        ["G-protein coupled (GPCR)", "G-protein → 2nd messenger (cAMP, IP3, DAG)", "Seconds", "Beta-AR, M2, Alpha-AR", "Beta blockers, atropine, adrenaline"],
        ["Tyrosine kinase linked", "Phosphorylation cascade", "Minutes-hours", "Insulin-R, growth factors", "Insulin, imatinib"],
        ["Nuclear / Intracellular", "Regulates gene transcription", "Hours-days", "Glucocorticoid-R, thyroid-R", "Steroids, thyroid hormones"],
    ]
    rec_t = Table(rec_data, colWidths=[110, 110, 65, 110, 105])
    rec_t.setStyle(TableStyle([
        ('BACKGROUND', (0, 0), (-1, 0), C_SUBHEAD),
        ('TEXTCOLOR', (0, 0), (-1, 0), white),
        ('FONTNAME', (0, 0), (-1, 0), 'Helvetica-Bold'),
        ('FONTSIZE', (0, 0), (-1, 0), 7.5),
        ('ROWBACKGROUNDS', (0, 1), (-1, -1), [C_LIGHT, white]),
        ('FONTNAME', (0, 1), (-1, -1), 'Helvetica'),
        ('FONTSIZE', (0, 1), (-1, -1), 7),
        ('GRID', (0, 0), (-1, -1), 0.4, C_BORDER),
        ('ALIGN', (0, 0), (-1, -1), 'LEFT'),
        ('VALIGN', (0, 0), (-1, -1), 'MIDDLE'),
        ('LEFTPADDING', (0, 0), (-1, -1), 4),
        ('TOPPADDING', (0, 0), (-1, -1), 3),
        ('BOTTOMPADDING', (0, 0), (-1, -1), 3),
        ('WORDWRAP', (0, 0), (-1, -1), True),
    ]))
    story.append(rec_t)
    story.append(sp(8))

    # ═══════════════════════════════════════════════════════════════
    # SECTION 2 - AUTONOMIC PHARMACOLOGY
    # ═══════════════════════════════════════════════════════════════
    story.append(h1("SECTION 2 — AUTONOMIC PHARMACOLOGY"))
    story.append(sp(4))

    story.append(h2("2.1  Autonomic Receptor Map"))
    aut_data = [
        ["Receptor", "Location", "Agonist Effect", "Key Drugs (Agonists)", "Key Drugs (Antagonists)"],
        ["Alpha-1 (α1)", "Blood vessels, iris, bladder", "Vasoconstriction, mydriasis", "Noradrenaline, phenylephrine", "Prazosin, phentolamine"],
        ["Alpha-2 (α2)", "Pre-synaptic, pancreas", "↓NA release, ↓insulin", "Clonidine, methyldopa", "Yohimbine"],
        ["Beta-1 (β1)", "Heart, kidney JGA", "↑HR, ↑contractility, ↑renin", "Dobutamine, isoprenaline", "Metoprolol, atenolol"],
        ["Beta-2 (β2)", "Bronchi, uterus, vessels", "Bronchodilation, uterine relax", "Salbutamol, terbutaline", "Propranolol (non-selective)"],
        ["M1 (Muscarinic)", "CNS, gastric parietal", "CNS effects, ↑acid", "Pilocarpine (all M)", "Pirenzepine (M1 selective)"],
        ["M2 (Muscarinic)", "Heart (SA, AV node)", "Bradycardia, ↓AV conduction", "Muscarine, acetylcholine", "Atropine (all M)"],
        ["M3 (Muscarinic)", "Smooth muscle, glands, eye", "Contraction, secretions, miosis", "Pilocarpine, bethanechol", "Ipratropium, glycopyrrolate"],
        ["Nm (Nicotinic-NMJ)", "Neuromuscular junction", "Muscle contraction", "Suxamethonium", "Tubocurarine, rocuronium"],
        ["Nn (Nicotinic-Ganglion)", "Autonomic ganglia", "Ganglionic stimulation", "Nicotine", "Hexamethonium, trimetaphan"],
    ]
    aut_t = Table(aut_data, colWidths=[75, 100, 105, 115, 105])
    aut_t.setStyle(TableStyle([
        ('BACKGROUND', (0, 0), (-1, 0), C_SUBHEAD),
        ('TEXTCOLOR', (0, 0), (-1, 0), white),
        ('FONTNAME', (0, 0), (-1, 0), 'Helvetica-Bold'),
        ('FONTSIZE', (0, 0), (-1, 0), 7.5),
        ('ROWBACKGROUNDS', (0, 1), (-1, -1), [C_LIGHT, white]),
        ('FONTNAME', (0, 1), (-1, -1), 'Helvetica'),
        ('FONTSIZE', (0, 1), (-1, -1), 7),
        ('GRID', (0, 0), (-1, -1), 0.4, C_BORDER),
        ('ALIGN', (0, 0), (-1, -1), 'LEFT'),
        ('VALIGN', (0, 0), (-1, -1), 'MIDDLE'),
        ('LEFTPADDING', (0, 0), (-1, -1), 4),
        ('TOPPADDING', (0, 0), (-1, -1), 3),
        ('BOTTOMPADDING', (0, 0), (-1, -1), 3),
        ('WORDWRAP', (0, 0), (-1, -1), True),
    ]))
    story.append(aut_t)
    story.append(sp(6))

    story.append(h2("2.2  Cholinergic Synapse Pathway"))
    story.append(PathwayDiagram(
        steps=[
            ("Choline +\nAcetyl-CoA", "ChAT enzyme"),
            ("ACh stored\nin vesicles", "Nerve terminal"),
            ("ACh released\ninto synapse", "Action potential"),
            ("ACh binds\nM or N receptor", "Post-synaptic"),
            ("Effect\n(PS response)", "SLUD + NMJ"),
        ],
        width=USABLE_W, height=60, title="Cholinergic Synapse (ACh Pathway)",
        colors_list=[C_SUBHEAD, C_SUBHEAD, C_ACC2, C_RECEPTOR, C_EFFECT]
    ))
    story.append(note("ACh is degraded by AChE (acetylcholinesterase). Anticholinesterases (neostigmine, physostigmine) block AChE → ↑ACh at synapse."))
    story.append(sp(4))

    story.append(h2("2.3  Adrenergic Synapse Pathway"))
    story.append(PathwayDiagram(
        steps=[
            ("Tyrosine\n→ DOPA → DA", "TH enzyme"),
            ("DA → NA\nstored in vesicles", "DBH enzyme"),
            ("NA released\ninto synapse", "Action potential"),
            ("NA binds\nα or β receptor", "Post-synaptic"),
            ("Effect\n(SNS response)", "↑HR, vasoconstric"),
        ],
        width=USABLE_W, height=60, title="Adrenergic Synapse (Noradrenaline Pathway)",
        colors_list=[C_ACC4, C_ACC4, C_ACC1, C_RECEPTOR, C_EFFECT]
    ))
    story.append(note("NA reuptake by NET (norepinephrine transporter). Cocaine, TCAs block NET. MAO/COMT degrade catecholamines."))
    story.append(sp(8))

