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Pharmaceutical Additives

G. Patrick Daubert, MD Sacramento, CA

Some (most) material plundered from various mentors and other talented toxicologists, with permission

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MENU

n  2.1.12 Pharmaceutical Additives n  2.1.13 Veterinary Products n  2.1.14 Vitamins

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Pharmaceutical Additives

n  Propylene glycol n  Polyethylene glycol n  Benzyl alcohol n  Vit E ferol n  Benzalkonium chloride n  Thimerosol n  Tryptophan n  Sorbitol

n  Chlorbutanol n  Parabens n  Diethylene glycol n  Thallium n  Thorotrast n  Thalidomide n  DES

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Pharmaceutical Additives

n  Propylene glycol n  IV preps pushed rapidly

n Hypotension, bradycardia, asystole

n  Prolonged infusions n Lactic acid production

n  Polyethylene glycol n  Toxicity concern with low MWs (< 400) n  Risk of acute tubular necrosis

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Gasping Syndrome

n  In 1981 16 neonatal deaths occurred in a NICU n  All were pre-term neonates < 2500 gm n  Symptoms included severe AGMA, respiratory

depression with gasping, and encephalopathy n  All neonates had received bacteriostatic NaCl or

water flushes containing 0.9% benzyl alcohol

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Gasping Syndrome

n  Benzyl alcohol is normally oxidized rapidly to benzoic acid, conjugated with glycine in the liver, and excreted as hippuric acid

n  This metabolic pathway is not well developed in premature infants

n  Accumulation of benzoic acid causing metabolic acidosis, seizures, coma, death

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DEG and Sulfanilamide

n  September-October 1937

n  S.E. Massengill Co., used DEG diluent in sulfanilamide elixir

n  Vomiting, abdominal pain, anuria, seizures, coma n  105 deaths in 15 states

n  34 children

n  Hydropic tubular nephrosis n  Development of the Food, Drug, and Cosmetic Act

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Polysorbate 80 and E-Ferol

n  Polysorbate 80 = polyproblems n  Released december 1983

n  IV form of a vitamin E preparation (E-Ferol) n  Fatalities among low birth weight (< 1,500 g) and

premature infants n  38 deaths and 43 cases of severe morbidity

n  Thrombocytopenia n  Renal failure n  Cholestasis n  Ascites

n  Inhibitory effect by this vitamin E preparation on the in vitro response of human lymphocytes to phytohemagglutinin

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Eosinophilia Myalgia Syndrome

n  October 1989, the health department in New Mexico was notified of 3 patients with an unexplained acute illness

n  Characterized by intense myalgia, dyspnea, extremity edema, neuropathy, and peripheral blood eosinophilia

n  By July 1991, 1543 cases and 31 deaths were attributed to EMS

n  Some L-tryptophan may have been produced by a new bacteria causing an unknown bi-product

n  EMS lead to the Dietary Supplement Health and Education Act of 1994

n  Syndrome resembled Toxic Oil Syndrome (rapeseed oil)

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Pharmaceutical Additives

n  Benzalkonium chloride n  Most common ophthalmic preservative n  Cytotoxic to corneal epithelium n  Compromised cornea (keratoconjunctivitis)

n  Chlorbutanol n  Structure similar to trichloroethanol (chloral hydrate

metabolite) n  IV thiamine preps

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Pharmaceutical Additives

n  Thorotrast (thorium dioxide 25%) n  IV radiocontrast medium (1928-1955) n  Delayed hepatic angiosarcoma

n  Thalidomide n  Antiemetic (1960s) n  5,000 infants born with severe congenital abnormalities

(phocomelia)

n  DES (Diethylstilbestrol) n  DES mothers – breast CA n  DES daughters – vaginal clear cell adenoCA

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Question

Which of the following pharmaceutical additives is associated with acute renal dysfunction?

A.  Chlorobutanol B.  Polysorbate 80 C.  Thimerosol D.  Vit E ferol E.  Xylitol

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Question

Which of the following pharmaceutical additives is associated with acute renal dysfunction?

A.  Chlorobutanol B.   Polysorbate 80 C.  Thimerosol D.  Vit E ferol E.  Xylitol

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Vitamins

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Question

Which of the following clinical manifestations is associated with excessive vitamin B6 (pyridoxine) use?

A.  Esophagitis B.  Flushing of the skin C.  Megaloblastic anemia D.  Nephrolithiasis E.  Peripheral neuropathy

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Question

Which of the following clinical manifestations is associated with excessive vitamin B6 (pyridoxine) use?

