Transcript 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
• Another term for poison is toxicant
• Toxin is used to describe ‘biological
poisons’
• Toxicosis a disease state that results
from exposure to a poison.
What are the sources of
toxicants?
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?
• 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
Disposition of Toxic Compounds
Factors influencing toxicity:
1. Absorption
•
•
•
•
•
oral
pulmonary
sublingual
injection (I.V., I.P., subcut, I.A.)
topical
2. Distribution
•
binding – plasma proteins, tissue (liver, bone, fat)
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
All these factors determine the drug/toxin bioavailability
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
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
3.
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.
4.
Bioavailability (F)
•
The fraction of the dose that reaches the systemic circulation
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
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
• 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
100
100
50
50
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 doselow(TDL)
MTD- maximum tolerated
dose (or minimum toxic
dose) (more than this will
produce signs of toxicity).
Also called highest nontoxic
dose (HNTD)
Other terms:
Therapeutic Index (TI) = LD50
ED50 - 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%
Principle causes of drug toxicity/side effects
a. the predictable
b. the less predictable
c. the unpredictable
a. the predictable
•
excessive action at a primary site (overdosage)
•
non-selectivity: acting at unrelated sites (more likely
with overdosage)
e.g. anaesthetics, warfarin
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)
•
unavoidable side-effects
e.g. benzodiazepines, opioids
e.g. immunosuppression by corticosteroids – opportunistic
infections
a. the predictable
Pharmacokinectic Drug interactions:
•absorption
e.g. gastric emptying, gut motility
Atropine and
metoclopramide
•distribution
aspirin and warfarin
e.g. displacement from plasma proteins
•metabolism
e.g. increased by enzyme induction
barbiturates and steroids
excretion
e.g. active transport competition
NSAIDS and
methotrexate
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
b. the less predictable
Genetic factors
e.g. polymorphism in NAT2 in the liver (Nacetyltransferase2).
-metabolises about 16 common drugs (phenytoin,
hydralazine)
Plasma esterase – suxamethonium (about 1 in 3,000
individuals)
Malignant Hyperthermia – Halothane (1 in 20,000)
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)
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
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
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
• 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
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.
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
Organic Poisons:
plants
source
active principles
nuts
corn
aflatoxins (B1, B2)
corn with aflatoxin
symptoms
anaphylactic shock, ataxia,
blindness, jaundice
Ergot on wheat
Organic Poisons:
plants
source
active principles
nuts
aflatoxins (B1, B2)
anaphylactic shock, ataxia,
blindness, jaundice
rhubarb
oxalic acid (in leaf)
nausea, vomiting,
convulsions
solanum family
deadly
nightshade
Dry mouth, hyperthermia
atropine
scopolamine (hyoscine) Tachycardia CNS depression/
stimulant
potato
glycoalkaloids
symptoms
(AChE inhibitors)
Salivation, hypothermia,
bradycardia, neuromuscular
block
Organic Poisons:
drugs
drug
Methadone
use
Pain relief, Drug addiction
TCA’s
(Tricyclic antidepresants)
Depression
Aspirin (salicylates)
neuroleptic
symptom
Coma, Respiratory
depression, pinpoint
pupils
Anticholinergic
CV effects, CNS effects
Hyperventilation,
tinnitus, deafness,
vasodilation,
sweating