Toxicity of Medicinal Substances All things are poisonous

Toxicity of Medicinal Substances “All things are poisonous and nothing is without poison. Solely the dose determines that a thing is poisonous or not”. Paracelsus

Non steroidal anti-inflammatories NSAID’s • More than 30 billion NSAID’s are consumed annually in US alone • Major effect of all NSAID’s is to decrease the synthesis of prostaglandins by reversibly inhibiting cyclooxygenase • Prostaglandins – enhance the inflammatory process – increase renal blood flow – cytoprotection of the GI mucosa

Non steroidal anti-inflammatories NSAID’s • Two forms of Cyclooxygenase have been Id-ed: – COX-1 - has gastroprotective effects – COX-2 - produces proinflammatory mediators • Older NSAID’s (ie. ibuprofen) inhibit COX-1 more than COX-2 whereas the newer class inhibit COX-2 predominately decreasing the GIT adverse effects • Problems associated with acute toxicity: – GIT symptoms are most common - dyspepsia – Renal effects are second most common problem

Non steroidal anti-inflammatories NSAID’s • 1998 AAPCC documented 52, 751 toxic exposures to ibuprofen with 4 deaths • AAPCC reported in 1998 complications arising from therapeutic use of NSAID’s accounted for 100, 000 toxic exposures resulting in hospitalizations with 10, 000 resulting in fatalities • Correlation between quantity ingested and toxic poisonings is poor however: – more than 4 g of phenylbutazone, 6 g of mefenamic acid and 400 mg/kg of ibuprofen is typically very serious

Non steroidal anti-inflammatories NSAID’s - Examples: • Pyrazolones - phenylbutazone - one of the most toxic – severe GIT signs, CV arrest, seizures, pulmonary edema • Fenamate - Ponstel, Meclomen • Diflunisal - Dolobid • Acetic acid derivatives - Diclofenac (Voltaren), indomethacin (Indocin), sulindac (Clinoril), etodolac (Lodine), tolmetin (Tolectin) • Propionic acid derivatives - Ibuprofen (Motrin), fenoprofen (Nalfon), flurbiprofen (Ansaid), carprofen (Rimadyl), naproxen (Naprosyn) • Oxicams - piroxicam (Feldene)

Non steroidal antiinflammatories NSAID’s • • Treatment for acute overdose: secure airway activated charcoal transport

Salicylate Toxicity • Posses anti-inflammatory, analgesic and antipyretic properties • Salicylates have been used since the times of Hippocrates • Derived from the bark of the willow tree (Salix alba vulgaris) • Bayer was a German company who developed aspirin in the late 1800’s • Drastic decline in pediatric poisonings since the Poison Prevention Packaging Act of 1970

Salicylate Toxicity, cont. • Mechanism of Action: Uncoupling of oxidative phosphorylation that leads to: – an increase in metabolic rate, – increase O 2 consumption, – increase CO 2 formation, – increase heat production and – increase glucose utilization and depletion of hepatic glycogen

Salicylate Toxicity, cont. • 1998 the AAPCC reported a total of 14, 533 exposures to pure aspirin formulations. • 3837 were in children > 6 years, 5053 in patients > 19 years, and 33 deaths were reported. • Mortality of patients with chronic intoxication is around 25% • Aspirin is potentially lethal at a dose of 500 mg/kg • Degree of toxicity is more severe in the elderly and infants

Salicylate Toxicity, cont. • Clinical features: – nausea and vomiting, dehydration, tachypnea, hyperthermia, confusion, coma, tinnitus, pulmonary edema, acute renal failure, hypoglycemia, metabolic acidosis, bleeding • Treatment: – induce vomiting in children, give activated charcoal, – stabilize the airway, breathing and circulation, transport

Acetaminophen Toxicity • Paracetamol, N-acetyl-p-aminophenol • Most widely used analgesic/antipyretic in the world today, contained in more than 100 products • Member of the coal tar family of analgesics • About 150 people/year die from acetaminophen overdose • Max daily adult dose is 4 g/day and 90 mg/kg in child • Acetaminophen toxicity is the most common cause of hepatic failure necessitating liver transplant in the U. S.

