1997 Clinical pharmacology

By Duy Thai

DOSE DEPENDENT VS IDIOSYNCRATIC TOXICITY

“‘All substances are poisons; there is non which is not a poison. The right dose
differentiates a poison and a remedy”

• The definition of drug toxicity are adverse effects which accompany therapeutic use
• Drug toxicity can be dose dependent, or can be the result of an idiosyncratic response.
• Dose dependent drug toxicity can manifest as
A. Side effects
B. Overdose
C. Idiosyncratic reaction

Side effects
• Unavoidable
• Frequent
• Occur at therapeutic levels
• Dose dependent
• Side effects are predictable by knowing the pharmacological behaviour of a drug
• Side effects manifest at sites different t o where you want a drug to act
• e.g . β blockers
• Block the β receptors i n the heart to slow down the heart, but if the β receptors in the bronchi are
affected as well, this can result in bronchoconstriction, which is a severe side effect especially in
asthmatics.
• e.g. Paracetamol
• An analgesic but can also decrease the pH in the stomach, leading to gastric ulceration
• The side effect curve and desired effect curve overlap each other. That means that there will
always be some side effect of a drug, no matter what concentration you choose.

• By knowing the side effect profile of a drug, we can change the type of drug according to a person’s unique
conditions. E.g. By knowing that some β blockers can cause bronchoconstriction we should try to avoid giving these
to asthmatics and look at an alternative drug.

• Side effects are context specific. In some conditions, the therapeutic effect may be regarded as a side effect in
another condition.
• e.g. Atropine:
1. Dilates the iris and causes cycloplegia
2. Preoperatively used to dry up secretions
3. In Parkinson’s, it is used to decrease tremor
• In each one of the examples above, the other 2 effects are also present, and may be regarded as side
effect . In Parkinson’s, it is not useful to have a dry throat or to have a dilated iris.
• Side effects are considered tolerable to an extent

Overdose
• Considered adverse effects of a drug when taken in doses which are in excess of the therapeutic range
• The adverse effects occur when the drug accumulates to high concentrations in the plasma. Can be due to:
1. Underlying problem
• A disease which may affect the metabolism and excretion of the drug from the body
• Any other drugs which may interact with the metabolism and excretion of the drug
2. Deliberate Overdose
• An overdose can cause pathological damage to tissues and may lead to death
• An overdose of atropine can lead to sedation
• Barbiturates are anxiolytics which decrease the excitability of neurons. If taken in excess. they can
depress the respiratory center.
• The best example is paracetamol overdose which leads to liver damage.
• An overdose of paracetamol saturates the normal conjugation reaction, thus pushing the
metabolic pathway towards cP450 metabolism which produces reactive intermediates.
• These excess reactive intermediates are neutralised by glutathione. However, if there is
too much, they will use up all the glutathione. Once the reactive intermediates build up,
they will bind to cellular proteins on liver cells, causing liver damage
• To treat a paracetamol overdose, N acetylcysteine is given, which is a precursor to
glutathione.

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 1997 Clinical pharmacology
By Duy Thai

Idiosyncratic reaction
• An odd response to a given dose which is usually normal (you give a dose of a drug which is within therapeutic
levels but the response you get is not what you would expect at that given dose)
• Occurs infrequently
• Qualitatively abnormal
• The effect is predictable but occurred at a concentration which was not expected
• Genetically determined
• e.g. Suxamethonium
• Suxamethonium is a depolarising neuromuscular blockers, causing muscle paralysis. Normal people would
get apnoea (due to paralysis of the respiratory muscles) at very high concentrations (an overdose effect).
However, in some people, they may get apnoea at concentrations which are in the therapeutic range or
even below that. Why?
• The metabolism of suxamethonium is via butyrylcholinesterase (plasma cholinesterase). Some
people have an inefficient plasma cholinesterase, hence , “normal” levels to these people could
be the equivalent of a high dosage.
• Another example: warfarin (an anticoagulant)
• In some people, normal doses gives no response, and hence higher doses (which may be considered
toxic in other people) are required to gain a response. This is due to the enhanced metabolism of warfarin.
• Idiosyncratic toxicity is reversible upon withdrawal of the drug.

Idiosyncratic toxicity (more correctly a hypersensitivity)

• May be a hypersensitivity response
• It is not dose dependent
• It occurs infrequently and is difficult to predict who will react to a drug in an idiosyncratic way
• The response is pharmacologically abnormal (you cannot explain it on the basis of the pharmacological action of
the drug)
• e.g. People suffering an anaphylactic reaction when given penicillin
• e.g. Children with certain viral infections given aspirin can develop Reyes Syndrome
• There appears to be an immunological basis to it. Evidence for this:
1. Prior exposure is necessary - there is a delay in toxicity
2. There is no delay on re exposure (react immediately - just like a secondary immune response)
3. Idiosyncratic toxicity can resemble many forms of hypersensitivity:
A. Type I
• Immediate, resulting in inflammation, leading to anaphylaxis
• Allergen specific IgE, mast cells
• e.g. Penicillin, atropine (atropine applied topically to the eye may result in a red eye in
some people)
B. Type II
• Cytotoxic - causing anaemia, thrombocytopenia
• Due to cell surface antigens IgG/IgM
• e.g. Halothane (can cause liver damage on re-exposure), paracetamol, sulphonamides
(can cause anaemia)
C. Type III
• Serum sickness
• Circulating immune complexes - complement activation causing damage to tissues,
basement membrane
• e.g. Antivenoms
D. Type IV
• Delayed, e.g. contact dermatitis (from poison ivy)
• Due to T lymphocytes releasing cytokines
• e.g. Phenothiazines can cause photosensitivity

• However, there are some aspects which are not suggestive of an immune system involvement:
1. Drugs are low molecular weight molecules whereas antigens are high molecular weight molecules
2. Sometimes people react to a drug the first time they are exposed to it
• It is possible to explain why:
1. The drug acts as a hapten (a small molecule which on its own is incapable of eliciting an immune response
but when bound to a larger molecule, can illicit a response). The hapten + a larger protein molecule = an
antigen, which is capable of provoking antibody formation.
2. a) The widespread use of penicillin may cause low level sensitisation, even though a person may not have
been treated with it, they may have had contact with it some time in their life.
2. B) Sulphonamides (pABA analogue) may possess an antigenic moiety (an allergenic determinant) which is
expressed on other closely related drugs. Hence, being exposed to one drug may render you sensitive to
another drug which, although different, may possess the antigenic moiety.
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 1997 Clinical pharmacology
By Duy Thai

Summary - using atropine as an example

1. Side effect
• Anti SLUD (salivation, lacrimation. urination, defecation)
2. Overdose
• Blurred vision, difficulty swallowing (dry throat), sedation
3. Idiosyncratic response
• Rabbits have a faster acting esterase than humans, so that the metabolism of atropine is slower in
humans. Hence a dose which is fine in rabbits may not be for humans.
4. Idiosyncratic toxicity
• Red eye (Type I hypersensitivity)

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