📚 Pharmacology of Diabetes Mellitus

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 Image as RLImage
import urllib.request, io

OUTPUT = "/tmp/workspace/diabetes-notes/DM_Pharmacology_Notes_FMGE_USMLE.pdf"

# ── Color palette ──────────────────────────────────────────────────────────
NAVY       = colors.HexColor("#1a3a5c")
TEAL       = colors.HexColor("#0d6e8f")
LIGHT_TEAL = colors.HexColor("#e6f4f8")
GOLD       = colors.HexColor("#d4a017")
LIGHT_GOLD = colors.HexColor("#fdf6e3")
RED_DARK   = colors.HexColor("#b22222")
GREEN_DARK = colors.HexColor("#1a5c2a")
GRAY_BG    = colors.HexColor("#f5f5f5")
GRAY_LINE  = colors.HexColor("#cccccc")
WHITE      = colors.white
BLACK      = colors.black
ORANGE     = colors.HexColor("#e07b00")

doc = SimpleDocTemplate(
    OUTPUT, pagesize=A4,
    rightMargin=1.8*cm, leftMargin=1.8*cm,
    topMargin=2*cm, bottomMargin=2*cm,
    title="Pharmacology of Diabetes Mellitus",
    author="Orris Medical Notes"
)

styles = getSampleStyleSheet()
W = A4[0] - 3.6*cm   # usable width

# ── Custom styles ──────────────────────────────────────────────────────────
def S(name, **kw):
    return ParagraphStyle(name, **kw)

st_cover_title = S("CoverTitle", fontSize=28, textColor=WHITE,
                   fontName="Helvetica-Bold", alignment=TA_CENTER, leading=34)
st_cover_sub   = S("CoverSub", fontSize=14, textColor=LIGHT_TEAL,
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st_cover_tag   = S("CoverTag", fontSize=11, textColor=GOLD,
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st_part  = S("Part", fontSize=16, textColor=WHITE, fontName="Helvetica-Bold",
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st_h2    = S("H2", fontSize=13, textColor=NAVY, fontName="Helvetica-Bold",
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st_h3    = S("H3", fontSize=11, textColor=TEAL, fontName="Helvetica-Bold",
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st_body  = S("Body", fontSize=9.5, fontName="Helvetica", leading=13,
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st_bullet= S("Bullet", fontSize=9.5, fontName="Helvetica", leading=13,
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st_pearl = S("Pearl", fontSize=9.5, fontName="Helvetica-BoldOblique",
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st_green = S("Green", fontSize=9.5, fontName="Helvetica-BoldOblique",
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st_src   = S("Source", fontSize=8, textColor=colors.gray,
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st_toc_h = S("TocH", fontSize=11, textColor=NAVY, fontName="Helvetica-Bold",
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st_toc_i = S("TocI", fontSize=10, fontName="Helvetica", textColor=BLACK,
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def part_heading(text):
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    tbl.setStyle(TableStyle([
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def drug_class_box(title_text, color=TEAL):
    tbl = Table([[Paragraph(title_text, S("dct", fontSize=12, textColor=WHITE,
                   fontName="Helvetica-Bold", alignment=TA_LEFT))]], colWidths=[W])
    tbl.setStyle(TableStyle([
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        ("LEFTPADDING", (0,0), (-1,-1), 10),
    ]))
    return tbl

def make_table(headers, rows, col_widths=None, stripe=True):
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           alignment=TA_CENTER, leading=12)
    ds = S("td", fontSize=8.5, fontName="Helvetica", leading=12, alignment=TA_LEFT)
    data = [[Paragraph(h, hs) for h in headers]]
    for i, row in enumerate(rows):
        data.append([Paragraph(str(c), ds) for c in row])
    t = Table(data, colWidths=col_widths, repeatRows=1)
    style = [
        ("BACKGROUND",  (0,0), (-1,0), NAVY),
        ("TEXTCOLOR",   (0,0), (-1,0), WHITE),
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    ]
    t.setStyle(TableStyle(style))
    return t

def pearl(text):
    return Paragraph(f"<b>★ Exam Pearl:</b> {text}", st_pearl)

def green_box(text):
    return Paragraph(f"<b>✔ Key Point:</b> {text}", st_green)

def bullet(text):
    return Paragraph(f"• {text}", st_bullet)

def sp(n=1):
    return Spacer(1, n*4*mm)

def hr():
    return HRFlowable(width="100%", thickness=0.5, color=GRAY_LINE, spaceAfter=4)