    # ═══════════════════════════════════════════════════════════════
    # SECTION 3 - CARDIOVASCULAR PHARMACOLOGY
    # ═══════════════════════════════════════════════════════════════
    story.append(h1("SECTION 3 — CARDIOVASCULAR PHARMACOLOGY"))
    story.append(sp(4))

    story.append(h2("3.1  Antihypertensive Drug Classes — Mechanism Map"))
    ah_data = [
        ["Drug Class", "Target / Mechanism", "Key Effect", "Examples", "Key Caution"],
        ["ACE Inhibitors", "Block ACE → ↓Angiotensin II\n→ ↓Aldosterone", "Vasodilation +\n↓Na retention", "Enalapril, Ramipril,\nLisinopril", "Dry cough (↑bradykinin)\nContraindicated in pregnancy"],
        ["ARBs", "Block AT1 receptor\n→ ↓AT-II effects", "Vasodilation +\n↓aldosterone", "Losartan, Valsartan,\nTelmisartan", "No cough; OK if ACEi\ncough occurs"],
        ["Beta Blockers", "Block β1 → ↓HR,\n↓contractility, ↓renin", "↓Cardiac output", "Atenolol, Metoprolol,\nBisoprolol", "Avoid in asthma,\nPVD, heart block"],
        ["Calcium Channel\nBlockers (CCB)", "Block L-type Ca2+\nchannels", "Vasodilation ±\n↓HR (non-DHP)", "Amlodipine (DHP)\nDiltiazem, Verapamil", "Verapamil: avoid\nwith beta blockers"],
        ["Thiazide Diuretics", "Block NCC in DCT\n→ ↓Na+ reabsorption", "↓Blood volume", "Hydrochlorothiazide,\nIndapamide", "Hypokalemia,\nhyperglycemia"],
        ["Alpha-1 Blockers", "Block α1 → vasodilation", "↓Peripheral\nresistance", "Prazosin, Doxazosin,\nTerazosin", "First-dose\northostatic hypotension"],
        ["Centrally acting", "α2 agonist → ↓SNS\noutflow from brain", "↓BP + ↓HR", "Clonidine,\nMethyldopa", "Methyldopa: drug of\nchoice in pregnancy HTN"],
    ]
    ah_t = Table(ah_data, colWidths=[80, 110, 70, 110, 90])
    ah_t.setStyle(TableStyle([
        ('BACKGROUND', (0, 0), (-1, 0), C_SUBHEAD),
        ('TEXTCOLOR', (0, 0), (-1, 0), white),
        ('FONTNAME', (0, 0), (-1, 0), 'Helvetica-Bold'),
        ('FONTSIZE', (0, 0), (-1, 0), 7.5),
        ('ROWBACKGROUNDS', (0, 1), (-1, -1), [C_LIGHT, white]),
        ('FONTNAME', (0, 1), (-1, -1), 'Helvetica'),
        ('FONTSIZE', (0, 1), (-1, -1), 7),
        ('GRID', (0, 0), (-1, -1), 0.4, C_BORDER),
        ('ALIGN', (0, 0), (-1, -1), 'LEFT'),
        ('VALIGN', (0, 0), (-1, -1), 'MIDDLE'),
        ('LEFTPADDING', (0, 0), (-1, -1), 4),
        ('TOPPADDING', (0, 0), (-1, -1), 3),
        ('BOTTOMPADDING', (0, 0), (-1, -1), 3),
        ('WORDWRAP', (0, 0), (-1, -1), True),
    ]))
    story.append(ah_t)
    story.append(sp(6))

    story.append(h2("3.2  RAAS Pathway (Renin-Angiotensin-Aldosterone System)"))
    story.append(PathwayDiagram(
        steps=[
            ("Renin\n(Kidney JGA)", "↓BP/↓Na/SNS"),
            ("Angiotensinogen\n→ Angiotensin I", "Liver substrate"),
            ("Angiotensin I\n→ Angiotensin II", "ACE (lung)"),
            ("AT-II binds\nAT1 receptor", "Vasoconstriction\n+ aldosterone"),
            ("Na+ retention\n↑Blood pressure", "Adrenal cortex"),
        ],
        width=USABLE_W, height=65,
        colors_list=[C_SUBHEAD, C_ACC4, C_ACC3, C_ACC1, C_EFFECT],
        title="RAAS Pathway — ACE inhibitors block Step 3; ARBs block Step 4"
    ))
    story.append(sp(6))

    story.append(h2("3.3  Anti-anginal Drugs — Mechanism Comparison"))
    ang_data = [
        ["Drug Class", "Mechanism", "Preload", "Afterload", "HR/Contractility", "O2 Demand"],
        ["Organic Nitrates\n(GTN, ISDN)", "Release NO → cGMP\n→ venodilation", "↓↓", "↓", "↑ (reflex)", "↓"],
        ["Beta Blockers", "↓HR and contractility\n(β1 block)", "→", "↓", "↓↓ HR, ↓↓ cont.", "↓↓"],
        ["CCB (DHP)\nAmlodipine", "L-Ca2+ block →\nArterial vasodilation", "→", "↓↓", "↑ (reflex)", "↓"],
        ["CCB (non-DHP)\nVerapamil", "L-Ca2+ block + rate\ncontrol", "→", "↓", "↓ HR, ↓ cont.", "↓↓"],
        ["Nicorandil", "K+ ATP channel opener\n+ nitrate effect", "↓", "↓", "→", "↓"],
    ]
    ang_t = Table(ang_data, colWidths=[85, 115, 48, 58, 100, 54])
    ang_t.setStyle(TableStyle([
        ('BACKGROUND', (0, 0), (-1, 0), C_SUBHEAD),
        ('TEXTCOLOR', (0, 0), (-1, 0), white),
        ('FONTNAME', (0, 0), (-1, 0), 'Helvetica-Bold'),
        ('FONTSIZE', (0, 0), (-1, 0), 7.5),
        ('ROWBACKGROUNDS', (0, 1), (-1, -1), [C_LIGHT, white]),
        ('FONTNAME', (0, 1), (-1, -1), 'Helvetica'),
        ('FONTSIZE', (0, 1), (-1, -1), 7),
        ('GRID', (0, 0), (-1, -1), 0.4, C_BORDER),
        ('ALIGN', (0, 0), (-1, -1), 'LEFT'),
        ('VALIGN', (0, 0), (-1, -1), 'MIDDLE'),
        ('LEFTPADDING', (0, 0), (-1, -1), 4),
        ('TOPPADDING', (0, 0), (-1, -1), 3),
        ('BOTTOMPADDING', (0, 0), (-1, -1), 3),
        ('WORDWRAP', (0, 0), (-1, -1), True),
    ]))
    story.append(ang_t)
    story.append(sp(6))

    story.append(h2("3.4  Digoxin — Mechanism of Action"))
    story.append(PathwayDiagram(
        steps=[
            ("Digoxin inhibits\nNa+/K+-ATPase", "Pump blocked"),
            ("↑Intracellular\nNa+", "Cell accumulates Na"),
            ("Na+/Ca2+\nexchanger reverses", "Less Ca2+ exit"),
            ("↑Intracellular\nCa2+", "Stores fill"),
            ("↑Myocardial\nContractility", "+ve Inotrope"),
        ],
        width=USABLE_W, height=60, title="Digoxin Mechanism — Positive Inotropy",
        colors_list=[C_ACC3, C_ACC4, C_SUBHEAD, C_ACC1, C_EFFECT]
    ))
    story.append(note("Vagal effect: Digoxin also enhances vagal tone → ↓HR and ↓AV conduction (useful in AF). Hypokalemia potentiates toxicity (competes with K+ at Na+/K+-ATPase)."))
    story.append(sp(8))

