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Topic 10

Part of the FMGE study roadmap. Botany topic pharma-010 of Botany.

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Toxicology, Pharmacology, and Dermatological Agents

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Toxicology, Pharmacology, and Dermatological Agents — Key Facts for FMGE Core concept: Poisoning management focuses on decontamination, antidotes, and supportive care; dermatological agents treat common skin conditions High-yield point: N-acetylcysteine is the antidote for acetaminophen; naloxone for opioids; flumazenil for benzodiazepines ⚡ Exam tip: Always consider the specific toxidrome (cholinergic, anticholinergic, sympathomimetic, opioid) when presented with poisoning scenarios

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Toxicology, Pharmacology, and Dermatological Agents — FMGE Study Guide

Toxicology

General Principles

Decontamination:

  • GI decontamination: Activated charcoal (most useful within 1-2 hours), gastric lavage (rarely used now), whole bowel irrigation (sustained-release drugs, metals)
  • Dilution: Milk or water (only if caustic ingestion)
  • Skin decontamination: Remove clothing, irrigate with water/soap

Enhanced elimination:

  • Urinary alkalinization: For salicylate, phenobarbital poisoning
  • Hemodialysis: For methanol, ethylene glycol, lithium, severe salicylate, severe methanol
  • Hemoperfusion: Rarely used

Specific Poisonings and Antidotes

Acetaminophen (Paracetamol) poisoning:

  • Mechanism: Toxic metabolite (NAPQI) depletes glutathione → hepatotoxicity
  • Toxic dose: >150 mg/kg (7.5g in adult) - metabolized by CYP2E1
  • Stages: 0-24h (asymptomatic), 24-72h (hepatotoxicity begins), 72-96h (peak transaminases, possible hepatic failure), >4 days (recovery or death)
  • Antidote: N-acetylcysteine (NAC) - replenishes glutathione; most effective within 8 hours of ingestion; given IV (loading dose then maintenance) or orally (72-hour protocol)
  • Check: Serum acetaminophen level plotted on Rumack-Matthew nomogram to determine need for treatment

Opioid poisoning:

  • Toxidrome: CNS depression, respiratory depression, miosis (pinpoint pupils), hypotension, bradycardia
  • Antidote: Naloxone (opioid receptor antagonist - competitive)
    • Short half-life (30-90 min) vs opioids (may require repeat dosing)
    • Titrate to respiratory effort (not complete reversal)
    • Can cause precipitated withdrawal in opioid-dependent patients
  • Naltrexone: Long-acting opioid antagonist for addiction treatment

Benzodiazepine poisoning:

  • Toxidrome: CNS depression, respiratory depression, normal pupils
  • Antidote: Flumazenil (GABA-A receptor antagonist)
    • Short half-life (0.5-1 hour) vs BZDs (long)
    • Contraindicated: Mixed ingestions with TCA (seizures), benzodiazepine-dependent patients (can cause seizures)
    • Use cautiously

Methanol and Ethylene glycol poisoning:

  • Sources: Windshield wiper fluid (methanol), antifreeze (ethylene glycol)
  • Metabolism: Alcohol dehydrogenase → formaldehyde → formic acid (methanol); → glycolic acid → oxalic acid (ethylene glycol) → causes severe metabolic acidosis, CNS symptoms, renal failure
  • Antidote: Fomepizole (4-methylpyrazole - competitive inhibitor of alcohol dehydrogenase) or Ethanol (same enzyme affinity)
  • Additional: Hemodialysis for severe cases, sodium bicarbonate for metabolic acidosis

Organophosphate poisoning:

  • Mechanism: Irreversible AChE inhibition → excessive cholinergic activity
  • Toxidrome (DUMBBELSS/SLUDGE): Diarrhea, Urination, Miosis, Bradycardia, Bronchospasm, Bronchorrhea, Emesis, Lacrimation, Salivation
  • Muscarinic effects: SLUDGE
  • Nicotinic effects: Muscle fasciculations, weakness, paralysis
  • Antidote: Atropine (muscarinic antagonist - high doses until secretions dry) + Pralidoxime (2-PAM) (reactivates AChE before aging)

Cyanide poisoning:

  • Sources: House fires (hydrogen cyanide from burning synthetics), industrial, laetrile (amygdalin), nitroprusside
  • Mechanism: Binds cytochrome oxidase → blocks oxidative phosphorylation → cellular hypoxia despite adequate oxygen
  • Presentation: Bright red venous blood, lactic acidosis, CNS symptoms, cardiovascular collapse
  • Antidote: Hydroxocobalamin (binds cyanide to form cyanocobalamin - Vitamin B12); also Sodium nitrite + sodium thiosulfate (nitrite creates methemoglobin which binds cyanide)

Digoxin poisoning:

  • Toxidrome: Nausea, vomiting, abdominal pain, confusion, visual disturbances (yellow-green halos), arrhythmias (AV block, premature ventricular contractions, bigeminy)
  • Antidote: Digoxin-specific antibody fragments (Fab) - for severe poisoning
  • Also: Correct potassium (hyperkalemia - treat; hypokalemia - correct carefully as it potentiates digoxin)

Iron poisoning:

  • Toxicity stages: 0-6h (GI symptoms), 6-24h (quiescent/latent), 12-48h (shock, metabolic acidosis), 2-3 days (hepatic failure), 2-4 weeks (scarring)
  • Antidote: Deferoxamine (chelator) - for severe cases

Toxidromes

Sympathomimetic toxidrome (cocaine, amphetamines, methamphetamine, PCP):

  • Hypertension, tachycardia, hyperthermia, mydriasis, agitation, seizures
  • Treatment: Benzodiazepines (for agitation, seizures), cooling measures, antihypertensives (phentolamine for alpha, nitroprusside, nitroglycerin for hypertensive emergency)

Anticholinergic toxidrome (TCAs, antihistamines, atropine, jimson weed):

  • Classic mnemonic: “Hot as a hare, dry as a bone, red as a beet, mad as a hatter, blind as a bat”
  • Hyperthermia, anhidrosis, flushed skin, tachycardia, urinary retention, mydriasis, confusion
  • Treatment: Physostigmine (acetylcholinesterase inhibitor - specific antidote), cooling, benzodiazepines for agitation

Cholinergic toxidrome (organophosphates, carbamates):

  • DUMBBELSS/SLUDGE
  • Treatment: Atropine, pralidoxime

Opioid toxidrome:

  • CNS depression, respiratory depression, miosis, hypotension, bradycardia
  • Treatment: Naloxone

Sedative-hypnotic toxidrome (barbiturates, benzodiazepines, alcohol):

  • CNS depression, respiratory depression, normal pupils
  • Treatment: Supportive care; flumazenil for BZDs if indicated

SSRI/SNRI toxicity:

  • Serotonin syndrome: Hyperthermia, rigidity, hyperreflexia, myoclonus, altered mental status
  • Treatment: Cyproheptadine (serotonin antagonist), cooling, benzodiazepines

Herb-Drug Interactions

St. John’s wort: CYP3A4 and P-gp inducer → ↓levels of OCPs, cyclosporine, warfarin, many drugs Garlic, Ginkgo, ginger: Antiplatelet effects → ↑bleeding risk with warfarin Ginseng: May ↑ INR of warfarin Grapefruit juice: CYP3A4 inhibitor → ↑levels of certain drugs (statins, some calcium channel blockers)

Dermatological Agents

Topical Corticosteroids

Potency ranking (low to very high):

  • Low: Hydrocortisone 1%
  • Medium: Triamcinolone, desoximetasone
  • High: Fluocinonide, betamethasone dipropionate
  • Very high: Clobetasol propionate

Uses: Eczema, dermatitis, psoriasis, allergic reactions

Side effects (long-term use):

  • Skin atrophy, striae, telangiectasias
  • Contact dermatitis (rare)
  • Systemic absorption (especially potent steroids over large areas, in children)

Retinoids

Topical (tretinoin, adapalene, tazarotene):

  • Used for acne vulgaris
  • Side effects: Dryness, irritation, photosensitivity

Systemic (isotretinoin):

  • Used for severe nodular acne
  • Teratogenic (Category X - causes severe birth defects; iPLEDGE program for females)
  • Side effects: Dry skin/mucous membranes, hepatotoxicity, hyperlipidemia, pseudotumor cerebri
  • Monitor: Lipids, liver function tests, pregnancy test

