Chapter 6 Drug Toxicity

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Chapter 6 Drug Toxicity

• Adverse drug reactions
• Paracelsus, a Swiss physician ( 1493-1541),
  proposed dose-toxicity relationshipall
  substances are poisons there is none which is
  not a poison. The right dose differentiates a
  poison and remedy
• Dose-related and Non-dose related
• genetic makeup, age, underlying pathology, status
  of immune system.

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DOSE

• similar to drugs effectiviness , drugs toxicity
  e.g. lethality (mortality) also shows
  dose-response relationship, typical S-shape
  curve.
• LD50 (the dosage of a substance that kills 50
  of the animals over a set period of time
  following an acute exposure).

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Therapeutic index (TI) LD50/ED50 The lower TI,
the smaller the margin of safety, e.g. digoxin,
2.0
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probit analysis

• In addition to LD50, other aspect of drugs
  toxicity can be measured.
• TD50 (toxic dose producing the effect in 50 of
  the population).
• LD1/ED99 is the margin of safety or the certain
  safety factor

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comparison of drug toxicity
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toxicity classification
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• cautions
• based on lethality alone, false sense,
• other toxicity ignored, e.g. thalidomide could be
  classified as slightly toxic
• extrapolation, animal species differences,
  uncertain for human

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Evaluating the toxicity time factor

• Acute basis over a 14-d period,
• subchronic /subacute, 90-d period (daily given),
  additional information gained, target organ,
  major toxic effects, slower onset,
• chronic , life time of animal, post-mortem
  examination.
• Story on an antiviral drug for hepatitis- a
  delayed toxic reaction occurred after
  administration was discontinued. 5/5 died
  suddenly, liver failure.

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Important factors in these tests Selections of
dosages, species, strain of animal, rout of
exposure
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Other types of toxicity tests

• Specific tests
• reproductive studies, effect of a drug on the
  reproductive process
• mutagenicity test genetic damage,
• carcinogencity test neoplastic change,
• skin sensitization test drugs irritancy
• The test should be carried out in compliance for
  Good Laboratory Practice (GLP) for drug approval

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GENETICS

• Other than dose, factor that influence the body
  response to drugs idiosyncratic (occurring for
  no known reason)
• affects pharmacodynamic and pharmacokinetic, e.g.
  normal difference within a species, between
  genders and strains, also, abnormal genetic
  expression occurs
• disparate response of different species to a
  drug e.g. LD50 of ipomeanol, rat- 12 mg/kg,
  hamster- 140 mg/kg
• thalidomide, rat- insensitive, New Zealand white
  rabbits -sensitive
• strain difference, hexobarbital, sleeping time,
  A/NC- 48 min, SWR/HeN- 18 min

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• Normal distribution, hyporeactive, average
  response, hyperreactive, e.g. coumadine,
  variation of 20 fold range, from bleeding to
  refractory,

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• Population distribution curve sometimes becomes
  bimodal or multimodal,

e.g. isoniazid in plasma, statistically
separated populations, left and right are fast
and slow metabolizers, respectively.
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Primaquine sensitivity

• Another genetically predisposed toxic reaction to
  drug
• Primaquine (an antimalarial drug) or other
  oxidant drugs, hemolytic anemia, X chromosome
  genetic alteration , G6PDH (glucose 6-phosphate
  dehydrogenase) paucity in erythrocytes
• G6P G6PDH ? 6-phosphogluconolactone NADPH
  2NADPH GSSG ? 2GSH 2NADP,
• fail to replenish NADPH and GSH ? red blood
  cells damage
• G6PDH in erythrocytes, trimodal distribution -
  1. normal 2. female carrier (heterozygous) 3.
  male carrier,

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Succinylcholine apnea

• Another example of abnormal gene expression
• Succinylcholine (muscle relaxant, reduce skeletal
  muscle rigidity during operation),
• normal duration of action is of minutes people
  with the atypical enzyme hrs, abnormal
  duration, atypical serum cholinestrase,
• dibucaine number an assay for the atypical
  enzyme carrier, benzoylcholine (substrate),
  dibucaine (competitor), inhibition of
  benzoylcholine hydrolysis
• trimodal distribution (20, 60 and 80
  inhibition), in carriers, less inhibition,

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GENDER

• ethanol consumption, first-pass metabolism, in
  female LDH lower,
• dinitrotoluene-induced hepatic tumor, higher
  incidence in male male glucuronide conjugation,
  biliary excretion, hydrolyzed and reabsorption
  urinary excretion predominates in female ?
  better clearance
• chloroform-induced kidney damage, higher
  incidence in male androgen effect,
  testosterone-mediated, castration diminished

