from reportlab.lib.pagesizes import A4
from reportlab.lib import colors
from reportlab.lib.styles import getSampleStyleSheet, ParagraphStyle
from reportlab.lib.units import mm, cm
from reportlab.platypus import (
    SimpleDocTemplate, Paragraph, Spacer, Table, TableStyle,
    HRFlowable, KeepTogether
)
from reportlab.lib.enums import TA_CENTER, TA_LEFT
from reportlab.platypus import PageBreak

OUTPUT = "/home/daytona/workspace/antidiabetic-pdf/Antidiabetic_Drug_Reference.pdf"

# ── Colour palette ──────────────────────────────────────────────────────────
NAVY       = colors.HexColor("#1a3a5c")
TEAL       = colors.HexColor("#0d7377")
AMBER      = colors.HexColor("#f5a623")
RED_LIGHT  = colors.HexColor("#fff0f0")
RED_DARK   = colors.HexColor("#c0392b")
GREEN_LIGHT= colors.HexColor("#f0fff4")
GREEN_DARK = colors.HexColor("#1e8449")
YELLOW_LT  = colors.HexColor("#fffde7")
BLUE_LIGHT = colors.HexColor("#e8f4fd")
GREY_LT    = colors.HexColor("#f5f6fa")
GREY_HD    = colors.HexColor("#2c3e50")
WHITE      = colors.white

# ── Styles ────────────────────────────────────────────────────────────────────
styles = getSampleStyleSheet()

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

cover_title = S("CoverTitle", fontName="Helvetica-Bold", fontSize=26,
                textColor=WHITE, alignment=TA_CENTER, leading=32)
cover_sub   = S("CoverSub",   fontName="Helvetica",      fontSize=13,
                textColor=colors.HexColor("#d6eaf8"), alignment=TA_CENTER, leading=18)
cover_date  = S("CoverDate",  fontName="Helvetica",      fontSize=10,
                textColor=colors.HexColor("#aed6f1"), alignment=TA_CENTER)

sec_head    = S("SecHead",    fontName="Helvetica-Bold", fontSize=13,
                textColor=WHITE, alignment=TA_LEFT, leading=18,
                backColor=NAVY, leftIndent=6, rightIndent=6,
                spaceBefore=10, spaceAfter=4)

drug_head   = S("DrugHead",   fontName="Helvetica-Bold", fontSize=11,
                textColor=TEAL, spaceBefore=8, spaceAfter=2)

body        = S("Body",       fontName="Helvetica",      fontSize=9,
                leading=13, spaceBefore=2, spaceAfter=2)

small       = S("Small",      fontName="Helvetica",      fontSize=8,
                leading=11, textColor=colors.HexColor("#555555"))

warn        = S("Warn",       fontName="Helvetica-Bold", fontSize=8,
                textColor=RED_DARK)

caption     = S("Caption",    fontName="Helvetica-Oblique", fontSize=7.5,
                textColor=colors.HexColor("#666666"), alignment=TA_CENTER)

tbl_hdr     = S("TblHdr",     fontName="Helvetica-Bold", fontSize=8.5,
                textColor=WHITE, alignment=TA_CENTER)

tbl_cell    = S("TblCell",    fontName="Helvetica",      fontSize=8,
                leading=11)

tbl_cell_c  = S("TblCellC",   fontName="Helvetica",      fontSize=8,
                leading=11, alignment=TA_CENTER)

tbl_bold    = S("TblBold",    fontName="Helvetica-Bold", fontSize=8,
                leading=11)

note_style  = S("Note",       fontName="Helvetica-Oblique", fontSize=8,
                textColor=colors.HexColor("#555555"), leftIndent=8)

footer_style= S("Footer",     fontName="Helvetica",      fontSize=7,
                textColor=colors.HexColor("#999999"), alignment=TA_CENTER)

# ── Helpers ────────────────────────────────────────────────────────────────────
def section_header(text):
    data = [[Paragraph(text, tbl_hdr)]]
    t = Table(data, colWidths=[175*mm])
    t.setStyle(TableStyle([
        ('BACKGROUND', (0,0), (-1,-1), NAVY),
        ('BOTTOMPADDING', (0,0), (-1,-1), 6),
        ('TOPPADDING', (0,0), (-1,-1), 6),
        ('LEFTPADDING', (0,0), (-1,-1), 8),
    ]))
    return t

def sub_header(text, color=TEAL):
    data = [[Paragraph(f"<b>{text}</b>", S("sh", fontName="Helvetica-Bold",
                        fontSize=10, textColor=WHITE))]]
    t = Table(data, colWidths=[175*mm])
    t.setStyle(TableStyle([
        ('BACKGROUND', (0,0), (-1,-1), color),
        ('BOTTOMPADDING', (0,0), (-1,-1), 4),
        ('TOPPADDING', (0,0), (-1,-1), 4),
        ('LEFTPADDING', (0,0), (-1,-1), 8),
    ]))
    return t

