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DRUG TOXICITY Dr. Peter Maskell

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1 DRUG TOXICITY Dr. Peter Maskell

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. Acute poisoning accounts for 10-20% of hospital admission for general medicine.

3 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

4 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

5 1.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

6 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


8 Dosage (mg/kg) Therapeutic response % ED 50 Death 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)

9 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%

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

11 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

12 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

13 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

14 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 3000 individuals)

15 c. the unpredictable untoward adverse reactions drug allergies and anaphylactic reactions e.g. penicillin (1 in 50,000 patients exposed)

16 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 4 th most common cause of death following self-poisoning in UK in 1989

17 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

18 General mechanisms of toxin-induced cell damage Mostly caused by toxic metabolites e.g. by being able to form covalent bonds Hepatotoxicity Toxicity usually manifested as hepatitis Examples include: paracetamol, halothane, chlorpromazine Nephrotoxicity Commonly seen with NSAIDs and ACEIs (acute renal failure) Normally a result of their pharmacological action in patients whose underlying disease renal function is dependent on PG or angII biosynthesis Toxicity normally by cell necrosis


20 Examples: 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. barbiturates, ketamine, opiates, phenothiazines, atropine

21 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 thalliumRat poisonsalivation, diarrhoea, muscular cramps ataxia, diarrhoea, convulsions salivation, sweating, muscular cramps, convulsions salivation, diarrhoea, muscular cramps

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

23 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

24 Organic Poisons: drugs druguseMechanism/symptom barbituratessedation, general anaesthesiaenhancement of GABA A receptor function ketaminedissociative anaesthesiaNMDA receptor antagonist phenothiazines e.g. chlorpromazine neurolepticD 2 receptor antagonist respiratory paralysis increased incranial pressure jaundice

25 BNF 50 (September 2005; BNF for Children ( Principals of Biochemical Toxicology (3 rd Edition) John Timbrell Casarett & Doulls Toxicology (6 th Edition) Goodman & Gilmans The Pharmacological Basis of Therapeutics (11 th Edition) Further Reading

26 Powerpoint presentation will be on the Clinical Pharmacology website

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