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AGE

• age related change 1. liver metabolism 2. renal
  elimination 3. body composition
• liver metabolism- less amount of drug
  metabolizing enzymes in newborn infants.
• Therapeutic disorders
• (1) gray baby syndrome inadequate
  glucuronidation of chloramphenicol ?
  chloramphenicol ?
• (2) sulfonamide induced kericterus displacement
  of bilirubin from plasma by sulfonamide

In general, reduced binding of drug to plasma
proteins in neonatal period.
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• Examples of paradoxical pharmacodynamic
  differences. antihistamine / barbiturates
  sedation in adults, hyper-excitation in children
  ? differences in receptor-mediated signal
  transudction
• renal function- lower in neonates, blood flow
  ?approx. 8 folds during 1-2 y of birth,
  development of glomerulus, GFR ? during first
  several weeks of life ? antibiotic (e.g.
  getamicin) half-life ?, clearance rate ?.

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In elderly (geriatric pharmacology)

• Declined physiological function during aging
  process,
• total body water ?, liver mass ?, blood flow ?,
  body fate ?,
• after 40 y, liver mass ? 1 / y, after 30 y,
  cardiac output ? 1 /y,
• Vd of water soluble drug ?, e.g. acetaminophen,
  alcohol, digoxin drug sensitivity ? because of
  drugs ?

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elderly (cont.)

• Vd of fat soluble drug ? e.g. valium ?valium in
  serum ?, but because of pharmacodynamic change
  ? Valium depression
• serum albumin ? , affecting protein bound drugs,
  highly protein bound drugs, e.g. sulfonylurea (an
  oral hypoglycemic drug) ? any drug displaces the
  drug may lead to toxicity
• Pharmacodynamic response change, e.g. b-receptor
  b -agonists sensitivity ? , may be due to c-AMP ?

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ALLERGY

• not follow dose-response relationship
• e.g. chronic beryllium disease, hypersensitivity
  lung disorder, exposure to beryllium, lack of
  dose-response relationship

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characteristics of various drug side effects
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• allergic reactions, immune response
• antigens of large molecules drugs only of
  250-500 daltons, carrier proteins, hapten -an
  antigenic determinant ( epitope).
• e.g. penicillin, penicilloyl groups, initial
  exposure, 7-10 d, period of sensitization.

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Various types of allergic reactions

• Type I. Immediate immune response, IgE fixed mast
  cells and basophiles, IgE-hapten-protein complex
• ? release of mediators (e.g. histamine, heparin
  and tryptase and leutotrienes, prostaglandins and
  cytokines)
• ? bronchiolar constriction, capillary dilation or
  urticaria, severe episode-life threatening
  anaphylaxis

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• Type II, cytotoxic response,
• binding of IgG, IgA and IgM, activation of
  complement, target of cytotoxic reactions cells
  in circulatory system,
• e.g. methyldopa and quinidine - induced
  hemolytic anemia, thrombocytopenia.

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• Type III, immune complex-mediated, deposition of
  hapten-protein-Abs (IgG) complex in vascular
  endothelium, subsequent complex fix, neutrophils
  attracted to phagocytize the complexes and
  liberate enzyme, damage vascular walls?
  inflammation (serum sickness),
• symptoms e. g. fever, swelling lymph nodes,
  arthritis, nephritis and neruopathy,
• drugs in risk e.g. sulfonamides, penicillins and
  anticonvulsants

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• Type IV, cell-mediated response,
• delayed reaction to the Ag , activated
  T-lymphocytes generated, release lymphokines
  activate macrophages neutrophiles, infiltration
  of these cells into organ, e.g. halothane-induced
  hepatitis

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Antihistamines

• Histamine,
• mediator of allergic reaction, receptors H1,2, 3-
  distinct effects via the various receptors,
• histidine, decarboxylation, complex with heparin
  or chondroitin sulfate, stored as granules,
  body-wide distribution, concentrated in skin,
  lung and GI mucosa,
• cimetidine, H2 blocker, gastric acid secretion
  inhibitor

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• Antihistamine referred to H1 antagonist anti- (
  urticaria, hay fever, insect bites)
• antiemetic, anti-motion sickness,
  antiparkinsonism, antitussive,
• old generation of antihistamines have side
  effects blocker of cholinergic muscarinic
  receptor sedation ( used in OTC sleeping pills)