def make_table(header_row, data_rows, col_widths, row_colors=None):
    """col_widths in mm, row_colors: list of (row_idx, color)"""
    cw = [c*mm for c in col_widths]
    all_rows = []
    all_rows.append([Paragraph(h, tbl_hdr) for h in header_row])
    for row in data_rows:
        all_rows.append([Paragraph(str(cell), tbl_cell) if cell else Paragraph("", tbl_cell) for cell in row])

    t = Table(all_rows, colWidths=cw, repeatRows=1)
    style_cmds = [
        ('BACKGROUND',   (0,0), (-1,0),  NAVY),
        ('TEXTCOLOR',    (0,0), (-1,0),  WHITE),
        ('FONTNAME',     (0,0), (-1,0),  'Helvetica-Bold'),
        ('FONTSIZE',     (0,0), (-1,-1), 8),
        ('ROWBACKGROUNDS',(0,1),(-1,-1), [WHITE, GREY_LT]),
        ('GRID',         (0,0), (-1,-1), 0.4, colors.HexColor("#cccccc")),
        ('VALIGN',       (0,0), (-1,-1), 'TOP'),
        ('TOPPADDING',   (0,0), (-1,-1), 4),
        ('BOTTOMPADDING',(0,0), (-1,-1), 4),
        ('LEFTPADDING',  (0,0), (-1,-1), 5),
        ('RIGHTPADDING', (0,0), (-1,-1), 5),
    ]
    if row_colors:
        for (ri, rc) in row_colors:
            style_cmds.append(('BACKGROUND', (0, ri), (-1, ri), rc))
    t.setStyle(TableStyle(style_cmds))
    return t

def legend_box(items):
    """items: list of (color, label)"""
    cells = []
    for bg, label in items:
        cells.append(Table([[Paragraph(f"<b>{label}</b>",
                    S("leg", fontName="Helvetica-Bold", fontSize=7.5,
                      textColor=colors.HexColor("#333333")))
                   ]],
            colWidths=[38*mm],
            style=TableStyle([
                ('BACKGROUND', (0,0), (-1,-1), bg),
                ('BOX', (0,0), (-1,-1), 0.5, colors.HexColor("#aaaaaa")),
                ('TOPPADDING', (0,0), (-1,-1), 3),
                ('BOTTOMPADDING', (0,0), (-1,-1), 3),
                ('LEFTPADDING', (0,0), (-1,-1), 5),
            ])))
    row = [cells]
    t = Table(row, colWidths=[40*mm]*len(items))
    t.setStyle(TableStyle([('VALIGN',(0,0),(-1,-1),'MIDDLE')]))
    return t

# ── Document setup ────────────────────────────────────────────────────────────
doc = SimpleDocTemplate(
    OUTPUT,
    pagesize=A4,
    leftMargin=15*mm, rightMargin=15*mm,
    topMargin=15*mm, bottomMargin=18*mm,
    title="Antidiabetic Drugs – Contraindications & Renal Adjustments",
    author="Orris Medical Reference",
)

story = []

# ════════════════════════════════════════════════════════════════════════════
# COVER PAGE
# ════════════════════════════════════════════════════════════════════════════
cover_bg = Table(
    [[Paragraph("ANTIDIABETIC DRUGS", cover_title)],
     [Spacer(1, 8)],
     [Paragraph("Quick Reference: Contraindications &amp; Renal Dose Adjustments", cover_sub)],
     [Spacer(1, 16)],
     [Paragraph("Based on Lippincott Illustrated Reviews: Pharmacology<br/>"
                "Comprehensive Clinical Nephrology 7th Ed. | Katzung 16th Ed.", cover_sub)],
     [Spacer(1, 10)],
     [Paragraph("July 2026  |  Orris Medical Reference", cover_date)],
    ],
    colWidths=[175*mm],
)
cover_bg.setStyle(TableStyle([
    ('BACKGROUND', (0,0), (-1,-1), NAVY),
    ('TOPPADDING', (0,0), (-1,-1), 18),
    ('BOTTOMPADDING', (0,0), (-1,-1), 18),
    ('LEFTPADDING', (0,0), (-1,-1), 12),
    ('RIGHTPADDING', (0,0), (-1,-1), 12),
    ('ROUNDEDCORNERS', [8]),
]))
story.append(Spacer(1, 50))
story.append(cover_bg)
story.append(Spacer(1, 18))

