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, PageBreak, KeepTogether
)
from reportlab.lib.enums import TA_CENTER, TA_LEFT, TA_JUSTIFY
from reportlab.platypus import BaseDocTemplate, Frame, PageTemplate
from reportlab.lib.colors import HexColor
from reportlab.pdfgen import canvas
import os

OUTPUT = "/tmp/workspace/antihypertensive-pdf/Antihypertensive_Drugs.pdf"

# ── Palette ──────────────────────────────────────────────────────────────────
DARK_BLUE   = HexColor("#0D2B55")   # deep navy
MID_BLUE    = HexColor("#1565C0")   # rich blue
ACCENT_TEAL = HexColor("#00897B")   # teal accent
LIGHT_BG    = HexColor("#E8F4FD")   # pale blue background
PILL_GREEN  = HexColor("#E8F5E9")   # soft green for key points
PILL_YELLOW = HexColor("#FFFDE7")   # soft yellow for warnings
PILL_RED    = HexColor("#FFEBEE")   # soft red for contraindications
WHITE       = colors.white
BLACK       = HexColor("#212121")
GRAY_LIGHT  = HexColor("#ECEFF1")
GRAY_MID    = HexColor("#B0BEC5")
ORANGE      = HexColor("#E65100")
PURPLE      = HexColor("#6A1B9A")

# ── Page header/footer ───────────────────────────────────────────────────────
def draw_page(canvas_obj, doc):
    w, h = A4
    # top banner
    canvas_obj.setFillColor(DARK_BLUE)
    canvas_obj.rect(0, h - 1.1*cm, w, 1.1*cm, fill=1, stroke=0)
    canvas_obj.setFillColor(WHITE)
    canvas_obj.setFont("Helvetica-Bold", 9)
    canvas_obj.drawString(1*cm, h - 0.75*cm, "PHARMACOLOGY EXAM GUIDE")
    canvas_obj.setFont("Helvetica", 8)
    canvas_obj.drawRightString(w - 1*cm, h - 0.75*cm, "Antihypertensive Drugs — Complete Reference")
    # bottom bar
    canvas_obj.setFillColor(MID_BLUE)
    canvas_obj.rect(0, 0, w, 0.8*cm, fill=1, stroke=0)
    canvas_obj.setFillColor(WHITE)
    canvas_obj.setFont("Helvetica", 8)
    canvas_obj.drawCentredString(w/2, 0.25*cm, f"Page {doc.page}")
    # thin accent line below header
    canvas_obj.setStrokeColor(ACCENT_TEAL)
    canvas_obj.setLineWidth(2)
    canvas_obj.line(0, h - 1.1*cm, w, h - 1.1*cm)

doc = BaseDocTemplate(
    OUTPUT,
    pagesize=A4,
    rightMargin=1.5*cm, leftMargin=1.5*cm,
    topMargin=1.8*cm, bottomMargin=1.6*cm,
    title="Antihypertensive Drugs — Pharmacology Exam Guide",
    author="Orris Medical AI",
)
frame = Frame(doc.leftMargin, doc.bottomMargin,
              doc.width, doc.height, id="main")
template = PageTemplate(id="std", frames=[frame], onPage=draw_page)
doc.addPageTemplates([template])

# ── Styles ────────────────────────────────────────────────────────────────────
base = getSampleStyleSheet()

def S(name, **kw):
    return ParagraphStyle(name, **kw)

title_style = S("MyTitle",
    fontName="Helvetica-Bold", fontSize=26, textColor=WHITE,
    leading=32, alignment=TA_CENTER, spaceAfter=4)

subtitle_style = S("MySubtitle",
    fontName="Helvetica", fontSize=12, textColor=LIGHT_BG,
    leading=16, alignment=TA_CENTER, spaceAfter=6)

chapter_style = S("ChapterTitle",
    fontName="Helvetica-Bold", fontSize=16, textColor=WHITE,
    leading=20, alignment=TA_CENTER, spaceBefore=4, spaceAfter=4)

drug_header = S("DrugHeader",
    fontName="Helvetica-Bold", fontSize=14, textColor=WHITE,
    leading=18, alignment=TA_LEFT, spaceBefore=2, spaceAfter=2)

section_head = S("SectionHead",
    fontName="Helvetica-Bold", fontSize=11, textColor=DARK_BLUE,
    leading=14, spaceBefore=6, spaceAfter=2)

body = S("Body",
    fontName="Helvetica", fontSize=9.5, textColor=BLACK,
    leading=14, alignment=TA_JUSTIFY, spaceBefore=2, spaceAfter=2)

body_bold = S("BodyBold",
    fontName="Helvetica-Bold", fontSize=9.5, textColor=BLACK,
    leading=14, spaceBefore=2, spaceAfter=2)

bullet_style = S("Bullet",
    fontName="Helvetica", fontSize=9.5, textColor=BLACK,
    leading=13, leftIndent=12, spaceBefore=1, spaceAfter=1,
    bulletIndent=0)

warn_style = S("Warn",
    fontName="Helvetica", fontSize=9, textColor=HexColor("#B71C1C"),
    leading=13, leftIndent=8, spaceBefore=1, spaceAfter=1)

key_style = S("Key",
    fontName="Helvetica-Bold", fontSize=9, textColor=HexColor("#1B5E20"),
    leading=13, leftIndent=8, spaceBefore=1, spaceAfter=1)

toc_style = S("TOC",
    fontName="Helvetica", fontSize=10, textColor=DARK_BLUE,
    leading=16, leftIndent=20, spaceBefore=1)

toc_head = S("TOCHead",
    fontName="Helvetica-Bold", fontSize=11, textColor=DARK_BLUE,
    leading=16, spaceBefore=3)

small_gray = S("SmallGray",
    fontName="Helvetica", fontSize=8, textColor=HexColor("#757575"),
    leading=11, alignment=TA_CENTER)

# ── Helpers ───────────────────────────────────────────────────────────────────
def hr(color=ACCENT_TEAL, w=1.5):
    return HRFlowable(width="100%", thickness=w, color=color, spaceAfter=4, spaceBefore=4)

def section_banner(text, color=MID_BLUE):
    tbl = Table([[Paragraph(text, chapter_style)]], colWidths=[doc.width])
    tbl.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,-1), color),
        ("ROUNDEDCORNERS", [6,6,6,6]),
        ("TOPPADDING", (0,0), (-1,-1), 7),
        ("BOTTOMPADDING", (0,0), (-1,-1), 7),
        ("LEFTPADDING", (0,0), (-1,-1), 12),
    ]))
    return tbl

def drug_banner(name, category, color=DARK_BLUE):
    tbl = Table([[Paragraph(f"💊 {name}", drug_header),
                  Paragraph(category, S("Cat", fontName="Helvetica", fontSize=9,
                                        textColor=LIGHT_BG, leading=11, alignment=2))
                 ]], colWidths=[doc.width*0.72, doc.width*0.28])
    tbl.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,-1), color),
        ("VALIGN", (0,0), (-1,-1), "MIDDLE"),
        ("TOPPADDING", (0,0), (-1,-1), 8),
        ("BOTTOMPADDING", (0,0), (-1,-1), 8),
        ("LEFTPADDING", (0,0), (-1,-1), 12),
        ("RIGHTPADDING", (0,0), (-1,-1), 10),
        ("ROUNDEDCORNERS", [4,4,4,4]),
    ]))
    return tbl

def labeled_box(label, items, bg=LIGHT_BG, label_color=MID_BLUE):
    """Colored box with a label and bullet items."""
    content = [Paragraph(f"<b><font color='#{label_color.hexval()[1:]}' size=10>{label}</font></b>", body)]
    for item in items:
        content.append(Paragraph(f"• {item}", bullet_style))
    tbl = Table([[content]], colWidths=[doc.width])
    tbl.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,-1), bg),
        ("TOPPADDING", (0,0), (-1,-1), 8),
        ("BOTTOMPADDING", (0,0), (-1,-1), 8),
        ("LEFTPADDING", (0,0), (-1,-1), 12),
        ("RIGHTPADDING", (0,0), (-1,-1), 10),
        ("BOX", (0,0), (-1,-1), 0.5, GRAY_MID),
        ("ROUNDEDCORNERS", [4,4,4,4]),
    ]))
    return tbl

