Drug tolerance

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Addiction and dependence glossary [1] [2] [3]
  • addiction – a 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 pharmacological concept describing subjects' reduced reaction to a drug following its repeated use. Increasing its dosage may re-amplify the drug's effects; however, this may accelerate tolerance, further reducing the drug's effects. Drug tolerance is indicative of drug use but is not necessarily associated with drug dependence or addiction. [4] The process of tolerance development is reversible (e.g., through a drug holiday [5] ) and can involve both physiological factors and psychological factors. [6]

Contents

One may also develop drug tolerance to side effects, [7] in which case tolerance is a desirable characteristic. A medical intervention that has an objective to increase tolerance (e.g., allergen immunotherapy, in which one is exposed to larger and larger amounts of allergen to decrease one's allergic reactions) is called drug desensitization. [8]

The opposite concept to drug tolerance is reverse tolerance, in which case the subject's reaction or effect will increase following its repeated use. The two notions are not incompatible and tolerance may sometimes lead to reverse tolerance. For example, heavy drinkers initially develop tolerance to alcohol (requiring them to drink larger amounts to achieve a similar effect) but excessive drinking can cause 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

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), other mechanisms leading to changes in action potential firing rate, or alterations in protein transcription among others adaptations. [12] [13] 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. [14]

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. [15] Behavioral sensitization describes the opposite phenomenon.

See also

Related Research Articles

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<span class="mw-page-title-main">Dextroamphetamine</span> CNS stimulant and isomer of amphetamine

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<span class="mw-page-title-main">Nucleus accumbens</span> Region of the basal forebrain

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<span class="mw-page-title-main">Adderall</span> Drug mixture used mainly to treat ADHD and narcolepsy

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<span class="mw-page-title-main">Acamprosate</span> Medication

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Reverse tolerance or drug sensitization is a pharmacological phenomenon describing subjects' increased reaction to a drug following its repeated use. Not all drugs are subject to reverse tolerance.

<span class="mw-page-title-main">Methamphetamine</span> Central nervous system stimulant

Methamphetamine is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug and less commonly as a second-line treatment for attention deficit hyperactivity disorder and obesity. Methamphetamine was discovered in 1893 and exists as two enantiomers: levo-methamphetamine and dextro-methamphetamine. Methamphetamine properly refers to a specific chemical substance, the racemic free base, which is an equal mixture of levomethamphetamine and dextromethamphetamine in their pure amine forms, but the hydrochloride salt, commonly called crystal meth, is widely used. Methamphetamine is rarely prescribed over concerns involving human neurotoxicity and potential for recreational use as an aphrodisiac and euphoriant, among other concerns, as well as the availability of safer substitute drugs with comparable treatment efficacy such as Adderall and Vyvanse. Dextromethamphetamine is a stronger CNS stimulant than levomethamphetamine.

Psychological dependence is a cognitive disorder that involves emotional–motivational withdrawal symptoms – such as anxiety or anhedonia – upon cessation of prolonged drug abuse or certain repetitive behaviors. It develops through frequent exposure to certain psychoactive substances or behaviors, which leads to an individual requiring further exposure to avoid withdrawal symptoms, as a result of negative reinforcement. Neuronal counter-adaptation is believed to play a role in generating withdrawal symptoms, which could be mediated through changes in neurotransmitter activity or altered receptor expression. Environmental enrichment and physical activity can attenuate withdrawal symptoms.

<span class="mw-page-title-main">FOSB</span> Protein

Protein fosB, also known as FosB and G0/G1 switch regulatory protein 3 (G0S3), is a protein that in humans is encoded by the FBJ murine osteosarcoma viral oncogene homolog B (FOSB) gene.

<span class="mw-page-title-main">Addiction</span> Disorder resulting in compulsive behaviours

Addiction is a neuropsychological disorder characterized by a persistent and intense urge to use a drug or engage in a behaviour that produces natural reward, despite substantial harm and other negative consequences. Repetitive drug use often alters brain function in ways that perpetuate craving, and weakens self-control. This phenomenon – drugs reshaping brain function – has led to an understanding of addiction as a brain disorder with a complex variety of psychosocial as well as neurobiological factors that are implicated in addiction's development. Classic signs of addiction include compulsive engagement in rewarding stimuli, preoccupation with substances or behavior, and continued use despite negative consequences. Habits and patterns associated with addiction are typically characterized by immediate gratification, coupled with delayed deleterious effects.

