1. DRUG TOXICITY

2. Toxicology is the science that deals with the amount of an agent that causes an adverse action in some living system ‘All substances are poisons; there is none which is not a poison. The right dose differentiates a poison from a remedy.’- Paracelus (16 th century physician-alchemist) ‘ A poison is any substance or matter which, when applied to the body outwardly, or in any way introduced into it, can destroy life by its own inherent qualities, without acting mechanically, and irrespective of temperature.’

3. Some definitions Another term for poison is toxicant Toxin is used to describe ‘biological poisons’ Toxicosis a disease state that results from exposure to a poison.

4. What are the sources of toxicants?

5.  Can be defined as, ‘an unwanted or harmful reaction experienced following administration of a drug, or combination of drugs, under normal conditions of use and is suspected as being related to the drug (or combination)’ Adverse Drug Reactions: ADRs  Causes considerable morbidity and mortality; treating this is very expensive  Data on incidence is poor considering the scope of the problem  UK Studies suggest:- ― 6.5% of Hospital admissions ― Associated mortality 0.15% ― Cost estimate £466m annually

6. How much of a problem is poisoning? Poisoning accounts for 2-3% of A + E department admissions Poisoning 7% of Accidents in Under 5’s Severe in children : Iron, Methadone, Tricyclic antidepressants. Adults: Paracetamol, Ibuprofen, Aspirin NPIS annual report 2005/2006

7. Disposition of Toxic Compounds

8. Factors influencing toxicity: 1.Absorption oral pulmonary sublingual injection (I.V., I.P., subcut, I.A.) topical 3.Metabolism Mainly liver (some in GI tract, kidneys, lungs) Phase I – introduce or expose a functional group on the parent compound – losing pharmacological effect Phase II – produces polar conjugates – generally inactive and easily excreted in urine and/or faeces 4. excretion 2.Distribution binding – plasma proteins, tissue (liver, bone, fat) All these factors determine the drug/toxin bioavailability

9. Pharmacokinetics 1.Clearance (Cl) Ratio relating to the rate of elimination (usually in ml/min) High values for efficient clearance Most important index of the capacity of an organ to remove a drug 3.Half life (t 1/2 ) The time it take for the plasma concentration of drug in the body to be reduced by 50% For practical purposes the drug is considered eliminated after 7 half-lives. 4.Bioavailability (F) The fraction of the dose that reaches the systemic circulation 2.Volume of Distribution (Vd) Relates the amount of drug in the body to the concentration of drug in the plasma Reflects the extent to which it is present in the extravascular tissue and not in the plasma

10. Absorption rate can be by zero-order kinetics rate is constant and independent of amount of drug absorbed e.g continuous intravenous drip or: rate can be by first-order kinetics diminishing and always in proportion to the amount of drug still to be absorbed most drug absorption follows first-order kinetics If drug is injected then consider drug is absorbed instantaneously

11. Clearance: plasma concentration – time curves Drug eliminated from a single compartment by a first order process half life ~ 4hrs If sample before 2 hrs, reveals drug elimination is a multiexponential process

13. The dose-response curve Most Basic and fundamental concept Dose (mg/Kg) Either Quantal ‘All or None’ or Graded response Assume –1) response proportional to concentration at target site –2) concentration at target related to dose –3) response is causally related to compound administered. Shape depends on toxic effect and mechanism

14. Dosage (mg/kg) Therapeutic response % 100 50 ED 50 Death 100 50 LD 50 MED MTD ED 50 - dose which will be therapeutically effective in 50% of animals (median effective dose) LD 50 - dose which will, on average, kill 50% of animals in a population MED- minimum effective dose (the least dose that is likely to be effective). Also called toxic dose- low(TDL) MTD- maximum tolerated dose (or minimum toxic dose) (more than this will produce signs of toxicity). Also called highest nontoxic dose (HNTD)

15. Other terms: Therapeutic Index (TI) = LD 50 ED 50 - indicates relative safety of drug Therapeutically: MTD MED - For: barbiturate anaesthesia – 3-4 benzodiazepines >20 ie: represents a therapeutic window Standard Safety Margin (SSM) = LD 1 ED 99 – more conservative estimate than TI LD 1 – dose required to kill 1% ED 99 – dose therapeutically effective in 99%

17. Principle causes of drug toxicity/side effects a. the predictable b. the less predictable c. the unpredictable

18. a. the predictable excessive action at a primary site (overdosage) e.g. anaesthetics, warfarin non-selectivity: acting at unrelated sites (more likely with overdosage) e.g. chlorpromazine incomplete selective toxicity: acts against the host as well as the target organism or cell e.g. protein synthesis inhibitors, antimicrobials, antifungals tolerance (dependence & abuse potential) e.g. benzodiazepines, opioids unavoidable side-effects e.g. immunosuppression by corticosteroids – opportunistic infections