def two_col_box(label1, items1, label2, items2, bg1=PILL_GREEN, bg2=PILL_RED):
    def make_cell(label, items, bg, lc):
        cell = [Paragraph(f"<b><font size=10>{label}</font></b>", body)]
        for it in items:
            cell.append(Paragraph(f"• {it}", bullet_style))
        return cell
    row = [make_cell(label1, items1, bg1, MID_BLUE),
           make_cell(label2, items2, bg2, ORANGE)]
    tbl = Table([row], colWidths=[doc.width/2 - 3, doc.width/2 - 3], hAlign="CENTER")
    tbl.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (0,0), bg1),
        ("BACKGROUND", (1,0), (1,0), bg2),
        ("VALIGN",     (0,0), (-1,-1), "TOP"),
        ("TOPPADDING", (0,0), (-1,-1), 8),
        ("BOTTOMPADDING", (0,0), (-1,-1), 8),
        ("LEFTPADDING", (0,0), (-1,-1), 10),
        ("RIGHTPADDING", (0,0), (-1,-1), 10),
        ("BOX", (0,0), (0,0), 0.5, GRAY_MID),
        ("BOX", (1,0), (1,0), 0.5, GRAY_MID),
        ("COLPADDING", (0,0), (-1,-1), 6),
    ]))
    return tbl

def mini_table(headers, rows, col_widths=None):
    if col_widths is None:
        n = len(headers)
        col_widths = [doc.width/n]*n
    data = [[Paragraph(f"<b>{h}</b>", S("TH", fontName="Helvetica-Bold",
             fontSize=9, textColor=WHITE, leading=12)) for h in headers]]
    for r in rows:
        data.append([Paragraph(str(c), S("TD", fontName="Helvetica",
                    fontSize=9, textColor=BLACK, leading=12)) for c in r])
    tbl = Table(data, colWidths=col_widths, repeatRows=1)
    style = [
        ("BACKGROUND", (0,0), (-1,0), DARK_BLUE),
        ("BACKGROUND", (0,1), (-1,-1), WHITE),
        ("ROWBACKGROUNDS", (0,1), (-1,-1), [WHITE, GRAY_LIGHT]),
        ("GRID", (0,0), (-1,-1), 0.4, GRAY_MID),
        ("TOPPADDING", (0,0), (-1,-1), 5),
        ("BOTTOMPADDING", (0,0), (-1,-1), 5),
        ("LEFTPADDING", (0,0), (-1,-1), 7),
        ("RIGHTPADDING", (0,0), (-1,-1), 7),
        ("VALIGN", (0,0), (-1,-1), "MIDDLE"),
    ]
    tbl.setStyle(TableStyle(style))
    return tbl

def exam_tip(text):
    inner = [[Paragraph(f"⭐ EXAM TIP: {text}", S("ET",
              fontName="Helvetica-Bold", fontSize=9,
              textColor=HexColor("#E65100"), leading=13))]]
    tbl = Table(inner, colWidths=[doc.width])
    tbl.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,-1), PILL_YELLOW),
        ("BOX", (0,0), (-1,-1), 1, HexColor("#FB8C00")),
        ("LEFTPADDING", (0,0), (-1,-1), 10),
        ("RIGHTPADDING", (0,0), (-1,-1), 10),
        ("TOPPADDING", (0,0), (-1,-1), 6),
        ("BOTTOMPADDING", (0,0), (-1,-1), 6),
        ("ROUNDEDCORNERS", [4,4,4,4]),
    ]))
    return tbl

def sp(n=6):
    return Spacer(1, n)

# ══════════════════════════════════════════════════════════════════════════════
# CONTENT
# ══════════════════════════════════════════════════════════════════════════════
story = []

# ── COVER PAGE ────────────────────────────────────────────────────────────────
cover_bg = Table(
    [[Paragraph("ANTIHYPERTENSIVE", title_style)],
     [Paragraph("DRUGS", S("T2", fontName="Helvetica-Bold", fontSize=32,
                           textColor=ACCENT_TEAL, leading=36, alignment=TA_CENTER))],
     [Paragraph("Complete Pharmacology Exam Reference", subtitle_style)],
     [sp(8)],
     [Paragraph("Classification · Mechanism · Indications · Contraindications",
                S("Cov3", fontName="Helvetica", fontSize=11, textColor=GRAY_LIGHT,
                  leading=16, alignment=TA_CENTER))],
     [sp(4)],
     [Paragraph("Route of Administration · Adverse Effects · Drug Interactions",
                S("Cov4", fontName="Helvetica", fontSize=11, textColor=GRAY_LIGHT,
                  leading=16, alignment=TA_CENTER))],
     [sp(20)],
     [Paragraph("Prepared for Pharmacy Examinations", small_gray)],
     [Paragraph("Based on Katzung's Basic & Clinical Pharmacology, 16e |"
                " Goodman & Gilman's | Brenner & Rector's Kidney",
                S("src", fontName="Helvetica-Oblique", fontSize=8,
                  textColor=HexColor("#90A4AE"), leading=11, alignment=TA_CENTER))],
    ],
    colWidths=[doc.width],
)
cover_bg.setStyle(TableStyle([
    ("BACKGROUND", (0,0), (-1,-1), DARK_BLUE),
    ("TOPPADDING", (0,0), (-1,-1), 14),
    ("BOTTOMPADDING", (0,0), (-1,-1), 6),
    ("LEFTPADDING", (0,0), (-1,-1), 20),
    ("RIGHTPADDING", (0,0), (-1,-1), 20),
    ("ROUNDEDCORNERS", [8,8,8,8]),
]))
story.append(cover_bg)
story.append(PageBreak())

# ── TABLE OF CONTENTS ─────────────────────────────────────────────────────────
story.append(section_banner("TABLE OF CONTENTS", DARK_BLUE))
story.append(sp(10))
toc_entries = [
    ("1.", "Overview & Definition of Hypertension"),
    ("2.", "Classification of Antihypertensive Drugs"),
    ("3.", "DIURETICS — Thiazides, Loop, Potassium-Sparing"),
    ("4.", "BETA-BLOCKERS (β-Adrenergic Antagonists)"),
    ("5.", "CALCIUM CHANNEL BLOCKERS (CCBs)"),
    ("6.", "ACE INHIBITORS"),
    ("7.", "ANGIOTENSIN RECEPTOR BLOCKERS (ARBs)"),
    ("8.", "DIRECT VASODILATORS — Hydralazine, Minoxidil"),
    ("9.", "CENTRALLY ACTING AGENTS — Clonidine, Methyldopa"),
    ("10.", "ALPHA-BLOCKERS"),
    ("11.", "Hypertensive Emergencies — Nitroprusside, Labetalol, Fenoldopam"),
    ("12.", "Drug Comparison Tables & Mnemonics"),
    ("13.", "High-Yield Exam Facts"),
]
for num, entry in toc_entries:
    story.append(Paragraph(f"<b>{num}</b>  {entry}", toc_style))
story.append(PageBreak())

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 1: OVERVIEW
# ══════════════════════════════════════════════════════════════════════════════
story.append(section_banner("1. OVERVIEW & DEFINITION", DARK_BLUE))
story.append(sp(8))
story.append(Paragraph(
    "<b>Hypertension (HTN)</b> is defined as persistently elevated arterial blood pressure "
    "≥ 130/80 mmHg (ACC/AHA 2017) or ≥ 140/90 mmHg (JNC 7). It is one of the most "
    "prevalent cardiovascular risk factors worldwide, classified as <b>primary (essential) ~90–95%</b> "
    "or <b>secondary ~5–10%</b>.", body))
story.append(sp(6))
story.append(labeled_box("JNC 7 Classification of Blood Pressure", [
    "Normal: SBP < 120 and DBP < 80 mmHg",
    "Pre-hypertension: SBP 120–139 or DBP 80–89 mmHg",
    "Stage 1 HTN: SBP 140–159 or DBP 90–99 mmHg",
    "Stage 2 HTN: SBP ≥ 160 or DBP ≥ 100 mmHg",
    "Hypertensive Crisis: SBP > 180 / DBP > 120 mmHg",
], bg=LIGHT_BG))
story.append(sp(6))
story.append(Paragraph(
    "<b>Blood Pressure Equation:</b>  BP = Cardiac Output (CO) × Peripheral Vascular Resistance (PVR). "
    "Antihypertensives act by reducing CO, PVR, or both.", body))
story.append(sp(6))
story.append(exam_tip(
    "BP = CO × PVR — know which drugs reduce CO (beta-blockers), PVR (vasodilators, CCBs), or both."))
story.append(PageBreak())