    # ═══════════════════════════════════════════════════════════════
    # SECTION 4 - CNS PHARMACOLOGY
    # ═══════════════════════════════════════════════════════════════
    story.append(h1("SECTION 4 — CNS PHARMACOLOGY"))
    story.append(sp(4))

    story.append(h2("4.1  Opioid Receptor Pathway"))
    story.append(ReceptorDiagram(
        drug="Morphine\nCodeine\nFentanyl\nPethidine",
        receptor="μ (Mu) opioid\nreceptor\n(GPCR - Gi)",
        effect="Analgesia\nRespiratory depression\nConstipation\nEuphoria",
        drug_action="AGONIST",
        width=USABLE_W, height=90
    ))
    story.append(note("Naloxone/Naltrexone = opioid receptor ANTAGONISTS (reversal agents). Contraindicated: morphine in head injury (↑ICP via CO2 retention), asthma, hepatic failure."))
    story.append(sp(6))

    story.append(h2("4.2  GABA-A Receptor — BZD vs Barbiturate"))
    gaba_data = [
        ["Property", "Benzodiazepines (BZDs)", "Barbiturates"],
        ["Binding site", "Specific BZD site (α subunit)", "Barbiturate site (β subunit)"],
        ["Mechanism", "↑Frequency of Cl- channel opening", "↑Duration of Cl- channel opening"],
        ["Ceiling effect", "Yes — safer overdose profile", "No — can cause respiratory arrest"],
        ["Reversal agent", "Flumazenil (BZD antagonist)", "None available"],
        ["Uses", "Anxiety, epilepsy, alcohol withdrawal,\npre-med, insomnia", "Induction of anaesthesia, epilepsy\n(now limited use)"],
        ["Examples", "Diazepam, Midazolam, Lorazepam,\nAlprazolam", "Thiopentone (IV anaesthesia),\nPhenobarbital (epilepsy)"],
    ]
    gaba_t = Table(gaba_data, colWidths=[95, 215, 190])
    gaba_t.setStyle(TableStyle([
        ('BACKGROUND', (0, 0), (-1, 0), C_SUBHEAD),
        ('TEXTCOLOR', (0, 0), (-1, 0), white),
        ('FONTNAME', (0, 0), (-1, 0), 'Helvetica-Bold'),
        ('FONTSIZE', (0, 0), (-1, 0), 7.5),
        ('ROWBACKGROUNDS', (0, 1), (-1, -1), [C_LIGHT, white]),
        ('FONTNAME', (0, 1), (-1, -1), 'Helvetica'),
        ('FONTSIZE', (0, 1), (-1, -1), 7),
        ('GRID', (0, 0), (-1, -1), 0.4, C_BORDER),
        ('ALIGN', (0, 0), (-1, -1), 'LEFT'),
        ('VALIGN', (0, 0), (-1, -1), 'MIDDLE'),
        ('LEFTPADDING', (0, 0), (-1, -1), 4),
        ('TOPPADDING', (0, 0), (-1, -1), 3),
        ('BOTTOMPADDING', (0, 0), (-1, -1), 3),
        ('WORDWRAP', (0, 0), (-1, -1), True),
    ]))
    story.append(gaba_t)
    story.append(sp(6))

    story.append(h2("4.3  Antiepileptic Drugs — Mechanism Table"))
    aed_data = [
        ["Drug", "Mechanism", "Seizure Type", "Key Side Effects"],
        ["Phenytoin", "Block fast Na+ channels\n(frequency-dependent)", "Tonic-clonic, Focal", "Gingival hyperplasia, hirsutism,\nnystagmus, teratogenic"],
        ["Carbamazepine", "Block Na+ channels\n(use-dependent)", "Focal, tonic-clonic,\ntrigeminal neuralgia", "Diplopia, aplastic anaemia,\nSJS, enzyme inducer"],
        ["Valproate", "Block Na+ channels +\n↑GABA (GABA-T inhibitor)", "All seizure types\n(broad spectrum)", "Hepatotoxic, teratogenic (NTD),\nweight gain, hair loss"],
        ["Phenobarbital", "Potentiates GABA-A\n(↑Cl- channel duration)", "Tonic-clonic, neonatal\nseizures", "Sedation, enzyme inducer,\ndependence"],
        ["Ethosuximide", "Block T-type Ca2+ channels\nin thalamus", "Absence seizures\n(ONLY)", "GI symptoms, headache"],
        ["Benzodiazepines\n(Diazepam)", "↑GABA-A Cl- channel\nfrequency", "Status epilepticus\n(acute)", "Sedation, tolerance"],
        ["Lamotrigine", "Block Na+ channels +\n↓glutamate release", "Focal, absence, broad", "Stevens-Johnson syndrome"],
        ["Levetiracetam", "Binds SV2A vesicle protein\n→ ↓neurotransmitter release", "Broad spectrum, focal", "Mood changes, behavioural"],
    ]
    aed_t = Table(aed_data, colWidths=[85, 140, 115, 160])
    aed_t.setStyle(TableStyle([
        ('BACKGROUND', (0, 0), (-1, 0), C_SUBHEAD),
        ('TEXTCOLOR', (0, 0), (-1, 0), white),
        ('FONTNAME', (0, 0), (-1, 0), 'Helvetica-Bold'),
        ('FONTSIZE', (0, 0), (-1, 0), 7.5),
        ('ROWBACKGROUNDS', (0, 1), (-1, -1), [C_LIGHT, white]),
        ('FONTNAME', (0, 1), (-1, -1), 'Helvetica'),
        ('FONTSIZE', (0, 1), (-1, -1), 7),
        ('GRID', (0, 0), (-1, -1), 0.4, C_BORDER),
        ('ALIGN', (0, 0), (-1, -1), 'LEFT'),
        ('VALIGN', (0, 0), (-1, -1), 'MIDDLE'),
        ('LEFTPADDING', (0, 0), (-1, -1), 4),
        ('TOPPADDING', (0, 0), (-1, -1), 3),
        ('BOTTOMPADDING', (0, 0), (-1, -1), 3),
        ('WORDWRAP', (0, 0), (-1, -1), True),
    ]))
    story.append(aed_t)
    story.append(sp(6))