<span class="mw-page-title-main">Psychoactive drug</span> Chemical substance that alters nervous system function

A psychoactive drug, psychopharmaceutical, psychoactive agent, or psychotropic drug is a chemical substance that changes the function of the nervous system and results in alterations of perception, mood, cognition, and behavior. These substances may be used medically, recreationally, for spiritual reasons, or for research. Some categories of psychoactive drugs may be prescribed by physicians and other healthcare practitioners because of their therapeutic value.

Addiction vulnerability is an individual's risk of developing an addiction during their lifetime. There are a range of genetic and environmental risk factors for developing an addiction that vary across the population. Genetic and environmental risk factors each account for roughly half of an individual's risk for developing an addiction; the contribution from epigenetic risk factors to the total risk is unknown. Even in individuals with a relatively low genetic risk, exposure to sufficiently high doses of an addictive drug for a long period of time can result in an addiction. In other words, anyone can become an individual with a substance use disorder under particular circumstances. Research is working toward establishing a comprehensive picture of the neurobiology of addiction vulnerability, including all factors at work in propensity for addiction.

References

  1. ↑ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 364–375. ISBN   9780071481274.
  2. ↑ Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. PMC   3898681 . 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. ↑ Volkow ND, Koob GF, McLellan AT (January 2016). "Neurobiologic Advances from the Brain Disease Model of Addiction". New England Journal of Medicine. 374 (4): 363–371. doi:10.1056/NEJMra1511480. PMC   6135257 . 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. ↑ Miller, NS; Dackis, CA; Gold, MS (1987). "The relationship of addiction, tolerance, and dependence to alcohol and drugs: a neurochemical approach". J Subst Abuse Treat. 4 (3–4): 197–207. doi:10.1016/s0740-5472(87)80014-4. PMID   3325655.
  5. ↑ Weiner, WJ; Koller, WC; Perlik, S; Nausieda, PA; Klawans, HL (1980). "Drug holiday and management of Parkinson disease". Neurology. 30 (12): 1257–61. doi:10.1212/wnl.30.12.1257. PMID   7192805. S2CID   23029500.
  6. ↑ Schöneberg, Torsten (2008). "Tolerance and Desensitization". Encyclopedia of Molecular Pharmacology. pp. 1203–1207. doi:10.1007/978-3-540-38918-7_140. ISBN   978-3-540-38916-3.
  7. ↑ Swift, CG; Swift, MR; Hamley, J; Stevenson, IH; Crooks, J (1984). "Side-effect 'tolerance' in elderly long-term recipients of benzodiazepine hypnotics". Age Ageing. 13 (6): 335–43. doi: 10.1093/ageing/13.6.335 . PMID   6440434.
  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. ↑ Bespalov, Anton; Müller, Reinhold; Relo, Ana-Lucia; Hudzik, Thomas (2016-05-01). "Drug Tolerance: A Known Unknown in Translational Neuroscience". Trends in Pharmacological Sciences. 37 (5): 364–378. doi:10.1016/j.tips.2016.01.008. ISSN   1873-3735. PMID   26935643.
  12. ↑ Klaassen, Curtis D. (2001-07-27). Casarett & Doull's Toxicology: The Basic Science of Poisons (6th ed.). McGraw-Hill Professional. p. 17. ISBN   978-0-07-134721-1.
  13. ↑ Pietrzykowski, Andrzej Z.; Treistman, Steven N. (2008). "The molecular basis of tolerance". Alcohol Research & Health: The Journal of the National Institute on Alcohol Abuse and Alcoholism. 31 (4): 298–309. ISSN   1930-0573. PMC   3860466 . PMID   23584007.
  14. ↑ Swanson, James; Gupta, Suneel; Guinta, Diane; Flynn, Daniel; Agler, Dave; Lerner, Marc; Williams, Lillie; Shoulson, Ira; Wigal, Sharon (1999-10-01). "Acute tolerance to methylphenidate in the treatment of attention deficit hyperactivity disorder in children*". Clinical Pharmacology &#38 Therapeutics. 66 (3): 295–305. doi:10.1016/S0009-9236(99)70038-X. ISSN   0009-9236. PMID   10511066. S2CID   32069845.
  15. ↑ Wolgin, D. L (2000-05-01). "Contingent tolerance to amphetamine hypophagia: new insights into the role of environmental context in the expression of stereotypy". Neuroscience & Biobehavioral Reviews. 24 (3): 279–294. doi:10.1016/S0149-7634(99)00070-6. PMID   10781692. S2CID   24570169.
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