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 2: CLASSIFICATION
# ══════════════════════════════════════════════════════════════════════════════
story.append(section_banner("2. CLASSIFICATION OF ANTIHYPERTENSIVE DRUGS", DARK_BLUE))
story.append(sp(8))
class_data = [
    ["CLASS", "SUBCLASS / EXAMPLES", "PRIMARY MECHANISM"],
    ["Diuretics", "Thiazides (HCTZ), Loop (Furosemide),\nK⁺-sparing (Spironolactone)", "↓ Blood volume → ↓ CO"],
    ["Beta-Blockers (β-blockers)", "Propranolol, Atenolol, Metoprolol,\nCarvedilol, Labetalol", "↓ HR, ↓ CO, ↓ Renin"],
    ["Calcium Channel Blockers", "Dihydropyridines: Nifedipine, Amlodipine\nNon-DHP: Verapamil, Diltiazem", "Vasodilation / ↓ HR & contractility"],
    ["ACE Inhibitors", "Captopril, Enalapril, Lisinopril,\nRamipril, Perindopril", "Block ACE → ↓ Ang II → vasodilation"],
    ["ARBs", "Losartan, Valsartan, Irbesartan,\nTelmisartan, Olmesartan", "Block AT1 receptor → vasodilation"],
    ["Direct Vasodilators", "Hydralazine, Minoxidil", "Relax arteriolar smooth muscle"],
    ["Central α₂ Agonists", "Clonidine, Methyldopa, Guanfacine", "↓ Sympathetic outflow from CNS"],
    ["Alpha-1 Blockers", "Prazosin, Doxazosin, Terazosin", "Vasodilation → ↓ PVR"],
    ["Renin Inhibitors", "Aliskiren", "Block renin → ↓ Ang I & II"],
    ["Emergency Agents", "Nitroprusside, Labetalol IV,\nFenoldopam, Nicardipine IV", "Rapid vasodilation / mixed"],
]
story.append(mini_table(class_data[0], class_data[1:],
    [2.5*cm, 6.2*cm, 6.5*cm]))
story.append(sp(6))
story.append(exam_tip(
    "First-line drugs for uncomplicated HTN (JNC 8): Thiazide diuretics, CCBs, ACEi, ARBs."))
story.append(PageBreak())

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 3: DIURETICS
# ══════════════════════════════════════════════════════════════════════════════
story.append(section_banner("3. DIURETICS", DARK_BLUE))
story.append(sp(6))

# 3A THIAZIDES
story.append(drug_banner("THIAZIDE DIURETICS", "First-Line Antihypertensive", MID_BLUE))
story.append(sp(4))
story.append(Paragraph("<b>Definition:</b> Thiazide and thiazide-like diuretics act on the distal convoluted tubule (DCT) of the nephron. They are among the most widely used first-line antihypertensives.", body))
story.append(sp(4))
story.append(Paragraph("<b>Examples:</b> Hydrochlorothiazide (HCTZ), Chlorthalidone, Indapamide, Metolazone", body_bold))
story.append(sp(4))
story.append(labeled_box("Route of Administration", ["Oral (PO) — once daily dosing", "Chlorthalidone preferred over HCTZ (longer half-life, better CV outcomes)"], LIGHT_BG))
story.append(sp(4))
story.append(labeled_box("Mechanism of Action", [
    "Inhibit Na⁺/Cl⁻ co-transporter (NCC) in the distal convoluted tubule",
    "Increase urinary excretion of Na⁺, Cl⁻ and water → ↓ blood volume → ↓ CO",
    "Long-term: vasodilation (reduced intracellular Ca²⁺ in vascular smooth muscle)",
    "Also cause K⁺ and Mg²⁺ wasting",
], LIGHT_BG))
story.append(sp(4))
story.append(two_col_box(
    "✅ Indications",
    ["Hypertension (first-line)",
     "Edema (mild heart failure, cirrhosis, nephrotic syndrome)",
     "Diabetes insipidus (nephrogenic — paradoxical effect)",
     "Hypercalciuria / calcium-containing kidney stones",
     "Osteoporosis (increases Ca²⁺ reabsorption)"],
    "❌ Contraindications",
    ["Anuria / severe renal failure (GFR < 30)",
     "Hypokalemia / hyponatremia",
     "Gout (raises uric acid)",
     "Pregnancy (fetal thrombocytopenia)",
     "Sulfonamide allergy (cross-reactivity)"],
))
story.append(sp(4))
story.append(labeled_box("Adverse Effects (GLUCOHH Mnemonic)", [
    "G — Glucose ↑ (hyperglycemia)",
    "L — Lipids ↑ (hyperlipidemia)",
    "U — Urate ↑ (hyperuricemia / gout)",
    "C — Ca²⁺ ↑ (hypercalcemia)",
    "O — (hyp)Osmolarity — hyponatremia",
    "H — Hypokalemia, Hypomagnesemia",
    "H — Hypotension (orthostatic)"], PILL_YELLOW))
story.append(sp(4))
story.append(exam_tip("Thiazides RETAIN calcium (↑ serum Ca²⁺) but WASTE potassium. Opposite of loop diuretics for Ca²⁺."))
story.append(sp(8))

# 3B LOOP DIURETICS
story.append(drug_banner("LOOP DIURETICS", "Hypertensive Emergencies / Volume Overload", ACCENT_TEAL))
story.append(sp(4))
story.append(Paragraph("<b>Definition:</b> Most potent diuretics, acting on the thick ascending limb of the Loop of Henle.", body))
story.append(Paragraph("<b>Examples:</b> Furosemide, Bumetanide, Torsemide, Ethacrynic acid", body_bold))
story.append(sp(4))
story.append(labeled_box("Route of Administration", ["Oral (PO) or IV (furosemide)", "IV used in hypertensive emergencies with pulmonary edema"], LIGHT_BG))
story.append(labeled_box("Mechanism of Action", [
    "Inhibit Na⁺/K⁺/2Cl⁻ co-transporter (NKCC2) in the thick ascending limb (TAL)",
    "Most potent diuretics — can remove large volumes of fluid",
    "Also inhibit tubuloglomerular feedback → works even in renal failure",
    "Cause loss of Na⁺, K⁺, Cl⁻, Ca²⁺, Mg²⁺"], LIGHT_BG))
story.append(two_col_box(
    "✅ Indications",
    ["Acute pulmonary edema (IV furosemide)",
     "Hypertensive emergency with volume overload",
     "Chronic renal failure (GFR < 30 — preferred over thiazides)",
     "Heart failure, cirrhosis, nephrotic syndrome",
     "Hypercalcemia",
     "Hyperkalemia"],
    "❌ Contraindications",
    ["Anuria (complete renal failure)",
     "Sulfonamide allergy (except Ethacrynic acid)",
     "Hypovolemia / dehydration",
     "Severe hypokalemia",
     "Hepatic coma (↑ ammonia risk with hypokalemia)"],
))
story.append(sp(4))
story.append(exam_tip("Ethacrynic acid is the ONLY loop diuretic safe in sulfonamide allergy. Loop diuretics WASTE calcium (used in hypercalcemia)."))
story.append(sp(8))

