Pharmacodynamics tolerance development

Desensitization describes the rapid signal attenuation in response to stimulation of cells by receptor agonists. Changes in the coupling efficiency of receptors to signal transduction pathways and receptor internalization can account for desensitization and the development of pharmacodynamic tolerance. 

Benzodiazepines do not induce their own metabolism, and thete is no evidence for the development of pharmacokinetic toletance (Gteenblatt and Shader 1986). The behavioral tolerance seen with chronic dosing is explicable entirely on the basis of pharmacodynamic tolerance (as described earlier in the overview of neuropharmacology). 

Pharmacodynamic tolerance to barbiturates develops over weeks to months, whereas pharmacokinetic tolerance occurs in a period of days. At maximum tolerance, the dosage of a barbiturate may be six times the original dosage. 

Glutethimide (3-ethyl-3-phenyl-2,6-piperidinedione) is a sedative-hypnotic drug that is now rarely used therapeutically because of wide variation in gastrointestinal absorption, fast development of pharmacodynamic tolerance, a fairly severe discontinuation syndrome, and potential for abuse. Reports of... 

Many drugs active on the CNS will be subject to pharmacodynamic tolerance, that is, effects will diminish on repeat dosing despite maintenance of plasma concentrations. If development of tolerance is considered likely, consideration should be given to designing dose-escalation steps within each cohort with pharmacodynamic and pharmacodynamic assessments at some of these interim steps. 

Pharmacodynamic tolerance, probably on the basis of down-regulation of receptors, develops more rapidly to the effects of barbiturates on mood and sedation than to the anticonvulsant and lethal action. This results in a marked decrease in therapeutic index and the ratio of LD50 and ED50 can approach 1. Furthermore, barbiturates induce P450 enzymes and thus increase their own metabolism resulting in time dependent pharmacokinetic behavior. 

Tolerance—decreased responsiveness to a drug following repeated exposure—is a common feature of sedative-hypnotic use. It may result in the need for an increase in the dose required to maintain symptomatic improvement or to promote sleep. It is important to recognize that partial cross-tolerance occurs between the sedative-hypnotics described here and also with ethanol (see Chapter 23)—a feature of some clinical importance, as explained below. The mechanisms responsible for tolerance to sedative-hypnotics are not well understood. An increase in the rate of drug metabolism (metabolic tolerance) may be partly responsible in the case of chronic administration of barbiturates, but changes in responsiveness of the central nervous system (pharmacodynamic tolerance) are of greater importance for most sedative-hypnotics. In the case of benzodiazepines, the development of tolerance in animals has been associated with down-regulation of brain benzodiazepine receptors. Tolerance has been reported to occur with the extended use of zolpidem. Minimal tolerance was observed with the use of zaleplon over a 5-week period and eszopiclone over a 6-month period. 

D. M. Ouellet and G. M. Plack, Pharmacodynamics and tolerance development during multiple intravenous bolus morphine administration in rats. J Pharmacol Exp Ther 281 713-720 (1997). 

The other three types of tolerance (pharmacokinetic, pharmacodynamic, and learned) are clubbed as acquired tolerance. In contrast to innate tolerance, this type of tolerance develops with continued opioid administration, and thus represents true tolerance rather than genetically mediated lack of sensitivity to opioids. 

Dumas, E. O., and G. M. Pollack. 2008. Opioid tolerance development a pharmacoki-netic/pharmacodynamic perspective. J. 10 537-551. 

Phase I studies evaluate the pharmacokinetics and safety of the drug in a small number (tens) of healthy volunteers. Phase I studies are sometimes conducted in a small patient population (Proof of Concept studies) with a specific objective such as the validation of the relevance of preclinical models in man. The purpose of these studies may be the rapid elimination of potential failures from the pipeline, definition of biological markers for efficacy or toxicity, or demonstration of early evidence of efficacy. These studies have a potential go/no-go decision criteria such as safety, tolerability, bioavailability/PK, pharmacodynamics, and efficacy. Dosage forms used in Phase I or Proof of Concept studies must be developed with the objectives of the clinical study in mind. 

The mechanisms underlying the development of tolerance seem to be partly pharmacodynamic, related to alterations in receptor sensitivity, but also cognitive, related to behavioural adaptation to the effects. 

AstraZeneca is developing a series of selective non-peptidic 5 opioid receptor agonists for the treatment of neuropathic pain. The compounds (e.g. cpd., 1) are in preclinical studies. In vivo, they are effective analgesics with negligible tolerance and dependence. They have parenteral and oral activity with suitable pharmacokinetics and pharmacodynamics. 

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