# Disclaimer box
disc = Table([[Paragraph(
    "<b>CLINICAL DISCLAIMER:</b> This quick-reference is for educational purposes. "
    "Always verify doses against current local guidelines and SmPC. "
    "eGFR thresholds given as CKD-EPI in mL/min/1.73 m<super>2</super>.",
    S("disc", fontName="Helvetica", fontSize=8, textColor=GREY_HD,
      leftIndent=4))]],
    colWidths=[175*mm])
disc.setStyle(TableStyle([
    ('BACKGROUND', (0,0),(-1,-1), YELLOW_LT),
    ('BOX', (0,0),(-1,-1), 1, AMBER),
    ('TOPPADDING',(0,0),(-1,-1),6),
    ('BOTTOMPADDING',(0,0),(-1,-1),6),
    ('LEFTPADDING',(0,0),(-1,-1),8),
]))
story.append(disc)
story.append(PageBreak())

# ════════════════════════════════════════════════════════════════════════════
# LEGEND
# ════════════════════════════════════════════════════════════════════════════
story.append(section_header("HOW TO USE THIS REFERENCE"))
story.append(Spacer(1, 6))
story.append(Paragraph(
    "Each drug class is presented with: (1) absolute contraindications, (2) precautions/relative contraindications, "
    "and (3) renal dosing guidance. Row shading in tables follows the key below.",
    body))
story.append(Spacer(1, 4))
story.append(legend_box([
    (RED_LIGHT, "  AVOID / Contraindicated"),
    (YELLOW_LT, "  Use with CAUTION / Reduce dose"),
    (GREEN_LIGHT,"  Generally safe in CKD"),
    (BLUE_LIGHT, "  Special note"),
]))
story.append(Spacer(1, 10))

# ════════════════════════════════════════════════════════════════════════════
# SECTION 1 — METFORMIN (BIGUANIDE)
# ════════════════════════════════════════════════════════════════════════════
story.append(section_header("1.  BIGUANIDE — METFORMIN"))
story.append(Spacer(1, 4))

# Contraindications table
story.append(sub_header("Absolute Contraindications", RED_DARK))
ci_hdr = ["Condition", "Reason"]
ci_data = [
    ["eGFR < 30 mL/min/1.73 m²", "Accumulates → lactic acidosis risk"],
    ["Acute/decompensated heart failure", "Tissue hypoperfusion → lactic acidosis"],
    ["Sepsis / haemodynamic instability", "Reduced renal perfusion"],
    ["Acute myocardial infarction", "Circulatory failure → lactic acidosis"],
    ["IV iodinated contrast (peri-procedure)", "Contrast nephropathy → metformin accumulation"],
    ["Severe hepatic impairment", "Impaired lactate clearance"],
    ["Alcohol abuse (heavy)", "Increased lactic acidosis risk"],
]
story.append(make_table(ci_hdr, ci_data, [85, 90],
    row_colors=[(i+1, RED_LIGHT) for i in range(len(ci_data))]))
story.append(Spacer(1, 6))

story.append(sub_header("Renal Dose Adjustments", TEAL))
ren_data = [
    ["eGFR ≥ 60", "Normal dose (500–2000 mg/day)", "No restriction"],
    ["eGFR 45–59", "Reduce dose; monitor renal function 3–6 monthly", "Caution"],
    ["eGFR 30–44", "Reduce to 50% of usual dose; monitor closely", "Use with caution"],
    ["eGFR < 30",  "CONTRAINDICATED", "Avoid"],
    ["eGFR < 30 (dialysis)", "CONTRAINDICATED — not removed by dialysis", "Avoid"],
]
story.append(make_table(
    ["eGFR (mL/min/1.73 m²)", "Recommendation", "Status"],
    ren_data, [50, 95, 30],
    row_colors=[
        (1, GREEN_LIGHT),(2, GREEN_LIGHT),
        (3, YELLOW_LT),(4, RED_LIGHT),(5, RED_LIGHT)
    ]))
story.append(Spacer(1, 4))
story.append(Paragraph(
    "Note: Hold metformin 48 h before and 48 h after IV contrast if eGFR 30–60; "
    "restart only after renal function confirmed stable. "
    "Monitor vitamin B12 annually with long-term use.",
    note_style))
story.append(Spacer(1, 10))

# ════════════════════════════════════════════════════════════════════════════
# SECTION 2 — SULFONYLUREAS
# ════════════════════════════════════════════════════════════════════════════
story.append(section_header("2.  SULFONYLUREAS"))
story.append(Spacer(1, 4))

story.append(sub_header("Contraindications (Class-wide)", RED_DARK))
su_ci = [
    ["Type 1 diabetes mellitus", "No functioning beta-cells"],
    ["Diabetic ketoacidosis", "Require insulin, not secretagogues"],
    ["Severe hepatic impairment", "Impaired metabolism → hypoglycaemia"],
    ["Sulfonamide / sulfonylurea allergy", "Cross-reactivity possible"],
    ["Pregnancy", "Teratogenicity; neonatal hypoglycaemia"],
]
story.append(make_table(["Contraindication","Reason"], su_ci, [85,90],
    row_colors=[(i+1, RED_LIGHT) for i in range(len(su_ci))]))
story.append(Spacer(1,6))