    story.append(h2("4.4  Antipsychotic Drugs — Dopamine Pathway Diagram"))
    story.append(PathwayDiagram(
        steps=[
            ("Mesolimbic\npathway", "D2 block\n→ antipsychotic"),
            ("Mesocortical\npathway", "D2 block\n→ cognitive ↓"),
            ("Nigrostriatal\npathway", "D2 block\n→ EPS"),
            ("Tuberoinfundibular\npathway", "D2 block\n→ hyperprolactin"),
        ],
        width=USABLE_W, height=65, title="Dopamine Pathways — D2 Blockade Effects (Typical Antipsychotics)",
        colors_list=[C_ACC2, C_ACC4, C_ACC1, C_ACC3]
    ))
    story.append(note("Atypical antipsychotics (clozapine, olanzapine): higher 5-HT2A/D2 ratio → less EPS. Clozapine: agranulocytosis risk (monitor WBC). Risperidone: highest prolactin elevation among atypicals."))
    story.append(sp(4))

    ap_data = [
        ["Drug", "Class", "D2", "5HT2A", "Key SE", "Use"],
        ["Chlorpromazine", "Typical (low potency)", "++", "+", "Sedation, hypotension", "Schizophrenia"],
        ["Haloperidol", "Typical (high potency)", "+++", "+", "High EPS, akathisia", "Schizophrenia, delirium"],
        ["Clozapine", "Atypical", "+", "+++", "Agranulocytosis, seizures", "Refractory schizophrenia"],
        ["Olanzapine", "Atypical", "++", "+++", "Weight gain, metabolic", "Schizophrenia, bipolar"],
        ["Risperidone", "Atypical", "+++", "+++", "Hyperprolactinemia, EPS at high dose", "Schizophrenia, autism"],
        ["Quetiapine", "Atypical", "+", "++", "Sedation, weight gain", "Schizo, bipolar depression"],
    ]
    ap_t = Table(ap_data, colWidths=[80, 95, 30, 45, 160, 90])
    ap_t.setStyle(TableStyle([
        ('BACKGROUND', (0, 0), (-1, 0), C_SUBHEAD),
        ('TEXTCOLOR', (0, 0), (-1, 0), white),
        ('FONTNAME', (0, 0), (-1, 0), 'Helvetica-Bold'),
        ('FONTSIZE', (0, 0), (-1, 0), 7.5),
        ('ROWBACKGROUNDS', (0, 1), (-1, -1), [C_LIGHT, white]),
        ('FONTNAME', (0, 1), (-1, -1), 'Helvetica'),
        ('FONTSIZE', (0, 1), (-1, -1), 7),
        ('GRID', (0, 0), (-1, -1), 0.4, C_BORDER),
        ('ALIGN', (0, 0), (-1, -1), 'LEFT'),
        ('VALIGN', (0, 0), (-1, -1), 'MIDDLE'),
        ('LEFTPADDING', (0, 0), (-1, -1), 4),
        ('TOPPADDING', (0, 0), (-1, -1), 3),
        ('BOTTOMPADDING', (0, 0), (-1, -1), 3),
        ('WORDWRAP', (0, 0), (-1, -1), True),
    ]))
    story.append(ap_t)
    story.append(sp(8))

    # ═══════════════════════════════════════════════════════════════
    # SECTION 5 - ANALGESICS / NSAIDs
    # ═══════════════════════════════════════════════════════════════
    story.append(h1("SECTION 5 — ANALGESICS, NSAIDs & ANTI-INFLAMMATORY"))
    story.append(sp(4))

    story.append(h2("5.1  Arachidonic Acid Pathway (COX Pathway)"))
    story.append(PathwayDiagram(
        steps=[
            ("Cell Membrane\nPhospholipids", "Injury/stimulus"),
            ("Arachidonic\nAcid", "Phospholipase A2\n(blocked by steroids)"),
            ("PGG2 / PGH2", "COX-1 / COX-2\n(blocked by NSAIDs)"),
            ("Prostaglandins\nThromboxane A2", "TXA2: platelet agg.\nPGE2: fever, pain"),
            ("Inflammation\nPain, Fever", "Clinical effects"),
        ],
        width=USABLE_W, height=65, title="Arachidonic Acid → COX Pathway",
        colors_list=[C_ACC4, C_ACC4, C_ACC3, C_ACC1, C_EFFECT]
    ))
    story.append(note("Lipoxygenase (LOX) pathway → Leukotrienes → Bronchoconstriction (asthma). Aspirin-exacerbated respiratory disease: COX inhibition shunts AA towards LOX → more leukotrienes."))
    story.append(sp(4))

    nsaid_data = [
        ["Drug", "COX Selectivity", "Key Use", "Key Adverse Effect", "Note"],
        ["Aspirin (low dose)", "COX-1 selective\n(irreversible)", "Antiplatelet", "GI bleed, Reye's syndrome", "Irreversible - platelets can't\nresynthesize COX"],
        ["Aspirin (high dose)", "COX-1 > COX-2", "Anti-inflammatory,\nantipyretic", "GI ulcer, tinnitus,\nsalicylism", "Hepatotoxic in children\nwith viral fever"],
        ["Ibuprofen", "COX-1 + COX-2\n(reversible)", "Pain, fever,\narthritis", "GI irritation, renal", "Safest OTC NSAID"],
        ["Diclofenac", "Mild COX-2 pref.", "Pain, dysmenorrhea", "GI, hepatotoxic", "Topical gel available"],
        ["Indomethacin", "COX-1 + COX-2", "Gout, PDA closure", "GI ulcers, headache", "Used to close PDA in neonates"],
        ["Celecoxib", "COX-2 selective", "Arthritis, less GI SE", "↑Cardiovascular risk", "Avoid in CV disease"],
        ["Paracetamol\n(Acetaminophen)", "Central COX-3?\n(not classical NSAID)", "Antipyretic, mild pain", "Hepatotoxic in overdose\n(NAPQI mechanism)", "No anti-inflammatory;\nno GI ulcer risk"],
    ]
    nsaid_t = Table(nsaid_data, colWidths=[75, 90, 80, 115, 100])
    nsaid_t.setStyle(TableStyle([
        ('BACKGROUND', (0, 0), (-1, 0), C_SUBHEAD),
        ('TEXTCOLOR', (0, 0), (-1, 0), white),
        ('FONTNAME', (0, 0), (-1, 0), 'Helvetica-Bold'),
        ('FONTSIZE', (0, 0), (-1, 0), 7.5),
        ('ROWBACKGROUNDS', (0, 1), (-1, -1), [C_LIGHT, white]),
        ('FONTNAME', (0, 1), (-1, -1), 'Helvetica'),
        ('FONTSIZE', (0, 1), (-1, -1), 7),
        ('GRID', (0, 0), (-1, -1), 0.4, C_BORDER),
        ('ALIGN', (0, 0), (-1, -1), 'LEFT'),
        ('VALIGN', (0, 0), (-1, -1), 'MIDDLE'),
        ('LEFTPADDING', (0, 0), (-1, -1), 4),
        ('TOPPADDING', (0, 0), (-1, -1), 3),
        ('BOTTOMPADDING', (0, 0), (-1, -1), 3),
        ('WORDWRAP', (0, 0), (-1, -1), True),
    ]))
    story.append(nsaid_t)
    story.append(sp(8))