Antipsoriatics

Methotrexate: For severe psoriasis (systemic) Cyclosporine: For severe psoriasis Biologics: Anti-TNF (infliximab, adalimumab), anti-IL-17 (secukinumab) for psoriasis Topical: Vitamin D analogs (calcipotriene), tacrolimus (for face/intertriginous areas)

Antifungals

Topical (clotrimazole, miconazole, ketoconazole, terbinafine):

  • Used for tinea (ringworm), candidiasis
  • Clotrimazole, miconazole: Imidazole spectrum
  • Terbinafine: Allylamine - better for dermatophytes

Systemic (griseofulvin - dermatophytes only; itraconazole - dermatophytes + systemic; fluconazole - systemic; ketoconazole - rarely used due to hepatotoxicity):

  • Used for onychomycosis, systemic fungal infections

Antivirals

Acyclovir: HSV encephalitis, genital herpes, chickenpox, shingles Valacyclovir: Better bioavailability than acyclovir; same indications Famciclovir: Shingles Oseltamivir: Influenza A and B (most effective within 48 hours)

Other Dermatological Agents

Calcineurin inhibitors (tacrolimus, pimecrolimus):

  • For atopic dermatitis (face, intertriginous areas)
  • Black box warning: Increased risk of skin malignancy (use cautiously)

Benzoyl peroxide: Acne (oxidizing agent → antibacterial) Salicylic acid: Keratolytic (acne, warts, psoriasis) Sulfur: Acne, seborrheic dermatitis Coal tar: Psoriasis, eczema (anti-inflammatory, anti-pruritic)

Immunopharmacology

Immunosuppressants

Corticosteroids (prednisone, methylprednisolone):

  • Used for organ transplantation, autoimmune diseases, severe inflammation
  • Side effects: Cushing syndrome, osteoporosis, immunosuppression, adrenal suppression, hyperglycemia

Calcineurin inhibitors:

  • Cyclosporine: Inhibits calcineurin → ↓IL-2 transcription → ↓T cell activation; used for transplant rejection, psoriasis, rheumatoid arthritis; nephrotoxic, hirsutism, gingival hyperplasia
  • Tacrolimus: Similar to cyclosporine; more potent; less hypertension and hirsutism; more neurotoxic

Antimetabolites:

  • Azathioprine: Purine synthesis inhibitor → ↓lymphocyte proliferation; used for transplant, autoimmune diseases; myelosuppression, hepatotoxicity
  • Mycophenolate mofetil: Inhibits IMPDH → ↓lymphocyte proliferation; used for transplant rejection; GI upset, myelosuppression

mTOR inhibitors:

  • Sirolimus (rapamycin): Inhibits mTOR → ↓T cell proliferation; used for transplant rejection; hyperlipidemia, poor wound healing
  • Everolimus: Similar

Biologics:

  • Anti-thymocyte globulin (ATG): Polyclonal antibodies against T cells; used for acute transplant rejection
  • Muromonab (OKT3): Anti-CD3 monoclonal antibody; acute rejection; cytokine release syndrome
  • Anti-TNF: Infliximab, adalimumab, etanercept; Crohn’s disease, rheumatoid arthritis, psoriasis; increased infection risk (especially TB reactivation)

Immunomodulators

Interferons (IFN-α, IFN-β, IFN-γ):

  • IFN-α: Hepatitis B/C, certain cancers (melanoma, renal cell carcinoma), condyloma acuminatum
  • IFN-β: Multiple sclerosis (reduces relapse rate)
  • Side effects: Flu-like symptoms, depression, hepatotoxicity, myelosuppression

Colony-stimulating factors:

  • Filgrastim (G-CSF): Stimulates neutrophil production; used for chemotherapy-induced neutropenia
  • Sargramostim (GM-CSF): Stimulates multiple myeloid lines

Intravenous immunoglobulin (IVIG):

  • Used for immunodeficiency, autoimmune diseases (ITP, Guillain-Barré, Kawasaki disease)
  • Side effects: Infusion reactions, aseptic meningitis, hemolysis

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