Ephedrine vs. Phenylephrine

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

OUTPUT = "/home/daytona/workspace/pharmacology-notes/Ephedrine_Phenylephrine_Notes.pdf"

doc = SimpleDocTemplate(
    OUTPUT,
    pagesize=A4,
    leftMargin=2*cm, rightMargin=2*cm,
    topMargin=2*cm, bottomMargin=2*cm
)

styles = getSampleStyleSheet()

# Custom styles
TITLE = ParagraphStyle("Title", parent=styles["Title"],
    fontSize=20, textColor=colors.HexColor("#1a1a2e"), spaceAfter=6,
    alignment=TA_CENTER, fontName="Helvetica-Bold")

SUBTITLE = ParagraphStyle("Subtitle", parent=styles["Normal"],
    fontSize=11, textColor=colors.HexColor("#555555"),
    spaceAfter=18, alignment=TA_CENTER, fontName="Helvetica-Oblique")

DRUG_HEADER = ParagraphStyle("DrugHeader",
    fontSize=16, textColor=colors.white, fontName="Helvetica-Bold",
    alignment=TA_LEFT, spaceAfter=0, spaceBefore=0,
    leftIndent=8)

SECTION = ParagraphStyle("Section",
    fontSize=11, textColor=colors.HexColor("#1a1a2e"), fontName="Helvetica-Bold",
    spaceBefore=10, spaceAfter=4, leftIndent=0)

BODY = ParagraphStyle("Body", parent=styles["Normal"],
    fontSize=9.5, leading=14, textColor=colors.HexColor("#222222"),
    fontName="Helvetica", spaceAfter=3, leftIndent=8)

BULLET = ParagraphStyle("Bullet", parent=styles["Normal"],
    fontSize=9.5, leading=14, textColor=colors.HexColor("#222222"),
    fontName="Helvetica", spaceAfter=2, leftIndent=16, bulletIndent=8)

TABLE_HEADER = ParagraphStyle("TH", fontSize=9, fontName="Helvetica-Bold",
    textColor=colors.white, alignment=TA_CENTER)
TABLE_CELL = ParagraphStyle("TC", fontSize=9, fontName="Helvetica",
    textColor=colors.HexColor("#222222"), alignment=TA_LEFT, leading=12)

FOOTER_TEXT = ParagraphStyle("Footer", fontSize=8, textColor=colors.grey,
    alignment=TA_CENTER, fontName="Helvetica-Oblique")

# ── Colours
EPHEDRINE_BG = colors.HexColor("#2e4057")
PHENYL_BG    = colors.HexColor("#048a81")
SECTION_LINE = colors.HexColor("#cccccc")
TABLE_HDR_BG = colors.HexColor("#2e4057")
ALT_ROW      = colors.HexColor("#f0f4f8")

def drug_header(name, subtitle):
    data = [[Paragraph(name, DRUG_HEADER), Paragraph(subtitle, ParagraphStyle(
        "Sub2", fontSize=10, textColor=colors.HexColor("#dddddd"),
        fontName="Helvetica-Oblique", alignment=TA_LEFT))]]
    bg = EPHEDRINE_BG if "Ephedrine" in name else PHENYL_BG
    t = Table(data, colWidths=[9*cm, 8*cm])
    t.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,-1), bg),
        ("ROWBACKGROUNDS", (0,0), (-1,-1), [bg]),
        ("TOPPADDING",    (0,0), (-1,-1), 10),
        ("BOTTOMPADDING", (0,0), (-1,-1), 10),
        ("LEFTPADDING",   (0,0), (-1,-1), 10),
        ("RIGHTPADDING",  (0,0), (-1,-1), 6),
        ("VALIGN",        (0,0), (-1,-1), "MIDDLE"),
        ("ROUNDEDCORNERS", (0,0), (-1,-1), [6,6,6,6]),
    ]))
    return t