story.append(sub_header("Renal Dose Adjustments by Agent", TEAL))
su_ren = [
    ["Glipizide",    "Hepatic (safe)",   "Normal dose throughout CKD",                      "Preferred in CKD"],
    ["Gliclazide",   "Hepatic (safe)",   "Normal dose; use with caution eGFR 30–60",          "Preferred in CKD"],
    ["Glimepiride",  "Hepatic → renal",  "Start low (1 mg); avoid if eGFR < 30",              "Caution"],
    ["Glyburide\n(Glibenclamide)", "Renal active metabolites",
     "AVOID in any degree of renal impairment",    "Contraindicated in CKD"],
    ["Tolbutamide",  "Hepatic",          "Relatively safe but avoid in severe renal disease",  "Older agent"],
]
story.append(make_table(
    ["Drug","Elimination","Recommendation","Notes"],
    su_ren, [30, 32, 72, 41],
    row_colors=[
        (1,GREEN_LIGHT),(2,GREEN_LIGHT),(3,YELLOW_LT),
        (4,RED_LIGHT),(5,YELLOW_LT)
    ]))
story.append(Paragraph(
    "Key risk: Hypoglycaemia is prolonged in renal impairment — renally cleared active metabolites accumulate. "
    "Glipizide and gliclazide are the preferred sulfonylureas in CKD.",
    note_style))
story.append(Spacer(1, 10))

# ════════════════════════════════════════════════════════════════════════════
# SECTION 3 — MEGLITINIDES
# ════════════════════════════════════════════════════════════════════════════
story.append(section_header("3.  MEGLITINIDES (Glinides)"))
story.append(Spacer(1, 4))

meg_data = [
    ["Repaglinide", "Mainly hepatic biliary", "Normal dose in mild–mod CKD\nStart 0.5 mg in severe CKD; titrate cautiously", "Preferred glinide in CKD"],
    ["Nateglinide", "Hepatic + renal (16%)", "Normal dose; caution in severe CKD\nActive metabolite accumulates in ESRD",          "Caution in eGFR < 30"],
]
story.append(make_table(
    ["Drug","Elimination","Renal Guidance","Notes"],
    meg_data, [32, 36, 68, 39],
    row_colors=[(1,GREEN_LIGHT),(2,YELLOW_LT)]))
story.append(Paragraph(
    "Contraindications: Type 1 DM, DKA, severe hepatic impairment. "
    "Both require functioning beta-cells. Hypoglycaemia risk is lower than sulfonylureas.",
    note_style))
story.append(Spacer(1, 10))

# ════════════════════════════════════════════════════════════════════════════
# SECTION 4 — THIAZOLIDINEDIONES
# ════════════════════════════════════════════════════════════════════════════
story.append(section_header("4.  THIAZOLIDINEDIONES (TZDs / Glitazones)"))
story.append(Spacer(1, 4))

story.append(sub_header("Absolute Contraindications", RED_DARK))
tzd_ci = [
    ["NYHA Class III–IV heart failure", "Cause fluid retention/oedema → worsen HF"],
    ["Active or history of bladder cancer (Pioglitazone)", "Association with bladder cancer risk"],
    ["Severe hepatic impairment (ALT > 2.5× ULN)", "Hepatotoxicity"],
    ["Pregnancy", "Teratogenicity risk"],
    ["Type 1 DM", "Require insulin; insulin sensitisers ineffective alone"],
]
story.append(make_table(["Contraindication","Reason"], tzd_ci, [85,90],
    row_colors=[(i+1, RED_LIGHT) for i in range(len(tzd_ci))]))
story.append(Spacer(1,6))

story.append(sub_header("Renal Dose Adjustments", TEAL))
tzd_ren = [
    ["Pioglitazone", "Hepatic (CYP2C8)", "No dose adjustment required in CKD",
     "Fluid retention worsens as CKD progresses — monitor"],
    ["Rosiglitazone", "Hepatic (CYP2C8)", "No dose adjustment required",
     "Largely withdrawn — cardiovascular concerns"],
]
story.append(make_table(
    ["Drug","Elimination","Renal Guidance","Caution"],
    tzd_ren, [30, 32, 60, 53],
    row_colors=[(1,GREEN_LIGHT),(2,YELLOW_LT)]))
story.append(Paragraph(
    "Although TZDs do not require dose reduction in renal impairment, the resulting fluid retention is particularly "
    "problematic in CKD and can precipitate or worsen heart failure. Monitor weight and oedema closely. "
    "Fracture risk is increased (especially distal limbs in women).",
    note_style))
story.append(Spacer(1, 10))

