Toxicology Final Exam (part 1)

what does N-acetyltransferase (NAT) do?

hydralazine acetylation

therapeutic dose

predictable, desired effects

what are unpredictable/undesired effects?

side effects, overdose, habituation/abuse, idiosyncratic effects, drug-drug interactions

what are the parameters of the therapeutic window?

from poor activity to unacceptable toxicity

what is acetaminophen called in Europe?

Paracetamol

what is acetaminophen called in the US?

Tylenol

what does acetaminophen do?

OTC analgesic (pain killer); affects pain perception

is acetaminophen an NSAID?

no!

which part of the body is damaged if overdosed on acetaminophen?

liver (fatal damage)

what is the safe amount of acetaminophen per dosage?

less than 500 mg

what does overdose of acetaminophen lead to?

saturation of phase 2 metabolism

what is essential for excretion of acetaminophen?

drug metabolism; water solubility = 12.78 g/L , log Kow = 0.45-0.9 , pka = 9.51

what is the effect of an accumulation of the reactive intermediate (NAPQ1) of acetaminophen?

liver necrosis (death of cells)

what enzyme metabolizes acetaminophen?

CYP2E1 (induced by excessive alcohol consumption)

what is the antidote for an acetaminophen overdose?

N-acetyl-cysteine

acetaminophen toxicology in reptilians

snakes do not get chronic liver damage bc of NAPQ1 accumulation; death of snakes is fast (less than 12 hours for 80 mg); snakes die from methemoglobinemia (also cats)

methemoglobinemia

dysfunction of hemoglobin, reduces release of oxygen leading to hypoxia (snakes and cats)

what is aspirin made of?

acetyl-salicylic acid (derived from natural compound)

what is aspirin?

an OTC anti-inflammatory analgesic (NSAID)

is aspirin an NSAID?

yes

how does aspirin work?

it is an inhibitor of COX enzyme activity, resulting in reduced prostaglandin (pain signal or inflammation)

when does aspirin become toxic?

after the saturation of metabolism

Phase 1 of aspirin metabolism

esterase creates functional group

Phase 2 of aspirin metabolism

conjugation to sugar or glycine

dose effect symptoms

higher dose = more toxic

what is the safe amount of Aspirin tablets to be taken in a day?

3

what is the first step of Aspirin toxicity?

uncoupling of ATP production in mitochondria (reduces protein gradient), hyperventilation, less carbon dioxide in plasma

what is the second step of Aspirin toxicity?

development of alkalosis; loss of carbon dioxide affects bicarbonate equilibrium; loss of protons and pH increases

what is the third step of Aspirin toxicity?

acidosis; the kidneys try to compensate by excreting too much bicarbonate and pH decreases

what is the fourth step of Aspirin toxicity?

accumulation of salicylic acid at low pH; unionized form = reuptake in kidney, brain, and mitochondria

what is the fifth step of Aspirin toxicity?

fever; accumulation of heat because energy not used for ATP production

what is the sixth and final step of Aspirin toxicity?

dehydration; increased kidney activity

antidote to Aspirin

bicarbonate and glucose; increase plasma/urine pH and stimulate ATP production

what is Hydralazine?

a prescription anti-hypertension drug (vasodilator)

Hydralazine side effects

(in 10% of patients under therapeutic dosing) causes lupus with signs of arthritis; there are multiple factors involved in side effects (lowering the dose reduced them but not enough)

Hydralazine side effect factors

1. acetylator type
2. blood type
3. gender
4. duration
5. prediction

acetylator type Hydralazine side effect factor

effects only in slow acetylators (50% of population); accumulation of parent compound; activation by CYP and peroxidases

blood type Hydralazine side effect factor

HLA (human leukocyte antigen) type DR4 in 27% of the population (not known why -- maybe a genetic marker)

gender Hydralazine side effect factor

occurs more in females (4:1)

duration Hydralazine side effect factor

more than 18 months of chronic exposure

prediction Hydralazine side effect factor

based on epidemiological observations; 7% will show effect

what is Halothane?

general anesthetic (widely used until recently)

Halothane predisposing factors

multiple exposures (immune reaction), being female, obesity, sensitivity to allergies

Halothane symptom

severe liver disease (idiosyncratic effect) is rare -- 1:10,000

what is Debrisoquine?

an antihypertensive drug (anti high BP)

Debrisoquine side effect

some patients experience an excessive drop in blood pressure

genetic defect affecting Debrisoquine

no functional CYP2D6 enzyme (breaks down the drug); occurs in 5-10% of the population

what form is the parent compound of Debrisoquine in?

active form

what is Thalidomide (Softenon)?

a sedative; prescribed for morning sickness in pregnant women in 1957-1961 bc it appeared to have low toxicity during animal tests, but it caused phocomelia (malformations of arms and legs) in children when it was dosed in days 24-29 after fertilization (more than 10,000 children affected)

what sedative was banned in the US by the FDA (Frances Oldham Kelsey)?