def section_title(text):
    return [
        Paragraph(f"▸  {text}", SECTION),
        HRFlowable(width="100%", thickness=0.5, color=SECTION_LINE, spaceAfter=4),
    ]

def bullets(items):
    return [Paragraph(f"• {item}", BULLET) for item in items]

def mini_table(headers, rows, col_widths=None):
    if col_widths is None:
        col_widths = [17*cm / len(headers)] * len(headers)
    header_row = [Paragraph(h, TABLE_HEADER) for h in headers]
    data = [header_row]
    for i, row in enumerate(rows):
        data.append([Paragraph(str(c), TABLE_CELL) for c in row])
    t = Table(data, colWidths=col_widths, repeatRows=1)
    ts = [
        ("BACKGROUND", (0,0), (-1,0), TABLE_HDR_BG),
        ("TEXTCOLOR",  (0,0), (-1,0), colors.white),
        ("FONTNAME",   (0,0), (-1,0), "Helvetica-Bold"),
        ("FONTSIZE",   (0,0), (-1,0), 9),
        ("TOPPADDING",    (0,0), (-1,-1), 5),
        ("BOTTOMPADDING", (0,0), (-1,-1), 5),
        ("LEFTPADDING",   (0,0), (-1,-1), 6),
        ("RIGHTPADDING",  (0,0), (-1,-1), 6),
        ("GRID",       (0,0), (-1,-1), 0.4, colors.HexColor("#cccccc")),
        ("VALIGN",     (0,0), (-1,-1), "TOP"),
    ]
    for i in range(1, len(data)):
        if i % 2 == 0:
            ts.append(("BACKGROUND", (0,i), (-1,i), ALT_ROW))
    t.setStyle(TableStyle(ts))
    return t

# ─────────────────────────────────────────────
# BUILD CONTENT
# ─────────────────────────────────────────────
story = []

# TITLE PAGE
story.append(Spacer(1, 1.5*cm))
story.append(Paragraph("Pharmacology Notes", TITLE))
story.append(Paragraph("Ephedrine  &  Phenylephrine — Mechanism, Pharmacokinetics, Indications, Adverse Effects, Dosing & Drug Interactions", SUBTITLE))
story.append(HRFlowable(width="100%", thickness=1.5, color=EPHEDRINE_BG, spaceAfter=6))
story.append(Paragraph("Sources: Morgan & Mikhail Clinical Anesthesiology 7e · Barash Clinical Anesthesia 9e · Goodman & Gilman 14e · Katzung 16e · Lippincott Illustrated Reviews Pharmacology", FOOTER_TEXT))
story.append(Spacer(1, 0.5*cm))

# ══════════════════════════════════════════════
# DRUG 1 — EPHEDRINE
# ══════════════════════════════════════════════
story.append(drug_header("1.  Ephedrine", "Mixed-acting sympathomimetic · Noncatecholamine phenylisopropylamine"))
story.append(Spacer(1, 0.3*cm))

# MOA
story += section_title("Mechanism of Action")
story += bullets([
    "Mixed-acting sympathomimetic: predominantly indirect, with direct component.",
    "Indirect mechanism: endocytosis into adrenergic nerve terminals → displaces norepinephrine (NE) from synaptic vesicles → released NE activates postsynaptic α and β receptors.",
    "Direct mechanism: directly stimulates α₁, α₂, β₁, and β₂ adrenoceptors.",
    "Net receptor profile: α₁ + α₂ + β₁ + β₂ (all adrenoceptors).",
    "Because it depends on presynaptic NE stores, drugs depleting NE (e.g., reserpine) or blocking uptake (e.g., cocaine) attenuate its effects.",
    "Tachyphylaxis: rapid depletion of presynaptic NE stores with repeated dosing; ephedrine is released as a false neurotransmitter.",
    "CNS penetrant — mild stimulant (unlike catecholamines).",
])
story.append(Spacer(1, 0.2*cm))

