1.11 Daubert 4.9.12 Pharmaceutical Additives€¦ · Hemorrhagic disease of the newborn occurs if...

Pharmaceutical Additives

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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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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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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 renal 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 well developed in premature infants

n  The benzyl alcohol was metabolized to benzoic acid causing metabolic acidosis


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

n  Chlorbutanol n  Structure similar to trichloroethanol n  Chloral hydrate active metabolite n  IV thiamine preps

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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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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


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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, ataxis, 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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Question

Which of the following clinical manifestations is associated with excessive vitamin C 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 C use?

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

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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!!

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PHARMACEUTICAL ADDIVITES, VETERINARY PRODUCTS, VITAMINS

G. Patrick Daubert, MD; Michelle Burns-Ewald, MD

CORE CONTENT

2.1.12 Pharmaceutical Additives 2.1.13 Veterinary Products 2.1.14 Vitamins

PHARMACEUTICAL ADDITIVES

• Pharmaceutical Additives o Benzalkonium chloride o Benzyl alcohol o Chlorbutanol o Diethylene glycol (DEG) o Diethylstilbestrol (DES) o Parabens o Polyethylene glycol o Propylene glycol o Sorbitol o Thalidomide o Thallium o Thimerosol o Thorotrast o Tryptophan o Vit E ferol

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

• Gasping Syndrome o In 1981, 16 neonatal deaths occurred in a NICU o All were pre-term neonates < 2500 gm o Symptoms included severe anion gap metabolic acidosis, respiratory

depression with gasping, and encephalopathy o All neonates had received bacteriostatic NaCl or water flushes containing

0.9% benzyl alcohol Benzyl alcohol is normally oxidized rapidly to benzoic acid,

conjugated with glycine in the liver, and excreted as hippuric acid This metabolic pathway is well developed in premature infants The benzyl alcohol was metabolized to benzoic acid causing

metabolic acidosis • Chlorbutanol

o Structure similar to trichloroethanol (chloral hydrate active metabolite) o IV thiamine preps in past

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• DEG o Sulfanilamide

September-October 1937 S.E. Massengill Co., used DEG diluent in sulfanilamide elixir Vomiting, abdominal pain, anuria, seizures, coma 105 deaths in 15 states with 34 pediatric fatalities

• Multiple other epidemics in Nigeria, Bangladesh, South Africa, Haiti

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

o Oxidative metabolism by ADH/ ALDH to hydroxyethoxy acetic acid (HEAA)

o Ether bond probably does not break o Renal biopsy typically reveals tubular necrosis and vacuolization o DEG has high fatality rate o Management with early hemodialysis in otherwise normal patients is still

controversial • DES (Diethylstilbestrol)

o DES mothers – breast CA o DES daughters – vaginal clear cell adenoCA

• Parabens o Hypersensitivity reactions o 2nd most common ingredient (2nd to water) in medications

• Polysorbate 80 and E-Ferol o Polysorbate 80 = polyproblems o Released December 1983 o IV form of a vitamin E preparation (E-Ferol) o Fatalities among low birth weight (< 1,500 g) and premature infants o 38 deaths and 43 cases of severe morbidity

Thrombocytopenia Renal failure Cholestasis Ascites

o Inhibitory effect by E-Ferol on the in vitro response of human lymphocytes to phytohemagglutinin

• Propylene glycol o IV preps pushed rapidly (> 50 mg/min for IV phenytoin (Dilantin) can

result in toxicity Hypotension, bradycardia, asystole

o Prolonged infusions Lactic acid production

• Polyethylene glycol o Toxicity concern with low MWs (< 400) o Risk of renal tubular necrosis

• Sorbitol (D-glucitrol) o Widely used as sweetening agent (activated charcoal)

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o Case reports of fatalities in patients with hereditary fructose intolerance (sorbitol metabolized to glucose and fructose) receiving IV formulation of sorbitol

• Thalidomide o Antiemetic (1960s) o 5,000 infants born with severe congenital abnormalities (phocomelia)

• Koremlu (thallium acetate) o 1920-1940 Koremlu was used topically as a treatment for ringworm

(depilatory agent) o Patients were experiencing various aliments including losing all scalp hair,

neuritis, myalgias, and arthralgias o Many of the nation’s leading department stores sold the product, and

Vogue and Cosmopolitan carried its advertizing o By 1934, 692 cases of thallium poisoning with 31 deaths