A.  Esophagitis B.  Flushing of the skin C.  Megaloblastic anemia D.  Nephrolithiasis E.   Peripheral neuropathy

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Vitamin A

n  Binds retinal binding proteins to maintain vision, epithelial cell integrity

n  Deficiency: night blindness, Bitot spots on conjunctiva with corneal drying (xerosis)

n  Acute toxicity defined > 12,000 IU/kg n  Chronic toxicity > 25,0000 IU/day for 2-3 weeks

n  Pseudotumor cerebri (IIH)

n  Hepatoxicity potential n  Teratogenic

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Vitamin D

n  Ca/Phos intestinal absorption, bone development, parathyroid gland function

n  Deficiency: adults - osteomalacia, peds – rickets (craniotabes, rachitic rosary, genu varum)

n  Toxicity n  Acute: hypercalcemia, muscle weakness n  Chronic: nephrocalcinosis, renal failure

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Vitamin E

n  Antioxidant n  Deficiency: preterm infants have large requirement

(ROP, BPD, IVH, hemolytic anemia) n  Recall polysorbate 80 and E-Ferol in Pharmaceutical

Additives n  Toxicity

n  Antagonizes epoxidation of vitamin K (anticoagulant effect) n  Muscle weakness, nausea, diarrhea, headache

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Vitamin K1

n  Vitamin K1 = phytonadione (vitamin K3 is not clinically relevant)

n  Synthesis of factors II, VII, IX, X, protein C n  Deficiency: rare except in newborns (bleeding episodes)

n  Hemorrhagic disease of the newborn occurs if vit K1 is not given at birth

n  Toxicity n  Jaundice in premature infants n  IV preps associated with anaphylaxis

n  Antidote – warfarin and coumarins

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Vitamin B1 (Thiamine)

n  Coenzyme (TTP) in oxidative metabolism of glucose and ketoacid decarboxylation

n  Deficiency: n  Wet beriberi – high output cardiac failure n  Dry beriberi – Wernicke-Korsakoff syndrome: oculomotor

changes, ataxia, global confusion. Seen in malnourished such as alcoholism and gastric bypass

n  Toxicity: antiquated literature reported anaphylactoid reactions with IV dosing. May be due to previous formulations containing chlorbutanol

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Vitamin B2 (Riboflavin)

n  FAD coenzyme in oxidative-reduction reactions n  Deficiency: anorexia, mucositis, cheilosis,

nasolabial seborrhea n  Toxicity:

n  Yellow urine n  Increased riboflavin excretion with boric acid

toxicity (blue-green vomit, boiled lobster appearance)

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Vitamin B3 (Niacin or Nicotinic acid)

n  NAD coenzyme for oxidative-reduction reactions n  Deficiency: pellagra (4 Ds: diarrhea, dermatitis,

dementia, death) n  Toxicity:

n  Niacin flush (skin flush, headache, pruritis, vasodilation). Mediated by prostaglandins, not histamine n  Use aspirin to treat

n  Used by some young adults to adulterate urine to “beat” drug tests

n  Vacor (PNU) antidote

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Vitamin B6 (Pyridoxine)

n  Cofactor for GAD in GABA synthesis n  Converted to active form pyridoxal phosphate by pyridoxine

phosphokinase

n  Deficiency: Seizures n  Isoniazid, Gyromitra esculenta (false morel), hydrazines

(high output fuels)

n  Toxicity: peripheral sensory neuropathy with excessive chronic dosing or large acute ingestions

n  Antidote: INH, G. esculenta, hyrdrazines, ethylene glycol poisoning

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Vitamin B12 (Cyanocobalamin)

n  Coenzyme for 5-methyltetrahydrofolate formation, DNA synthesis, myelin

n  Deficiency: megaloblastic anemia with peripheral neuropathy (post/lat columns, foot drop)

n  Toxicity: probably none n  Nitrous oxide abusers (dentists): bone marrow

suppression, and pernicious anemia. Histochemistry reveals inactive cobalt and inhibition of methionine synthetase

n  Antidote: CN – Hydroxycobalamin (synthetic B12)

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Vitamin C

n  Reducing agent and antoxidant, Cr6+ Cr3+, collagen metabolism

n  Deficiency: scurvy (poor wound healing, bleeding gums, bone pain)

n  Toxicity: > 1.5 grams IV or chronic oral intake > 4 grams/day n  Calcium oxalate with ARF (urinary acidification), chronic

nephropathy n  G6PD hemolysis n  Gouty arthritis due to decreased urate excretion n  Fe absorption leading to hemochromatosis

n  Antidote: congenital methemoglobinemia

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Food Additives

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Food Additives

n  Regulated by FDA and categorized into 5 groups n  Enhance texture n  Improve nutritional value (ie, vitamins) n  Maintain freshness/safety n  Regulate acidity n  Provide flavoring/coloring

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Food Additives

n  Sulfites (red wines): hypersensitivity reactions n  Nitrates

n  Hypotension (hotdog syndrome) n  Infants convert nitrates to nitrites –

methemoglobinemia

n  NaOH and KOH: skin, mucous membrane irritation

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Food Additives

n  MSG: “Chinese restaurant syndrome” – flushing, headache, chest pain, vomiting, rare angioedema, bronchospasm

n  Yellow dye #5: hypersensitivity reactions n  Aspartame: three metabolites – aspartic acid,

phenylalanine, methanol (minute) n  Patients with PKU unlikely to accumulate toxic

levels of phenylalanine

n  Saccharin: bladder CA in animals

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Question

A young boy presents to the hospital with acute urticaria after eating lemon cake. What was the likely food additive to which he is allergic?

A.  Aspartame B.  Metabisulfite C.  Monosodium glutamate D.  Saccharin E.  Tartrazine

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Question

A young boy presents to the hospital with acute urticaria after eating lemon cake. What was the likely food additive to which he is allergic?

A.  Aspartame B.  Metabisulfite C.  Monosodium glutamate D.  Saccharin E.   Tartrazine (Yellow dye #5)

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Questions?

Good Luck!!