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

# ── COVER PAGE ────────────────────────────────────────────────────
cover_bg = Table([
    [Paragraph("PHARMACOLOGY OF", st_cover_sub)],
    [Paragraph("DIABETES MELLITUS", st_cover_title)],
    [Spacer(1, 6)],
    [Paragraph("Complete Notes for FMGE &amp; USMLE", st_cover_tag)],
    [Spacer(1, 4)],
    [Paragraph("Insulin · Oral Antidiabetics · Treatment Algorithm · Drug Interactions", st_cover_sub)],
    [Spacer(1, 10)],
    [Paragraph("Based on Lippincott Illustrated Reviews Pharmacology 7th Ed.", st_src)],
    [Paragraph("Barash Clinical Anesthesia 9th Ed. · ADA Standards of Medical Care", st_src)],
], colWidths=[W])
cover_bg.setStyle(TableStyle([
    ("BACKGROUND", (0,0), (-1,-1), NAVY),
    ("TOPPADDING",    (0,0), (-1,-1), 8),
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    ("LEFTPADDING",   (0,0), (-1,-1), 20),
    ("RIGHTPADDING",  (0,0), (-1,-1), 20),
    ("ROUNDEDCORNERS", [8]),
]))
story.append(sp(4))
story.append(cover_bg)
story.append(sp(6))

# Gold accent bar
accent = Table([["FMGE · USMLE · Medical Examinations"]], colWidths=[W])
accent.setStyle(TableStyle([
    ("BACKGROUND", (0,0), (-1,-1), GOLD),
    ("FONTNAME", (0,0), (-1,-1), "Helvetica-Bold"),
    ("FONTSIZE", (0,0), (-1,-1), 12),
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    ("BOTTOMPADDING", (0,0), (-1,-1), 8),
    ("TOPPADDING", (0,0), (-1,-1), 8),
]))
story.append(accent)
story.append(PageBreak())

# ── PART 1: Overview & Classification ────────────────────────────
story.append(part_heading("PART 1 — OVERVIEW & CLASSIFICATION OF DIABETES MELLITUS"))
story.append(sp())

story.append(Paragraph("Definition", st_h2))
story.append(Paragraph(
    "Diabetes Mellitus (DM) is a group of metabolic diseases characterized by chronic hyperglycemia "
    "resulting from defects in insulin secretion, insulin action, or both.", st_body))
story.append(sp())

story.append(Paragraph("Types of Diabetes Mellitus", st_h2))
story.append(make_table(
    ["Feature", "Type 1 DM", "Type 2 DM", "Gestational DM"],
    [
        ["Pathology", "Autoimmune destruction of beta cells", "Insulin resistance + relative insulin deficiency", "Insulin resistance during pregnancy"],
        ["Insulin levels", "Very low / absent", "Normal→high early, then reduced", "Variable"],
        ["Body habitus", "Thin", "Obese (usually)", "N/A"],
        ["Onset", "Childhood / young adults", "Middle-aged / elderly", "During pregnancy"],
        ["Ketoacidosis", "Common", "Rare", "Rare"],
        ["Treatment", "Insulin (mandatory)", "Lifestyle + oral agents + insulin", "Diet + insulin if needed"],
        ["Genetic basis", "HLA-DR3, HLA-DR4", "Polygenic, strong FH", "Genetic + hormonal"],
    ],
    col_widths=[3.2*cm, 4*cm, 5*cm, 4.4*cm]
))
story.append(sp())
story.append(Paragraph(
    "<b>Additional types:</b> MODY (Maturity Onset Diabetes of the Young), "
    "drug-induced DM (steroids, thiazides, atypical antipsychotics), pancreatitis-related.", st_body))
story.append(sp())

story.append(Paragraph("Diagnostic Criteria (ADA)", st_h2))
story.append(make_table(
    ["Criterion", "Threshold"],
    [
        ["HbA1c", "≥ 6.5%"],
        ["Fasting plasma glucose (≥8 h fast)", "≥ 126 mg/dL (7 mmol/L)"],
        ["2-h plasma glucose (75 g OGTT)", "≥ 200 mg/dL (11.1 mmol/L)"],
        ["Random plasma glucose + classic symptoms", "≥ 200 mg/dL"],
    ],
    col_widths=[10*cm, 6.6*cm]
))
story.append(sp(0.5))
story.append(pearl("All results (except symptomatic random glucose) require confirmation by repeat testing."))
story.append(PageBreak())

# ── PART 2: Insulin ───────────────────────────────────────────────
story.append(part_heading("PART 2 — INSULIN"))
story.append(sp())

story.append(Paragraph("Normal Physiology", st_h2))
for t in [
    "Insulin is secreted by pancreatic <b>beta (β) cells</b> of islets of Langerhans.",
    "Binds to <b>insulin receptor tyrosine kinase</b> → glucose uptake via <b>GLUT-4</b> transporters (muscle, adipose).",
    "Promotes: glycogenesis, lipogenesis, protein synthesis.",
    "Inhibits: gluconeogenesis, glycogenolysis, lipolysis, ketogenesis.",
]:
    story.append(bullet(t))
story.append(sp())