• Eosinophilia Myalgia Syndrome (EMS) o October 1989, the health department in New Mexico was notified of 3

patients with an unexplained acute illness o Characterized by intense myalgia, dyspnea, extremity edema, neuropathy,

and peripheral blood eosinophilia o By July 1991, 1543 cases and 31 deaths were attributed to EMS o Some L-tryptophan may have been produced by a new bacteria causing an

unknown bi-product o EMS Histology

Endothelial cell hyperplasia in the capillaries, with evidence of swelling and necrosis

Inflammatory cell infiltrate of predominantly monocytes, histiocytes, lymphocytes, macrophages, and plasma cells and occasionally eosinophils in nerve, muscle, and connective tissue, including the subdermal fascial layer (fasciitis)

Increased fibrosis, mostly in the fascia o EMS lead to the Dietary Supplement Health and Education Act of 1994

• Thorotrast (thorium dioxide 25%) o IV radiocontrast medium (1928-1955) o Delayed hepatic angiosarcoma o Leukemia and skeletal sarcomas (thorotrastomas at sites of extravasation)

VETERINARY PRODUCTS

• Xylazine o Animal sedative with central alpha-agonist and imidazoline properties

similar to clonidine o CNS depression, miosis, respiratory depression, bradycardia symptoms

• Ivermectin: o Antiparasitic drug that potentiates GABA release

• 4-aminopyridine o Avian pesticide

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o Potassium channel blocker and enhances release of ACh from nerve endings

o Marketed in humans as Fampridine and Neurelan Muliple sclerosis therapy Shown to reverse tetrodotoxin toxicity in animal models

o Seizures: probably the only drug-induced seizures that respond to phenytoin

VITAMINS

• Fat soluble = A, D, E, K • Vitamin A

o Binds retinal binding proteins to maintain vision, epithelial cell integrity o Deficiency: night blindness, Bitot spots on conjunctiva with corneal

drying (xerosis) o Acute toxicity defined > 12,000 IU/kg, chronic toxicity > 25,0000 IU/day

for 2-3 weeks Pseudotumor cerebri (IHH): also consider tetracycline, steroids,

OCPs Hepatoxicity – uptake into Ito cells, cirrhosis, alcohol may

potential Teratogenic – facial and ear deformities, rare CNS/CV Misc – dry skin, alopecia, premature epiphyseal closure in infants

• Vitamin D o Ca/Phos intestinal absorption, bone development, parathyroid gland

function o Deficiency: adults - osteomalacia, peds – rickets (craniotabes, rachitic

rosary, genu varum) o Toxicity

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

• Vitamin E o Antioxidant o Deficiency: preterm infants have large requirement (i ROP, BPD, IVH,

hemolytic anemia) o Review polysorbate 80 and E-Ferol in Pharmaceutical additives o Toxicity

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

• Vitamin K1 o Vitamin K1 = phytonadione (vitamin K3 is not clinically relevant) o Essential cofactor in hepatic synthesis of coagulation factors II, VII, IX,

X, protein C o Deficiency: rare except in newborns (bleeding episodes)

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

o Toxicity

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Jaundice in premature infants, elevated levels could impair effects of anticoagulants

IV preps uncommonly cause anaphylaxis, IM preps hematomas • Vitamin B1 (Thiamine)

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

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

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

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

• Vitamin B2 (Riboflavin) o FAD coenzyme in oxidative-reduction reactions o Deficiency: anorexia, mucositis, cheilosis, nasolabial seborrhea o Toxicity: Yellow urine. Increased riboflavin excretion with boric acid

toxicity (blue-green vomit, boiled lobster appearance). No evidence that riboflavin is useful in the treatment of boric acid toxicity.

• Vitamin B3 (Niacin or Nicotinic acid) o NAD coenzyme for oxidative-reduction reactions o Deficiency: pellagra (4 Ds: diarrhea, dermatitis, dementia, death) o Toxicity:

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

Used by some young adults to adulterate urine to “beat” drug tests o Vacor (PNU) antidote

• Vitamin B6 (Pyridoxine) o Cofactor for GAD in GABA synthesis. Converted to active form pyridoxal

phosphate by pyridoxine phosphokinase o Deficiency: Seizures

Isoniazid, Gyromitra esculenta (false morel), hydrazine rocket fuel o Toxicity: peripheral sensory neuropathy with excessive chronic dosing or

large acute ingestions o Antidote: INH, G. esculenta, hyrdrazines, ethylene glycol poisoning