Acetaminophen Toxicity, cont. • Mechanism of action: – acetaminophen is one of the rare examples of drug toxification upon metabolism as opposed to drug detoxification – 2% is excreted in the urine unchanged – 90% is conjugated with sulfate or glucuronide – the rest is metabolized by the cytochrome P 450 mixed function oxidase system which liberates the toxic metabolite N-acetyl-p-benzoquinoneimine (NAPQI)

Acetaminophen Toxicity, cont. • Mechanism of action, cont. – NAPQI attaches to the hepatic cell membrane and injures the lipid bilayer if not neutralized by an antioxidant – the primary antioxidant used is hepatic glutathione – if levels of NAPQI exceed hepatic stores of glutathione then hepatic cell death will occur • Toxicity is worse in chronic alcoholics due to induction of hepatic microsomal enzyme systems

Acetaminophen Toxicity, cont. • Clinical presentation: Phase I: 30 min. to 24 hrs. post ingestion, anorexia, nausea, vomiting, malaise, diaphoresis Phase II: 24 - 72 hrs. post ingestion, decreasing symptoms of phase I, right upper abdominal quadrant pain Phase III: 72 -96 hrs. post ingestion, centrilobular hepatic necrosis, jaundice, coagulation defects, renal failure, hepatic encephalopathy, possible death due to multi-organ failure Phase IV: 4 - 14 days post ingestion, if patient survives, complete resolution of hepatic dysfunction and liver can heal without fibrosis

Patients at increased risk • Patients with: – malnutrition – AIDS – chronic alcoholics – anorexia nervosa – all have deficient levels of glutathione and inadequate detoxification of NAPQI

Acetaminophen Toxicity, cont. • Treatment: – induce vomiting – give activated charcoal – N acetylcysteine (mucomyst) and methionine restore intracellular levels of glutathione and sulfur that helps in the conversion of acetaminophen to the sulfur metabolite – dose of mucomyst - 140 mg/kg q. 4 h. for 18 doses

Vitamin Toxicity • More than 100 million Americans regularly use vitamins • Americans spend $6. 5 billion annually (doubled in last 6 years) • Iron containing vitamins are most toxic • Adult toxicity usually due to people taking megadoses. a megadose is defined as a dose which is 10 x the RDA • 40% of Americans take megadoses of one or more vitamins • The fat soluble vitamins represent the greatest danger to over dose (Vit. ADEK)

Vitamin Toxicity • Group of essential organic nutrients required in the diet • Accidental poisoning is a problem in children < 5 yrs. • 1998 AAPCC reports 49, 709 exposures, 14 major adverse outcomes and no deaths. • Of the above 39, 396 exposures occurred in children younger than 6 years of age. • Non specific signs and symptoms such as nausea, vomiting, diarrhea are common.

Vitamin A Toxicity • 1500 BC night blindness in Egypt was treated by the topical application of roasted liver • Hippocrates recommended the ingestion of cow liver as the cure for night blindness • 1857 Arctic explorer Elisha Kane described a syndrome of severe headache, vomiting and irritability a few hours after ingestion of polar bear liver

Vitamin A toxicity, cont. • Large doses of Vit. A are teratogenic • Chronic renal disease can cause a relative hypervitaminosis A • Retinol is Vit. A 1 - the alcohol form and found in the liver of animals and saltwater fish • Retinal is the Vit. A aldehyde and functions as the chromophore of the retina when it combines with the protein opsin to form rhodopsin • B-carotene is provitamin A and occurs in plants

Vitamin A toxicity, cont. • Functions of Vitamin A: – essential for normal vision – maintenance of functional and structural integrity of epithelium in mucus secreting or keratinizing tissues – necessary for normal bone growth, osteoblastic function – necessary for normal reproductive health – necessary for normal embryonic development – enhances immune function – plays a significant role as an anticarcinogen

