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Clinical toxicology Dep. of Biopharmaceutics and Clinical Pharmacy Drug-induced poisoning: Relevance! • • • Substances people purposefully take or use to relieve their illness or produce symptoms of pleasure and cause dissociation from reality (illicit psychotomimetics) The incidence of adverse reactions related drugs is reported up to 30% of all hospitalized patients From 2 to 9% of all admissions to medical clinics are due to adverse drug reactions • Reasons: Children accidentally from unguarded containers Children given inappropriate doses Adults Tx with overdose accidentally or intentionally Drug-drug, drug-food & drug-ethanol interactions Drug-induced poisoning: Relevance! • Drug reactions have increased in number and severity due to: Increased availability of potent prescription and OTC drugs Increased number of variety of illicit drugs • 85% due to the pharmacologic action of the drug!!! • 15% due to immunologic mechanisms (as anaphylaxis) NSAID’S INTOXICATION Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) Overview: Definition: NSAIDs are a chemically diverse class of drugs (>70 NSAIDs in use) that have antiinflammatory, analgesic, and antipyretic, antiaggregant properties KINETICS — Oral absorption of NSAIDs approaches 100 percent and peak serum levels usually occur within one to two hours. Large toxic ingestions or concomitant food consumption can delay peak levels up to three to four hours. NSAIDS are weak acids that are extensively (up to 99 percent) protein bound, with a small volume of distribution (0.1 to 0.2 L/kg). Diseases causing low protein levels or large NSAID ingestions can decrease plasma protein binding, resulting in an increased volume of distribution and greater penetration into body tissues, including the central nervous system. NSAIDs Among the most frequently prescribed drugs worldwide: 70 million people/day prescribed NSAIDs 230 million people/day take OTC NSAIDs USA: 80 billion aspirin tablets consumed/year USES 1. Anti-inflammation 2. Analgesic 3. Anti-pyretic 4. Treatment of gout, arthritis 5. Prophylaxis of heart disease (myocardial infarction and stroke) 6. Prophylaxis of colorectal cancer 7. Prevention of development of Alzheimer disease Background Patients who ingest NSAIDs in overdose, manifest only mild GI upset and CNS disturbances that are usually self limiting However, serious and fatal outcome may result after overdose with oxyphenbutazone, phenylbutazone, mefenamic acid, piroxicam, or diflunisal ….from acute renal failure, hepatic failure, respiratory depression, coma, convulsion and cardiac arrest Mechanism of action Normal inflammatory response • series of events that aid our survival in response to injury Mediated by a host of endogenous compounds -histamine -serotonin -bradykinin -prostaglandins -leukotrienes Mechanism of action & toxicity: inhibit cyclooxygenase, the enzyme that mediates the initial step in PGs synthesis Properties of Prostaglandins NSAID Mechanism a) NSAIDs inhibit cyclooxygenase (COX) b) Three types of cyclooxygenase: - COX-1 is constitutively expressed - COX-2 is induced at sites of inflammation by inflammatory mediators - COX-3 recently identified COX-2 Hypothesis (1990s) Normal Tissue Inflammation Site Arachidonic Acid + COX-1 Constitutive Cytokines Growth factors COX-2 Inducible COX-2 Inhibitors NSAIDs Physiolgical Prostaglandin Production Normal Functions Pathological Prostaglandin Production Inflammation, pain, fever Properties of Prostaglandins Physiological Functions of PG: • Pain: PGI2 and PGE2 sensitize nerve endings to bradykinin, histamine and substance P • Inflammation: PGI2, PGD2 and PGE2 are vasodilators (edema, erythema) • Protection of the gastric mucosa: PGI2 • Maintenance of renal blood flow: PGE2 • Fever: PGE2 • Platelets: PGI2 inhibit platelet aggregation; TXA2 stimulates platelet aggregation • Uterus: PGD2 contracts uterus Side Effects of NSAIDs • GI: N, V, abdominal pain, GI hemorrhage from local irritation • Hematologic: blood dyscrasias and hemorrhage resulted from impaired platelet aggregation • Renal: Na, K & water retention. Nephrotoxicity is due, in part, to interference with the autoregulation of renal blood flow • Cardiac: worsening of congestive heart failure due to water and sodium retention • Obstetric: delay in the onset of labor, prolonged labor, increased risk of hemorrhage and may close ductus arteriosum by inhibition of PG • Neurologic: minor CNS disturbances….drowsiness, blurred vision • Hypersensitivity reactions Inhibition of the Cyclooxygenases a. Competitive inhibition of the substrate (arachidonic acid) binding site of COX. The inhibition is reversible when the drug washes out. COX-1 COX-1 COX-2 COX-2 From Nature Structural Biology, vol 3, number 11, 1996 COX-2 Specific Inhibitors • • • • The newest generation of NSAIDs, (rofecoxib [Vioxx], celecoxib [Celebrex], valdecoxib [Bextra]), selectively inhibits the COX-2 isoform at therapeutic doses The likelihood of GI bleeding is less with these drugs than with conventional NSAIDs There is limited information regarding overdoses of COX-2 