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DRUG TOXICITY

DRUG TOXICITY. Toxicology is the science that deals with the amount of an agent that causes an adverse action in some living system

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DRUG TOXICITY

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  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 (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.’

  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. Adverse Drug Reactions: ADRs • 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)’ • 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: • 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

  9. 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

  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

  12. 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

  13. 100 100 Therapeutic response % 50 50 Death ED50 LD50 Dosage (mg/kg) MED MTD ED50- dose which will be therapeutically effective in 50% of animals (median effective dose) 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)

  14. 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% Therapeutic Index (TI) = LD50 ED50 - indicates relative safety of drug Other terms:

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

  16. 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

  17. 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

  18. 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

  19. 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)

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

  21. 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

  22. 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

  23. 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

  24. 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

  25. 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.

  26. ataxia, diarrhoea, convulsions salivation, sweating, muscular cramps, convulsions • Mineral or Inorganic Poisons: • metals, metalloids and non-metals metal source symptoms lead inorganic oil paint, batteries ataxia, diarrhoea, convulsions organic petrol Hair loss, joint swelling, anaemia barium Insecticides salivation, sweating, muscular cramps, convulsions Iron Supplement Vomiting, Shock, Abdominal pain, diarrhoea, rectal bleeding, Coma

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

  28. Organic Poisons: plants active principles source symptoms 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 Dry mouth, hyperthermia Tachycardia CNS depression/ stimulant (AChE inhibitors) Salivation, hypothermia, bradycardia, neuromuscular block solanum family deadly nightshade potato atropine scopolamine (hyoscine) glycoalkaloids

  29. Organic Poisons: drugs drug use symptom Coma, Respiratory depression, pinpoint pupils Methadone Pain relief, Drug addiction TCA’s (Tricyclic antidepresants) Depression Anticholinergic CV effects, CNS effects Aspirin (salicylates) neuroleptic Hyperventilation, tinnitus, deafness, vasodilation, sweating

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