• Vitamin B12 (Cyanocobalamin) o Coenzyme for 5-methyltetrahydrofolate formation, DNA synthesis, myelin o Deficiency: megaloblastic anemia with peripheral neuropathy (post/lat

columns, foot drop) o Toxicity: probably none o Nitrous oxide abusers (dentists): bone marrow suppression, and pernicious

anemia. Histochemistry reveals inactive cobalt and inhibition of methionine synthetase

o Antidote: CN – Hydroxycobalamin (synthetic B12) exchanges hydroxyl group with free CN to produce cyanocobalamin (renally excreted)

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• Vitamin C o Reducing agent and antoxidant, Cr6+ g Cr3+, collagen metabolism o Deficiency: scurvy (poor wound healing, bleeding gums, bone pain) o Toxicity: > 1.5 grams IV or chronic oral intake > 4 grams/day

Calcium oxalate with ARF (urinary acidification), chronic nephropathy

G6PD hemolysis Gouty arthritis due to i urate excretion h Fe absorption leading to hemochromatosis

o Antidote: congential methemoglobinemia

FOOD ADDITIVES

• Regulated by FDA and categorized into 5 groups o Enhance texture o Improve nutritional value (ie, vitamins) o Maintain freshness/safety

Sulfites (red wines): hypersensitivity reactions Nitrates

• Hypotension (hotdog syndrome) • Infants convert nitrates to nitrites – methemoglobinemia

o Regulate acidity NaOH and KOH: skin, mucous membrane irritation

o Provide flavoring/coloring MSG: “Chinese restaurant syndrome” – flushing, headache, chest

pain, vomiting, rare angioedema, bronchospasm Yellow dye #5: hypersensitivity reactions Aspartame: three metabolites – aspartic acid, phenylalanine,

methanol (minute). Patients with PKU unlikely to accumulate toxic levels of phenylalanine

Saccharin: bladder CA in animals

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QUESTIONS

1. The structure of chlorobutanol most closely resembles which of the following compounds?

A. Chloral hydrate B. Dibromochloropropane C. Hexachlorobenzene D. Hydroxyethoxy acetic acid E. Trichloroethanol

The structure of chlorobutanol most closely resembles trichloroethanol, the metabolite of chloral hydrate. Hydroxyethoxy acetic acid is the metabolited of DEG. The other choices are note related to chlorobutanol. Dibromochloropropane is a pesticide that causes sterility and altered sex ratio in offspring. Hexachlorobenzene is a fungicide associated with porphyria, pemba yara, and spongiform encephalopathy.

2. Which of the following statements best describes the pathophysiology of the neonatal “gasping” syndrome?

A. Benzyl alcohol metabolized to benzoic acid resulting in metabolic acidosis B. Chlorobutanol in thiamine preparation resulting in coma C. Diethylene glycol metabolized to HEAA resulting in renal failure D. Hydrogen peroxide in the dialysate resulting in severe hemolysis E. Propylene glycol infusions producing hypotension, bradycardia, asystole

The gasping syndrome in 1981 was due to bacteriostatic NaCl or water flushes containing 0.9% benzyl alcohol. The benzyl alcohol was metabolized to benzoic acid resulting in severe metabolic acidosis.

3. Propylene glycol is metabolized by alcohol dehydrogenase to which of the following?

A. Acetone B. Ethylene glycol C. Lactic acid D. Oxalic acid E. Trichloroethanol

Propylene glycol is metabolized to lactic acid in a complex metabolic pathway. This is most likely to be of clinical importance during prolonged infusions. Oxalic acid is the metabolite of ethylene glycol. Trichloroethanol is the metabolite of chloral hydrate. Acetone is the metabolite of isopropyl alcohol

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4. Which of the following toxicological disasters lead to the Dietary Supplement Health and Education Act of 1994?

A. Diethylstilbestrol clear cell adenocarcinoma B. Eosinophilia Myalgia Syndrome C. Gasping syndrome D. Sulfanilamde and DEG E. Vitamin E-Ferol-induced renal failure

Eosinophilia Myalgia Syndrome was caused by L-tryptophan and lead to the Dietary Supplement Health and Education Act of 1994. The sulfanilamide disaster with DEG lead to the development of the Food, Drug, and Cosmetic Act. Gasping syndrome, vitamin E-ferol and diethylstilbestrol were tragic toxicologic events but did not lead to any national legislation.

5. Which of the following pharmaceutical additives is second only to water as the most common ingredient in medications?

A. Benzalkonium chloride B. Parabens C. Polyethylene glycol D. Propylene glycol E. Sorbitol

The parabens are very common ingredients in medications and cosmetics. They probably have little toxicity other than allergic reactions. 1E 2A 3C 4B 5B

1.11 Daubert 4.9.12 Pharmaceutical Additives€¦ · Hemorrhagic disease of the newborn occurs if...

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