# 3C K+ SPARING
story.append(drug_banner("POTASSIUM-SPARING DIURETICS", "Adjunct / Aldosterone Antagonism", PURPLE))
story.append(sp(4))
story.append(Paragraph("<b>Examples:</b> Spironolactone, Eplerenone (aldosterone antagonists); Amiloride, Triamterene (Na⁺ channel blockers)", body_bold))
story.append(labeled_box("Route of Administration", ["Oral (PO)"], LIGHT_BG))
story.append(labeled_box("Mechanism of Action", [
    "Spironolactone/Eplerenone: competitive aldosterone receptor antagonists → block aldosterone effects in collecting duct → ↑ Na⁺ excretion, ↓ K⁺ excretion",
    "Amiloride/Triamterene: block ENaC (epithelial Na⁺ channels) in collecting duct directly",
    "Weak diuretic effect alone — used in combination with thiazides/loop diuretics"], LIGHT_BG))
story.append(two_col_box(
    "✅ Indications",
    ["Primary hyperaldosteronism (Conn syndrome) — spironolactone",
     "Heart failure (spironolactone/eplerenone — reduce mortality)",
     "Prevent hypokalemia with thiazide/loop diuretics",
     "Liver cirrhosis with ascites",
     "Resistant hypertension",
     "Hirsutism, acne (spironolactone — anti-androgen)"],
    "❌ Contraindications",
    ["Hyperkalemia (K⁺ > 5.5 mEq/L)",
     "Renal failure (can worsen hyperkalemia)",
     "Combined with ACEi/ARB (serious hyperkalemia risk)",
     "Pregnancy (spironolactone — anti-androgen effects on fetus)",
     "Addison's disease"],
))
story.append(exam_tip("Spironolactone side effect: GYNECOMASTIA (anti-androgen). Eplerenone is selective → no gynecomastia."))
story.append(PageBreak())

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 4: BETA-BLOCKERS
# ══════════════════════════════════════════════════════════════════════════════
story.append(section_banner("4. BETA-BLOCKERS (β-Adrenergic Antagonists)", DARK_BLUE))
story.append(sp(6))
story.append(Paragraph("<b>Definition:</b> Beta-blockers competitively block catecholamine binding at β-adrenergic receptors, reducing heart rate, contractility, and renin release.", body))
story.append(sp(4))

story.append(Paragraph("<b>Classification of Beta-Blockers:</b>", section_head))
bb_class = [
    ["TYPE", "SELECTIVITY", "EXAMPLES", "KEY FEATURE"],
    ["Non-selective", "β₁ + β₂", "Propranolol, Nadolol, Timolol", "First β-blocker; crosses BBB"],
    ["Cardioselective (β₁)", "β₁ > β₂", "Atenolol, Metoprolol, Bisoprolol", "Preferred in asthma/COPD"],
    ["With α₁-block", "β₁+β₂+α₁", "Labetalol, Carvedilol", "Used in HTN emergency, HF"],
    ["With ISA", "β₁+β₂ partial agonist", "Pindolol, Acebutolol", "Less bradycardia/bronchospasm"],
    ["β₃ agonist (not BB)", "β₃", "Mirabegron", "Overactive bladder — for ref"],
]
story.append(mini_table(bb_class[0], bb_class[1:], [2.5*cm, 3.5*cm, 4.8*cm, 4.4*cm]))
story.append(sp(6))

story.append(labeled_box("Route of Administration", [
    "Oral (PO) — atenolol, metoprolol, propranolol, carvedilol",
    "IV — labetalol (hypertensive emergency), esmolol (perioperative)",
    "Topical — timolol eye drops (glaucoma)"], LIGHT_BG))
story.append(sp(4))
story.append(labeled_box("Mechanism of Action", [
    "Block β₁ receptors in heart → ↓ HR (negative chronotropy), ↓ contractility (negative inotropy) → ↓ CO",
    "Block β₁ in juxtaglomerular cells → ↓ renin → ↓ Ang II → ↓ aldosterone → ↓ fluid retention",
    "Central action: ↓ sympathetic outflow",
    "Non-selective agents also block β₂ → bronchoconstriction, vasoconstriction, ↑ hypoglycemia masking"], LIGHT_BG))
story.append(sp(4))
story.append(two_col_box(
    "✅ Indications",
    ["Hypertension (especially with co-existing CAD)",
     "Angina pectoris",
     "Post-MI (reduce mortality)",
     "Heart failure with reduced EF (metoprolol, carvedilol, bisoprolol)",
     "Arrhythmias (SVT, AF rate control)",
     "Thyrotoxicosis (control symptoms)",
     "Migraine prophylaxis (propranolol)",
     "Glaucoma (timolol)",
     "Anxiety / performance anxiety (propranolol)",
     "Hypertensive emergency (labetalol IV)"],
    "❌ Contraindications",
    ["Asthma / COPD (non-selective BB)",
     "Bradycardia / AV block (2nd/3rd degree)",
     "Decompensated heart failure",
     "Prinzmetal's angina (vasospastic)",
     "Peripheral arterial disease",
     "Pheochromocytoma (give alpha-blocker first)",
     "Diabetes with hypoglycemia unawareness (masks tachycardia)",
     "Abrupt withdrawal — rebound HTN"],
))
story.append(sp(4))
story.append(labeled_box("Adverse Effects", [
    "Bradycardia, AV block, heart failure exacerbation",
    "Bronchoconstriction (non-selective agents)",
    "Masking of hypoglycemia symptoms (except sweating)",
    "Cold extremities (β₂ block → peripheral vasoconstriction)",
    "Fatigue, depression, nightmares (propranolol — lipophilic, crosses BBB)",
    "Sexual dysfunction, dyslipidemia",
    "Rebound HTN on abrupt withdrawal"], PILL_YELLOW))
story.append(sp(4))
story.append(exam_tip("In pheochromocytoma: NEVER give beta-blocker alone — must give alpha-blocker (phenoxybenzamine) FIRST to prevent hypertensive crisis from unopposed α stimulation."))
story.append(PageBreak())

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 5: CALCIUM CHANNEL BLOCKERS
# ══════════════════════════════════════════════════════════════════════════════
story.append(section_banner("5. CALCIUM CHANNEL BLOCKERS (CCBs)", DARK_BLUE))
story.append(sp(6))
story.append(Paragraph("<b>Definition:</b> CCBs block voltage-gated L-type calcium channels in vascular smooth muscle and cardiac tissue, reducing intracellular Ca²⁺ and causing vasodilation and/or decreased cardiac contractility.", body))
story.append(sp(6))

ccb_class = [
    ["SUBCLASS", "EXAMPLES", "PRIMARY ACTION", "CLINICAL USE"],
    ["Dihydropyridines (DHP)\n(Vasoselective)", "Nifedipine, Amlodipine,\nNicardipine, Felodipine,\nIsradipine", "Vascular smooth muscle\n↓ PVR, vasodilation\n↑ Reflex tachycardia", "HTN, Angina,\nRaynaud's, Subarachnoid\nhemorrhage (Nimodipine)"],
    ["Non-DHP\n(Cardiac selective)", "Verapamil\n(Phenylalkylamine)", "Heart > Vessels\n↓ HR, ↓ contractility\n↓ AV conduction", "SVT, AF, Angina,\nHTN"],
    ["Non-DHP\n(Mixed)", "Diltiazem\n(Benzothiazepine)", "Heart + Vessels\n(intermediate)", "SVT, Angina,\nHTN"],
]
story.append(mini_table(ccb_class[0], ccb_class[1:], [3.5*cm, 4.2*cm, 4.5*cm, 3.0*cm]))
story.append(sp(6))