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Immune-related drug effects

• glucocorticoids or azathioprine (prevent organ
  rejection), tumor incidence ?
• others modifying the antigenic properties of
  endogenous molecules without binding, e.g.,
  hydralazine antihypertensive induce autoimmune
  e.g. SLE disorder

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Primary mechanisms of direct drug-induced cell
injury

• biochemical lesion initial metabolic alteration
  ? morphological change
• (1) covalent binding
• (2) lipid peroxidation
• (3) oxidative stress

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• Covalent binding
• bioactivation, covalent bonds with endogenous
  macromolecules e.g. halothane anesthetic, 2
  types hepatotoxicity one is direct cytotoxicity,
  the other is immune-related,
• another example acetaminophen, oxidation product
  NAPQI N-acetyl-p-benzoquinoneimine, conjugation
  with GSH, overdose, Phase II enzymes saturated, ?
  covalent linked with proteins e.g. p58 (sensor
  for homeostasis) immune-related response may
  occur also.

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• Lipid peroxidation
• free radical, electrophilic species, O2 ?
  superoxide anion, polyunsaturated fatty acids in
  membrane undergo lipid peroxidation? cellular
  injury

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• Oxidative stress
• superoxide anion radical, hydrogen peroxide,
  enzymes to clear the reactive oxygen species
  superoxide dismutase, catalase, peroxidase
• oxidation stress ? depletion of cellular reducing
  agents (e.g. thiols, and NADP/NADPH) can lead to
  cell necrosis or apoptosis

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• Teratogenesis
• thalidomide- effects on development of embryo,
• alcohol- CNS dysfunction mental retardation,
  long-lasting effects
• diethylstibestrol (was used for miscarriage
  prevention)- carcinogenesis, cervical and vaginal
  carcinoma found in daughters of treated mothers
• Sadly, DES did not prove efficacious in
  miscarriage prevention

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• Recent teratogenes
• isotretoin for acne and etretinate for
  psoriasis-synthetic retinoids (vitamin A deriv.)
• isotretoin-category X contraindication for use
  during pregnancy physicians unnoticed the
  warning label until the problem broke out.
• etretinate- serum concentration may last long 2
  years, extended period of toxicity

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• Bendectin story
• antinausea
• a report 1979 concerned bendectins 80 increase
  of risk in congenital effects of heart disease
• 1983, removed from market by the company
• further studies ? only 0.89 risk
• hospital admission due to excessive vomiting ?

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Treating Drug Overdose

• Drug responsible for poisonings analgesic,
  antidepressants, sedative/hypnotics, stimulants
  and street drugs
• American Association of Poison Control Centers,
  ingestion the most likely route (75) accidental
  or intentional

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• Aspirin
• before 1972, aspirin the most frequent in
  child-poisioning
• Poison prevention packaging act, 1970,
  children-resistant closures
• numbers of death (1972?1989) ? from 46 to 2

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• Iron supplements
• iron deficiency anemia
• FDA required iron tablets wrapped and capsules
  individually, time and dexterity discouraging
  young child

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• Age-related drug poisoning
• Intentional poisoning in adolescents (11-17)
• elderly 64 y older, dementia and confusion,
  improper use or storage, serum albumin and GFR ?,
  drug displacement

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• Management trends
• initial decontamination
• enhanced elimination
• specific antidote administration

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• Initial decontamination
• Ipecac syrup, chemoreceptor trigger zone in
  brain, local irritation of GI tract (gastric
  lavage ), contraindications with coma or
  convulsions, ingestion of corrosive substances,
  impaired gag reflex,
• followed by activated charcoal, high adsorptive
  capacity, 60 if simultaneous administration, 9
  if 3 h delay

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• Enhanced elimination- facilitated renal excretion
  or extracorporeal methods
• facilitated renal excretion fluid diuresis,
  excess fluid, ionized diuresis, ? or ? urine pH
• extracorporeal methods -dialysis or
  hemoperfussion for coma

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• Specific antidote administration
• Naloxone competes for m and k opoid receptors,
  reverse sedation and respiratory depression of
  morphine-like drugs
• N-aceylcysteine (NAC) e.g. acetaminophen
  overdose, provides -SH groups
• deferoxamine- for iron poisoning, an chelator
• Ab e.g. digoxin-specific Fab antibody

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The single most important treatment of poisoned
patients is supportive care. You must treat
patient not the poison
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11/5 mid-term exam, covering the first 4 lectures