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Drug tolerance

Definition:

when a patient's reaction to a specific drug and / or the concentration of that drug is no longer has its effect. As a result we require an increase in concentration in order to achieve the desired effect. Drug tolerance can involve both psychological factors and physiological drug tolerance.
Some of the characteristics of drug tolerance:
  1. it is reversible
  2. the rate depends on the particular drug
  3. dosage and frequency of use
  4. differential development occurs for different effects of the same drug

There is another way of tolerance which is called Physiological tolerance occurs when an organism builds up a resistance to the effects of a substance after repeated exposure. This can occur with environmental substances, such as salt or pesticides.
A rapid drug tolerance is termed tachyphylaxis.

Tachyphylaxis:

Tachyphylaxis is a sudden onset drug tolerance which is not dose dependent.

Mechanisms:

  • Pharmacokinetic Tolerance:


Pharmacokinetic Tolerance - Also known as Dispositional tolerance: occurs because of a decreased quantity of the substance reaching the site it affects. This may be caused by an increase in induction of the enzymes required for degradation of the drug e.g. CYP450 enzymes.
  • Pharmacodynamic Tolerance:

Pharmacodynamic Tolerance - Also known as Reduced responsiveness: the response to the substance is decreased by cellular mechanisms. This may be caused by a down regulation of receptor numbers.
Tolerance: reduced response to repeated administration of the same dose or increase in the dose are required to produce the same magnitude of response.

Morphine as an Example:

Tolerance to the analgesic effects of morphine is fairly rapid. There are several hypotheses about how tolerance develops, including opioid receptor phosphorylation (which would change the receptor conformation), functional decoupling of receptors from G-proteins (leading to receptor desensitization), mu-opioid receptor internalization and/or receptor down-regulation (reducing the number of available receptors for morphine to act on), and upregulation of the cAMP pathway (a counterregulatory mechanism to opioid effects) (For a review of these processes, see Koch and Hollt.) CCK might mediate some counter-regulatory pathways responsible for opioid tolerance. CCK-antagonist drugs, specifically proglumide, have been shown to slow the development of tolerance to morphine or any other kind of drug, including alcohol.
Significant involvement of the intracellular Beta-arrestin-2 protein expression in the agonist-mediated desensitization of G protein-coupled receptors, such as the μ-opioid receptor (MOR), has been elucidated.
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