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Dr. Peter Maskell peter.maskell@bris.ac.uk DRUG TOXICITY Dr. Peter Maskell peter.maskell@bris.ac.uk.

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Presentation on theme: "Dr. Peter Maskell peter.maskell@bris.ac.uk DRUG TOXICITY Dr. Peter Maskell peter.maskell@bris.ac.uk."— Presentation transcript:

1 Dr. Peter Maskell peter.maskell@bris.ac.uk
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 (16th 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:
Absorption oral pulmonary sublingual injection (I.V., I.P., subcut, I.A.) topical Distribution binding – plasma proteins, tissue (liver, bone, fat) 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 All these factors determine the drug/toxin bioavailability

4 Volume of Distribution (Vd)
Pharmacokinetics 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 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 Half life (t1/2) 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. Bioavailability (F) The fraction of the dose that reaches the systemic circulation

5 rate can be by zero-order kinetics
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

7

8 LD50- dose which will, on average, kill 50% of animals in a population
ED50- dose which will be therapeutically effective in 50% of animals (median effective dose) Dosage (mg/kg) Therapeutic response % 100 50 ED50 Death LD50 MED MTD LD50- 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) = LD50
ED indicates relative safety of drug Therapeutically: MTD MED - For: barbiturate anaesthesia – 3-4 benzodiazepines >20 ie: represents a therapeutic window Standard Safety Margin (SSM) = LD1 ED99 – more conservative estimate than TI LD1 – dose required to kill 1% ED99 – dose therapeutically effective in 99%

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

11 excessive action at a primary site (overdosage)
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 - most drugs tested on young to middle-aged volunteers
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 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 4th 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 Toxicity normally by cell necrosis 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

19

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 metal source symptoms Mineral or Inorganic Poisons:
metals, metalloids and non-metals metal source symptoms lead inorganic oil paint, batteries ataxia, diarrhoea, convulsions salivation, sweating, muscular cramps, convulsions salivation, diarrhoea, muscular cramps ataxia, diarrhoea, convulsions organic petrol Hair loss, joint swelling, anaemia barium Insecticides salivation, sweating, muscular cramps, convulsions thallium Rat poison salivation, diarrhoea, muscular cramps

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

23 source active principles symptoms Organic Poisons: plants nuts
aflatoxins (B1, B2) anaphylactic shock, ataxia, blindness, jaundice anaphylactic shock, ataxia, blindness, jaundice rhubarb oxalic acid (in leaf) nausea, vomiting, convulsions nausea, vomiting, convulsions solanum family deadly nightshade potato atropine scopolamine (hyoscine) glycoalkaloids Dry mouth, hyperthermia Tachycardia CNS depression/ stimulant (AChE inhibitors) Salivation, hypothermia, bradycardia, neuromuscular block

24 drug use Mechanism/symptom Organic Poisons: drugs barbiturates
sedation, general anaesthesia enhancement of GABAA receptor function respiratory paralysis ketamine dissociative anaesthesia NMDA receptor antagonist increased incranial pressure phenothiazines e.g. chlorpromazine neuroleptic D2 receptor antagonist jaundice

25 Further Reading BNF 50 (September 2005; BNF.org)
BNF for Children (BNFC.org) Principals of Biochemical Toxicology (3rd Edition) John Timbrell Casarett & Doull’s Toxicology (6th Edition) Goodman & Gilman’s The Pharmacological Basis of Therapeutics (11th Edition)

26 Powerpoint presentation will be on the Clinical Pharmacology website


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