# ════════════════════════════════════════════════════════════════════════════
# SECTION 5 — GLP-1 RECEPTOR AGONISTS
# ════════════════════════════════════════════════════════════════════════════
story.append(section_header("5.  GLP-1 RECEPTOR AGONISTS"))
story.append(Spacer(1, 4))

story.append(sub_header("Contraindications (Class)", RED_DARK))
glp_ci = [
    ["Personal/family history of medullary thyroid carcinoma", "Thyroid C-cell tumour risk (rodent data)"],
    ["Multiple Endocrine Neoplasia type 2 (MEN2)", "Same thyroid risk"],
    ["History of pancreatitis", "Relative CI — may worsen pancreatitis"],
    ["Severe gastroparesis", "Slow gastric emptying contraindicated"],
    ["Type 1 DM (as monotherapy)", "Risk of DKA; not approved for T1DM"],
]
story.append(make_table(["Contraindication","Reason"], glp_ci, [90,85],
    row_colors=[(i+1, RED_LIGHT) for i in range(len(glp_ci))]))
story.append(Spacer(1,6))

story.append(sub_header("Renal Dose Adjustments", TEAL))
glp_ren = [
    ["Semaglutide (SC/oral)","Proteolytic degradation","No dose adjustment in CKD\nUse with caution in severe CKD (limited data)","Monitor nausea/dehydration"],
    ["Dulaglutide","Proteolytic degradation","No dose adjustment required","Data limited in ESRD"],
    ["Liraglutide","Proteolytic degradation","No dose adjustment; use caution eGFR < 15","Monitor renal function"],
    ["Exenatide (twice daily)","Renal excretion","Avoid if eGFR < 30\nNo dose adj if eGFR 30–50 but monitor","Renally excreted"],
    ["Exenatide (once weekly)","Renal excretion","Avoid if eGFR < 45","Slower release — risk accumulates"],
    ["Lixisenatide","Renal excretion","Avoid if eGFR < 30","Limited data in severe CKD"],
]
story.append(make_table(
    ["Drug","Elimination","Renal Guidance","Notes"],
    glp_ren, [32, 32, 75, 36],
    row_colors=[
        (1,GREEN_LIGHT),(2,GREEN_LIGHT),(3,GREEN_LIGHT),
        (4,RED_LIGHT),(5,YELLOW_LT),(6,RED_LIGHT)
    ]))
story.append(Paragraph(
    "GLP-1 RAs can cause dehydration (nausea/vomiting) which worsens renal function — "
    "monitor eGFR in CKD. Liraglutide and semaglutide have proven cardiovascular benefit and "
    "are preferred in T2DM with ASCVD.",
    note_style))
story.append(Spacer(1, 10))

# ════════════════════════════════════════════════════════════════════════════
# SECTION 6 — DPP-4 INHIBITORS
# ════════════════════════════════════════════════════════════════════════════
story.append(section_header("6.  DPP-4 INHIBITORS (Gliptins)"))
story.append(Spacer(1, 4))

story.append(sub_header("Contraindications", RED_DARK))
dpp_ci = [
    ["History of DPP-4 inhibitor-induced pancreatitis", "Class-wide risk of pancreatitis"],
    ["Severe heart failure — Saxagliptin specifically", "Saxagliptin increases HF hospitalizations"],
    ["Hypersensitivity to drug or excipients", "Anaphylaxis / angioedema reported"],
    ["Do NOT combine DPP-4i with GLP-1 RA", "No additive benefit; increased GI ADR"],
]
story.append(make_table(["Contraindication","Reason"], dpp_ci, [90,85],
    row_colors=[(i+1, RED_LIGHT) for i in range(len(dpp_ci))]))
story.append(Spacer(1,6))

story.append(sub_header("Renal Dose Adjustments", TEAL))
dpp_ren = [
    ["Sitagliptin",  "Renal (87% unchanged)",
     "eGFR ≥ 50: 100 mg once daily (full dose)\n"
     "eGFR 30–49: Reduce to 50 mg once daily\n"
     "eGFR < 30 / dialysis: Reduce to 25 mg once daily",
     "Dose-reduce; safe in ESRD with adjustment"],
    ["Saxagliptin",  "Renal + CYP3A4 (active metabolite)",
     "eGFR ≥ 50: 5 mg once daily\n"
     "eGFR < 50 / dialysis: Reduce to 2.5 mg once daily",
     "Caution in HF"],
    ["Alogliptin",   "Renal (76% unchanged)",
     "eGFR ≥ 60: 25 mg once daily\n"
     "eGFR 30–59: 12.5 mg once daily\n"
     "eGFR < 30 / dialysis: 6.25 mg once daily",
     "Dialysis: give after session"],
    ["Linagliptin",  "Enterohepatic (biliary/faecal)",
     "NO dose adjustment in any stage of CKD\n"
     "Safe in dialysis — not renally eliminated",
     "PREFERRED in CKD"],
]
story.append(make_table(
    ["Drug","Elimination","Dose Adjustment Detail","Notes"],
    dpp_ren, [28, 30, 80, 37],
    row_colors=[(1,YELLOW_LT),(2,YELLOW_LT),(3,YELLOW_LT),(4,GREEN_LIGHT)]))
story.append(Paragraph(
    "Linagliptin is the ONLY gliptin that requires NO dose reduction in CKD — the preferred DPP-4i when renal function is impaired.",
    note_style))
story.append(Spacer(1, 10))