# PHARMACOKINETICS
story += section_title("Pharmacokinetics")
story.append(mini_table(
    ["Parameter", "Detail"],
    [
        ["Route", "Oral (high bioavailability), IV, IM"],
        ["Onset (IV)", "~1 min"],
        ["Duration (IV bolus)", "10–60 min (longer than direct-acting catecholamines)"],
        ["Half-life", "3–6 hours"],
        ["Metabolism", "Minor hepatic; not metabolised by MAO or COMT (unlike catecholamines)"],
        ["Elimination", "Renal excretion — largely unchanged drug in urine"],
        ["CNS penetration", "Yes — crosses blood-brain barrier; mild CNS stimulant"],
    ],
    col_widths=[5*cm, 12*cm]
))
story.append(Spacer(1, 0.2*cm))

# INDICATIONS
story += section_title("Indications")
story += bullets([
    "Hypotension during anesthesia — preferred when accompanied by bradycardia.",
    "Spinal / neuraxial anesthesia-induced hypotension (when heart rate is low or normal).",
    "Bronchospasm / asthma — largely superseded by selective β₂ agonists.",
    "Urinary incontinence (stress) — stimulates α receptors at bladder neck.",
    "Nasal decongestant (oral / topical).",
    "Narcolepsy / myasthenia gravis (historical use).",
    "Intraoperative: vasopressor of choice when hypotension + bradycardia coexist.",
])
story.append(Spacer(1, 0.2*cm))

# ADVERSE EFFECTS
story += section_title("Adverse Effects")
story.append(mini_table(
    ["System", "Effect"],
    [
        ["Cardiovascular", "Hypertension, tachycardia, palpitations, arrhythmias (β₁ stimulation)"],
        ["CNS", "Insomnia, anxiety, tremor, headache, CNS stimulation"],
        ["Genitourinary", "Urinary retention — especially in BPH patients (α receptor activation at bladder neck)"],
        ["Tachyphylaxis", "Rapid tolerance with repeated doses due to NE depletion from nerve terminals"],
        ["Metabolic", "Hyperglycaemia (β₂ effect on glycogenolysis)"],
        ["Obstetric concern", "Crosses placenta → fetal tachycardia and fetal acidosis (lower umbilical pH)"],
        ["Overdose", "Severe hypertension, arrhythmias, haemorrhagic stroke"],
        ["Regulatory", "FDA banned ephedra-containing dietary supplements (safety concerns, deaths reported)"],
    ],
    col_widths=[4*cm, 13*cm]
))
story.append(Spacer(1, 0.2*cm))

# DOSING
story += section_title("Dosing (Clinical Anesthesia / Inpatient)")
story.append(mini_table(
    ["Route / Indication", "Dose"],
    [
        ["IV bolus (anesthesia-induced hypotension)", "5–25 mg; titrate to effect"],
        ["IV infusion", "25–50 mg in 250 mL → titrate 5–25 mg/h"],
        ["IM", "25–50 mg"],
        ["Oral (decongestant)", "25–50 mg every 4 h (max 150 mg/day)"],
    ],
    col_widths=[7*cm, 10*cm]
))
story.append(Spacer(1, 0.2*cm))