story.append(labeled_box("Route of Administration", [
    "Oral (PO) — all oral formulations (immediate and extended-release)",
    "IV — Nicardipine, Verapamil, Diltiazem (emergency)",
    "Amlodipine — very long half-life ~35–50 hours (once daily)"], LIGHT_BG))
story.append(sp(4))
story.append(labeled_box("Mechanism of Action", [
    "Block L-type (long-lasting) voltage-gated Ca²⁺ channels in smooth muscle and heart",
    "DHP: preferentially act on vascular smooth muscle → arteriolar vasodilation → ↓ PVR",
    "Non-DHP: act on heart → ↓ HR (SA node), ↓ AV conduction, ↓ contractility",
    "Reduction in cytoplasmic Ca²⁺ → inhibits actin-myosin interaction → relaxation"], LIGHT_BG))
story.append(sp(4))
story.append(two_col_box(
    "✅ Indications",
    ["Hypertension (first-line — DHP preferred)",
     "Stable angina (especially with HTN)",
     "Vasospastic / Prinzmetal's angina (DHP)",
     "SVT / AF rate control (verapamil, diltiazem)",
     "Hypertrophic cardiomyopathy (verapamil)",
     "Raynaud's phenomenon",
     "Subarachnoid hemorrhage — nimodipine (prevents cerebral vasospasm)",
     "Migraine prophylaxis (verapamil)"],
    "❌ Contraindications",
    ["Cardiogenic shock",
     "Severe bradycardia / AV block (verapamil, diltiazem)",
     "Decompensated heart failure with reduced EF (non-DHP)",
     "WPW syndrome + AF (verapamil — life-threatening)",
     "Hypotension",
     "Nifedipine short-acting: not for acute HTN (reflex tachycardia)"],
))
story.append(sp(4))
story.append(labeled_box("Adverse Effects", [
    "DHP: Flushing, headache, peripheral edema (ankle), reflex tachycardia (nifedipine)",
    "Verapamil: Constipation (most common!), bradycardia, AV block, negative inotropy",
    "Diltiazem: Bradycardia (less than verapamil), AV block",
    "Gingival hyperplasia (all CCBs)",
    "Verapamil + Beta-blocker combination → severe bradycardia / heart block (dangerous!)"], PILL_YELLOW))
story.append(sp(4))
story.append(exam_tip("Verapamil = 'V'erapamil = 'V'entricular rate control, 'V'omiting (constipation). NEVER combine verapamil with beta-blockers — fatal bradycardia!"))
story.append(PageBreak())

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 6: ACE INHIBITORS
# ══════════════════════════════════════════════════════════════════════════════
story.append(section_banner("6. ACE INHIBITORS (ACEi)", DARK_BLUE))
story.append(sp(6))
story.append(Paragraph("<b>Definition:</b> ACE inhibitors block the angiotensin-converting enzyme (ACE / kininase II), preventing conversion of angiotensin I to the potent vasoconstrictor angiotensin II, and also preventing bradykinin degradation.", body))
story.append(sp(4))

acei_examples = [
    ["DRUG", "PRODRUG?", "ROUTE", "ELIMINATION", "KEY NOTES"],
    ["Captopril", "No", "PO", "Renal", "Prototype; short-acting; contains -SH group"],
    ["Enalapril", "Yes → Enalaprilat", "PO / IV", "Renal", "IV form = enalaprilat"],
    ["Lisinopril", "No", "PO", "Renal", "Most commonly used; no hepatic conversion needed"],
    ["Ramipril", "Yes → Ramiprilat", "PO", "Renal", "Proven mortality benefit post-MI (HOPE trial)"],
    ["Perindopril", "Yes", "PO", "Renal", "Stable angina + HTN"],
    ["Fosinopril", "Yes", "PO", "Renal + Hepatic", "Safe in renal failure (dual elimination)"],
    ["Benazepril", "Yes", "PO", "Renal", "CKD + HTN"],
]
story.append(mini_table(acei_examples[0], acei_examples[1:],
    [2.8*cm, 3.2*cm, 1.8*cm, 3.5*cm, 4.0*cm]))
story.append(sp(6))
story.append(labeled_box("Mechanism of Action", [
    "Block ACE (Angiotensin Converting Enzyme / kininase II) in the lungs and vascular endothelium",
    "ACE normally: Ang I → Ang II (vasoconstrictor) and Bradykinin → inactive peptides",
    "ACEi → ↓ Ang II → vasodilation (arteriolar > venular), ↓ aldosterone (↓ Na⁺/H₂O retention), ↓ ADH",
    "↑ Bradykinin (potent vasodilator; causes ACE inhibitor cough and angioedema)",
    "↑ Prostaglandins (anti-platelet, vasodilatory)",
    "Reduce intraglomerular pressure → renoprotective",
], LIGHT_BG))
story.append(sp(4))
story.append(two_col_box(
    "✅ Indications",
    ["Hypertension (especially + CKD, DM, proteinuria)",
     "Heart failure (reduced EF) — cornerstone therapy",
     "Post-MI — reduce remodeling, mortality",
     "Diabetic nephropathy — reduce proteinuria",
     "Chronic kidney disease — slow progression",
     "Scleroderma renal crisis",
     "Left ventricular hypertrophy",
     "Secondary stroke prevention"],
    "❌ Contraindications",
    ["Bilateral renal artery stenosis (acute renal failure)",
     "Pregnancy (Category D/X — fetal renal dysgenesis, oligohydramnios, skull defects — 2nd/3rd trimester)",
     "Hyperkalemia (K⁺ > 5.5)",
     "Angioedema (history) — lifelong",
     "Combined with ARB + Aliskiren in DM (ONTARGET)",
     "Severe renal failure (relative)"],
))
story.append(sp(4))
story.append(labeled_box("Adverse Effects", [
    "DRY COUGH — most common (↑ bradykinin in lungs; occurs in 10–15% of patients)",
    "Angioedema — rare but life-threatening (swelling of face, tongue, throat)",
    "Hyperkalemia (↓ aldosterone)",
    "Acute renal failure (bilateral RAS, or severe dehydration)",
    "First-dose hypotension (especially in volume-depleted patients)",
    "Teratogenicity (ABCDE of ACE inhibitors — Avoid in pregnancy)",
    "Fetopathy if used in 2nd/3rd trimester"], PILL_YELLOW))
story.append(sp(4))
story.append(exam_tip("Dry cough = ACEi (bradykinin ↑). Switch to ARB if cough occurs. NEVER use ACEi in pregnancy (bilateral RAS risk → use CCB or methyldopa). Fosinopril = only ACEi with dual (renal + hepatic) elimination."))
story.append(PageBreak())

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 7: ARBs
# ══════════════════════════════════════════════════════════════════════════════
story.append(section_banner("7. ANGIOTENSIN RECEPTOR BLOCKERS (ARBs / Sartans)", DARK_BLUE))
story.append(sp(6))
story.append(Paragraph("<b>Definition:</b> ARBs block the AT₁ (angiotensin II type 1) receptor, preventing all effects of angiotensin II. Unlike ACEi, they do NOT inhibit bradykinin degradation, so they do NOT cause cough.", body))
story.append(sp(4))
story.append(labeled_box("Route of Administration", ["Oral (PO) — all ARBs are oral"], LIGHT_BG))
story.append(labeled_box("Mechanism of Action", [
    "Selectively block AT₁ receptors (Gq-coupled) on blood vessels, adrenals, kidneys, heart",
    "Ang II is still produced but cannot act on AT₁ → vasodilation, ↓ aldosterone, ↓ remodeling",
    "AT₂ receptors remain unblocked → vasodilatory, antiproliferative (beneficial)",
    "↑ Bradykinin does NOT occur → NO cough"], LIGHT_BG))
story.append(sp(4))

arbs = [
    ["DRUG", "DOSE (mg/day)", "HALF-LIFE", "NOTES"],
    ["Losartan", "25–100", "~2 h (active metabolite ~6–9 h)", "First ARB; uricosuric effect"],
    ["Valsartan", "80–320", "~9 h", "HF, post-MI indication"],
    ["Irbesartan", "150–300", "~11–15 h", "DM nephropathy"],
    ["Telmisartan", "20–80", "~24 h (longest)", "Also PPAR-γ agonism → metabolic benefits"],
    ["Olmesartan", "20–40", "~13 h", "Potent; sprue-like enteropathy (rare)"],
    ["Candesartan", "4–32", "~9 h", "HF-reduced EF"],
]
story.append(mini_table(arbs[0], arbs[1:], [3.0*cm, 3.0*cm, 5.5*cm, 4.0*cm]))
story.append(sp(6))
story.append(two_col_box(
    "✅ Indications",
    ["Hypertension (first-line)",
     "Diabetic nephropathy",
     "Heart failure (when ACEi not tolerated)",
     "Post-MI with LV dysfunction",
     "CKD with proteinuria",
     "ACEi-induced cough (switch to ARB)",
     "Stroke prevention (losartan)"],
    "❌ Contraindications",
    ["Pregnancy (same teratogenicity as ACEi)",
     "Bilateral renal artery stenosis",
     "Hyperkalemia",
     "Avoid dual RAAS blockade (ACEi + ARB + Aliskiren)",
     "Hypersensitivity"],
))
story.append(sp(4))
story.append(exam_tip("ARBs = same indications as ACEi but NO cough, NO angioedema (well, rare). Telmisartan has longest half-life. Losartan is uricosuric (lowers uric acid) — useful in gout + HTN."))
story.append(PageBreak())

