Tolleranza (fisiologia)

La tolleranza è la perdita di risposta ad un farmaco.

Considerando la curva di un grafico dose-risposta alla somministrazione di un farmaco, all'aumentare della dose di farmaco, aumenta l'effetto; con l'uso ripetuto la curva si sposta verso destra (tolleranza) ed è quindi richiesta una dose maggiore per produrre lo stesso effetto precedentemente ottenuto alla dose inferiore. Esistono molte forme di tolleranza che si basano su molteplici meccanismi.

La tolleranza può essere selettiva e svilupparsi ad alcuni effetti di un farmaco molto più rapidamente rispetto ad altri. Per esempio, la tolleranza all'euforia prodotta da oppioidi quali l'eroina si sviluppa rapidamente, mentre la tolleranza agli effetti su funzioni vitali, quali la respirazione e la pressione arteriosa si sviluppa più lentamente. Quindi un tossicodipendente tende ad aumentare la dose per mantenere la funzione euforizzante, ma va così incontro a blocco respiratorio.

^ Nestler EJ, Cellular basis of memory for addiction, in Dialogues Clin. Neurosci., vol. 15, n. 4, dicembre 2013, pp. 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.»
^ Malenka RC, Nestler EJ, Hyman SE, Chapter 15: Reinforcement and Addictive Disorders, in Molecular Neuropharmacology: A Foundation for Clinical Neuroscience, 2nd, New York, McGraw-Hill Medical, 2009, pp. 364–375, ISBN 978-0-07-148127-4.
^ Glossary of Terms, su Mount Sinai School of Medicine, Department of Neuroscience. URL consultato il 9 febbraio 2015 (archiviato dall'url originale il 10 maggio 2019).
^ Volkow ND, Koob GF, McLellan AT, Neurobiologic Advances from the Brain Disease Model of Addiction, in N. Engl. J. Med., vol. 374, n. 4, gennaio 2016, pp. 363–371, DOI:10.1056/NEJMra1511480, PMID 26816013.

[Cellular_basis-1] Nestler EJ, Cellular basis of memory for addiction, in Dialogues Clin. Neurosci., vol. 15, n. 4, dicembre 2013, pp. 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.»

[Addiction_glossary-2] Malenka RC, Nestler EJ, Hyman SE, Chapter 15: Reinforcement and Addictive Disorders, in Molecular Neuropharmacology: A Foundation for Clinical Neuroscience, 2nd, New York, McGraw-Hill Medical, 2009, pp. 364–375, ISBN 978-0-07-148127-4.

[Nestler_Labs_Glossary-3] Glossary of Terms, su Mount Sinai School of Medicine, Department of Neuroscience. URL consultato il 9 febbraio 2015 (archiviato dall'url originale il 10 maggio 2019).

[Brain_disease-4] Volkow ND, Koob GF, McLellan AT, Neurobiologic Advances from the Brain Disease Model of Addiction, in N. Engl. J. Med., vol. 374, n. 4, gennaio 2016, pp. 363–371, DOI:10.1056/NEJMra1511480, PMID 26816013.

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