Vitamin A toxicity, cont. • Toxic doses: – acute toxic dose is 25, 000 IU/kg – chronic toxic dose is 4000 IU/kg every day for 6 -15 months – USRDA is 5000 IU (2500 IU for children aged 1 -4 years)

Vitamin A toxicity, cont. • Clinical features: – acute toxicity - not common - irritability, tiredness, somnolence, increased intracranial pressure (Pseudotumor cerebri), anorexia, vomiting, cheilitis, hair loss, skin peeling, hepatomegaly, epistaxis – chronic - more common - headache, fatigue (but difficulty sleeping), visual disturbances, anorexia, weight loss, increased intracranial pressure, dry skin that is pruritic and scaly and peeling; hair loss; brittle nails; cheilitis, gingivitis and stomatitis; hepatomegaly, nausea, abdominal pain and ascites

Vitamin A toxicity, cont. • Clinical features, cont. – chronic toxicity, cont. - bone pain and tenderness, radiographs show areas of hypermineralization and osteoporosis, periosteal calcification and cortical hyperostosis of the cranium, clavicle, long bones, and metatarsals; premature closure of the epiphyseal plate in children, elevated alkaline phosphatase; – is teratogenic to the developing embryo causing hydrocephalus, cleft palate, tetralogy of Fallot, thymic hypoplasia

Vitamin A toxicity, cont. • Diagnosis - clinical signs, history of exposure, serum retinol levels exceeding 100 ug/d. L • Treatment - discontinue Vit. A and most symptoms resolve over several weeks to months – in acute exposure induce vomiting – supportive care

Vitamin D toxicity • Vitamin D 3 - cholecalciferol - formed in the skin by exposure to UV light • Source - fish liver oils, fortified milk • Function: – key role in calcium homeostasis • Daily requirements - 200 -400 IU/day (5 -10 ug) • Vitamin D deficiency manifests as rickets in growing children and osteomalacia in adults

Vitamin D toxicity, cont. • Toxic doses: – children - 400 IU/d – adults - 50, 000 IU/d for weeks to months • Clinical features: – hypercalcemia, weakness, headache, fatigue, nausea, vomiting, soft tissue calcification, hypertension, polyuria, polydipsia, nephrocalcinosis; possible death • Treatment - stop Vit. D administration, acute exposure - induce vomiting, supportive treatment

Vitamin E toxicity • alpha tocopherol is the most important vitamer • Functions: – necessary for normal reproduction and neuromuscular function, also important as an antioxidant • Toxicity: – chronic ingestion of 400 - 3000 IU/d - fever, headache, fatigue, nausea, intestinal cramps, diarrhea - but difficult to document as results are very inconsistent – may antagonize Vit. K with a resultant increase in clotting time • USRDA is 30 IU (10 IU for children 1 -4 years)

Vitamin K toxicity • 2 natural forms – plant derived phytonadione, Vitamin K 1 – intestinal bacterial synthesized - menaquinone - Vit. K 2 • Essential cofactors in the hepatic biosynthesis of blood coagulation factors II, VII, IX, and X • Toxicity is rare because Vit. K is not a component of most vitamin supplements

Vitamin C toxicity • Ascorbic acid • Scurvy has been recognized since the Middle Ages • Humans, guinea pigs and the Indian fruit bat are the mammals who can not synthesize Vit C from glucose • Functions: – cofactor for hydroxlylation reactions, powerful antioxidant; vital to normal synthesis of collagen, proteoglycans and other components of intracellular matrix

Vitamin C toxicity, cont. • Clinical features: – diarrhea, nausea, cramping, urinary calculi (from oxalates), rebound scurvy (in patients taking megadoses who abruptly stop, also occurs in infants of mothers taking mega-doses); elevated levels of estradiol in women taking oral contraceptives and mega-doses; increased iron absorption (dangerous in patients with hemochromatosis) – Treatment - discontinue Vit C, supportive care – USRDA is 60 mg (40 mg in children 1 -4 years)