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 8: DIRECT VASODILATORS
# ══════════════════════════════════════════════════════════════════════════════
story.append(section_banner("8. DIRECT VASODILATORS", DARK_BLUE))
story.append(sp(6))

story.append(drug_banner("HYDRALAZINE", "Arteriolar Direct Vasodilator", MID_BLUE))
story.append(sp(4))
story.append(Paragraph("<b>Definition:</b> Hydralazine is a phthalazine derivative that causes direct relaxation of arteriolar smooth muscle. It dilates arterioles but NOT veins.", body))
story.append(labeled_box("Route of Administration", ["Oral (PO) and IV (hypertensive emergencies)", "Bioavailability ~25% (extensive first-pass metabolism)", "Pharmacogenetics: slow vs fast acetylators (bimodal distribution)"], LIGHT_BG))
story.append(labeled_box("Mechanism of Action", [
    "Releases nitric oxide (NO) from vascular endothelium → activates guanylyl cyclase → ↑ cGMP → smooth muscle relaxation",
    "Acts on arterioles (reduces PVR), NOT on veins",
    "Compensatory reflex: ↑ HR (reflex tachycardia), ↑ renin, ↑ Na⁺/H₂O retention (limit antihypertensive effect)",
    "Must combine with a β-blocker + diuretic to counteract compensatory effects"], LIGHT_BG))
story.append(two_col_box(
    "✅ Indications",
    ["Severe/resistant hypertension",
     "Hypertensive emergency (IV)",
     "Pre-eclampsia / eclampsia (IV — drug of choice)",
     "Heart failure + HTN (with nitrates when ACEi intolerant)",
     "Used in combination therapy"],
    "❌ Contraindications",
    ["CAD/angina (reflex tachycardia worsens ischemia)",
     "Mitral valve rheumatic disease",
     "Dissecting aortic aneurysm",
     "SLE (drug-induced lupus risk)"],
))
story.append(labeled_box("Adverse Effects", [
    "Reflex tachycardia, palpitations, flushing, headache",
    "Na⁺/H₂O retention → edema",
    "Drug-induced lupus (SLE-like) — slow acetylators at higher risk; ANA positive",
    "Peripheral neuritis (pyridoxine/B₆ deficiency — treat with B₆ supplementation)",
    "Angina precipitation"], PILL_YELLOW))
story.append(exam_tip("Hydralazine: Drug-induced LUPUS (check ANA) — remember 'Hydra' (monster = lupus). Preferred IV drug in PRE-ECLAMPSIA. Slow acetylators at higher lupus risk."))
story.append(sp(8))

story.append(drug_banner("MINOXIDIL", "Severe Resistant Hypertension / Alopecia", PURPLE))
story.append(sp(4))
story.append(Paragraph("<b>Definition:</b> Minoxidil is a potassium channel opener that causes potent arteriolar vasodilation. One of the most powerful oral antihypertensives.", body))
story.append(labeled_box("Route of Administration", ["Oral (PO) for hypertension", "Topical (solution/foam) for alopecia (androgenetic alopecia, alopecia areata)"], LIGHT_BG))
story.append(labeled_box("Mechanism of Action", [
    "Prodrug → converted to minoxidil sulfate → opens ATP-sensitive K⁺ channels in vascular smooth muscle",
    "↑ K⁺ permeability → hyperpolarization → closure of voltage-gated Ca²⁺ channels → smooth muscle relaxation",
    "Acts only on arterioles (not veins)",
    "Powerful compensatory: ↑ HR, ↑ Na⁺/H₂O retention, ↑ cardiac output"], LIGHT_BG))
story.append(two_col_box(
    "✅ Indications",
    ["Severe resistant hypertension (reserved for refractory cases)",
     "Renal failure with HTN",
     "Topical: male and female pattern baldness"],
    "❌ Contraindications",
    ["Pheochromocytoma",
     "MI, dissecting aortic aneurysm",
     "Not monotherapy — must combine with β-blocker + diuretic"],
))
story.append(labeled_box("Adverse Effects", [
    "HYPERTRICHOSIS (hair growth all over body) — most distinctive side effect",
    "Sodium and water retention → edema",
    "Reflex tachycardia",
    "Pericardial effusion (long-term, high dose)",
    "ECG changes: T-wave changes"], PILL_YELLOW))
story.append(exam_tip("Minoxidil = HYPERTRICHOSIS (the irony — same drug causes hair growth topically but hypertrichosis systemically!). Most potent oral vasodilator."))
story.append(PageBreak())

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 9: CENTRALLY ACTING AGENTS
# ══════════════════════════════════════════════════════════════════════════════
story.append(section_banner("9. CENTRALLY ACTING ANTIHYPERTENSIVES", DARK_BLUE))
story.append(sp(6))

story.append(drug_banner("CLONIDINE", "Central α₂ Agonist", ACCENT_TEAL))
story.append(sp(4))
story.append(Paragraph("<b>Definition:</b> Clonidine is a centrally acting α₂-adrenergic agonist that reduces sympathetic outflow from the CNS.", body))
story.append(labeled_box("Route of Administration", ["Oral (PO), Transdermal patch (weekly), IV (rare)", "Available as TTS (transdermal therapeutic system)"], LIGHT_BG))
story.append(labeled_box("Mechanism of Action", [
    "Stimulates α₂ receptors in the nucleus tractus solitarius (NTS) and rostral ventrolateral medulla (RVLM)",
    "→ ↓ Sympathetic outflow → ↓ HR, ↓ CO, ↓ PVR, ↓ renin",
    "Also: stimulates peripheral α₂ receptors (presynaptic) → inhibits NE release",
    "Imidazoline I₁ receptor agonism also contributes to BP lowering"], LIGHT_BG))
story.append(two_col_box(
    "✅ Indications",
    ["Hypertension (resistant/severe)",
     "Hypertensive urgency (oral loading)",
     "Opioid/nicotine withdrawal",
     "ADHD (guanfacine)",
     "Menopausal hot flashes",
     "Tourette syndrome",
     "Analgesia (epidural — post-op pain)"],
    "❌ Contraindications",
    ["Severe coronary artery disease",
     "Cerebrovascular disease",
     "Sick sinus syndrome",
     "Depression (can worsen)",
     "Avoid abrupt withdrawal!"],
))
story.append(labeled_box("Adverse Effects", [
    "Dry mouth (xerostomia) — most common",
    "Sedation, drowsiness, fatigue",
    "Bradycardia",
    "REBOUND HYPERTENSION on abrupt withdrawal (catecholamine surge) — dangerous!",
    "Depression",
    "Transdermal: contact dermatitis"], PILL_YELLOW))
story.append(exam_tip("Clonidine: REBOUND HYPERTENSION on sudden discontinuation — taper slowly! Same mechanism (α₂ agonist) as Methyldopa. Dry mouth = most common side effect."))
story.append(sp(8))

