Chapter 6 Drug Toxicity 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.

DOSEDOSE

• similar to drug‘s effectiviness , drug’s 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).

Therapeutic index (TI)= LD50/ED50The 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 classificationtoxicity 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: timeEvaluating the toxicity: time factor 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 testsOther 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

GENETICSGENETICS

• 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

• 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, 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 .

• 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]

In elderly (geriatric pharmacology)

• 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. -receptor; -agonists sensitivity , may be due to c-AMP

elderly (cont.)

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.

• 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

Various types of allergic reactions

• 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 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

• 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

– 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;

Antihistamines

– 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)

– 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

Immune-related drug effects

• biochemical lesion: initial metabolic alteration morphological change

– (1) covalent binding

– (2) lipid peroxidation

– (3) oxidative stress

Primary mechanisms of direct drug-induced cell injury

• 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, 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

• 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 child-poisioning

– Poison prevention packaging act, 1970, children-resistant closures

– numbers of death (19721989) 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 and 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