story.append(Paragraph("Mechanism of Action", st_h2))
for t in [
    "Binds insulin receptor (alpha subunit) → activates <b>tyrosine kinase</b> (beta subunit).",
    "Triggers phosphorylation cascade → GLUT-4 translocation to cell membrane.",
    "Increases glucose uptake in muscle and adipose tissue.",
    "Suppresses hepatic gluconeogenesis and glycogenolysis.",
]:
    story.append(bullet(t))
story.append(sp())

story.append(Paragraph("Insulin Preparations — Classification", st_h2))
story.append(make_table(
    ["Category", "Drugs", "Onset", "Peak", "Duration", "Key Notes"],
    [
        ["Rapid-acting", "Lispro, Aspart, Glulisine, Inhaled", "15–30 min", "30–90 min", "3–5 h", "Give 15 min before meal"],
        ["Short-acting", "Regular (Soluble) insulin", "30–60 min", "50–120 min", "5–8 h", "IV use possible; give 30 min before meal"],
        ["Intermediate", "NPH (Isophane)", "1–2 h", "4–8 h", "10–20 h", "Zinc + protamine complex"],
        ["Long-acting", "Glargine, Detemir", "1–2 h", "Flat / no peak", "20–24 h", "Glargine = peakless basal"],
        ["Ultra-long", "Degludec", "1–2 h", "Flat", ">42 h", "Once daily"],
        ["Inhaled", "Inhaled insulin (dry powder)", "Rapid", "10–20 min", "~3 h", "Pulmonary route"],
    ],
    col_widths=[2.5*cm, 4.2*cm, 1.8*cm, 2.2*cm, 2.2*cm, 3.7*cm]
))
story.append(sp(0.5))
story.append(pearl("Lispro = inverted Pro28-Lys29 amino acids. Glargine precipitates at subcutaneous pH — peakless. NEVER mix glargine with other insulins."))
story.append(sp())

story.append(Paragraph("Insulin Indications", st_h2))
for t in ["Type 1 DM (mandatory)", "Type 2 DM uncontrolled on oral agents",
          "Diabetic ketoacidosis (DKA)", "Hyperglycemic hyperosmolar state (HHS)",
          "Gestational diabetes", "Perioperative hyperglycemia",
          "Hyperkalemia (regular insulin IV + dextrose)"]:
    story.append(bullet(t))
story.append(sp())

story.append(Paragraph("Insulin Adverse Effects", st_h2))
story.append(make_table(
    ["Adverse Effect", "Notes"],
    [
        ["Hypoglycemia", "Most common and dangerous; more risk with intensive regimens"],
        ["Weight gain", "All insulins except inhaled (minimal)"],
        ["Lipodystrophy", "Local atrophy OR hypertrophy at injection site; rotate sites"],
        ["Hypokalemia", "Insulin drives K+ into cells"],
        ["Injection site reactions", "Pain, redness, swelling"],
        ["Insulin allergy", "Rare with recombinant human insulin"],
    ],
    col_widths=[5.5*cm, 11.1*cm]
))
story.append(sp())

story.append(Paragraph("Intensive vs. Standard Insulin Therapy", st_h2))
story.append(make_table(
    ["Feature", "Standard Therapy", "Intensive Therapy"],
    [
        ["Injections/day", "2 injections", "3 or more injections"],
        ["HbA1c target", ">7%", "≤7% (ADA target)"],
        ["Hypoglycemia risk", "Lower", "Higher"],
        ["Microvascular complications", "Higher risk", "Significantly reduced"],
        ["When to AVOID intensive Rx", "—", "Elderly, long-standing DM, hypoglycemic unawareness"],
    ],
    col_widths=[4.5*cm, 5.5*cm, 6.6*cm]
))
story.append(PageBreak())

# ── PART 3: Oral Antidiabetics ────────────────────────────────────
story.append(part_heading("PART 3 — ORAL & INJECTABLE ANTIDIABETIC DRUGS"))
story.append(sp())

# Helper for drug section
def drug_section(num, name, color, rows_prop, indications, contraindications, adr, pearls):
    story.append(drug_class_box(f"Class {num}: {name}", color))
    story.append(sp(0.5))
    # Properties table
    story.append(make_table(["Property", "Detail"], rows_prop, col_widths=[4.5*cm, 12.1*cm]))
    story.append(sp(0.5))
    story.append(Paragraph("<b>Indications:</b> " + indications, st_body))
    story.append(Paragraph("<b>Contraindications:</b> " + contraindications, st_body))
    story.append(Paragraph("<b>Adverse Effects:</b> " + adr, st_body))
    for p in pearls:
        story.append(pearl(p))
    story.append(sp())