story.append(drug_banner("METHYLDOPA", "Safe in Pregnancy HTN", MID_BLUE))
story.append(sp(4))
story.append(Paragraph("<b>Definition:</b> Methyldopa is a prodrug converted centrally to α-methylnorepinephrine, a potent α₂ agonist that reduces sympathetic outflow.", body))
story.append(labeled_box("Route of Administration", ["Oral (PO), IV (methyldopate)", "Drug of CHOICE for hypertension in PREGNANCY (Category B)"], LIGHT_BG))
story.append(labeled_box("Mechanism of Action", [
    "Prodrug: methyldopa → α-methylDOPA → α-methyldopamine → α-methylnorepinephrine (false neurotransmitter)",
    "α-Methylnorepinephrine stimulates central α₂ receptors → ↓ sympathetic outflow",
    "Also reduces renin activity",
    "Net effect: ↓ CO and ↓ PVR"], LIGHT_BG))
story.append(two_col_box(
    "✅ Indications",
    ["Hypertension in PREGNANCY (drug of choice)",
     "Hypertension in breastfeeding (safe)",
     "Hypertensive urgency",
     "Rarely used for non-pregnant HTN today"],
    "❌ Contraindications",
    ["Active liver disease (hepatotoxicity risk)",
     "Pheochromocytoma",
     "Hemolytic anemia (history)",
     "MAO inhibitor use",
     "Depression"],
))
story.append(labeled_box("Adverse Effects", [
    "Positive direct Coombs test (in ~20%) — hemolytic anemia rare",
    "Sedation (common early)",
    "Dry mouth, bradycardia",
    "Hepatotoxicity (abnormal LFTs — check regularly)",
    "Drug-induced SLE",
    "Galactorrhea (↑ prolactin due to anti-dopaminergic effect)",
    "Rebound HTN on withdrawal (less severe than clonidine)"], PILL_YELLOW))
story.append(exam_tip("Methyldopa = DRUG OF CHOICE IN PREGNANCY (along with Labetalol and Nifedipine for acute HTN in pregnancy). Causes +ve Coombs test and hemolytic anemia!"))
story.append(PageBreak())

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 10: ALPHA-BLOCKERS
# ══════════════════════════════════════════════════════════════════════════════
story.append(section_banner("10. ALPHA-1 BLOCKERS", DARK_BLUE))
story.append(sp(6))
story.append(Paragraph("<b>Definition:</b> α₁-adrenergic blockers competitively antagonize α₁ receptors on vascular smooth muscle, causing vasodilation and reduced peripheral vascular resistance.", body))
story.append(sp(4))
story.append(labeled_box("Examples & Route", [
    "Prazosin (PO) — prototype, shorter acting",
    "Doxazosin (PO) — once daily, also BPH",
    "Terazosin (PO) — once daily",
    "Phentolamine (IV/IM) — non-selective α₁+α₂ blocker — pheochromocytoma crisis",
    "Phenoxybenzamine (PO) — irreversible non-selective — pre-op pheochromocytoma"], LIGHT_BG))
story.append(labeled_box("Mechanism of Action", [
    "Competitive block of postsynaptic α₁ receptors (Gq-coupled) on arterioles and veins",
    "→ Vasodilation of arterioles AND veins → ↓ PVR and ↓ venous return",
    "Unlike beta-blockers: do NOT affect heart rate directly",
    "Phentolamine: blocks both α₁ and α₂ → prevents presynaptic NE inhibition → ↑ NE release (reflex tachycardia more marked)"], LIGHT_BG))
story.append(sp(4))
story.append(two_col_box(
    "✅ Indications",
    ["Hypertension (3rd-line)",
     "Benign Prostatic Hyperplasia — BPH (prazosin, doxazosin, terazosin)",
     "Pheochromocytoma (phenoxybenzamine pre-op, phentolamine for crisis)",
     "Raynaud's phenomenon",
     "Hypertensive emergency (phentolamine IV)"],
    "❌ Contraindications",
    ["First-dose phenomenon / orthostatic hypotension risk",
     "Concurrent PDE-5 inhibitors (sildenafil — severe hypotension)",
     "Heart failure with volume depletion",
     "History of syncope"],
))
story.append(labeled_box("Adverse Effects", [
    "FIRST-DOSE PHENOMENON: profound orthostatic hypotension and syncope after first dose",
    "Dizziness, lightheadedness",
    "Reflex tachycardia (prazosin)",
    "Nasal stuffiness",
    "Sodium and water retention",
    "Intraoperative floppy iris syndrome (IFIS) — prior alpha-blocker use + cataract surgery"], PILL_YELLOW))
story.append(exam_tip("Alpha-blockers: FIRST-DOSE HYPOTENSION — always start low, give at bedtime! Dual benefit in BPH + HTN. Phentolamine for pheochromocytoma crisis."))
story.append(PageBreak())

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 11: HYPERTENSIVE EMERGENCIES
# ══════════════════════════════════════════════════════════════════════════════
story.append(section_banner("11. HYPERTENSIVE EMERGENCIES — IV Agents", DARK_BLUE))
story.append(sp(6))
story.append(Paragraph(
    "<b>Definition:</b> Hypertensive emergency = SBP > 180/DBP > 120 mmHg WITH evidence of acute target-organ damage (TOD). Requires immediate IV therapy in ICU.", body))
story.append(Paragraph(
    "<b>Hypertensive urgency</b> = severely elevated BP WITHOUT acute TOD — treat orally over 24–48 hours.", body))
story.append(sp(6))

emergency_table = [
    ["DRUG", "MECHANISM", "ONSET", "SPECIAL INDICATIONS"],
    ["Sodium Nitroprusside", "Releases NO → cGMP → vasodilation\n(arteries + veins)", "Seconds", "Most HTN emergencies; encephalopathy\n⚠ Cyanide/thiocyanate toxicity"],
    ["Labetalol IV", "α₁ + β₁ + β₂ block\n(α:β ratio 1:7 IV)", "5–10 min", "Aortic dissection, pre-eclampsia,\nPost-op HTN"],
    ["Nicardipine IV", "DHP CCB → vasodilation", "5–15 min", "Post-op, acute ischemic stroke HTN,\nCocaine-induced HTN"],
    ["Fenoldopam", "Selective dopamine D₁ agonist\n↑ renal blood flow", "5–15 min", "HTN emergency with renal impairment\n(renoprotective)"],
    ["Hydralazine IV", "Direct arteriolar vasodilator\n(NO release)", "10–30 min", "Pre-eclampsia / eclampsia\nDrug of choice in pregnancy"],
    ["Esmolol IV", "Selective β₁-blocker\nUltra short-acting (t½ = 9 min)", "1–2 min", "Aortic dissection (with nitroprusside),\nPerioperative HTN"],
    ["Phentolamine IV", "Non-selective α-blocker", "1–5 min", "Pheochromocytoma crisis,\nCocaine/MAOI-induced HTN"],
    ["Nitroglycerin IV", "Venodilator > arteriodilator\n↑ NO → ↑ cGMP", "1–5 min", "Hypertensive emergency with ACS,\nAcute pulmonary edema"],
    ["Clevidipine IV", "Ultra-short DHP CCB", "2–4 min", "Post-cardiac surgery HTN"],
]
story.append(mini_table(emergency_table[0], emergency_table[1:], [3.2*cm, 4.5*cm, 1.8*cm, 5.7*cm]))
story.append(sp(6))
story.append(exam_tip("Aortic dissection: Reduce BP to SBP <120 in 20 min — use Labetalol or Nitroprusside + Esmolol. AVOID pure vasodilators alone (↑ shear force). Nitroprusside toxicity: cyanide poisoning (treat with sodium thiosulfate/hydroxocobalamin)."))
story.append(PageBreak())