Antihistamines (Histamine blockers) • Functions of histamine: – Histamine is the mediator of the allergic response – regulator of gastric acid secretion – CNS neurotransmitter • Three types of receptors : – H 1 - stimulation constricts bronchioles, dilates peripheral vasculature, increase vascular permeability – H 2 - regulators of gastric acid secretion – In CNS H 1 and H 2 - modulate arousal, thermoregulation and neuroendocrine functions – H 3 - presynaptic regulator of histamine synthesis and release

“Antihistamine” toxicity, cont. • First generation H 1 receptor antagonists are responsible for vast majority of poisonings • H 1 receptor blockers are reversible competitive inhibitors of H 1 receptors and competitive inhibitors of muscarine receptors. They also block sodium channels and can disrupt cortical neurotransmission. • 1999 AAPCC reported 52, 118 exposures, 3884 resulted in moderate to major toxicity and 28 resulted in fatalities • Most cases occurred in children > 6 years

“Antihistamine” toxicity, cont. • Examples: – diphenhydramine - Benadryl, Caladryl – doxylamine – chlorpheniramine - Chlor Trimeton, Ornade – hydroxyzine - Atarax – loratadine - Claritin – fexofenadine - Allegra – cetirizine

“Antihistamine” toxicity, cont. • Clinical features: – sedation - common at therapeutic doses – headache – dry mouth – nausea – Allegra has been reported to cause menstrual pain • Treatment - supportive and symptomatic care

“Antihistamine” toxicity, cont. • H 2 receptor blockers: used to treat “heartburn” • Examples: – cimetadine - Tagamet – ranitidine - Zantac – famotidine - Pepcid – nizatidine - Axid • Clinical features: bradycardia or tachycardia, confusion, agitation, delirium and seizures (rare)

Antibiotic toxicity, cont. • Antibiotics are the most commonly prescribed drugs in primary care • Toxic effects include hypersensitivity, and direct organ toxicity • Penicillin is the leading cause of hypersensitive reactions and causes about 400 deaths/yr. • Each antibiotic is associated with a unique toxicity

Antibiotic toxicity, cont. • • B-lactase antibiotics - penicillin - hypersensitivity sulfonamides - hypersensitivity macrolides - erythromycin - gastric irritation chloramphenicol - aplastic anemia tetracyclines - photosensitivity, renal tubular necrosis aminoglycosides - ototoxic fluroquinolones - disrupt cartilage synthesis polymyxin B - urtacaria

Caffeine toxicity • Methylxanthines - theobromine, theophylline and caffeine • Caffeine - plant alkaloid • Source: – found in a wide assortment of foods and beverages and medicinal compounds. – used in the treatment of migraine headaches

Caffeine content Coffee (5 oz. ) brewed instant 40 -200 mg 30 -150 Tea (5 oz. ) brewed instant iced (12 oz. glass) 20 -100 25 -50 65 -80 Carbonated beverages 1 oz. dark chocolate Analgesics 25 -200 5 -30 30 -65

Caffeine toxicity, cont. • Toxic dose: undesirable effects are seen after doses of as little as 50 mg, more significant toxicity seen after ingestion of 15 -30 mg/kg. lethal dose is 100 -200 mg/kg. • Clinical features – low doses - nervousness, restlessness, insomnia, abdominal pain – high doses - vomiting, myoclonus, myocardial irritability, seizures

Caffeine toxicity, cont. • Chronic caffeine intoxication - irritability, insomnia, anxiety, chronic abdominal pain, cardiovascular disease, fibrocystic disease of the breast. • Caffeine is teratogenic in lab animals • Research shows that more than 600 mg of caffeine daily could result in increased incidence of spontaneous abortion and premature birth

Caffeine toxicity, cont. • Is addictive and abrupt cessation of consumption causes withdrawal – signs of withdrawal include insomnia, malaise and headache within 48 hours of stopping caffeine usage • Treatment: – acute - give activated charcoal and cathartics, maintain airway, treat seizures, monitor cardiac function – chronic - slow withdrawal, treat symptomatically