inhibitors……hypertension, acute renal failure, respiratory depression, and coma may occur in overdose Rofecoxib and valdecoxib have been removed from the market because increased risk for CV events (including MI & stroke) NSAIDs Classification NSAIDs are subdivided into six groups based on their chemical structure 1. Salicylates 2. Pyrazolones: phenylbutazone 3. Indoleacetic acid (pyroles): diclofenac, indomethacin 4. Phenylpropionic acids: ibuprofen, ketoprofen, naproxen 5. Anthranilic acids: mefenamic acid 6. Oxicam: piroxicam Inhibition of the Cyclooxygenases b. Acetylation of a key serine within the active site. This reaction is not reversible and is unique to aspirin. Pyrazolones Phenylbutazone; oxyphenbutazone: available for veterinary use, may present in some herbal preparation (withdrawn from the market) Aplastic anemia and agranulocytosis have been associated with the use of phenylbutazone Indoleacetic acid (pyroles) Indomethacin, diclofenac, etodolac, ketorolac, sulindac: Rapidly absorbed from GI, they undergoes hepatic circulation Clinical presentation: nausea, vomiting, abdominal pain, tinnitus, drowsiness, confusion, restlessness Self-limiting Indoleacetic acid (pyroles) 1. 2. 3. Management: Gastric lavage should be performed in cases of serious overdose Activated charcoal should be given and repeated every 4 hrs Supportive and symptomatic treatment Phenylpropionic acids Ibuprofen, fenoprofen, flurboprofen, ketoprofen, naproxen In general, overdose with “propionic acids” do not result in significant morbidity or mortality, although death after overdoses of ibuprofen & fenoprofen have occurred Ibuprofen: the most widely used and rapidly absorbed from GI Neither the rate of absorption nor elimination seems to be altered by overdose Ibuprofen Therapeutic range: adult 400-2400 mg/day children 20-50 mg/kg/day Poisoning is usually manifested by mild GI symptoms: N, V, abdominal pain, anorexia, GI hemorrhage (rare) CNS depression Nystagmus, tinnitus Respiratory depression Metabolic acidosis Headache, seizures Hypotension, bradycardia, hypothermia Ibuprofen In the presence of normal renal function, patients usually fully recover within 24hrs Reports of severe and fatal outcomes following the onset of acute renal or hepatic failure, hypotension and coma Ibuprofen Treatment…..GI decontamination 1. Ingestion less than 100mg/kg: dilute with water to reduce gastric irritation 2. More than 100mg/kg: Gastric lavage After gastric emptying, activated charcoal and a saline cathartics should be administered Ibuprofen 4. 5. 6. 7. 8. Hypotension: treated with i.v. fluids , if it persist dopamine or NE may be required Seizures: treated with diazepam Bradycardia may respond to atropine Metabolic acidosis (PH < 7.1) may require administration of sodium bicarbonate Ibuprofen weak acid….urine alkalinization? NO coz short half-life and extensive protein binding Anthranilic acids Mefenamic acid & maclofenamate Is well absorbed, more than 50% excreted unchanged in urine, the reminder as conjugate Clinical presentation: 1. May produce no symptoms 2. Muscle twitching either focal or generalized has been reported 3. Seizures are common following overdose 4. Diarrhea, rash, elevated BUN and coma Anthranilic acids Management: Tx with gastric lavage, and administration of activated charcoal Observation for seizures development Oxicam Piroxicam It undergoes enterohepatic circulation, long half-life (45h) Clinical presentation: Usually not develop severe symptoms Can cause photosensitivity reaction (use sunscreen when outside) GI hemorrhage, dizziness, difficulty in breathing, hematuria, proteinuria, renal and hepatic dysfunction Management: Gastric lavage, followed by repeated doses of AC N.B Specific levels of NSAIDs are not usually readily available and management do not contribute to clinical Antacids may be used for mild GI upset There is no antidote….vitamin K may be used for patients with elevated prothrombin time caused by hypoprothrombinemia Enhanced elimination? NSAIDs are highly protein- bound and extensively metabolized…… PGs and uterus TOCOLYSIS • • • • • • COX inhibitors (selective or not) Beta-2 agonists CCB Oxytocin antagonist Nitric oxide donors Magnesium sulfate • Fetal side effects — The primary fetal concerns with use of indomethacin and other COX inhibitors (are constriction of the ductus arteriosus. • COX INHIBITORS — Prostaglandin E2 (PGE2) is a vasodilator that promotes ductal patency. In the 1970s, two studies demonstrated pharmacologic closure of patent ductus arteriosus (PDA) within 24 hours with the administration of indomethacin, an inhibitor of cyclooxygenase (COX), the pivotal enzyme in the synthesis of PGE2 [6,7]. Currently, the two cyclooxygenase inhibitors used to medically close PDAs are indomethacin and ibuprofen. • Dose — The dose of indomethacin for labor inhibition is a 50 to 100 mg loading dose (may be given per rectum), followed by 25 mg orally every four to six hours. Fetal blood concentrations are 50 percent of maternal values, but the half-life in the neonate is substantially longer than that in the mother (15 versus 2.2 hours).