Drug toxicity
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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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Drug toxicity

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

  • ‘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.’


Some definitions

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.


Drug toxicity

What are the sources of toxicants?


Drug toxicity

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


How much of a problem is poisoning

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


Drug toxicity

Disposition of Toxic Compounds


Drug toxicity

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


Drug toxicity

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


Drug toxicity

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


Drug toxicity

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


The dose response curve

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


Drug toxicity

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)


Drug toxicity

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:


Drug toxicity

Principle causes of drug toxicity/side effects

a. the predictable

b. the less predictable

c. the unpredictable


Drug toxicity

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


Drug toxicity

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


Drug toxicity

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


Drug toxicity

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)


Drug toxicity

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)


Drug toxicity

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


Drug toxicity

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


Drug toxicity

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


Toxic mechanisms

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


Drug toxicity

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.


Drug toxicity

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


Drug toxicity

corn with aflatoxin

Organic Poisons:

plants

active principles

source

symptoms

nuts

corn

aflatoxins (B1, B2)

anaphylactic shock, ataxia, blindness, jaundice

Ergot on wheat


Drug toxicity

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


Drug toxicity

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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