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Chapter 6 Drug Toxicity
• Adverse drug reactions
• Paracelsus, a Swiss physician ( 1493-1541), proposed
dose-toxicity relationship“all 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.
DOSE
• similar to drug‘s effectiviness ,
drug’s toxicity e.g. lethality
(mortality) also shows doseresponse relationship, typical Sshape curve.
• LD50 (the dosage of a
substance that kills 50% of the
animals over a set period of
time following an acute
exposure).
Therapeutic index (TI)= LD50/ED50
The lower TI, the smaller the margin of safety, e.g. digoxin, 2.0
• In addition to LD50,
other aspect of drug’s
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
probit analysis
comparison of drug toxicity
toxicity classification
• 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
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.
Important factors in these tests:
Selections of dosages, species, strain of animal, rout of
exposure
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: drug’s irritancy
• The test should be carried out in compliance for Good
Laboratory Practice (GLP) for drug approval
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/NC48 min, SWR/HeN- 18 min
• Normal distribution,
hyporeactive, average
response, hyperreactive,
e.g. coumadine, variation
of 20 fold range, from
bleeding to refractory,
• 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.
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,
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,
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
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.
• Examples of paradoxical pharmacodynamic differences.
antihistamine / barbiturates: sedation in adults, hyperexcitation 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 .
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] 
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 
ALLERGY
• not follow dose-response relationship
• e.g. chronic beryllium disease, hypersensitivity lung
disorder, exposure to beryllium, lack of dose-response
relationship
characteristics of various drug side effects
• 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.
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
• 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.
• Type III, immune complex-mediated, deposition of haptenprotein-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
• 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
Antihistamines
– Histamine,
• mediator of allergic reaction, receptors H1,2, 3distinct 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;
– 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)
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
Primary mechanisms of direct drug-induced cell injury
• biochemical lesion: initial metabolic alteration 
morphological change
– (1) covalent binding
– (2) lipid peroxidation
– (3) oxidative stress
• 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.
• Lipid peroxidation
– free radical, electrophilic species, O2  superoxide
anion, polyunsaturated fatty acids in membrane
undergo lipid peroxidation cellular injury
• 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
• Teratogenesis
– thalidomide- effects on development of embryo,
– alcohol- CNS dysfunction: mental retardation, longlasting 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
• 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
• Bendectin story
– antinausea
– a report 1979 concerned bendectin’s 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 
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
• Aspirin
– before 1972, aspirin the most frequent in childpoisioning
– Poison prevention packaging act, 1970, childrenresistant closures
– numbers of death (19721989)  from 46 to 2
• Iron supplements
– iron deficiency anemia
– FDA required :iron tablets wrapped and capsules
individually, time and dexterity discouraging young
child
• 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
• Management trends
– initial decontamination;
– enhanced elimination;
– specific antidote administration
• 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
• 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
• 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
The single most important treatment of poisoned patients is
supportive care.
You must treat patient not the poison
11/5 mid-term exam, covering the first 4 lectures