# DRUG INTERACTIONS
story += section_title("Drug Interactions")
story.append(mini_table(
    ["Drug / Class", "Interaction", "Clinical Consequence"],
    [
        ["MAO inhibitors (phenelzine, tranylcypromine)",
         "MAO normally breaks down displaced NE; MAOIs block this → massive NE accumulation",
         "Severe hypertensive crisis; potentially fatal. Avoid — use direct-acting agents instead."],
        ["Tricyclic antidepressants (TCAs)",
         "TCAs block NE reuptake transporter (NET) → augmented pressor response to released NE",
         "Exaggerated hypertension; arrhythmias. Use with extreme caution; reduce dose."],
        ["β-blockers",
         "Block β₁/β₂ effects of ephedrine → unopposed α stimulation",
         "Paradoxical hypertension and bradycardia; reduced bronchodilation."],
        ["Volatile anaesthetics (halothane)",
         "Sensitise myocardium to catecholamines",
         "Increased arrhythmia risk — use cautiously."],
        ["Reserpine / α-methyldopa",
         "Deplete presynaptic NE stores",
         "Attenuated or absent response to ephedrine (loss of indirect action)."],
        ["Cocaine",
         "Blocks NE reuptake transporter, preventing ephedrine uptake into nerve terminal",
         "Reduced indirect effect; unpredictable pressor response."],
        ["Tocolytics (β-sympathomimetics, e.g., ritodrine)",
         "Additive β stimulation",
         "Increased risk of arrhythmias and cardiovascular instability — use cautiously in labour."],
        ["Oxytocin",
         "Synergistic vasoconstriction in some vascular beds",
         "Monitor blood pressure closely in obstetric patients."],
        ["Theophylline",
         "Additive β₂ and CNS stimulation",
         "Risk of arrhythmias and seizures."],
        ["Digoxin",
         "Increased sympathetic tone may worsen digoxin-related arrhythmias",
         "Cardiac monitoring required."],
    ],
    col_widths=[4.5*cm, 6.5*cm, 6*cm]
))
story.append(Spacer(1, 0.4*cm))

# ══════════════════════════════════════════════
# DRUG 2 — PHENYLEPHRINE
# ══════════════════════════════════════════════
story.append(PageBreak())
story.append(drug_header("2.  Phenylephrine", "Direct-acting selective α₁ agonist · Noncatecholamine"))
story.append(Spacer(1, 0.3*cm))

# MOA
story += section_title("Mechanism of Action")
story += bullets([
    "Direct-acting, selective α₁ adrenoceptor agonist — does NOT depend on presynaptic NE stores.",
    "Structural difference from epinephrine: lacks the 4-hydroxyl group on the phenyl ring → abolishes β-receptor activity.",
    "Activates α₁ on vascular smooth muscle → Gq coupling → ↑ intracellular Ca²⁺ → actin-myosin shortening → vasoconstriction.",
    "Constricts venous capacitance vessels, cutaneous, skeletal muscle, mesenteric, splenic, and renal vasculature → ↑ LV preload and afterload → ↑ arterial pressure.",
    "Baroreceptor-mediated reflex bradycardia (vagal tone increases in response to ↑ BP).",
    "NOT arrhythmogenic — no β-receptor stimulation of myocardium.",
    "Pulmonary vasoconstriction → ↑ pulmonary artery pressures.",
])
story.append(Spacer(1, 0.2*cm))

# PHARMACOKINETICS
story += section_title("Pharmacokinetics")
story.append(mini_table(
    ["Parameter", "Detail"],
    [
        ["Routes", "IV bolus, IV infusion, topical intranasal, ophthalmic, oral (decongestant — limited systemic absorption)"],
        ["Onset (IV)", "< 1 min"],
        ["Duration (IV bolus)", "~15 min"],
        ["Half-life (IV)", "~2–3 min (redistribution); terminal t½ ~2–3 h"],
        ["Metabolism", "Hepatic (MAO and COMT independent — not a catechol); also intestinal MAO"],
        ["Elimination", "Renal; metabolised to inactive glucuronide conjugates"],
        ["CNS penetration", "Minimal — does not cross BBB readily"],
    ],
    col_widths=[5*cm, 12*cm]
))
story.append(Spacer(1, 0.2*cm))