drug_section(
    1, "BIGUANIDES — Metformin (First-line for T2DM)", TEAL,
    [
        ["Mechanism of Action", "Activates AMPK → reduces hepatic gluconeogenesis (primary effect); increases insulin sensitivity in peripheral tissues; delays intestinal glucose absorption"],
        ["Route", "Oral"],
        ["Hypoglycemia risk", "NONE — does not stimulate insulin secretion"],
        ["Effect on weight", "Neutral or slight weight loss"],
        ["HbA1c reduction", "1–2%"],
    ],
    "Type 2 DM (first-line), PCOS, prediabetes prevention",
    "eGFR &lt;30 mL/min (renal failure), hepatic failure, alcoholism, sepsis/shock, IV contrast (hold 48h before and after)",
    "GI upset — nausea/vomiting/diarrhea (take with food), lactic acidosis (rare but serious), metallic taste, B12 deficiency with long-term use",
    [
        "Metformin is the ONLY oral antidiabetic proven to reduce cardiovascular mortality (UKPDS trial).",
        "HOLD metformin before IV contrast — risk of lactic acidosis if contrast causes acute kidney injury.",
    ]
)

drug_section(
    2, "SULFONYLUREAS — Glipizide, Glyburide, Glimepiride, Chlorpropamide", colors.HexColor("#1565a0"),
    [
        ["Mechanism of Action", "Block ATP-sensitive K+ (KATP) channels on beta cell membrane → membrane depolarization → Ca2+ influx → insulin secretion"],
        ["Generations", "1st gen: Tolbutamide, Chlorpropamide, Tolazamide. 2nd gen: Glipizide, Glyburide (Glibenclamide), Glimepiride"],
        ["Hypoglycemia risk", "HIGH — stimulate insulin regardless of blood glucose"],
        ["Effect on weight", "Weight GAIN"],
        ["HbA1c reduction", "1–2%"],
    ],
    "Type 2 DM (add-on or monotherapy)",
    "Type 1 DM, renal failure (avoid glyburide), sulfa allergy, pregnancy, hepatic failure",
    "Hypoglycemia (most common), weight gain, disulfiram-like reaction with alcohol (chlorpropamide), SIADH (chlorpropamide)",
    [
        "Glibenclamide/Glyburide = most potent sulfonylurea. Chlorpropamide = longest half-life (~35 h) — causes SIADH.",
        "Glimepiride is safest in elderly/CKD (less hypoglycemia risk). 2nd gen sulfonylureas are more potent with fewer side effects than 1st gen.",
    ]
)

drug_section(
    3, "MEGLITINIDES (Glinides) — Repaglinide, Nateglinide", colors.HexColor("#5c6bc0"),
    [
        ["Mechanism of Action", "Block KATP channels (same as sulfonylureas) but faster onset and shorter duration — 'prandial glucose regulators'"],
        ["Administration", "Before each meal (3x/day dosing)"],
        ["Hypoglycemia risk", "Lower than sulfonylureas (short-acting, glucose-dependent)"],
        ["Effect on weight", "Slight weight gain"],
    ],
    "Type 2 DM with irregular meal schedule, postprandial hyperglycemia",
    "Hepatic failure (repaglinide caution)",
    "Hypoglycemia, weight gain",
    [
        "Repaglinide = more hepatic metabolism → safer in mild–moderate renal impairment. Nateglinide derived from phenylalanine.",
        "If a meal is skipped, SKIP the dose — prevents hypoglycemia.",
    ]
)

drug_section(
    4, "THIAZOLIDINEDIONES (TZDs/Glitazones) — Pioglitazone, Rosiglitazone", colors.HexColor("#6a1010"),
    [
        ["Mechanism of Action", "Agonists at PPAR-γ (peroxisome proliferator-activated receptor gamma) in adipose/muscle → increase insulin sensitivity; reduce hepatic glucose output"],
        ["Onset of full effect", "Weeks to months (slow onset)"],
        ["Hypoglycemia risk", "NONE alone"],
        ["Effect on weight", "Weight GAIN + edema"],
    ],
    "Type 2 DM with insulin resistance; NASH (pioglitazone)",
    "Heart failure (NYHA Class III/IV) — ABSOLUTE contraindication; active liver disease; bladder cancer (pioglitazone caution); pregnancy",
    "Edema/fluid retention, weight gain, osteoporosis/fractures (especially in women), heart failure exacerbation, hepatotoxicity (rosiglitazone — now restricted), bladder cancer risk (pioglitazone)",
    [
        "Rosiglitazone restricted/withdrawn in many countries due to increased MI risk. Pioglitazone used cautiously.",
        "TZDs are the most potent insulin sensitizers. NEVER use in heart failure.",
    ]
)