    # ═══════════════════════════════════════════════════════════════
    # SECTION 6 - ANTIMICROBIALS
    # ═══════════════════════════════════════════════════════════════
    story.append(h1("SECTION 6 — ANTIMICROBIAL PHARMACOLOGY"))
    story.append(sp(4))

    story.append(h2("6.1  Antibiotic Mechanisms — Overview Diagram"))
    story.append(PathwayDiagram(
        steps=[
            ("Cell Wall\nSynthesis\nInhibitors", "Penicillins,\nCephalosporins,\nVancomycin"),
            ("Protein\nSynthesis\n30S (tRNA)", "Aminoglycosides,\nTetracyclines"),
            ("Protein\nSynthesis\n50S (transpep)", "Macrolides,\nChloramphenicol,\nClindamycin"),
            ("DNA\nSynthesis /\nGyrase", "Fluoroquinolones\nMetronidazole"),
            ("Folate\nSynthesis\npathway", "Sulfonamides,\nTrimethoprim"),
        ],
        width=USABLE_W, height=80, title="Sites of Antibiotic Action",
        colors_list=[C_ACC1, C_ACC3, C_ACC3, C_SUBHEAD, C_ACC2]
    ))
    story.append(sp(5))

    story.append(h2("6.2  Beta-Lactam Antibiotic Mechanism"))
    story.append(ReceptorDiagram(
        drug="Penicillins\nCephalosporins\nCarbapenems",
        receptor="Penicillin-Binding\nProteins (PBPs)\n= Transpeptidase",
        effect="Cell wall synthesis\nblocked → lysis\n(Bactericidal)",
        drug_action="IRREVERSIBLE INHIBITOR",
        width=USABLE_W, height=90
    ))
    story.append(note("Beta-lactamase resistance: bacteria produce enzymes that cleave beta-lactam ring. Overcome with beta-lactamase inhibitors: clavulanic acid (co-amoxiclav), sulbactam (ampicillin-sulbactam), tazobactam (piperacillin-tazobactam)."))
    story.append(sp(4))

    story.append(h2("6.3  Antibiotic Classification by Action"))
    ab_data = [
        ["Category", "Drugs", "Mechanism", "Key Indication"],
        ["BACTERICIDAL", "", "", ""],
        ["Cell wall", "Penicillins, Cephalosporins,\nVancomycin, Carbapenems", "PBP inhibition / glycopeptide\nbinding to D-Ala-D-Ala", "Pneumonia, meningitis,\nendocarditis"],
        ["DNA/RNA", "Fluoroquinolones (ciprofloxacin,\nlevofloxacin)", "Inhibit DNA gyrase (GyrA)\n+ topoisomerase IV", "UTI, respiratory, enteric,\nanthrax"],
        ["Cell membrane", "Polymyxins (Colistin)", "Disrupt bacterial\nouter membrane", "MDR gram-negative\n(last resort)"],
        ["BACTERIOSTATIC", "", "", ""],
        ["30S ribosome", "Tetracyclines, Aminoglycosides*", "Block tRNA entry\n(30S A-site)", "Acne, Lyme, plague,\nMAC infection"],
        ["50S ribosome", "Macrolides, Chloramphenicol,\nClindamycin", "Block transpeptidation/\ntranslocation", "Resp infections, anaerobes,\nSTIs"],
        ["Folate pathway", "Sulfonamides, Trimethoprim", "Sequential blockade\nof DHPS + DHFR", "UTI, PCP prophylaxis,\ntoxoplasma"],
    ]
    ab_t = Table(ab_data, colWidths=[90, 135, 135, 100])
    ab_t.setStyle(TableStyle([
        ('BACKGROUND', (0, 0), (-1, 0), C_SUBHEAD),
        ('TEXTCOLOR', (0, 0), (-1, 0), white),
        ('FONTNAME', (0, 0), (-1, 0), 'Helvetica-Bold'),
        ('FONTSIZE', (0, 0), (-1, 0), 7.5),
        ('BACKGROUND', (0, 1), (-1, 1), C_ACC2),
        ('TEXTCOLOR', (0, 1), (-1, 1), white),
        ('FONTNAME', (0, 1), (-1, 1), 'Helvetica-Bold'),
        ('BACKGROUND', (0, 5), (-1, 5), C_ACC3),
        ('TEXTCOLOR', (0, 5), (-1, 5), white),
        ('FONTNAME', (0, 5), (-1, 5), 'Helvetica-Bold'),
        ('ROWBACKGROUNDS', (0, 2), (-1, 4), [C_LIGHT3, white]),
        ('ROWBACKGROUNDS', (0, 6), (-1, -1), [C_LIGHT4, white]),
        ('FONTNAME', (0, 2), (-1, -1), 'Helvetica'),
        ('FONTSIZE', (0, 2), (-1, -1), 7),
        ('GRID', (0, 0), (-1, -1), 0.4, C_BORDER),
        ('ALIGN', (0, 0), (-1, -1), 'LEFT'),
        ('VALIGN', (0, 0), (-1, -1), 'MIDDLE'),
        ('LEFTPADDING', (0, 0), (-1, -1), 4),
        ('TOPPADDING', (0, 0), (-1, -1), 3),
        ('BOTTOMPADDING', (0, 0), (-1, -1), 3),
        ('WORDWRAP', (0, 0), (-1, -1), True),
        ('SPAN', (1, 1), (3, 1)),
        ('SPAN', (1, 5), (3, 5)),
    ]))
    story.append(ab_t)
    story.append(note("*Aminoglycosides are bactericidal despite 30S binding — due to mistranslation leading to faulty proteins that disrupt cell membrane integrity."))
    story.append(sp(6))