19. a. the predictable Pharmacokinectic Drug interactions: absorption e.g. gastric emptying, gut motility Atropine and metoclopramide distribution e.g. displacement from plasma proteins aspirin and warfarin metabolism e.g. increased by enzyme induction barbiturates and steroids excretion e.g. active transport competition NSAIDS and methotrexate

20. a. the predictable age - most drugs tested on young to middle-aged volunteers -causing problems such as: -drug clearance mechanisms (renal and hepatic) are limited in newborns -clearance is reduced in elderly (increasing half life) reduction in lean body mass, serum albumin, total body water. increased body fat declined renal function reduced hepatic blood flow reduced activities of cytochrome P450 enzymes gender -a relative increase of body fat in females -Pregnancy / Breast feeding

21. b. the less predictable Genetic factors e.g. polymorphism in NAT2 in the liver (N- acetyltransferase2). -metabolises about 16 common drugs (phenytoin, hydralazine) Plasma esterase – suxamethonium (about 1 in 3,000 individuals) Malignant Hyperthermia – Halothane (1 in 20,000)

22. Non-dose related drug reactions –Commonly called ‘idiosyncratic’ –Immunological pathogenesis Hypersensitivity syndrome Drug allergy (e.g. Penicillin 1 in 50, 000 patients exposed) c. the unpredictable

23. Chemical forms that produce toxicity The parent drug is often the cause of toxic effects However, toxic effects may result from metabolites: For example: paracetamol Most common cause of death following self-poisoning in UK

24. Induction of microsomal enzymes A number of drugs such as ethanol and carbamazepine, increase the activity of microsomal oxidase and conjugating systems when administered repeatedly. For example: phenobarbitone significantly increases phase I microsomal oxidases Phase I metabolism causes accumulation of toxic metabolites of paracetamol

25. Target Organs: adverse effect is dependent upon the concentration of active compound at the target site for enough time Not all organs are affected equally –greater susceptibility of the target organ –higher concentration of active compound Liver--high blood flow, oxidative reactions Kidney--high blood flow, concentrates chemicals Lung--high blood flow, site of exposure Neurons--oxygen dependent, irreversible damage Myocardium--oxygen dependent Bone marrow, intestinal mucosa--rapidly divide

26. Toxic Mechanisms 3 Basic Mechanisms –Primary Occurs at the molecular level –Secondary Events resulting from primary events Damage to macromolecules changes in structure/function –Tertiary Necrosis, Apoptosis, Steatosis

27. Examples of Toxicants: Mineral or Inorganic Poisons: metals, metalloids and non-metals e.g. lead, mercury, arsenic, phosphorus, sulphur salts of metals and non-metals e.g. copper sulphate, arsenious oxide, zinc phosphide acids and alkalis Organic Poisons: pesticides e.g. fungicides, herbicides and insecticides plants e.g. ergot– fungus grows on wheat/rye, aflatoxins – ground nut meal oxalic acid– rhubarb, drugs e.g. Methadone, TCA’s Aspirin.

28. Mineral or Inorganic Poisons: metals, metalloids and non-metals metalsourcesymptoms lead inorganicoil paint, batteries organicpetrol ataxia, diarrhoea, convulsions Hair loss, joint swelling, anaemia bariumInsecticidessalivation, sweating, muscular cramps, convulsions IronSupplementVomiting, Shock, Abdominal pain, diarrhoea, rectal bleeding, Coma ataxia, diarrhoea, convulsions salivation, sweating, muscular cramps, convulsions

29. Organic Poisons: plants sourcesymptoms active principles nuts corn aflatoxins (B1, B2)anaphylactic shock, ataxia, blindness, jaundice corn with aflatoxin Ergot on wheat

30. Organic Poisons: plants sourcesymptoms active principles nutsaflatoxins (B1, B2)anaphylactic shock, ataxia, blindness, jaundice rhubarboxalic acid (in leaf)nausea, vomiting, convulsions solanum family deadly nightshade potato atropine scopolamine (hyoscine) glycoalkaloids anaphylactic shock, ataxia, blindness, jaundice nausea, vomiting, convulsions Dry mouth, hyperthermia Tachycardia CNS depression/ stimulant (AChE inhibitors) Salivation, hypothermia, bradycardia, neuromuscular block

31. Organic Poisons: drugs drugusesymptom MethadonePain relief, Drug addiction TCA’s (Tricyclic antidepresants) DepressionAnticholinergic Aspirin (salicylates) neurolepticHyperventilation, tinnitus, deafness, vasodilation, sweating CV effects, CNS effects Coma, Respiratory depression, pinpoint pupils