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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

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Chapter 6 Drug Toxicity

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  1. 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.

  2. DOSE • 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).

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

  4. probit analysis • 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

  5. comparison of drug toxicity

  6. toxicity classification

  7. 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

  8. Evaluating the toxicity: timefactor • 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.

  9. Important factors in these tests: Selections of dosages, species, strain of animal, rout of exposure

  10. 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

  11. 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

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

  13. 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.

  14. 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,

  15. 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,

  16. 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

  17. 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.

  18. 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 .

  19. 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] 

  20. 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 

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

  22. characteristics of various drug side effects

  23. 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.

  24. 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

  25. 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.

  26. 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

  27. 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

  28. 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;

  29. 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)

  30. 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

  31. Primary mechanisms of direct drug-induced cell injury • biochemical lesion: initial metabolic alteration  morphological change • (1) covalent binding • (2) lipid peroxidation • (3) oxidative stress

  32. 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.

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

  34. 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

  35. 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

  36. 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

  37. 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 

  38. 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

  39. 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

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

  41. 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

  42. Management trends • initial decontamination; • enhanced elimination; • specific antidote administration

  43. 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

  44. 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

  45. 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

  46. The single most important treatment of poisoned patients is supportive care. You must treat patient not the poison

  47. 11/5 mid-term exam, covering the first 4 lectures

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