Lecture 1 14 th March, 11

1. Lecture 1 14th March, 11 Toxicology Introduction to Toxicology

2. What is toxicology • Toxicology is the study of the adverse effects of chemical or physical agents on living organisms.

3. Risk assessment • Quantitative estimate of the potential effects on human health and environmental significance of various types of chemical exposures (e.g., pesticide residues on food, contaminants in drinking water).

4. Graphical representation of the interconnections between different areas of toxicology.

5. Different areas of toxicology • Mechanistic Toxicologist • Identifying and understanding the cellular, biochemical, and molecular mechanisms by which chemicals exert toxic effects on living organisms • Mechanistic data (saccharin to cause bladder cancer, thalidomide in leprosy and AIDS, 6-mercaptopurine in leukemias) • Relative toxic potential of organophosphate insecticides

6. 2. Descriptive toxicologist • concerned directly with toxicity testing, which provides information for safety evaluation and regulatory requirements. • Risk posed by a company chemical (insecticides, herbicides, solvents) to humans but also to animals • Omics technologies

7. 3. Regulatory toxicologists • Responsibility for deciding, on the basis of data provided by descriptive and mechanistic toxicologists, whether a drug poses a sufficiently low risk to be marketed for a stated purpose or subsequent human or environmental exposure resulting from its use. • Food and Drug Administration • Federal Food, Drug and Cosmetic Act • Environmental Protection Agency • Federal Insecticide, Fungicide and Rodenticide Act

8. General characteristics of toxic response • LD 50 • Microgram doses • Physical state (gas, dust, liquids) • chemical structure (aromatic amines, halogenated hydrocarbons) • Poisoning potential (slight………extreme) • MOA (alkylating agent, cholinesterase inhibitors)

9. Lecture 2 14th March, 11 Toxicology Principles of Toxicology

10. Spectrum of undesired effects • Some effects deleterious others not • Some side effects……others indication • Diphenhydramine (1st generation antihistamine”benadryl”) effective against allergies but produces CNS drwsiness as it crosses BBB. Often used as sleep remedy e.g. tylenol PM • Sometimes undesirable effects also reffered to as deleterious effects

11. Allergic reactions • For given allergic individuals the allergic reaction are dose dependent • Pattern of allergic response (in humans skin and eyes and in guinae pigs bronchial constriction) • Anaphylactic shock • Hapten-protein complex required time for eliciting the formation of antibodies • Time dependent

12. Idiosyncratic • Immediate vs delayed toxicity • Local vs systemic • Reversible vs irreversible

13. Idiosyncratic reactions • Chemical idiosyncrasy refers to a genetically determined abnormal reactivity to a chemical • A classic example of an idiosyncratic reaction is provided by patients who exhibit prolonged muscular relaxation and apnea (inability to breathe) lasting several hours after a standard dose of succinylcholine.

14. Patients exhibiting this reaction have genetic polymorphism in the gene for the enzyme butyrylcholinesterase

15. Immediate vs delayed txicity • Immediate toxic effects can be defined as those that occur or develop rapidly after a single administration of a substance, whereas delayed toxic effects are those that occur after the lapse of some time. • Carcinogenic effects of chemicals usually have a long latency period, often 20 to 30 years after the initial exposure, before tumors are observed in humans.

16. e.gDiethylstilbestrol (DES) during pregnancy have a greatly increased risk of developing vaginal cancer, but not other types of cancer, in young adulthood, some 20 to 30 years after their in utero exposure to DES

17. Reversible vs irreversible toxic effects • Some toxic effects of chemicals are reversible, and others are irreversible. • For example tissue injury of liver nad tissue injury of CNS

18. Local vs systemic effects • Chlorine gas reacts with lung tissue at the site of contact, causing damage and swelling of the tissue, with possibly fatal consequences, even though very little of the chemical is absorbed into the bloodstream. (local)

19. Tetraethyl lead produces effects on skin at the site of absorption and then is transported systemically to produce its typical effects on the CNS and other organs.

20. Lecture 3 18th March, 11 Toxicology Principles of Toxicology

21. Interactions of chemicals • Additive (2+3=5) • Synergistic (2+2=20) e.g. carbon tetrachloride + ethanol leads to hepatotoxicity • Potentiative (0+2=10) e.g. isopropranolol + ethanol • Antagonistic (4+6=8) e.g. barbiturates and vasopressor

22. Tolerance • State of decreased responsiveness to a toxic effect of a chemical resulting from prior exposure to that chemical or to a structurally related chemical. E.g. carbon tetrachloride and cadmium, penicillins and cephalosporins

23. Potential stages in the development of toxicity after chemical exposure.

24. Potential stages in the development of toxicity • Puffer fish poison (tetrodotoxin) ingestion and reaches the voltage gated Na+ channels of motor neurons, interaction with target ions, result in blockade of channels, inhibition of the activity of motor neurons & ultimately skeletal muscle paralysis (no repair for such toxicity).