drug_section(
    5, "ALPHA-GLUCOSIDASE INHIBITORS — Acarbose, Miglitol, Voglibose", colors.HexColor("#2e7d32"),
    [
        ["Mechanism of Action", "Inhibit alpha-glucosidase enzyme at intestinal brush border → delay carbohydrate digestion and absorption → blunt postprandial glucose spikes"],
        ["Hypoglycemia risk", "NONE alone"],
        ["Effect on weight", "Neutral"],
        ["HbA1c reduction", "0.5–1%"],
    ],
    "Type 2 DM (postprandial hyperglycemia); adjunct therapy",
    "IBD, intestinal obstruction, cirrhosis, renal failure (serum creatinine >2 mg/dL)",
    "FLATULENCE, bloating, diarrhea, abdominal cramps (most common and most limiting side effects)",
    [
        "If hypoglycemia occurs (when combined with insulin/sulfonylurea), treat with GLUCOSE (dextrose tablets) — NOT sucrose, because sucrose breakdown is inhibited by the drug.",
    ]
)

drug_section(
    6, "DPP-4 INHIBITORS (Gliptins) — Sitagliptin, Saxagliptin, Linagliptin, Alogliptin, Vildagliptin", colors.HexColor("#00695c"),
    [
        ["Mechanism of Action", "Inhibit dipeptidyl peptidase-4 (DPP-4) enzyme → prevent breakdown of endogenous GLP-1 and GIP → increased glucose-dependent insulin secretion + decreased glucagon"],
        ["Hypoglycemia risk", "LOW (glucose-dependent mechanism)"],
        ["Effect on weight", "NEUTRAL"],
        ["HbA1c reduction", "0.5–1%"],
    ],
    "Type 2 DM; add-on to metformin or other agents",
    "Pancreatitis history (caution); severe renal failure (dose-adjust most agents; linagliptin = NO dose adjustment needed)",
    "Nasopharyngitis, UTI, rare pancreatitis, arthralgia (joint pain), increased HF hospitalization (saxagliptin, alogliptin)",
    [
        "Linagliptin is the ONLY DPP-4 inhibitor that does NOT require dose adjustment in renal failure — excreted via bile/feces, not kidneys.",
        "Saxagliptin and alogliptin associated with increased heart failure hospitalization risk — avoid in HF patients.",
    ]
)

drug_section(
    7, "GLP-1 RECEPTOR AGONISTS — Exenatide, Liraglutide, Dulaglutide, Semaglutide, Lixisenatide", colors.HexColor("#4a148c"),
    [
        ["Mechanism of Action", "Mimic incretin hormone GLP-1 → glucose-dependent insulin secretion ↑, glucagon ↓, gastric emptying delayed, satiety ↑ (weight loss)"],
        ["Route", "Subcutaneous injection (semaglutide also available as oral)"],
        ["Hypoglycemia risk", "LOW (glucose-dependent)"],
        ["Effect on weight", "Significant WEIGHT LOSS (2–5 kg)"],
        ["CV benefit", "Liraglutide (LEADER trial) and semaglutide (SUSTAIN trial) — proven CV mortality reduction"],
    ],
    "Type 2 DM + obesity; T2DM + CVD; T2DM + CKD",
    "History of medullary thyroid carcinoma (MTC) or MEN type 2 (C-cell tumors in animal studies); active pancreatitis; pregnancy",
    "Nausea, vomiting, diarrhea (most common, often transient), pancreatitis (rare), potential thyroid C-cell tumors",
    [
        "GLP-1 agonists = weight loss + CV benefit. Preferred in T2DM with established CVD or obesity.",
        "Contraindication: personal/family history of medullary thyroid carcinoma or MEN2.",
        "Incretin effect: oral glucose stimulates MORE insulin than IV glucose due to gut-released GLP-1/GIP — this effect is reduced in T2DM.",
    ]
)

drug_section(
    8, "SGLT-2 INHIBITORS (Gliflozins) — Empagliflozin, Canagliflozin, Dapagliflozin, Ertugliflozin", colors.HexColor("#bf360c"),
    [
        ["Mechanism of Action", "Inhibit SGLT-2 (sodium-glucose cotransporter-2) in proximal convoluted tubule → block renal glucose reabsorption → glucosuria → lower blood glucose (insulin-independent)"],
        ["Hypoglycemia risk", "LOW (insulin-independent mechanism)"],
        ["Effect on weight", "WEIGHT LOSS (osmotic diuresis, caloric loss)"],
        ["BP effect", "Reduces blood pressure"],
        ["CV benefit", "Empagliflozin (EMPA-REG), Canagliflozin (CANVAS), Dapagliflozin (DECLARE) — reduce MACE and HF hospitalization"],
        ["HF benefit", "Reduce HF hospitalization even in non-diabetics (now indicated for HFrEF independently)"],
    ],
    "Type 2 DM + CVD; T2DM + HF; T2DM + CKD; HFrEF (dapagliflozin, empagliflozin — even without diabetes)",
    "eGFR &lt;45 mL/min (canagliflozin &lt;30); Type 1 DM (euglycemic DKA risk); recurrent genitourinary infections; pregnancy",
    "Genital mycotic infections (most common), UTI, EUGLYCEMIC DKA (glucose may be normal), Fournier's gangrene (rare, necrotizing fasciitis of perineum), bone fractures/limb amputation (canagliflozin)",
    [
        "SGLT-2 inhibitors cause glucosuria WITHOUT hypoglycemia because the mechanism is insulin-independent.",
        "EUGLYCEMIC DKA: DKA may occur with normal/near-normal glucose — classic USMLE trap. Suspect in SGLT-2 inhibitor users with anion gap metabolic acidosis.",
        "Fournier's gangrene: FDA black box warning — necrotizing fasciitis of the genital/perineal area. Rare but life-threatening.",
    ]
)