# ════════════════════════════════════════════════════════════════════════════
# SECTION 7 — SGLT2 INHIBITORS
# ════════════════════════════════════════════════════════════════════════════
story.append(section_header("7.  SGLT2 INHIBITORS (Gliflozins)"))
story.append(Spacer(1, 4))

story.append(sub_header("Contraindications", RED_DARK))
sglt_ci = [
    ["eGFR < 30 (glycaemic indication)", "Mechanism requires adequate GFR — ineffective + risky"],
    ["Type 1 Diabetes Mellitus", "High risk of euglycaemic DKA"],
    ["Recurrent urinary tract or genital infections", "SGLT2i significantly increase mycotic infections"],
    ["Prior DKA on SGLT2 inhibitor", "Absolute contraindication"],
    ["Severe volume depletion / dehydration", "Osmotic diuresis worsens hypovolaemia"],
    ["Canagliflozin + peripheral artery disease / prior amputation", "Increased amputation risk with canagliflozin"],
]
story.append(make_table(["Contraindication","Reason"], sglt_ci, [85,90],
    row_colors=[(i+1, RED_LIGHT) for i in range(len(sglt_ci))]))
story.append(Spacer(1,6))

story.append(sub_header("Renal Dose Adjustments & eGFR Thresholds", TEAL))
sglt_ren = [
    ["Empagliflozin",
     "eGFR ≥ 45: 10–25 mg once daily (full glycaemic dose)\n"
     "eGFR 20–44: 10 mg daily for HF/CKD indication (not glycaemic)\n"
     "eGFR < 20: Avoid for glycaemic control; HF indication use 10 mg",
     "Approved HFrEF + HFpEF"],
    ["Dapagliflozin",
     "eGFR ≥ 45: 10 mg once daily (glycaemic)\n"
     "eGFR 25–44: 10 mg for HF or CKD indication (not glycaemia)\n"
     "eGFR < 25: Avoid for glycaemic control; continue if CKD/HF indication",
     "Approved HFrEF + CKD"],
    ["Canagliflozin",
     "eGFR ≥ 60: 100–300 mg once daily\n"
     "eGFR 45–59: 100 mg once daily (glycaemic)\n"
     "eGFR 30–44: 100 mg (CKD/CVD indication); avoid for glycaemia alone\n"
     "eGFR < 30: CONTRAINDICATED for glycaemia; CKD benefit data available",
     "Amputation & fracture risk"],
    ["Ertugliflozin",
     "eGFR ≥ 60: Full dose (5–15 mg)\n"
     "eGFR 30–59: Do not initiate (reduced efficacy)\n"
     "eGFR < 30: Contraindicated",
     "No special organ benefit proven"],
]
story.append(make_table(
    ["Drug","Renal Dose Guidance","Notes"],
    sglt_ren, [28, 112, 35],
    row_colors=[(1,GREEN_LIGHT),(2,GREEN_LIGHT),(3,YELLOW_LT),(4,YELLOW_LT)]))
story.append(Paragraph(
    "Key concept: SGLT2 inhibitors have distinct thresholds for GLYCAEMIC vs CARDIORENAL indications. "
    "Even below the glycaemic eGFR threshold, empagliflozin/dapagliflozin/canagliflozin may still be "
    "continued for cardiovascular or CKD benefits — always confirm the indication.",
    note_style))
story.append(Spacer(1, 10))

# ════════════════════════════════════════════════════════════════════════════
# SECTION 8 — INSULIN
# ════════════════════════════════════════════════════════════════════════════
story.append(section_header("8.  INSULIN"))
story.append(Spacer(1, 4))

story.append(Paragraph("Insulin has NO absolute renal contraindication, but requires dose monitoring due to reduced renal clearance.", body))
story.append(Spacer(1,4))

ins_ren = [
    ["eGFR 60–89 (CKD G2)", "Normal doses; monitor for hypoglycaemia"],
    ["eGFR 30–59 (CKD G3)", "Reduce total daily dose by 25%; increase monitoring"],
    ["eGFR 15–29 (CKD G4)", "Reduce total daily dose by 50%; increased hypoglycaemia risk"],
    ["eGFR < 15 / Dialysis",
     "Reduce dose by 50–75%; insulin clearance reduced\n"
     "Patients on dialysis may need significantly less insulin\n"
     "Hold if patient is fasting or not eating"],
]
story.append(make_table(
    ["Stage of CKD","Guidance"],
    ins_ren, [55, 120],
    row_colors=[
        (1,GREEN_LIGHT),(2,GREEN_LIGHT),(3,YELLOW_LT),(4,RED_LIGHT)
    ]))
story.append(Paragraph(
    "Rationale: Kidney is responsible for ~20–30% of insulin degradation. As GFR declines, "
    "insulin half-life increases → hypoglycaemia risk rises. Gluconeogenesis is also impaired in CKD.",
    note_style))
story.append(Spacer(1, 10))