    story.append(h2("6.4  Anti-TB Drug Mechanisms (HRZE Regimen)"))
    tb_data = [
        ["Drug", "Abbreviation", "Mechanism", "Unique Toxicity", "Note"],
        ["Isoniazid", "H", "Inhibits InhA → blocks mycolic\nacid synthesis (active bacteria)", "Peripheral neuropathy\n(pyridoxine deficiency)", "Prophylaxis drug; hepatotoxic;\nhepatic acetylator status matters"],
        ["Rifampicin", "R", "Inhibits bacterial DNA-dependent\nRNA polymerase (β subunit)", "Orange-red body fluids;\nhepatotoxic; enzyme inducer", "Most potent sterilizing agent;\nshortens treatment to 6 months"],
        ["Pyrazinamide", "Z", "Active in acidic pH of macrophage\n→ disrupts membrane potential", "Hyperuricemia, gout;\nhepatotoxic", "Kills semi-dormant organisms\nin macrophages"],
        ["Ethambutol", "E", "Inhibits arabinosyl transferase\n→ blocks arabinogalactan synthesis", "Optic neuritis\n(↓red-green color vision)", "Monitor vision; dose-dependent"],
        ["Streptomycin", "S", "Binds 30S → inhibits protein\nsynthesis (aminoglycoside)", "Ototoxicity, nephrotoxicity", "Replaced by ethambutol in HRZE;\nIM only"],
    ]
    tb_t = Table(tb_data, colWidths=[65, 45, 145, 110, 95])
    tb_t.setStyle(TableStyle([
        ('BACKGROUND', (0, 0), (-1, 0), C_SUBHEAD),
        ('TEXTCOLOR', (0, 0), (-1, 0), white),
        ('FONTNAME', (0, 0), (-1, 0), 'Helvetica-Bold'),
        ('FONTSIZE', (0, 0), (-1, 0), 7.5),
        ('ROWBACKGROUNDS', (0, 1), (-1, -1), [C_LIGHT, white]),
        ('FONTNAME', (0, 1), (-1, -1), 'Helvetica'),
        ('FONTSIZE', (0, 1), (-1, -1), 7),
        ('GRID', (0, 0), (-1, -1), 0.4, C_BORDER),
        ('ALIGN', (0, 0), (-1, -1), 'LEFT'),
        ('VALIGN', (0, 0), (-1, -1), 'MIDDLE'),
        ('LEFTPADDING', (0, 0), (-1, -1), 4),
        ('TOPPADDING', (0, 0), (-1, -1), 3),
        ('BOTTOMPADDING', (0, 0), (-1, -1), 3),
        ('WORDWRAP', (0, 0), (-1, -1), True),
    ]))
    story.append(tb_t)
    story.append(sp(8))

    # ═══════════════════════════════════════════════════════════════
    # SECTION 7 - ENDOCRINE PHARMACOLOGY
    # ═══════════════════════════════════════════════════════════════
    story.append(h1("SECTION 7 — ENDOCRINE PHARMACOLOGY"))
    story.append(sp(4))

    story.append(h2("7.1  Insulin Action Pathway"))
    story.append(PathwayDiagram(
        steps=[
            ("Insulin binds\nInsulin Receptor", "Tyrosine kinase"),
            ("IRS-1 / PI3K\nactivation", "Signal cascade"),
            ("GLUT-4 vesicle\ntranslocation", "→ cell surface"),
            ("↑Glucose uptake\nmuscle/fat", "Glucose enters cell"),
            ("↓Blood glucose\nGlycogen synthesis", "Metabolic effects"),
        ],
        width=USABLE_W, height=65, title="Insulin Mechanism of Action",
        colors_list=[C_SUBHEAD, C_ACC4, C_ACC2, C_EFFECT, C_EFFECT]
    ))
    story.append(sp(4))

    ins_data = [
        ["Insulin Type", "Onset", "Peak", "Duration", "Use"],
        ["Rapid-acting (Lispro, Aspart)", "10-15 min", "1-2 h", "3-5 h", "Meal-time bolus"],
        ["Short-acting (Regular/Soluble)", "30-60 min", "2-4 h", "6-8 h", "Meal-time, DKA IV"],
        ["Intermediate (NPH/Isophane)", "1-2 h", "4-8 h", "12-18 h", "Twice daily basal"],
        ["Long-acting (Glargine, Detemir)", "1-2 h", "No peak", "20-24 h", "Once daily basal"],
        ["Biphasic (Mixtard 30/70)", "30-60 min", "Dual peak", "12-18 h", "Twice daily combo"],
    ]
    ins_t = Table(ins_data, colWidths=[140, 60, 60, 60, 140])
    ins_t.setStyle(TableStyle([
        ('BACKGROUND', (0, 0), (-1, 0), C_SUBHEAD),
        ('TEXTCOLOR', (0, 0), (-1, 0), white),
        ('FONTNAME', (0, 0), (-1, 0), 'Helvetica-Bold'),
        ('FONTSIZE', (0, 0), (-1, 0), 7.5),
        ('ROWBACKGROUNDS', (0, 1), (-1, -1), [C_LIGHT, white]),
        ('FONTNAME', (0, 1), (-1, -1), 'Helvetica'),
        ('FONTSIZE', (0, 1), (-1, -1), 7),
        ('GRID', (0, 0), (-1, -1), 0.4, C_BORDER),
        ('ALIGN', (0, 0), (-1, -1), 'LEFT'),
        ('VALIGN', (0, 0), (-1, -1), 'MIDDLE'),
        ('LEFTPADDING', (0, 0), (-1, -1), 4),
        ('TOPPADDING', (0, 0), (-1, -1), 3),
        ('BOTTOMPADDING', (0, 0), (-1, -1), 3),
    ]))
    story.append(ins_t)
    story.append(sp(5))

    story.append(h2("7.2  Oral Antidiabetic Drugs — Mechanisms"))
    oad_data = [
        ["Drug Class", "Mechanism", "Key Feature", "Examples", "SE"],
        ["Biguanides", "↓Hepatic glucose output\n(AMPK activation)", "DOC for type 2 DM;\nno hypoglycemia", "Metformin", "Lactic acidosis;\nGI upset; stop in RF"],
        ["Sulfonylureas", "Close K-ATP channel in β-cell\n→ ↑insulin secretion", "Cause hypoglycemia;\nrequire functioning β-cells", "Glibenclamide,\nGlipizide, Glimepiride", "Hypoglycemia,\nweight gain"],
        ["Meglitinides", "Close K-ATP channel (rapid)\n→ short-acting insulin", "Post-prandial control;\nshort acting", "Repaglinide,\nNateglinide", "Hypoglycemia\n(less than SU)"],
        ["Thiazolidinediones\n(TZDs)", "PPARγ agonist → ↑insulin\nsensitivity in fat/muscle", "Insulin sensitizer;\nno hypoglycemia", "Pioglitazone,\nRosiglitazone", "Weight gain, fluid\nretention, fractures"],
        ["DPP-4 inhibitors", "Inhibit DPP-4 → ↑GLP-1 & GIP\n→ ↑insulin, ↓glucagon", "Glucose-dependent;\nnot weight-neutral", "Sitagliptin,\nVildagliptin", "Nasopharyngitis,\npancreatitis risk"],
        ["GLP-1 agonists", "GLP-1 receptor agonist →\n↑insulin, ↓glucagon, ↓appetite", "↓Weight; CV benefit", "Exenatide, Liraglutide,\nSemaglutide", "Nausea, vomiting;\ninjectable"],
        ["SGLT-2 inhibitors", "Inhibit renal SGLT-2 →\nglucosuria", "↓BP, ↓weight,\ncardio+renal protection", "Empagliflozin,\nDapagliflozin", "UTI, genital mycosis,\nDKA (rare)"],
        ["Alpha-glucosidase\ninhibitors", "Inhibit intestinal α-glucosidase\n→ ↓postprandial glucose", "Post-prandial only;\nno systemic absorption", "Acarbose,\nMiglitol", "Flatulence, GI"],
    ]
    oad_t = Table(oad_data, colWidths=[85, 130, 90, 90, 65])
    oad_t.setStyle(TableStyle([
        ('BACKGROUND', (0, 0), (-1, 0), C_SUBHEAD),
        ('TEXTCOLOR', (0, 0), (-1, 0), white),
        ('FONTNAME', (0, 0), (-1, 0), 'Helvetica-Bold'),
        ('FONTSIZE', (0, 0), (-1, 0), 7.5),
        ('ROWBACKGROUNDS', (0, 1), (-1, -1), [C_LIGHT, white]),
        ('FONTNAME', (0, 1), (-1, -1), 'Helvetica'),
        ('FONTSIZE', (0, 1), (-1, -1), 7),
        ('GRID', (0, 0), (-1, -1), 0.4, C_BORDER),
        ('ALIGN', (0, 0), (-1, -1), 'LEFT'),
        ('VALIGN', (0, 0), (-1, -1), 'MIDDLE'),
        ('LEFTPADDING', (0, 0), (-1, -1), 4),
        ('TOPPADDING', (0, 0), (-1, -1), 3),
        ('BOTTOMPADDING', (0, 0), (-1, -1), 3),
        ('WORDWRAP', (0, 0), (-1, -1), True),
    ]))
    story.append(oad_t)
    story.append(sp(8))

