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USMLE (Fach) / Pharmacology - Toxicities and side effects (Lektion)
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- Fanconi syndrome - Cisplatin- Ifosfamide- Expired tetracyclines- Tenofovir
- Hemorrhagic cystitis - Cyclophosphamide- Ifosfamide - Prevent by coadministering with mesna
- Interstitial nephritis - Penicillins- Furosemide- NSAIDs- Proton pump inhibitors- Sulfa drugs
- Pulmonary fibrosis - Methotrexate- Bleomycin- Busulfan- Amiodarone- Nitrofurantoin- Carmustine
- Disulfiram-like reaction - Metronidazole- Griseofulvin- Procarbazine- 1st-generation sulfonylureas- Certain cephalosporines
- Nephrotoxicity/ototoxicity - Cisplatin- Aminoglycosides- Loop diuretics- Vancomycin- Amphotericin B Cisplatin toxicity may respond to amifostine.
- Drugs affecting pupil size ↑ pupil size- Anticholinergics (atropine, TCA, tropicamide, scopolamide, antihistamines)- Drugs of abuse (amphetamines, cocaine, LSD)- Symphathomimetics ↓ pupil size- Antipsychotics (haloperidol, risperidone, olanzapine)- Drugs of abuse (eg, heroin/opioids)- Parasympathomimetics (pilocarpine), organophosphates
- Cytochrome P-450 inducers - Rifampin- Modafinil- Chronic alcohol use- St. John's wort (antidepressant features)- Anticonvulsants (phenytoin, phenobarbital, carbamazepine)- Griseofulvin- Nevirapine (NNRTI)
- Cytochrome P-450 substrates - Anti-epileptics- Warfarin- Theophylline- Oral contraceptives
- Cytochrome P-450 inhibitors - Isoniazid- Grapefruit juice- Valproate- Cimetidine- Ketoconazole, fluconazole- Acute alcohol abuse- Chloramphenicol- Erythromycin/clarithromycin- Sulfonamides- Ciprofloxacin- Omeprazole- Metronidazole- Amiodarone
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- Sulfa drugs - Sulfonamide antibiotics- Sulfasalazine- Probenecid- Furosemide- Acetazolamide- Celecoxib- Thiazides- Sulfonylureas Patients with sulfa allergies may develop fever, urinary tract infection, Stevens-Johnson syndrome, hemolytic anemia, thrombocytopenia, agranulocytosis, acute interstitial nephritis, and urticaria.
- Ethylene glycol toxicity Toxic alcohol that is metabolized to glycolate, which is cytotoxic to the renal tubules and causes acute tubular necrosis. Glycolate is further metabolized to oxalate, which contributes to oliguric renal failure by precipitating in the kidneys and causing tubular obstruction. Sources of exposure:- Ingested as ethanol substitute by alcoholics- Self-harm attempts Clinical feature:- Sweet-smelling breath- Altered mental status, hallucinations, seizures- Dyspnea, tacypnea- Calcium oxalate deposition in the kidneys → Flank pain, gross hematuria, oliguria and acute kidney injury- Signs of tetany Lab:- High anion gap metabolic acidosis (>10-14 mEq/L)- Elevated osmolar gap Treatment: - Fomepizol, ethanol, dialysis
- Androgen abuse Cardiovascular: ↑ Hematocrit, ↑ LDL, ↓ HDL cholesterol Dermatologic: Acne, hirsutism, male-pattern hair loss Genitourinaty: Testicular atrophy, ↓ spermatogenesis; clitoromegaly, oligomenorrhea Psychiatric: Depression, hypomania; aggressiveness, mood disorders Breast: Atrophy (female), gynecomastia (male) Other: Deepening of voice, premature epiphyseal closure (adolescents)
- Cyanide poisoning Deadly poison that binds irreversibly to cytochroma a/a3, preventing electron transfer to oxygen. Sources: Burning of rubber or plastic Presentation:- Reddish skin discoloration- Bitter almond breath- Tachypnea, tachycardia- Headache, confusion- Nausea/vomiting- Weakness- Symptoms can quickly progress to seizures and cardiovascular collapse. Blood tests: high anion gap metabolic acidosis, ↑ lactic acid Treatment: - Decontamination of the patient (e.g., remove clothes, wash skin)- Administration of 100% oxygen, supportive care- Patients with a smoke inhalation injury should be treated empirically for cyanide toxicity.- Antidote:→ Hydroxycobalamin (precursor of vitamin B12): binds cyanide directly and forms cyanocobalamin, which is excreted in urine.→ IV sodium nitrite, amyl nitrite, or 4-dimethylaminophenol (4-DMAP): induce methemoglobinemia; methemoglobinbinds to cyanide to form cyanomethemoglobin, which diverts cyanide from cytochrome complex IV and increases oxidative phosphorylation.→ IV sodium thiosulfate: supplies sulfur donors to the mitochondrial enzyme rhodanese, which detoxifies cyanide into thiocyanate, which is excreted in urine.
- Nitrate poisoning Nitrates cause poisoning by inducing the conversion of this heme iron to the oxidized ferric (Fe3+) state, leading to the formation of methemoglobin.With iron in the oxidized ferric state, methemoglobin is unable to bind oxygen. - In addition, the affinity of any residual ferrous iron in the hemoglobin tetramer is increased, causing a leftward shift of the oxygen-dissociation curve.- The partial pressure of oxygen is unchanged. Methemoglobulinemia causes dusky discoloration of the skin (similar to cyanosis) and because methemoglobin is unable to carry oxygen, a state of functional anemia is induced.
- Carbon monoxide Carbon monoxide binds to cytochrome a/a3 but less tightly than cyanide. It also binds to hemoglobin, displacing oxygen. Sources:- Propane heaters and gas grills- Vehicle exhause- Tobacco smoke- House fires Symptoms:- Headache- Nausea- Tachykardia- Tachypnea- Lips and cheeks turn a cherry-red color
- Arsenic poisoning Arsenic inhibits lipoic acid- Binds to sulfhydryl groups- Disrupts cellular respiration & gluconeogenesis Sources:- Pesticides/insecticides- Contaminated water (often from wells)- Pressure-treated wood Manifestations:- Acute: Garlic breath, vomiting, watery diarrhea, QTc prolongation- Chronic: Hypo/hyperpigmentation, hyperkeratosis, stocking-glove neuropathy Treatment:- Dimercaprol- Succimer
- Methemoglobinuria Clinical features:0-3% of total hemoglobin: physiological>3%: visible cyanosis (a brownish-blue or greyish coloration of the skin and membranes)>20%: clinical symptoms of oxygen deprivation, brown blood ("chocolate-colored blood") Causes:- Exposure to nitrate or nitrite- Drugs (nitroglycerin, sulfonamides, dapsone, inhaled nitric oxide, topical anesthetics such as lidocaine, and aniline derivatives) Lab findings:- Pulse oxymetry readings of ~85% (methemoglobin absorbs light at a different wavelength than hemoglobin)- ABGA shows normal PaO2 (only analyzes unbound arterial oxygen)- Saturation gap (>5% difference between oxygen saturation on pulse oximetry & ABG) Therapy:- Methylene blue- Vitamin C (reducing agent)