# ════════════════════════════════════════════════════════════════════════════
# SECTION 9 — ALPHA-GLUCOSIDASE INHIBITORS
# ════════════════════════════════════════════════════════════════════════════
story.append(section_header("9.  ALPHA-GLUCOSIDASE INHIBITORS"))
story.append(Spacer(1, 4))

agi_data = [
    ["Acarbose", "GI (minimal systemic)",
     "Avoid if serum creatinine > 2 mg/dL (eGFR < 30 approx)\nNot recommended in ESRD",
     "GI side-effects limit use; if hypoglycaemia occurs — must treat with GLUCOSE, not sucrose"],
    ["Miglitol", "Renal (absorbed systemically)",
     "Contraindicated if eGFR < 30\nAccumulates significantly in renal impairment",
     "Absorbed unlike acarbose — renal accumulation is clinically significant"],
]
story.append(make_table(
    ["Drug","Elimination","Renal Guidance","Notes"],
    agi_data, [28, 28, 66, 53],
    row_colors=[(1,YELLOW_LT),(2,RED_LIGHT)]))
story.append(Spacer(1,4))
story.append(Paragraph(
    "Contraindications (class): IBD, colonic ulceration, intestinal obstruction, malabsorption syndromes, liver cirrhosis.",
    note_style))
story.append(Spacer(1, 10))

# ════════════════════════════════════════════════════════════════════════════
# SECTION 10 — MASTER SUMMARY TABLE
# ════════════════════════════════════════════════════════════════════════════
story.append(PageBreak())
story.append(section_header("MASTER SUMMARY: RENAL THRESHOLDS AT A GLANCE"))
story.append(Spacer(1, 6))

master_data = [
    ["Metformin",          "eGFR < 30",  "eGFR 30–44",  "eGFR ≥ 45",   "Risk: Lactic acidosis"],
    ["Glyburide",          "Any CKD",    "Any CKD",      "Use alt. agent","Active metabolites"],
    ["Glipizide/Gliclazide","eGFR < 30", "Caution",      "Full dose",    "Preferred SU in CKD"],
    ["Repaglinide",        "Caution",    "Low start dose","Full dose",    "Low CKD risk"],
    ["Pioglitazone/TZD",   "N/A",        "Monitor oedema","Full dose",   "No renal adjustment"],
    ["Sitagliptin",        "25 mg/day",  "50 mg/day",    "100 mg/day",   "Dose reduce"],
    ["Linagliptin",        "Full dose",  "Full dose",    "Full dose",    "No adjustment needed"],
    ["Saxagliptin",        "2.5 mg/day", "2.5 mg/day",   "5 mg/day",    "Avoid in HF"],
    ["Liraglutide/Semaglutide","Caution","Caution",      "Full dose",    "Dehydration risk"],
    ["Exenatide (BID)",    "Avoid",      "Monitor",      "Full dose",    "Renally cleared"],
    ["Empagliflozin",      "10 mg (HF)", "10 mg (HF/CKD)","10–25 mg",   "Dual glycaemic/HF use"],
    ["Dapagliflozin",      "Avoid gluc.","10 mg (HF/CKD)","10 mg",      "CKD + HF benefit"],
    ["Canagliflozin",      "Avoid gluc.","100 mg (CKD)", "100–300 mg",  "Amputation risk"],
    ["Insulin (all)",      "Reduce 50–75%","Reduce 50%", "Reduce 25%",   "Monitor carefully"],
    ["Acarbose",           "Avoid",      "Caution",      "Full dose",    "Avoid eGFR < 30"],
]

def colored_cell(text, bg):
    return Paragraph(text, S("mc", fontName="Helvetica", fontSize=7.5,
                              leading=10, backColor=bg))

master_header = ["Drug", "eGFR < 30\n(Severe CKD/ESRD)", "eGFR 30–44\n(Mod-Severe CKD)",
                 "eGFR ≥ 45\n(Mild-Mod CKD)", "Key Note"]