drug_section(
    9, "AMYLIN ANALOG — Pramlintide", colors.HexColor("#37474f"),
    [
        ["Mechanism of Action", "Synthetic amylin analog → delays gastric emptying, decreases postprandial glucagon secretion, increases satiety"],
        ["Route", "Subcutaneous injection immediately BEFORE meals"],
        ["Hypoglycemia risk", "Moderate (used with insulin — reduce insulin dose!)"],
    ],
    "Adjunct to mealtime insulin in Type 1 AND Type 2 DM",
    "Diabetic gastroparesis (delays gastric emptying further), hypoglycemic unawareness, cresol hypersensitivity",
    "Nausea, anorexia, vomiting",
    [
        "When starting pramlintide, REDUCE mealtime insulin dose by 50% to avoid severe hypoglycemia.",
        "CANNOT be mixed in the same syringe as insulin.",
    ]
)

story.append(PageBreak())

# ── PART 4: Quick Comparison Table ────────────────────────────────
story.append(part_heading("PART 4 — QUICK COMPARISON TABLE (HIGH YIELD)"))
story.append(sp())
story.append(make_table(
    ["Drug Class", "MOA", "Hypoglycemia", "Weight", "Key ADR", "Contraindication"],
    [
        ["Metformin", "↓ hepatic gluconeogenesis (AMPK)", "None", "Neutral/↓", "Lactic acidosis", "Renal failure"],
        ["Sulfonylureas", "↑ insulin secretion (KATP block)", "HIGH", "↑", "Hypoglycemia", "Renal failure / sulfa allergy"],
        ["Meglitinides", "↑ insulin (fast/short KATP block)", "Low", "↑", "Hypoglycemia", "Hepatic failure"],
        ["TZDs", "PPAR-γ agonist, ↑ insulin sensitivity", "None", "↑↑", "Edema, fractures, HF", "Heart failure"],
        ["α-Glucosidase inhibitors", "↓ carb digestion/absorption", "None", "Neutral", "Flatulence", "IBD, renal failure"],
        ["DPP-4 inhibitors", "↑ GLP-1/GIP (incretin)", "Low", "Neutral", "Nasopharyngitis", "Pancreatitis hx"],
        ["GLP-1 agonists", "↑ glucose-dep. insulin, ↓ glucagon", "Low", "↓↓", "Nausea, pancreatitis", "MTC, MEN2"],
        ["SGLT-2 inhibitors", "↓ renal glucose reabsorption", "Low", "↓", "Genital infections, euDKA", "eGFR &lt;45, T1DM"],
        ["Insulin", "Receptor tyrosine kinase activation", "HIGH", "↑", "Hypoglycemia, lipodystrophy", "Hypoglycemia"],
        ["Pramlintide", "Amylin analog: ↓ glucagon, ↓ gastric emptying", "Moderate", "↓", "Nausea, vomiting", "Gastroparesis"],
    ],
    col_widths=[3.5*cm, 4.5*cm, 2.2*cm, 1.8*cm, 3.5*cm, 3.1*cm]
))
story.append(PageBreak())

# ── PART 5: Treatment Algorithm ───────────────────────────────────
story.append(part_heading("PART 5 — TREATMENT ALGORITHM"))
story.append(sp())

story.append(Paragraph("Type 1 DM", st_h2))
story.append(green_box("Insulin is MANDATORY in Type 1 DM. No oral agents work alone."))
story.append(make_table(
    ["Regimen", "Details"],
    [
        ["Basal-Bolus (Ideal)", "Long-acting basal (glargine/detemir) + rapid-acting bolus (lispro/aspart) before each meal"],
        ["Split-Mixed", "NPH + Regular insulin twice daily (less physiologic)"],
        ["Insulin pump (CSII)", "Continuous subcutaneous insulin infusion using rapid-acting insulin"],
        ["Add pramlintide", "As adjunct to mealtime insulin for postprandial control"],
    ],
    col_widths=[4.5*cm, 12.1*cm]
))
story.append(sp())

