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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