Transcript Tolerance and Idiosyncrasy

Pharmacology-1 PHL 351
Abdelkader Ashour, Ph.D.
Desensitization (Tachyphylaxis) and
Tolerance
 The loss of a drug’s effect, when it is given continuously or repeatedly
 On a short time-scale, such as a few minutes, this situation is called desensitization
or tachyphylaxis and on a longer time-scale, such as days or weeks, the term
tolerance is preferred.
 Receptor-mediated responses to drugs and hormonal agonists often
desensitize with time, when they are given continuously or repeatedly
 After reaching an initial high level, the response (eg, cellular cAMP
accumulation, Na+ influx, contractility, etc) gradually diminishes over seconds or
minutes, even in the continued presence of the agonist
 This is usually reversible; a second exposure to agonist, if provided a few
minutes after termination of the first exposure, results in a response similar to
the initial response
Desensitization (Tachyphylaxis) and
Tolerance, mechanisms
1.
Change in receptors (Rapid desensitization):
i.
A slow conformational change in the receptor, resulting in tight binding of the
agonist molecule without the opening of the ionic channel (e.g., ligand-gated
ion channels such as nicotinic receptors at the neuromuscular junction) 
rapid and reversible
ii.
Phosphorylation of intracellular region of the receptor protein, leading to:
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Desensitization of ion channel, or
Interference with the receptor’s (e.g., GPCR) ability to activate second messenger
cascade, though it can still bind the agonist molecule  slow and reversible
Example: b-adrenoceptors 
Desensitization (Tachyphylaxis) and
Tolerance, mechanisms
2.
Loss of receptors (down-regulation)
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Prolonged exposure to agonists often results in a gradual decrease in the actual number
of receptors expressed on the cell surface

The vanishing receptors are taken into the cell by endocytosis of patches of the
membrane, a process that also depends on phosphorylation
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It occurs more slowly than rapid desensitization and is less readily reversible.
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This is because down-regulation involves a net degradation of receptors present in the
cell, requiring new receptor biosynthesis for recovery, in contrast to rapid desensitization
which involves reversible phosphorylation of existing receptors
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Many G protein–coupled receptors and many hormone receptors are down-regulated by
undergoing ligand-induced endocytosis and delivery to lysosomes
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Down-regulation generally occurs only after prolonged or repeated exposure of cells to
agonist (over hours to days).
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Example: chronic salbutamol (b2 agonist) can cause internalisation of receptors → less
receptors available for stimulation → decreased bronchodilation
Desensitization (Tachyphylaxis) and
Tolerance, mechanisms
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3.
Note: Brief periods of agonist exposure (several minutes) can also induce
internalization of receptors.
In this case, many receptors, including the b-adrenoceptor, do not down-regulate
but instead recycle intact to the plasma membrane.
This rapid cycling through endocytic vesicles promotes dephosphorylation of
receptors, increasing the rate at which fully functional receptors are replenished in
the plasma membrane.
How about Chronic antagonist administration? Can this lead to UP
REGULATION??? ……………………………..YES
Example: chronic propranolol (b blocker) can cause increased synthesis
of β1 receptors in the heart → less antagonism → decreased drug effect
(increased heart rate and blood pressure)
Desensitization (Tachyphylaxis) and
Tolerance, mechanisms
3.
Exhaustion of mediators:
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4.
depletion of a signaling molecule or an essential intermediate substance
required for biological response
Example 1: prolonged stimulation of G-protein coupled receptors can lead to
depletion of intracellular secondary messengers
Example 2: Indirectly acting sympathomimetics (e.g. amphetamine) act by
releasing tissue stores of adrenaline and noradrenaline and other amines
from the nerve terminal  tachyphalaxis occurs because the amine stores
become depleted
Increased metabolic degradation
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increase in the rate of metabolism and/or elimination of drug
lowers plasma drug concentrations
Example: barbiturates and ethanol induce the expression of metabolic
enzymes (cytochrome P450s) that degrade the drug  low plasma drug
concentration
Desensitization (Tachyphylaxis) and
Tolerance, mechanisms
5.
Physiological adaptation
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A drug’s decreasing effects may occur because it is nullified by a homeostatic
response.
These homeostatic mechanisms are very common and if they occur slowly
the result will be a very gradually developing tolerance.
Example 1: the blood pressure-lowering effect of thiazide diuretics is limited
because of a gradual activation of the renin-angiotensin system
Example 2: It is a common experience that many side effects of drugs such
as nausea and sleepiness tend to subside even though administration is
continued
WHY desensitization?
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many receptor-effector systems incorporate desensitization mechanisms for
preventing excessive activation when agonist molecules continue to be
present for long periods.
Idiosyncrasy
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A structural or behavioral characteristic peculiar to an individual or
group.
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Idiosyncratic drug reaction is a qualitatively abnormal, and usually
harmful, drug effect that occurs in a small proportion of individuals
 chloramphenicol causes aplastic anemia in approximately 1 in
50,000 patients
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In many cases, genetic materials are responsible.
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Example, individuals with G6PD (an enzyme that maintains the
content of GSH in red cells, and thus prevent hemolysis) deficiency
cannot tolerate primaquine or some sulfonamide drugs (well tolerated
in most individuals)
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Those individuals will suffer from hemolysis leading to severe anemia
Primaquine and related substances reduce red cell GSH harmlessly in
normal cells, but enough to cause hemolysis in G6PD-deficient cells