story.append(Paragraph("Type 2 DM — ADA Stepwise Approach", st_h2))
story.append(make_table(
    ["Step", "Action"],
    [
        ["Step 1", "Lifestyle modification — diet, exercise, weight loss"],
        ["Step 2", "Metformin (first-line drug, unless contraindicated)"],
        ["Step 3 — CVD/HF", "Add SGLT-2 inhibitor OR GLP-1 agonist (CV/renal benefit proven)"],
        ["Step 3 — CKD", "Add SGLT-2 inhibitor (empagliflozin, canagliflozin)"],
        ["Step 3 — Obesity", "Add GLP-1 agonist or SGLT-2 inhibitor (weight loss benefit)"],
        ["Step 3 — Cost concern", "Add sulfonylurea or TZD"],
        ["Step 4", "Triple combination or add insulin if HbA1c remains uncontrolled"],
    ],
    col_widths=[4.5*cm, 12.1*cm]
))
story.append(sp())

story.append(Paragraph("Glycemic Targets", st_h2))
story.append(make_table(
    ["Parameter", "Target"],
    [
        ["HbA1c (most patients)", "&lt;7%"],
        ["HbA1c (elderly/comorbidities/hypoglycemia unawareness)", "&lt;8%"],
        ["Fasting plasma glucose", "80–130 mg/dL"],
        ["2-h postprandial glucose", "&lt;180 mg/dL"],
        ["Blood pressure", "&lt;130/80 mmHg"],
        ["LDL cholesterol", "&lt;70 mg/dL (with CVD) / &lt;100 mg/dL (without CVD)"],
    ],
    col_widths=[8*cm, 8.6*cm]
))
story.append(sp())

story.append(Paragraph("DKA (Diabetic Ketoacidosis) — Emergency Treatment", st_h2))
story.append(make_table(
    ["Step", "Treatment"],
    [
        ["1. Fluids", "0.9% NaCl IV — 1 L over 1st hour, then guided by clinical status"],
        ["2. Insulin", "Regular insulin IV infusion (0.1 units/kg/h); NOT subcutaneous in acute DKA"],
        ["3. Potassium", "Monitor K+ closely — insulin drives K+ into cells; replace if K+ &lt;5.5 mEq/L"],
        ["4. Bicarbonate", "Only if pH &lt;6.9 (controversial)"],
        ["5. Treat precipitant", "Infection, missed insulin dose, MI, stress"],
    ],
    col_widths=[3.5*cm, 13.1*cm]
))
story.append(PageBreak())

# ── PART 6: Complications ─────────────────────────────────────────
story.append(part_heading("PART 6 — COMPLICATIONS OF DM & PHARMACOLOGICAL RELEVANCE"))
story.append(sp())

story.append(Paragraph("Microvascular Complications", st_h2))
story.append(make_table(
    ["Complication", "Pharmacological Approach"],
    [
        ["Retinopathy", "Tight glycemic control (HbA1c ≤7%); laser photocoagulation; anti-VEGF injections (severe)"],
        ["Nephropathy", "SGLT-2 inhibitors + ACE inhibitors/ARBs (first-line renoprotective); tight BP control"],
        ["Neuropathy (painful)", "Glycemic control + Gabapentin/Pregabalin, Duloxetine, Amitriptyline, Capsaicin"],
    ],
    col_widths=[4*cm, 12.6*cm]
))
story.append(sp())

story.append(Paragraph("Macrovascular Complications", st_h2))
story.append(make_table(
    ["Complication", "Pharmacological Approach"],
    [
        ["Coronary artery disease / Stroke", "GLP-1 agonists + SGLT-2 inhibitors (proven CV benefit); statins; aspirin; BP control"],
        ["Hypertension in DM", "ACE inhibitors or ARBs (first-line — also renoprotective); thiazides, CCBs"],
        ["Dyslipidemia", "High-intensity statin (atorvastatin 40–80 mg) for all T2DM patients >40 yr with CVD risk"],
        ["Heart failure in DM", "SGLT-2 inhibitors (dapagliflozin, empagliflozin) reduce HF hospitalization + mortality"],
    ],
    col_widths=[4.5*cm, 12.1*cm]
))
story.append(PageBreak())

# ── PART 7: High-Yield Pearls ──────────────────────────────────────
story.append(part_heading("PART 7 — HIGH-YIELD EXAM PEARLS"))
story.append(sp())

story.append(Paragraph("FMGE Favorites", st_h2))
fmge_pearls = [
    ("1", "First-line drug for Type 2 DM", "Metformin"),
    ("2", "Drug causing SIADH", "Chlorpropamide (1st gen sulfonylurea)"),
    ("3", "Lactic acidosis risk", "Metformin (especially in renal failure)"),
    ("4", "Contraindicated in heart failure", "TZDs — pioglitazone, rosiglitazone"),
    ("5", "Peakless long-acting insulin", "Glargine (insulin glargine)"),
    ("6", "Most potent sulfonylurea", "Glibenclamide (Glyburide)"),
    ("7", "Antidiabetic causing weight loss", "GLP-1 agonists, SGLT-2 inhibitors"),
    ("8", "Euglycemic DKA", "SGLT-2 inhibitors"),
    ("9", "Contraindicated in medullary thyroid cancer", "GLP-1 receptor agonists"),
    ("10", "DPP-4 inhibitor safe in renal failure", "Linagliptin (no dose adjustment needed)"),
    ("11", "Antidiabetic causing disulfiram-like reaction", "Chlorpropamide + alcohol"),
    ("12", "Antidiabetic causing bladder cancer", "Pioglitazone (long-term use)"),
    ("13", "Insulin that can be given IV", "Regular insulin ONLY"),
    ("14", "Drug used in PCOS", "Metformin"),
    ("15", "Hypoglycemia treatment when on acarbose", "Dextrose (NOT sucrose)"),
]
story.append(make_table(
    ["#", "Question", "Answer"],
    fmge_pearls,
    col_widths=[1*cm, 8*cm, 7.6*cm]
))
story.append(sp())

