1. 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

2. 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

3. 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

4. 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 400mg/kg of ibuprofen is typically very serious

5. 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)

6. Non steroidal anti- inflammatories NSAID’s Treatment for acute overdose: secure airway activated charcoal transport

7. 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

8. Salicylate Toxicity, cont. Mechanism of Action: Uncoupling of oxidative phosphorylation that leads to: –an increase in metabolic rate, –increase O2 consumption, –increase CO2 formation, –increase heat production and –increase glucose utilization and depletion of hepatic glycogen

9. 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 500mg/kg Degree of toxicity is more severe in the elderly and infants

10. 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

11. 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 90mg/kg in child Acetaminophen toxicity is the most common cause of hepatic failure necessitating liver transplant in the U.S.

12. 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 P450 mixed function oxidase system which liberates the toxic metabolite N-acetyl-p-benzoquinoneimine (NAPQI)

13. 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

14. 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

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

16. 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 - 140mg/kg q. 4 h. for 18 doses

17. 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 10x 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)

18. Vitamin Toxicity Group of essential organic nutrients required in the diet Accidental poisoning is a problem in children < 5yrs. 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.

19. 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

20. Vitamin A toxicity, cont. Large doses of Vit. A are teratogenic Chronic renal disease can cause a relative hypervitaminosis A Retinol is Vit. A1 - 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

21. 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

22. 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)

23. 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

24. 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

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

26. Vitamin D toxicity Vitamin D3 - 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

27. 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

28. 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)

29. Vitamin K toxicity 2 natural forms –plant derived phytonadione, Vitamin K1 –intestinal bacterial synthesized - menaquinone - Vit. K2 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

30. 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

31. Vitamin C toxicity, cont. Clinical features: –diarrhea, nausea, cramping, urinary calculi (from oxalates), rebound scurvy (in patients taking mega- doses 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 60mg (40mg in children 1-4 years)

32. 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 : –H1 - stimulation constricts bronchioles, dilates peripheral vasculature, increase vascular permeability –H2 - regulators of gastric acid secretion –In CNS H1 and H2 - modulate arousal, thermoregulation and neuroendocrine functions –H3 - presynaptic regulator of histamine synthesis and release

33. “Antihistamine” toxicity, cont. First generation H1 receptor antagonists are responsible for vast majority of poisonings H1 receptor blockers are reversible competitive inhibitors of H1 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

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

35. “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

36. “Antihistamine” toxicity, cont. H2 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)

37. 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

38. 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

39. 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

40. Caffeine content Coffee (5 oz.) brewed40-200 mg instant30-150 Tea (5 oz.) brewed20-100 instant25-50 iced (12 oz. glass)65-80 Carbonated beverages25-200 1 oz. dark chocolate5-30 Analgesics30-65

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

42. 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 600mg of caffeine daily could result in increased incidence of spontaneous abortion and premature birth

43. 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