Thalidomide (Softenon)

what drugs act as inducers?

Phenobarbital and Rifampicin

what drug acts as a mimic?

Phenylbutazone

what is Phenobarbital?

seizure medicine; induces CYP isoforms

what is Rifampicin?

tuberculosis medicine; increases steroid metabolism (pill) leading to pregnancies

what is Phenylbutazone?

an anti-inflammatory drug that replaces warfarin on albumin (excessive bleeding)

what is Glucose-6-phosphate dehydrogenase?

needed for NADPH production to maintain reduced glutathione (GSH) in red blood cells; genetic defect on X chromosome can lead to anemia (RBC's destroyed through oxidative stress); high in African Americans (5-10%) and Sephardic Jews (53%); anemia also induced by specific G6P dehydrogenase inhibitors (primaquine, aniline, and fava beans)

occupational hazards of industrial toxicology

working hours are 1/3 of life span (close contact with chemicals); history of occupational exposure; dangerous jobs like mining, printing, and metal working; regulations as a result of accidents and epidemiology (no/few regulations in developing countries)

what is Chimney Sweep Cancer?

genital cancer from exposure to soot; first described by Percivall Pott in 1775 in England; toxicity of polycyclic aromatic hydrocarbons (PAHs)

what is the Mad Hatter Disease?

exposure to mercury vapors (mercury was used to make felt out of animal hair); neurological effects like irritability, depression, and shaking

what were the dangers of pottery glaze and paint?

painters licked their brushes (radium girls) and the solvents in the paint led to painters syndrome (dangers of cheap pottery); toxic metals with vibrant colors were used in glaze and paints

what are some examples of some toxic metals with vibrant colors that were used in glaze and paints?

arsenic, nickel, uranium, cobalt, lead, etc.

what is inhalation toxicology?

occupational exposure in mostly skin and lungs

acute lung responses to inhalation toxicology

reduced ventilation, broncho-constriction, pulmonary edema

chronic lung responses to inhalation toxicology

fibrosis, emphysema, asthma/bronchitis, cancer (biotransformation enzymes)

what skin problems arise from inhalation toxicology?

protein damage (Hapten formation); immune reaction; sensitization; allergic reactions like contact dermatitis and inflammation; skin sensitizers are metals, solvents, acids, and alkalis

what is Vinyl Chloride?

the starting material to make PVC gas; absorption is through lungs and skin

health effects from Vinyl Chloride

acute narcosis from exposure to gas, Vinyl Chloride Disease which is the degeneration of small blood vessels in bone, hands, toes, liver, etc.; involvement of immune system, liver cancer (Hemangiosarcoma); metabolic activation (adduct formation on biomolecules)

what is Cadmium?

a metal used for plating, alloys, batteries, and pigments; it is bound to Metallothionein (MT), so has a long half life (7-30 years)

how does Cadmium get into the body?

it has poor GI tract absorption, but 40% in lungs from cigarette smoke

what are the effects of Cadmium?

kidney damage, testicular damage (vascular damage), carcinogen, Itai-Itai Disease (brittle bones bc of calcium loss)

what is Metallothionein (MT)?

relatively small proteins (in several forms) that are rich in cysteine; aid in hiding and storing of metals; cause kidney damage when Cd released through protease activity

what are Aromatic Amines?

chemicals used in rubber and the dye industry; napthylamine causes bladder cancer (CYP hydroxylation, UGT conjugation); detoxification of amines by acetylation (slow/fast acetylators); Epping jaundice (DADPM exposure induced bile duct damage); aniline causes oxidation of hemoglobin (blue blood)

what are Asbestos?

several forms of widely used fibrous silicates; industrial use for insulation and building material; causes about 10,000 deaths per year (importance of fiber length)

what causes Asbestos Diseases?

inhalation hazards during mining, production, and demolition; role of macrophages in causing DNA damage; synergistic effect of smoking

what are some examples of Asbestos Diseases?

asbestosis (fibrosis of lung tissue); pleural disease (benign); bronchial carcinoma; mesothelioma (malignant)

what legislation and control of toxicology is in the US?