story.append(Paragraph("USMLE Favorites", st_h2))
usmle_pearls = [
    ("1", "CV mortality reduction in T2DM", "Metformin (UKPDS), Liraglutide (LEADER trial), Empagliflozin (EMPA-REG)"),
    ("2", "HF hospitalization reduction", "SGLT-2 inhibitors — even in non-diabetic HFrEF patients"),
    ("3", "Pancreatitis association", "GLP-1 agonists and DPP-4 inhibitors"),
    ("4", "Fournier's gangrene (necrotizing fasciitis)", "SGLT-2 inhibitors — FDA black box warning"),
    ("5", "Hold before IV contrast", "Metformin — 48h hold, risk of lactic acidosis"),
    ("6", "Reduce insulin dose by 50% when adding", "Pramlintide — severe hypoglycemia risk"),
    ("7", "Glyburide contraindicated in", "Pregnancy — crosses placenta; use insulin instead"),
    ("8", "Sulfonylurea mechanism", "Block KATP channels on pancreatic beta cells"),
    ("9", "GLP-1 agonist contraindication", "MTC or MEN type 2 (C-cell tumor risk)"),
    ("10", "Drug effective in T2DM + HFrEF (non-DM too)", "Dapagliflozin, empagliflozin (SGLT-2 inhibitors)"),
    ("11", "Incretin effect definition", "Oral glucose → more insulin than IV glucose; due to GLP-1/GIP; reduced in T2DM"),
    ("12", "Cannot mix in same syringe as insulin", "Pramlintide; also glargine cannot mix with other insulins"),
]
story.append(make_table(
    ["#", "Question/Scenario", "Answer"],
    usmle_pearls,
    col_widths=[1*cm, 8.5*cm, 7.1*cm]
))
story.append(PageBreak())

# ── PART 8: Drug Interactions ─────────────────────────────────────
story.append(part_heading("PART 8 — DRUG–DRUG INTERACTIONS"))
story.append(sp())
story.append(make_table(
    ["Drug", "Interacting Agent", "Mechanism", "Effect"],
    [
        ["Sulfonylureas", "Fluconazole / CYP2C9 inhibitors", "Inhibit CYP2C9 metabolism of sulfonylurea", "↑ Sulfonylurea levels → hypoglycemia"],
        ["Sulfonylureas", "NSAIDs (phenylbutazone)", "Displace from protein binding + inhibit metabolism", "↑ Hypoglycemia risk"],
        ["Metformin", "IV iodinated contrast", "Contrast → nephrotoxicity → impaired metformin excretion", "Lactic acidosis — HOLD metformin"],
        ["Insulin", "Alcohol", "Alcohol inhibits hepatic gluconeogenesis", "Potentiates hypoglycemia (especially fasting)"],
        ["Chlorpropamide", "Alcohol", "Disulfiram-like reaction", "Flushing, nausea, vomiting, tachycardia"],
        ["Saxagliptin / Alogliptin", "None specific", "Unknown mechanism", "Increased HF hospitalization risk"],
        ["Canagliflozin", "Rifampin (inducer)", "Induces UGT enzymes → ↑ canagliflozin clearance", "Reduced efficacy — increase dose if needed"],
        ["Thiazolidinediones", "Insulin", "Additive fluid retention", "Increased edema and HF risk"],
        ["GLP-1 agonists", "Oral medications (any)", "Delayed gastric emptying → delayed oral drug absorption", "May alter absorption of other oral drugs"],
    ],
    col_widths=[3.5*cm, 4*cm, 5*cm, 4.1*cm]
))
story.append(sp())

# ── Footer / Sources ─────────────────────────────────────────────
story.append(hr())
story.append(Paragraph(
    "<b>Sources:</b> Lippincott Illustrated Reviews Pharmacology 7th Ed. | "
    "Barash, Cullen & Stoelting's Clinical Anesthesia 9th Ed. | "
    "ADA Standards of Medical Care in Diabetes 2024",
    st_src
))
story.append(Paragraph("Compiled by Orris Medical Notes — For Educational Use Only", st_src))

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