Define the terms tolerance and tachyphylaxis. (20% of marks) Describe the different mechanisms by which tolerance can develop, and give examples for each. (80% of marks) 

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College Answer

Tolerance is the requirement of higher doses of a drug to produce a given response. When this  develops rapidly (with only a few administrations of the drug) this is termed tachyphylaxis.  Various mechanisms exist by which tolerance occurs and these include cellular tolerance (e.g. neuronal adaptation to opioids or alcohol), enzyme induction and depletion of neurotransmitters. Few candidates knew a comprehensive list or had a classification system for the different types of tolerance. No candidate had a good definition of tachyphylaxis.

Discussion

It would be important to point out that nowhere in the published literature is there a well-accepted definition of tachyphylaxis, and there is no shame in being unable to generate one at a moments notice during the ten minute SAQ timeframe, particularly when the dividend is a meager 20% of the mark. Similarly, there is very little material out there to classify a "comprehensive list" of tolerance mechanisms. The following list was concocted and classified on the basis of several competing and frequently contradictory textbook entries.

Acquired tolerance: a drug-induced reduction in subsequent drug effect.

Innate tolerance: a genetically determined resistance to the drug effect.

Tachyphylaxis: a rapid decrease in response to repeated doses over a short time period

Mechanisms of tolerance:

  • Pharmacokinetic tolerance: the persistent exposure makes the drug clearance mechanisms more active; eg. effect of ethanol and CYP450
  • Pharmacodynamic tolerance: 
    • Receptor downregulation  where receptors are inactivated or endocytosed and degraded in response to sustained stimulation.
    • Receptor deactivation; where the receptor protein is phosphorylated in response to excess stimulus (eg. the nicotonic receptor and nicotine - Huganir et al, 1987)
    • Receptor subunit modification, where a modified receptor complex is selectively expressed, with diminished sensitivity for the drug but maintained sensitivity for the endogenous ligand (eg. the GABA-A receptor and benzodiazepines - Littleton, 2001)
    • Receptor refractory period, which is a transient period of tolerance after the last drug-receptor interaction (by stretching the imagination, one can make this look like a form of drug tolerance)
    • Second messenger changes where the post-receptor second messenger system is deactivated, as with β-2 agonists (Haney et al, 2005).
    • Drug target depletion where some key molecule is used up in the course of drug action; subsequent drug doses will therefore have diminished activity until the key molecule is regenerated. A classical example is presynaptic noradrenaline depletion due to ephedrine therapy.
  • Physiological tolerance is tolerance to the effects of the drug rather than to the drug itself (at a receptor level). Receptor responses may remain the same but physiological adaptive mechanisms restore homeostasis, such that the effect of the drug appear to be reduced. A good example of this is the physiological adaptation to the use of vasodilator antihypertensives, by the increased heart rate and cardiac output which maintains blood pressure.
  • Learned tolerance, or behavioural tolerance is the development of learned behavioral adjustments that compensate for the drug's effects. The result is an apparently diminished drug effect. A good example of this is the alcoholic who might remain safely functional within their own home in spite of scandalous intoxication. A sub-variety of this is conditioned tolerance, the development of behavioural tolerance which is strongly dependent on some specific environmental or behavioural trigger. For instance, conditioned tolerance to the effects of opiates was observed by Ehrman et al (1992) who found that pre-injection "rituals" (spoon, cooking, etc) were associated with a decrease in drug effect, whereas unexpected injections were not.

There are a few other sub-varieties for acquired tolerance which defeat efforts at classification; one might describe these as tolerance-related phenomena.

  • Sensitisation  is the development of "reverse tolerance", or "intolerance" if one extends the metaphor. It is the increase in drug effect associated with intermittent doses. This is seen with amphetamines (Scholl et al, 2009)
  • Cross-tolerance is the development of tolerance to multiple drugs belonging to the same class, after exposure to only one of them. An example of this is seen in the administration of nitrates.
  •  

References

References

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Meyboom, Ronald HB, et al. "The value of reporting therapeutic ineffectiveness as an adverse drug reaction." Drug Safety 23.2 (2000): 95-99.

Freeman, Brian, and Jeffrey Berger. Anesthesiology Core ReviewMcGraw-Hill Education, 2014.

Katz, Gregory. "Tachyphylaxis/tolerance to antidepressive medications: a review." The Israel journal of psychiatry and related sciences 48.2 (2011): 129.

De Moraes, S., and Varela De Carvalho. "On the mechanism of action of tachyphylaxis by ephedrine." Pharmacology 1.1 (1968): 53-59.

Cowan, F. F., T. Koppanyi, and G. D. Maengwyn‐Davies. "Tachyphylaxis III. Ephedrine." Journal of pharmaceutical sciences 52.9 (1963): 878-883.

Swanson, James M. "Long-acting stimulants: development and dosing.The Canadian Child and Adolescent Psychiatry Review 14.Suppl 1 (2005): 4.

Agvald, Per, et al. "Nitric oxide generation, tachyphylaxis and cross-tachyphylaxis from nitrovasodilators in vivo." European journal of pharmacology 385.2-3 (1999): 137-145.

Sage, Peter R., et al. "Nitroglycerin tolerance in human vessels: evidence for impaired nitroglycerin bioconversion.Circulation 102.23 (2000): 2810-2815.

Haney, Sarah, and Robert J. Hancox. "Rapid onset of tolerance to beta-agonist bronchodilation." Respiratory medicine 99.5 (2005): 566-571.

Barnes, Peter J. "Beta-adrenergic receptors and their regulation." American journal of respiratory and critical care medicine 152.3 (1995): 838-860.

Zuo, Yantao, et al. "Acute nicotine-induced tachyphylaxis is differentially manifest in the limbic system." Neuropsychopharmacology 36.12 (2011): 2498.

Packer, Milton, et al. "Hemodynamic and clinical tachyphylaxis to prazosin-mediated afterload reduction in severe chronic congestive heart failure." Circulation 59.3 (1979): 531-539.

Littleton, John. "Receptor regulation as a unitary mechanism for drug tolerance and physical dependence‐not quite as simple as it seemed!.Addiction 96.1 (2001): 87-101.

Orberg, PAULO K., and WILLIAM E. Sandine. "Common occurrence of plasmid DNA and vancomycin resistance in Leuconostoc spp." Applied and environmental microbiology48.6 (1984): 1129-1133.

Ehrman, Ronald, et al. "Conditioned tolerance in human opiate addicts." Psychopharmacology 108.1-2 (1992): 218-224.

Scholl, Jamie L., et al. "Individual differences in amphetamine sensitization, behavior and central monoamines.Physiology & behavior 96.3 (2009): 493-504.

Lê, A. D., and Jatinder M. Khanna. "Dispositional mechanisms in drug tolerance and sensitization.Psychoactive Drugs. Humana Press, Totowa, NJ, 1989. 281-351.

Goudie, Andrew J., and Michael W. Emmett-Oglesby. Psychoactive drugs: Tolerance and sensitization. Springer Science & Business Media, 1989.

Pandey, Subhash C. "Neuronal signaling systems and ethanol dependence." Molecular neurobiology 17.1-3 (1998): 1-15.

Huganir, Richard L., and Paul Greengard. "Regulation of receptor function by protein phosphorylation." Trends in Pharmacological Sciences 8.12 (1987): 472-477.