# INDICATIONS
story += section_title("Indications")
story += bullets([
    "Hypotension during anesthesia with normal or elevated heart rate (e.g., after vasodilating agents).",
    "Spinal / neuraxial anesthesia-induced hypotension — preferred agent in obstetric (cesarean) spinal anesthesia; prophylactic infusion reduces nausea and physician interventions.",
    "Paroxysmal supraventricular tachycardia (PSVT) — reflex vagal slowing can terminate SVT.",
    "Nasal decongestant: topical spray or oral; has replaced pseudoephedrine in many OTC products.",
    "Mydriasis: ophthalmic drops for pupil dilation during fundoscopy.",
    "Hypotension in patients on PDE5 inhibitors (e.g., after sildenafil + nitrate interaction) — used as vasopressor of last resort.",
    "Septic shock (as vasopressor when tachyarrhythmias preclude other agents).",
    "Refractory hypotension in cases where β stimulation is undesirable (e.g., HOCM, aortic stenosis).",
])
story.append(Spacer(1, 0.2*cm))

# ADVERSE EFFECTS
story += section_title("Adverse Effects")
story.append(mini_table(
    ["System", "Effect"],
    [
        ["Cardiovascular", "Reflex bradycardia (can be severe); increased pulmonary artery pressure"],
        ["Cardiac output", "May ↓ CO in patients with HFrEF — failing ventricle is afterload-sensitive"],
        ["Renal / splanchnic", "Renal and mesenteric vasoconstriction with high doses"],
        ["Tissue ischaemia", "Risk of peripheral ischaemia with prolonged infusion"],
        ["Hypertensive headache", "With large doses"],
        ["Ophthalmic", "Prolonged mydriasis; angle-closure glaucoma risk in predisposed patients"],
        ["Tachyphylaxis", "With infusions — mechanism: receptor desensitisation; requires dose titration upward"],
        ["Nasal rebound", "Rhinitis medicamentosa with prolonged topical use (> 3 days)"],
        ["Spinal additive", "As spinal adjuvant: associated with transient neurological symptoms (TNS)"],
    ],
    col_widths=[4*cm, 13*cm]
))
story.append(Spacer(1, 0.2*cm))

# DOSING
story += section_title("Dosing (Clinical Anesthesia / Inpatient)")
story.append(mini_table(
    ["Route / Indication", "Dose"],
    [
        ["IV bolus (adult anesthesia-induced hypotension)", "50–100 mcg (0.5–1 mcg/kg); repeat every 1–2 min PRN"],
        ["IV infusion (prophylaxis / treatment)", "25–100 mcg/min; titrate to target MAP"],
        ["Preparation", "Dilute 1% solution (10 mg/mL ampule) → 100 mcg/mL working solution"],
        ["Obstetric prophylactic infusion", "25–50 mcg/min; start at induction of spinal block"],
        ["Intranasal (decongestant)", "0.25–0.5% solution — 2–3 sprays per nostril every 4 h (max 3 days)"],
        ["Ophthalmic (mydriasis)", "2.5% or 10% solution — 1 drop; 10% avoided in elderly / infants"],
        ["SVT (historical)", "0.5–1 mg IV slow push — largely replaced by adenosine"],
    ],
    col_widths=[7*cm, 10*cm]
))
story.append(Spacer(1, 0.2*cm))