    # ═══════════════════════════════════════════════════════════════
    # SECTION 8 - ANTICOAGULANTS / HAEMATOLOGY
    # ═══════════════════════════════════════════════════════════════
    story.append(h1("SECTION 8 — ANTICOAGULANTS & HAEMATOLOGY"))
    story.append(sp(4))

    story.append(h2("8.1  Coagulation Cascade and Drug Targets"))
    story.append(PathwayDiagram(
        steps=[
            ("Extrinsic\nPathway\nFactor VII", "Tissue factor\ntrigger"),
            ("Common\nPathway\nFactor X → Xa", "Prothrombin →\nThrombin"),
            ("Fibrinogen →\nFibrin\n(clot formed)", "Thrombin action"),
            ("Platelet\nActivation\n& aggregation", "TXA2, ADP, PAF"),
        ],
        width=USABLE_W, height=65,
        title="Coagulation Cascade — Drug Intervention Points",
        colors_list=[C_ACC1, C_ACC3, C_SUBHEAD, C_ACC4]
    ))
    story.append(sp(3))

    ac_data = [
        ["Drug", "Mechanism", "Route", "Monitoring", "Reversal", "Key Notes"],
        ["Heparin (UFH)", "Binds antithrombin III →\n↑inhibition of Xa + IIa", "IV/SC", "aPTT (1.5-2.5x)", "Protamine sulfate", "HIT (thrombocytopenia);\ncheck platelets"],
        ["LMWH\n(Enoxaparin)", "AT-III → mainly anti-Xa\n(some anti-IIa)", "SC", "Anti-Xa levels\n(if needed)", "Protamine (partial)", "More predictable;\nused in pregnancy"],
        ["Warfarin", "Inhibits Vit K reductase\n→ ↓Factors II,VII,IX,X", "Oral", "PT / INR\n(target 2-3)", "Vitamin K,\nFFP, PCC", "Slow onset (3-5d);\nmany drug interactions"],
        ["Dabigatran", "Direct thrombin (IIa)\ninhibitor", "Oral", "Not routinely", "Idarucizumab\n(specific antidote)", "DOAC; less monitoring;\nrenal excretion"],
        ["Rivaroxaban\nApixaban", "Direct Factor Xa\ninhibitor", "Oral", "Not routinely", "Andexanet alfa", "DOAC; avoid in\nsevere renal failure"],
        ["Aspirin", "Irreversible COX-1 inhibition\n→ ↓TXA2 (antiplatelet)", "Oral", "None", "Transfuse platelets", "Used 75-150mg for\ncardiovascular prophylaxis"],
        ["Clopidogrel", "P2Y12 ADP receptor\nantagonist (irreversible)", "Oral", "None", "Transfuse platelets", "Prodrug → CYP2C19\nactivation; dual therapy"],
        ["Streptokinase", "Combines with plasminogen\n→ plasmin → fibrinolysis", "IV", "Fibrinogen level", "Tranexamic acid\naprotinin", "Antigenic; cannot\nrepeat within 6-12 mo"],
    ]
    ac_t = Table(ac_data, colWidths=[65, 120, 35, 65, 80, 95])
    ac_t.setStyle(TableStyle([
        ('BACKGROUND', (0, 0), (-1, 0), C_SUBHEAD),
        ('TEXTCOLOR', (0, 0), (-1, 0), white),
        ('FONTNAME', (0, 0), (-1, 0), 'Helvetica-Bold'),
        ('FONTSIZE', (0, 0), (-1, 0), 7.5),
        ('ROWBACKGROUNDS', (0, 1), (-1, -1), [C_LIGHT, white]),
        ('FONTNAME', (0, 1), (-1, -1), 'Helvetica'),
        ('FONTSIZE', (0, 1), (-1, -1), 7),
        ('GRID', (0, 0), (-1, -1), 0.4, C_BORDER),
        ('ALIGN', (0, 0), (-1, -1), 'LEFT'),
        ('VALIGN', (0, 0), (-1, -1), 'MIDDLE'),
        ('LEFTPADDING', (0, 0), (-1, -1), 4),
        ('TOPPADDING', (0, 0), (-1, -1), 3),
        ('BOTTOMPADDING', (0, 0), (-1, -1), 3),
        ('WORDWRAP', (0, 0), (-1, -1), True),
    ]))
    story.append(ac_t)
    story.append(sp(8))

    # ═══════════════════════════════════════════════════════════════
    # SECTION 9 - HIGH-YIELD QUICK REFERENCE BOX
    # ═══════════════════════════════════════════════════════════════
    story.append(h1("SECTION 9 — HIGH-YIELD CONTRAINDICATIONS & EXAM TIPS"))
    story.append(sp(4))