25. 2,4-dinitrophenol’s entrance in mitochondrial matrix space, collapsing directly outward across the inner membrane causing mitochondrial dysfunction and manifested by hyperthermia and seizures

26. The process of toxicant delivery is the first step in the development of toxicity

27. Delivery of toxicant • Gastrointestinal transporters (monocarboxylate transporters for salicylates, valporates and peptide transporters for β-lactam antibiotics and ACE inhibitors) • Rate of absorption • Conc.of chemical • Thickness of stratum corneum • Physiochemical properties e.g. lipid solubility • Epithelial circulation

28. First pass effect e.g. oxidation of ethanol by alcohol dehydrogenase in gastric mucosa and enterohepatic circulation of cyclosporine by P-glycoprotein transporter and hydroxylation by CYP450. • Distribution towards target mediated by transporters e.g. monocarboxylate transporters, peptide transporters, P-glycoprotein transporters, dopaminergic transporters.

29. Distribution away from target is facilitated by BBB, binding to plasma proteins, distribution in storage tissues like lead in bone and of lipophilic drugs in adipose tissue

30. Absorption • Gastrointestinal transporters (monocarboxylate transporters for salicylates, valporates and peptide transporters for β-lactam antibiotics and ACE inhibitors) • Rate of absorption and Conc.of chemical • Thickness of stratum corneum • Physiochemical properties e.g. lipid solubility • Epithelial circulation

31. Pre-systemic Elimination • First pass effect e.g. oxidation of ethanol by alcohol dehydrogenase in gastric mucosa and enterohepatic circulation of cyclosporine by P-glycoprotein transporter and hydroxylation by CYP450.

32. Distribution towards and away from Target • Distribution towards target mediated by transporters e.g. monocarboxylate transporters, peptide transporters, P-glycoprotein transporters, dopaminergic transporters. • Distribution away from target is facilitated by BBB, binding to plasma proteins, distribution in storage tissues like lead in bone and of lipophilic drugs in adipose tissue

33. Excretion • Excretion of drugs from blood to external environment • Renal transporters SLC family for diffusion of ions and smaller molecule < 300 Da • Excretion on the basis of lipid contents and acidity • Highly hydrophillic, organic acids and bases efficiently removed by liver and kidney

34. Highly non volatile and highly lipophilic eliminate slowly and tend to accumulate • Gases and volatile liquids liquids diffuse from pulmonary capillaries into the alveoli and are exhaled

35. Reabsorption • Toxicants delivered into the renal tubules may diffuse back across the tubular cells into the peritubular capillaries. • This process is facilitated by tubular fluid reabsorption, which increases the intratubular concentration as well as the residence time of the chemical by slowing urine flow.

36. For organic acids and bases, diffusion is inversely related to the extent of ionization,because the nonionized molecule is more lipid-soluble. • The ionization of weak organic acids, such as salicylic acid and phenobarbital, and bases, such as amphetamine, procainamide, and quinidine, is strongly pH-dependent in the physiologic range.

37. Toxication • A number of xenobiotics (e.g., strong acids and bases, nicotine, aminoglycosides, ethylene oxide, methylisocyanate,heavy-metal ions )are directly toxic, whereas the toxicity of others is due largely to metabolites. • Biotransformation to harmful products is called toxication or metabolic activation.

38. With some xenobiotics, toxication confers physicochemical properties that adversely alter the microenvironment of biological processes or structures. • For example, oxalic acid formed from ethylene glycol may cause acidosis and hypocalcaemia as well as obstruction of renal tubules by precipitation as calcium oxalate.

39. Reaction of the ultimate toxicant with the target molecule: the second step in the development of toxicity

40. Alteration of the regulatory or maintenance function of the cell: third first step in the development of toxicity

41. Lecture 4 21st March, 11 Toxicology Adverse Drug Reactions

42. Adverse Drug Reactions • ADR’s (definition and statistical figures) • Classification of ADR’s • Type A and Type B reactions (characteristics and types) • Anaphylaxis (signs and symptoms, diagnosis, management)

43. Lecture 5 25th March, 11 Toxicology antidote : ATROPINE

44. ACTH Neurotransmitter in both the peripheral nervous system (PNS) and central nervous system (CNS) Ester of acetic acid and choline with chemical formula CH3COOCH2CH2N+(CH3)3 Bethanechol, Melathione,Nicotine, Pilocarpine, Suxamethonium

45. ACTH In the peripheral nervous system, acetylcholine activates muscles, and is a major neurotransmitter in the autonomic nervous system. In the central nervous system, acetylcholine and the associated neurons form a neurotransmitter system, the cholinergic system, which tends to cause anti-excitatory actions.

46. Atropine • Therapeutic category • Dosage forms • Available brands • Mechanism of action • Blocks the action of ACTH at parasympathetic sites in smooth muscles, secretory glands and heart. Increases cardiac output, dries secretions, antagonizes histamine.

47. Use • Dosing • Organophosphate pesticides: I/V 0.02-0.05 mg/kg every 10 to 20 minutes until dry flushed skin, tachycardia and mydriasis are observed then every 1-4 hours for at least 24 hours • Bradycardia: I/V maximum total dose of 1 mg in children and 2 mg in adolescents in repeated doses.

48. Monitoring parameters Heart rate, blood pressure, pulse, mental status, cardiac monitoring • Adverse reactions (palpitation, drowsiness, hallucinations, urticaria, loss of taste, NVD, urinary retention, blurred vision, pulmonary edema, )

49. Interactions with drugs having anti cholinrgic activities( phenothiazines and TCA’s) • Overdosage treatment Physostigmine 1-2 mg (children: 0.5 mg or 0.02 mg/kg) S/C or slow I/V

50. Lecture 6 28th March, 11 Toxicology Antidote : DEFEROXAMINE