# colour code the eGFR columns
def status_color(text):
    t = text.strip().lower()
    if "avoid" in t or "contraindicated" in t:
        return RED_LIGHT
    elif "caution" in t or "reduce" in t or "monitor" in t or "mg (hf" in t or "mg (ckd" in t:
        return YELLOW_LT
    else:
        return GREEN_LIGHT

from reportlab.platypus import Table as RLTable, TableStyle as RLTableStyle

all_master_rows = [[Paragraph(h, tbl_hdr) for h in master_header]]
for row in master_data:
    styled_row = [
        Paragraph(row[0], tbl_bold),
        Paragraph(row[1], S("mc1", fontName="Helvetica", fontSize=7.5, leading=10,
                             backColor=status_color(row[1]))),
        Paragraph(row[2], S("mc2", fontName="Helvetica", fontSize=7.5, leading=10,
                             backColor=status_color(row[2]))),
        Paragraph(row[3], S("mc3", fontName="Helvetica", fontSize=7.5, leading=10,
                             backColor=status_color(row[3]))),
        Paragraph(row[4], S("mc4", fontName="Helvetica-Oblique", fontSize=7.5, leading=10)),
    ]
    all_master_rows.append(styled_row)

master_t = RLTable(all_master_rows, colWidths=[35*mm, 37*mm, 37*mm, 37*mm, 29*mm], repeatRows=1)
master_t.setStyle(RLTableStyle([
    ('BACKGROUND', (0,0), (-1,0), NAVY),
    ('TEXTCOLOR', (0,0), (-1,0), WHITE),
    ('FONTNAME', (0,0), (-1,0), 'Helvetica-Bold'),
    ('GRID', (0,0), (-1,-1), 0.3, colors.HexColor("#cccccc")),
    ('VALIGN', (0,0), (-1,-1), 'TOP'),
    ('TOPPADDING', (0,0), (-1,-1), 4),
    ('BOTTOMPADDING', (0,0), (-1,-1), 4),
    ('LEFTPADDING', (0,0), (-1,-1), 4),
    ('RIGHTPADDING', (0,0), (-1,-1), 4),
    ('ROWBACKGROUNDS', (0,1), (0,-1), [WHITE, GREY_LT]),
]))
story.append(master_t)
story.append(Spacer(1, 10))
story.append(legend_box([
    (RED_LIGHT,  "  Avoid / Contraindicated"),
    (YELLOW_LT,  "  Caution / Dose Reduce"),
    (GREEN_LIGHT, "  Generally safe (usual or adjusted dose)"),
]))
story.append(Spacer(1, 10))

# ════════════════════════════════════════════════════════════════════════════
# SECTION 11 — SPECIAL POPULATIONS
# ════════════════════════════════════════════════════════════════════════════
story.append(section_header("SPECIAL POPULATIONS & ADDITIONAL NOTES"))
story.append(Spacer(1,4))

sp_data = [
    ["Elderly",
     "Increased hypoglycaemia risk with sulfonylureas/insulin\n"
     "Prefer metformin (if eGFR permits), DPP-4i, or low-dose SGLT2i\n"
     "Avoid glyburide and chlorpropamide\n"
     "Use short-acting insulins with close monitoring"],
    ["Hepatic Impairment",
     "Avoid: Metformin (lactic acidosis), TZDs (hepatotoxicity), glyburide\n"
     "Safe options: DPP-4i (most), GLP-1 RA (proteolytic degradation)\n"
     "Reduce sulfonylurea doses in severe impairment\n"
     "Insulin titration may be required; unpredictable gluconeogenesis"],
    ["Pregnancy",
     "Insulin is the preferred treatment for all types of diabetes in pregnancy\n"
     "Metformin used in GDM but crosses placenta; long-term infant data limited\n"
     "Avoid: Sulfonylureas (neonatal hypoglycaemia), SGLT2i, GLP-1 RA, TZDs\n"
     "DPP-4 inhibitors: insufficient data — avoid"],
    ["Contrast Nephropathy\nPrevention",
     "Hold metformin 48 h before AND 48 h after IV contrast if eGFR 30–60\n"
     "Do not restart until renal function is confirmed normal\n"
     "SGLT2 inhibitors: hold 3 days before major surgery/procedures\n"
     "Euglycaemic DKA risk with SGLT2i perioperatively"],
    ["Dialysis (ESRD)",
     "Metformin: CONTRAINDICATED\n"
     "Linagliptin: Safe (no renal elimination) — preferred DPP-4i\n"
     "Sitagliptin/Alogliptin: Reduce to lowest dose; give post-dialysis\n"
     "SGLT2i: Generally ineffective (mechanism depends on GFR) except for cardiac indications\n"
     "Insulin: Continue with up to 75% dose reduction; monitor closely"],
]
story.append(make_table(
    ["Population","Key Prescribing Points"],
    sp_data, [40, 135]))
story.append(Spacer(1, 12))

# Footer / reference
story.append(HRFlowable(width="100%", thickness=0.5, color=colors.HexColor("#cccccc")))
story.append(Spacer(1, 4))
story.append(Paragraph(
    "Sources: Lippincott Illustrated Reviews: Pharmacology; Comprehensive Clinical Nephrology 7th Ed. (Elsevier); "
    "Katzung's Basic and Clinical Pharmacology 16th Ed. | Generated by Orris Medical Reference · July 2026",
    footer_style))

# ── Build ─────────────────────────────────────────────────────────────────────
doc.build(story)
print(f"PDF saved → {OUTPUT}")