# DRUG INTERACTIONS
story += section_title("Drug Interactions")
story.append(mini_table(
    ["Drug / Class", "Interaction", "Clinical Consequence"],
    [
        ["MAO inhibitors",
         "MAO is a minor metabolic pathway for phenylephrine; MAOIs prolong and intensify action",
         "Exaggerated hypertension; use with caution and at reduced doses."],
        ["Tricyclic antidepressants",
         "TCAs block NET → augmented response to direct α₁ stimulation",
         "Severe hypertension with even small doses; reduce dose significantly."],
        ["β-blockers (non-selective)",
         "Unopposed α stimulation when β-mediated vasodilation is blocked",
         "Paradoxical hypertension and reflex bradycardia worsened."],
        ["PDE5 inhibitors (sildenafil, tadalafil)",
         "PDE5 inhibitors cause profound vasodilation; phenylephrine used to counteract hypotension from PDE5i + nitrate interaction",
         "Phenylephrine is vasopressor of choice in this setting; titrate carefully."],
        ["Oxytocin",
         "Additive vasoconstrictive effects",
         "Monitor BP closely in post-partum patients."],
        ["Guanethidine / reserpine",
         "NE depletion has no effect on phenylephrine (direct-acting) — no attenuation",
         "Unlike ephedrine, phenylephrine response is preserved."],
        ["Halogenated anaesthetics",
         "Phenylephrine does not sensitise myocardium (no β effect) — advantage over ephedrine",
         "Lower arrhythmia risk compared to ephedrine in volatile anaesthetic context."],
        ["Ergot alkaloids (ergometrine)",
         "Additive vasoconstriction",
         "Risk of severe peripheral and coronary vasospasm — avoid combination."],
        ["Atropine",
         "Blocks reflex bradycardia caused by phenylephrine",
         "Useful if bradycardia is problematic; heart rate may rise substantially."],
        ["α-blockers (prazosin, phentolamine)",
         "Competitive antagonism at α₁ receptors",
         "Attenuated or abolished vasoconstrictor response."],
    ],
    col_widths=[4.5*cm, 6.5*cm, 6*cm]
))
story.append(Spacer(1, 0.4*cm))

# ══════════════════════════════════════════════
# QUICK COMPARISON TABLE
# ══════════════════════════════════════════════
story.append(PageBreak())
story.append(Paragraph("Quick Comparison Summary", ParagraphStyle("QC", fontSize=14,
    textColor=colors.HexColor("#1a1a2e"), fontName="Helvetica-Bold",
    spaceBefore=8, spaceAfter=10, alignment=TA_CENTER)))

story.append(mini_table(
    ["Feature", "Ephedrine", "Phenylephrine"],
    [
        ["Class", "Noncatecholamine, phenylisopropylamine", "Noncatecholamine, synthetic"],
        ["Mechanism", "Mixed (indirect + direct)", "Direct only"],
        ["Receptor profile", "α₁, α₂, β₁, β₂ (all)", "α₁ only"],
        ["Depends on NE stores?", "Yes", "No"],
        ["Heart rate", "↑ (β₁)", "↓ (reflex bradycardia)"],
        ["Cardiac output", "↑", "↓ or unchanged"],
        ["SVR", "↑ (variable)", "↑↑ (primary effect)"],
        ["Arrhythmogenicity", "Yes (β₁ stimulation)", "No"],
        ["CNS effects", "Stimulant (insomnia, anxiety)", "Minimal"],
        ["Duration (IV)", "10–60 min", "~15 min"],
        ["Half-life", "3–6 h", "Short (2–3 min redistribution)"],
        ["Tachyphylaxis mechanism", "NE depletion from terminals", "Receptor desensitisation"],
        ["Preferred in bradycardia?", "Yes", "No (worsens it)"],
        ["Preferred in tachycardia?", "No", "Yes"],
        ["Obstetric spinal anesthesia", "Causes fetal acidosis — less preferred", "Preferred; better fetal pH"],
        ["Mydriasis", "Not used", "Yes (topical)"],
        ["Decongestant", "Yes (oral/topical)", "Yes (oral/topical; OTC)"],
        ["Key interaction", "MAOIs → hypertensive crisis (indirect mechanism)", "TCAs → exaggerated hypertension"],
    ],
    col_widths=[5*cm, 6*cm, 6*cm]
))

story.append(Spacer(1, 0.6*cm))
story.append(HRFlowable(width="100%", thickness=0.5, color=colors.grey))
story.append(Spacer(1, 0.2*cm))
story.append(Paragraph(
    "References: Morgan & Mikhail's Clinical Anesthesiology 7e | Barash, Cullen & Stoelting's Clinical Anesthesia 9e | "
    "Goodman & Gilman's Pharmacological Basis of Therapeutics 14e | Katzung's Basic and Clinical Pharmacology 16e | "
    "Lippincott Illustrated Reviews: Pharmacology | Miller's Anesthesia 10e",
    FOOTER_TEXT
))

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