Drug tolerance

Source: Wikipedia, the free encyclopedia.
This article is about human resistance to the effects of drugs. For pathogenic resistance to the effects of drugs, see Drug resistance.
Addiction and dependence glossary[1][2][3]
  • biopsychosocial
    disorder characterized by persistent use of drugs (including alcohol) despite substantial harm and adverse consequences
  • addictive drug – psychoactive substances that with repeated use are associated with significantly higher rates of substance use disorders, due in large part to the drug's effect on brain reward systems
  • dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake)
  • drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose
  • drug withdrawal – symptoms that occur upon cessation of repeated drug use
  • physical dependence – dependence that involves persistent physical–somatic withdrawal symptoms (e.g., fatigue and delirium tremens)
  • psychological dependence – dependence socially seen as being extremely mild compared to physical dependence (e.g., with enough willpower it could be overcome)
  • reinforcing stimuli – stimuli that increase the probability of repeating behaviors paired with them
  • rewarding stimuli – stimuli that the brain interprets as intrinsically positive and desirable or as something to approach
  • sensitization – an amplified response to a stimulus resulting from repeated exposure to it
  • substance use disorder – a condition in which the use of substances leads to clinically and functionally significant impairment or distress
  • tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose

Drug tolerance or drug insensitivity is a

psychological factors.[6]

One may also develop drug tolerance to

allergic reactions) is called drug desensitization.[8]

The opposite concept to drug tolerance is

liver damage, which then puts them at risk of intoxication when drinking even very small amounts of alcohol.[9]

Drug tolerance should not be confused with

drug tolerability, which refers to the degree to which overt adverse effects
of a drug can be tolerated by a patient.

Tachyphylaxis

Main article: Tachyphylaxis

Tachyphylaxis is a subcategory of drug tolerance referring to cases of sudden, short-term onset of tolerance following the administration of a drug.[10]

Pharmacodynamic tolerance

Pharmacodynamic tolerance begins when the cellular response to a substance is reduced with repeated use. A common cause of pharmacodynamic tolerance is high concentrations of a substance constantly binding with the receptor, desensitizing it through constant interaction.[11] Other possibilities include a reduction in receptor density (usually associated with receptor agonists), or other mechanisms leading to changes in action potential firing rate.[12] Pharmacodynamic tolerance to a receptor antagonist involves the reverse, i.e., increased receptor firing rate, an increase in receptor density, or other mechanisms.

While most occurrences of pharmacodynamic tolerance occur after sustained exposure to a drug, instances of acute or instant tolerance (tachyphylaxis) can occur.[13]

Pharmacokinetic (metabolic) tolerance

Pharmacokinetics refers to the absorption, distribution, metabolism, and excretion of drugs (ADME). All psychoactive drugs are first absorbed into the bloodstream, carried in the blood to various parts of the body including the site of action (distribution), broken down in some fashion (metabolism), and ultimately removed from the body (excretion). All of these factors are very important determinants of crucial pharmacological properties of a drug, including its potency, side effects, and duration of action.

Pharmacokinetic tolerance (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. This is most commonly seen with substances such as ethanol.

This type of tolerance is most evident with oral ingestion, because other routes of drug administration bypass first-pass metabolism. Enzyme induction is partly responsible for the phenomenon of tolerance, in which repeated use of a drug leads to a reduction of the drug's effect. However, it is only one of several mechanisms leading to tolerance.

Behavioral tolerance

Behavioral tolerance occurs with the use of certain psychoactive drugs, where tolerance to a behavioral effect of a drug, such as increased motor activity by methamphetamine, occurs with repeated use. It may occur through drug-independent learning or as a form of pharmacodynamic tolerance in the brain; the former mechanism of behavioral tolerance occurs when one learns how to actively overcome drug-induced impairment through practice. Behavioral tolerance is often context-dependent, meaning tolerance depends on the environment in which the drug is administered, and not on the drug itself.

Behavioral sensitization
describes the opposite phenomenon.

See also

References

  1. ISBN 9780071481274
    .
  2. PMID 24459410
    . Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41. ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict.
  3. PMID 26816013
    . Substance-use disorder: A diagnostic term in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) referring to recurrent use of alcohol or other drugs that causes clinically and functionally significant impairment, such as health problems, disability, and failure to meet major responsibilities at work, school, or home. Depending on the level of severity, this disorder is classified as mild, moderate, or severe.
    Addiction: A term used to indicate the most severe, chronic stage of substance-use disorder, in which there is a substantial loss of self-control, as indicated by compulsive drug taking despite the desire to stop taking the drug. In the DSM-5, the term addiction is synonymous with the classification of severe substance-use disorder.
  4. PMID 3325655
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  5. S2CID 23029500
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  6. ISBN 978-3-540-38916-3
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  7. PMID 6440434
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  8. ^ "Rapid Drug Desensitization for Hypersensitivity Reactions to Chemotherapy and Monoclonal Antibodies in the 21st Century" (PDF).
  9. ^ "What Is Reverse Tolerance?".
  10. ^ Bunnel, Craig A. Intensive Review of Internal Medicine, Harvard Medical School 2009.[page needed]
  11. PMID 26935643
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  12. ISBN 978-0-07-134721-1
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  13. S2CID 32069845
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  14. S2CID 24570169
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