    story.append(h2("9.1  Drugs Contraindicated in Specific Conditions"))
    ci_data = [
        ["Condition", "Contraindicated Drug", "Reason"],
        ["Bronchial Asthma", "Non-selective beta blockers\n(propranolol)", "Beta-2 blockade → bronchoconstriction"],
        ["Angle-closure Glaucoma", "Atropine, antimuscarinics", "Mydriasis → blocks aqueous drainage → ↑IOP"],
        ["Head Injury", "Morphine", "CO2 retention → cerebral vasodilation → ↑ICP"],
        ["Pregnancy (1st trim.)", "Carbamazepine, Valproate,\nMethotrexate, Thalidomide", "Teratogenicity (neural tube defects, limb defects)"],
        ["Children with viral fever", "Aspirin", "Reye's syndrome (hepatic failure + encephalopathy)"],
        ["Neonates", "Chloramphenicol", "Grey Baby Syndrome (immature glucuronyl transferase)"],
        ["Pheochromocytoma", "Beta blockers alone", "Unopposed alpha → hypertensive crisis"],
        ["MAOI use", "SSRIs, Pethidine, TCAs", "Serotonin syndrome (potentially fatal)"],
        ["Hepatic failure", "Paracetamol (high dose),\nMethotrexate", "Further hepatotoxicity"],
        ["Renal failure", "NSAIDs, Aminoglycosides,\nMetformin (lactic acidosis)", "Drug accumulation / worsening renal function"],
        ["Myasthenia Gravis", "Aminoglycosides, Magnesium,\nChloroquine", "Worsen NMJ blockade"],
        ["Porphyria", "Barbiturates, Griseofulvin", "Induce ALA synthase → precipitate attack"],
    ]
    ci_t = Table(ci_data, colWidths=[110, 130, 220])
    ci_t.setStyle(TableStyle([
        ('BACKGROUND', (0, 0), (-1, 0), C_SUBHEAD),
        ('TEXTCOLOR', (0, 0), (-1, 0), white),
        ('FONTNAME', (0, 0), (-1, 0), 'Helvetica-Bold'),
        ('FONTSIZE', (0, 0), (-1, 0), 7.5),
        ('ROWBACKGROUNDS', (0, 1), (-1, -1), [C_LIGHT4, white]),
        ('FONTNAME', (0, 1), (-1, -1), 'Helvetica'),
        ('FONTSIZE', (0, 1), (-1, -1), 7),
        ('GRID', (0, 0), (-1, -1), 0.4, C_BORDER),
        ('ALIGN', (0, 0), (-1, -1), 'LEFT'),
        ('VALIGN', (0, 0), (-1, -1), 'MIDDLE'),
        ('LEFTPADDING', (0, 0), (-1, -1), 4),
        ('TOPPADDING', (0, 0), (-1, -1), 3),
        ('BOTTOMPADDING', (0, 0), (-1, -1), 3),
        ('WORDWRAP', (0, 0), (-1, -1), True),
    ]))
    story.append(ci_t)
    story.append(sp(6))

    story.append(h2("9.2  Drug of Choice (DOC) — Key Exam List"))
    doc_data = [
        ["Condition", "Drug of Choice", "Backup / Notes"],
        ["Type 2 Diabetes", "Metformin", "Add SGLT-2i or GLP-1 if CV risk"],
        ["Hypertension in pregnancy", "Methyldopa (1st line), Labetalol", "ACEi/ARB contraindicated"],
        ["Status epilepticus", "IV Diazepam (Lorazepam)", "Then IV phenytoin or phenobarbital"],
        ["Absence seizures", "Ethosuximide (if pure absence)\nValproate (if mixed seizures)", "Phenytoin worsens absence"],
        ["Anaphylaxis", "IM Adrenaline (Epinephrine)", "1:1000, 0.5 mg IM anterolateral thigh"],
        ["Malaria - P. falciparum", "Artemisinin combination therapy (ACT)", "Artesunate IV for severe malaria"],
        ["Malaria - P. vivax", "Chloroquine + Primaquine", "Primaquine eradicates hypnozoites"],
        ["H. pylori eradication", "PPI + Clarithromycin + Amoxicillin\n(Triple therapy)", "Quadruple if resistance"],
        ["MRSA", "Vancomycin (IV), Linezolid", "Teicoplanin alternative"],
        ["Opioid overdose", "Naloxone IV", "Repeat PRN; short half-life"],
        ["Warfarin over-anticoagulation", "Vitamin K (oral/IV)\n+ PCC if major bleed", "Stop warfarin, monitor INR"],
        ["Digoxin toxicity arrhythmia", "Digoxin-specific antibody\nfragments (Digibind/DigiFab)", "Correct hypokalemia; monitor ECG"],
        ["Pulmonary edema (acute LVF)", "IV Furosemide + IV Morphine\n+ O2 + GTN", "PEEP/NIV if severe"],
        ["Acute gout attack", "Colchicine / NSAIDs\n(Indomethacin)", "Allopurinol: prophylaxis only, not acute"],
        ["Trigeminal neuralgia", "Carbamazepine", "Phenytoin 2nd line"],
    ]
    doc_t = Table(doc_data, colWidths=[135, 155, 170])
    doc_t.setStyle(TableStyle([
        ('BACKGROUND', (0, 0), (-1, 0), C_SUBHEAD),
        ('TEXTCOLOR', (0, 0), (-1, 0), white),
        ('FONTNAME', (0, 0), (-1, 0), 'Helvetica-Bold'),
        ('FONTSIZE', (0, 0), (-1, 0), 7.5),
        ('ROWBACKGROUNDS', (0, 1), (-1, -1), [C_LIGHT2, white]),
        ('FONTNAME', (0, 1), (-1, -1), 'Helvetica'),
        ('FONTSIZE', (0, 1), (-1, -1), 7),
        ('GRID', (0, 0), (-1, -1), 0.4, C_BORDER),
        ('ALIGN', (0, 0), (-1, -1), 'LEFT'),
        ('VALIGN', (0, 0), (-1, -1), 'MIDDLE'),
        ('LEFTPADDING', (0, 0), (-1, -1), 4),
        ('TOPPADDING', (0, 0), (-1, -1), 3),
        ('BOTTOMPADDING', (0, 0), (-1, -1), 3),
        ('WORDWRAP', (0, 0), (-1, -1), True),
    ]))
    story.append(doc_t)
    story.append(sp(8))

    # Footer note
    footer_data = [[Paragraph(
        "<b>Reference:</b> KD Tripathi — Essentials of Medical Pharmacology (7th/8th Ed.) | "
        "Compiled for 2nd MBBS Prof Examination preparation | All India University Pattern | "
        "<i>For educational use only. Verify dosages with current clinical guidelines before clinical application.</i>",
        ParagraphStyle("foot", fontSize=6.5, fontName="Helvetica-Oblique",
                       textColor=C_GRAY, alignment=TA_CENTER, leading=9))]]
    footer = Table(footer_data, colWidths=[USABLE_W])
    footer.setStyle(TableStyle([
        ('BACKGROUND', (0, 0), (-1, -1), HexColor("#f0f4f8")),
        ('TOPPADDING', (0, 0), (-1, -1), 6),
        ('BOTTOMPADDING', (0, 0), (-1, -1), 6),
        ('LEFTPADDING', (0, 0), (-1, -1), 8),
        ('BOX', (0, 0), (-1, -1), 0.5, C_BORDER),
    ]))
    story.append(footer)

    doc.build(story)
    print(f"PDF created: {out_path}")


if __name__ == "__main__":
    out = "/tmp/workspace/pharma-quickref/MBBS_Pharmacology_Quick_Reference.pdf"
    build_pdf(out)

Successfully replaced 1 instance(s) of the string in '/tmp/workspace/pharma-quickref/generate_pdf.py'