DRUG TOXICITY

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DRUG TOXICITY

• Dr. Peter Maskell
• peter.maskell_at_bris.ac.uk

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• 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.

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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.

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What are the sources of toxicants?
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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

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How much of a problem is poisoning?

• National Poisons Information Service (NPIS)
• Poisoning accounts for 2-3 of A E department
  admissions (100,000 Patients)
• Poisoning 7 of Accidents in Under 5s (45,500
  attendances)
• Severe in children Iron, Methadone, Tricyclic
  antidepressants.
• Adults Paracetamol, Ibuprofen, Aspirin

NPIS annual report 2005/2006
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Disposition of Toxic Compounds
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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
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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

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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
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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
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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

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

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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
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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

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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)

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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)

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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
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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
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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

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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

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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, TCAs Aspirin.

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• 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
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Organic Poisons
plants
active principles
source
symptoms
nuts corn
aflatoxins (B1, B2)
anaphylactic shock, ataxia, blindness, jaundice
Ergot on wheat
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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
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Organic Poisons
drugs
drug
use
symptom
Coma, Respiratory depression, pinpoint pupils
Methadone
Pain relief, Drug addiction
TCAs (Tricyclic antidepresants)
Depression
Anticholinergic
CV effects, CNS effects
Aspirin (salicylates)
neuroleptic
Hyperventilation, tinnitus, deafness,
vasodilation, sweating
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Further Reading

• BNF (BNF.org)
• BNF for Children (BNFC.org)
• Clinical pharmacology and drug therapy (3rd
  Edition) Grahame-Smith Aronson
• Goodman Gilmans The Pharmacological Basis of
  Therapeutics (11th Edition)
• Principals of Biochemical Toxicology (3rd
  Edition) John Timbrell
• Casarett Doulls Toxicology (6th Edition)

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Powerpoint presentation will be on the Clinical
Pharmacology website http//www.zyworld.com/cliv
e_roberts/CPT.htm