OSHA sets safe exposure levels called TLV (threshold limit value); based on animal studies, epidemiological studies, and accident evaluations; importance of NOAEL values

what legislation and control of toxicology is in Europe?

REACH program (registration, evaluation, authorization, and restriction of chemical substances) of 2007; protection of humans and environment; international ramifications

why are there food additives?

to preserve food from going bad and enhance sales (currently about 2500 additives)

regulated food additives in Europe

E numbers (ex. E102)

regulated food additives in the US

approved numbers (ex. FDA yellow 5)

what is the Delaney Clause of 1959

no carcinogens in food

what was the 1959 cranberry scare?

Arthur Flemming declared just before Thanksgiving that cranberries could have aminotriazole contamination (herbicide; carcinogen in rats); cranberries were taken off the shelves of grocery stores and restaurant menus

types of food additives

colorings, artificial flavors, flavor enhancers, sweeteners, preservatives, anti-oxidants, stabilizers, anti-caking agents, emulsifiers, propellants, buffers, bleaches

what is butter-yellow food additive?

added to butter for constant color; liver carcinogen

what is Tartrazine?

orange/yellow food coloring (additive); E102/Yellow 5; metabolism by GI microbiome (mutagenic metabolites)

what is the feingold diet?

no artificial colors, sweeteners, etc. in food; helped reduce symptoms of ADHD in certain children

what are some allergic reactions of Tartrazine?

urticaria (hives), asthma, relation to Aspirin sensitivity; behavioral toxicology difficulties (feingold diet)

what is Saccharin?

artificial sweetener (additive); discovered in 1880 as a coal tar derivative; no acute toxicity; not metabolized, excreted unchanged in urine but bladder cancer in rats found at very high doses so it was banned in 1977 under the Delaney Clause; there were public protests bc no epidemiological evidence and new research about rat urine came out that they had high pH, calcium, and micro-crystals lead to tumors (aka it was being metabolized in mice), so the warning label was taken off in 2000

what is Aflatoxin?

aspergillus mold growing on grains and peanuts in a hot and humid climate; liver cancer at 1 ppb in humans and rats but not in mice; causes hepatitis (slows biotransformation)

what is "Ginger Jake"?

Jamacian ginger extract in 70% alcohol approved for sale during prohibition bc it passed the solids test (the high ginger solids made it undrinkable); batches were adulterated with tri-orthocresyl phosphate (replacing the ginger) bc the organophosphate plasticizer passed the inspection; causes neurological damage 10-15 days after use (foot drop, jake leg) with 50,000 victims with permanent paralysis

what was the Spanish Oil Syndrome?

unusual outbreak of pulmonary disease and fever in Madrid in 1981 traced back to certain cooking oil causing 20,000 cases and 351 deaths; rapeseed oil (canola) was denatured with aniline; refining process to make it edible again

effects of food preparation

dangers of high heat could lead to the formation of carcinogens (benzoapyrene and nitrosamines) or the formation of sugar derivatives (enhancers for diabetes?)

examples of food contamination

Epping jaundice; lead acetate as sweetener; ethylene glycol in white wine (anti-freeze as sweetener); bacterial contamination (E. coli outbreaks and botulism); toxic algae in seafood (domoic acid); pesticides

special diets

sugar and no carb (keto, atkins); meat (vegetarianism/veganism); gluten (paleo); economics of food supply (locovores)

selective toxicity

pesticides are developed based on the concept of species differences in toxic response; there are target species and non-target species (humans are a non-target species but have been effected by mass poisoning incidences like pesticides in flour, sugar, or seed grain)

what are the 4 types of pesticides?

1. insecticides
2. herbicides
3. fungicides
4. rodenticides

examples of insecticides

organochlorines, organophosphates, carbamates, pyrethrins, neonicotinoids; mostly neurotoxins

examples of herbicides

plant hormones or inhibitors of photosynthesis

examples of fungicides

organometallics (Hg, Sn) and organohalides (Cl, Br)

examples of rodenticides

anti-coagulants (warfarin) and cyanides