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 12: COMPARISON TABLES
# ══════════════════════════════════════════════════════════════════════════════
story.append(section_banner("12. DRUG COMPARISON & COMPELLING INDICATIONS", DARK_BLUE))
story.append(sp(6))

story.append(Paragraph("<b>Compelling Indications — Preferred Drug Classes:</b>", section_head))
compelling = [
    ["CONDITION", "PREFERRED DRUG CLASS"],
    ["Diabetes + HTN + Proteinuria", "ACEi or ARB (FIRST choice)"],
    ["Chronic Kidney Disease", "ACEi or ARB"],
    ["Heart Failure (reduced EF)", "ACEi (or ARB) + Beta-blocker + Spironolactone + Loop diuretic"],
    ["Post-MI", "ACEi (or ARB) + Beta-blocker"],
    ["Coronary Artery Disease / Angina", "Beta-blocker + CCB (amlodipine)"],
    ["Atrial Fibrillation (rate control)", "Beta-blocker or Verapamil / Diltiazem"],
    ["Isolated Systolic HTN (elderly)", "Thiazide or DHP-CCB"],
    ["Pregnancy-induced HTN", "Labetalol, Nifedipine (acute), Methyldopa"],
    ["Benign Prostatic Hyperplasia + HTN", "Alpha-1 blocker (doxazosin)"],
    ["Gout + HTN", "Losartan (ARB — uricosuric effect)"],
    ["Pheochromocytoma", "Phenoxybenzamine (pre-op) then surgery"],
    ["Black patients", "Thiazide or DHP-CCB (ACEi less effective monotherapy)"],
    ["Aortic Dissection", "Labetalol IV, Esmolol + Nitroprusside"],
    ["Prinzmetal's Angina + HTN", "DHP-CCB (avoid beta-blockers — worsen spasm)"],
    ["Hypertension + Asthma/COPD", "DHP-CCB or Thiazide (AVOID beta-blockers)"],
]
story.append(mini_table(compelling[0], compelling[1:], [7.5*cm, 8.0*cm]))
story.append(sp(8))

story.append(Paragraph("<b>Drug Effects on Metabolic Parameters:</b>", section_head))
meta_table = [
    ["DRUG CLASS", "GLUCOSE", "K⁺", "LIPIDS", "URIC ACID", "RENAL"],
    ["Thiazides", "↑ (hyperglycemia)", "↓ (hypokalemia)", "↑ TG, ↑ LDL", "↑ (hyperuricemia)", "↓ GFR (mild)"],
    ["Loop Diuretics", "↑ (mild)", "↓↓ (wasting)", "↑ TG", "↑", "Nephroprotective (high dose)"],
    ["K⁺-Sparing", "Neutral", "↑ (hyperkalemia)", "Neutral", "Neutral", "↓ proteinuria"],
    ["Beta-Blockers", "↓ (mask hypogly.)", "↑ (mild)", "↑ TG, ↓ HDL", "Neutral", "↓ GFR (mild)"],
    ["CCBs", "Neutral", "Neutral", "Neutral", "Neutral", "Mild ↑ GFR"],
    ["ACEi / ARBs", "↓ (improve IS)", "↑ (hyperkalemia)", "Neutral", "Neutral (Losartan ↓)", "↓↓ proteinuria"],
    ["Alpha-blockers", "↓ (improve IS)", "Neutral", "↓ LDL, ↑ HDL", "Neutral", "Neutral"],
]
story.append(mini_table(meta_table[0], meta_table[1:], [3.0*cm, 3.2*cm, 2.3*cm, 2.5*cm, 2.5*cm, 2.0*cm]))
story.append(PageBreak())

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 13: HIGH-YIELD EXAM FACTS & MNEMONICS
# ══════════════════════════════════════════════════════════════════════════════
story.append(section_banner("13. HIGH-YIELD EXAM FACTS & MNEMONICS", DARK_BLUE))
story.append(sp(8))

story.append(Paragraph("MNEMONICS", section_head))
mnemonics = [
    ("Thiazide adverse effects — GLUCOHH",
     "G=Glucose↑, L=Lipids↑, U=Urate↑, C=Ca²⁺↑, O=Osmolarity (hyponatremia), H=Hypokalemia, H=Hypotension"),
    ("ACEi adverse effects — mnemonic 'CAPTOPRIL'",
     "C=Cough, A=Angioedema, P=Proteinuria↓ (good), T=Teratogenic, O=Other hypotension, P=Potassium↑, R=Rash, I=Indomethacin blocks, L=Liver (captopril)"),
    ("Drugs causing Drug-Induced LUPUS — 'HIPPIES'",
     "H=Hydralazine, I=Isoniazid, P=Procainamide, P=Phenytoin, I=quinIdine, E=Etanercept, S=Sulfasalazine"),
    ("Beta-Blocker Selectivity — 'A-B-E-M'",
     "Acebutolol, Bisoprolol, Esmolol, Metoprolol = selective β₁ blockers (heart)"),
    ("Drugs safe in Pregnancy HTN — 'LMNOP'",
     "L=Labetalol, M=Methyldopa, N=Nifedipine, O=nO ACEi/ARB, P=Pindolol"),
]
for title_m, desc_m in mnemonics:
    row = [[Paragraph(f"<b>{title_m}</b>", body_bold),
            Paragraph(desc_m, body)]]
    tbl = Table(row, colWidths=[6.5*cm, 8.5*cm])
    tbl.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (0,0), DARK_BLUE),
        ("BACKGROUND", (1,0), (1,0), PILL_GREEN),
        ("TEXTCOLOR", (0,0), (0,0), WHITE),
        ("TOPPADDING", (0,0), (-1,-1), 7),
        ("BOTTOMPADDING", (0,0), (-1,-1), 7),
        ("LEFTPADDING", (0,0), (-1,-1), 10),
        ("RIGHTPADDING", (0,0), (-1,-1), 10),
        ("BOX", (0,0), (-1,-1), 0.5, GRAY_MID),
        ("VALIGN", (0,0), (-1,-1), "TOP"),
    ]))
    story.append(tbl)
    story.append(sp(4))

story.append(sp(6))
story.append(Paragraph("TOP 20 HIGH-YIELD EXAM FACTS", section_head))
facts = [
    "1. ACEi cause DRY COUGH (bradykinin↑); switch to ARB if cough occurs.",
    "2. NEVER use ACEi/ARB in PREGNANCY — teratogenic (oligohydramnios, renal agenesis).",
    "3. Methyldopa = drug of choice for chronic HTN in PREGNANCY.",
    "4. Hydralazine IV = preferred for ACUTE HTN in pregnancy (pre-eclampsia).",
    "5. Thiazides RETAIN calcium, Loop diuretics WASTE calcium.",
    "6. Spironolactone causes GYNECOMASTIA; Eplerenone is selective, does not.",
    "7. Verapamil + Beta-blocker = dangerous combination (fatal bradycardia/AV block).",
    "8. Nimodipine (CCB) used for SUBARACHNOID HEMORRHAGE (cerebral vasospasm prevention).",
    "9. Minoxidil = most potent oral antihypertensive; causes HYPERTRICHOSIS.",
    "10. First-dose ORTHOSTATIC HYPOTENSION with alpha-blockers (prazosin) — give at bedtime.",
    "11. Clonidine: abrupt withdrawal → REBOUND HYPERTENSION (taper slowly!).",
    "12. In PHEOCHROMOCYTOMA: give alpha-blocker FIRST, then beta-blocker — never reverse order.",
    "13. Losartan is uricosuric — useful in HTN + GOUT.",
    "14. Telmisartan has the LONGEST half-life among ARBs.",
    "15. Fosinopril = only ACEi with dual elimination (renal + hepatic) — safe in renal failure.",
    "16. Sodium nitroprusside toxicity: CYANIDE POISONING (treat with sodium thiosulfate/hydroxocobalamin).",
    "17. Fenoldopam: only antihypertensive that INCREASES renal perfusion (D₁ agonist).",
    "18. Ethacrynic acid = only non-sulfonamide loop diuretic — safe in sulfa allergy.",
    "19. Captopril contains -SH (sulfhydryl) group → rash, taste disturbance, proteinuria.",
    "20. JNC 8 guideline: target BP < 150/90 in patients ≥ 60 yr without DM/CKD; < 140/90 for others.",
]
for f in facts:
    story.append(Paragraph(f"{'⭐' if int(f.split('.')[0]) <= 10 else '✦'} {f}", bullet_style))
story.append(sp(4))
story.append(hr())
story.append(sp(4))
story.append(Paragraph(
    "Sources: Katzung's Basic and Clinical Pharmacology 16e | Goodman & Gilman's Pharmacological Basis of Therapeutics | "
    "Brenner and Rector's The Kidney | JNC 7/8 Guidelines | ACC/AHA 2017 Hypertension Guidelines",
    small_gray))

# ── BUILD ─────────────────────────────────────────────────────────────────────
doc.build(story)
print(f"PDF created: {OUTPUT}")

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