Pharmacological tolerance

Shaffer et al. (1992) also confirmed our observations in normal rabbits. Taken together, the sydnonimine and S-nitrosothiol data suggest that the hemodynamic tolerance so often observed with nitrate therapy is not a general phenomenon for all NO donors. Further studies are needed to determine whether replacement of traditional NO donors with these or other novel agents can lead to therapeutic improvements. 

This work was supported in part by National Institutes of Health grants HL-22273 and GM-42850. 

Abrams, J. (1985). Hemodynamic effects of nitroglycerin and long-acting nitrates. Am. Heart J. no, 216-224. 

Bassenge, E., and Kukovetz, W. R. (1984). Molsidimine, New Drugs Annu., Cardiovasc. Drugs. Vol. 2. Raven, New York. 

Bassenge, E., and Zanzinger, J. (1993). Effectiveness of an NO-releasing pirsidomine derviative on coronary conductance during long-term administration. J. Cardiovasc. Pharmacol. 22, S22-S26. 

---

The ultra short-acting hypnotic, zaleplon was assessed in insomniac outpatients [48], The doses of zaleplon were 5, 10, and 20 mg and compared to placebo over 4 weeks. Pharmacological tolerance did not develop during treatment with zaleplon, nor were rebound insomnia and withdrawal phenomena apparent. 

The WHO define the psychic dependence as a sensation of absolute need and the psychological tendency to periodical or continuous use. Craving is defined as a very strong desire for a psychoactive substance or for the intoxicating effects of that substance. Pharmacological tolerance is the need to progressively increase the dose to be administered to achieve the desired effects. Addictive potential is the ability of a substance to determine tolerance and dependence. This potential is used as a risk index for the consumption of a substance. 

Three doses of zaleplon have been compared with placebo in outpatients with insomnia in a 4-week study (11). During week 1, sleep latency was significantly shorter with zaleplon 5, 10, and 20 mg than with placebo. The significant reduction in sleep latency persisted to week 3 with zaleplon 10 mg and to week 4 with zaleplon 20 mg. Compared with placebo, zaleplon 10 mg and 20 mg also had significant positive effects on sleep duration, number of awakenings, and sleep quality. Pharmacological tolerance did not develop with zaleplon and there were no indications of rebound insomnia or withdrawal symptoms after discontinuation. There was no significant difference in the frequency of adverse events with zaleplon compared with placebo. The authors concluded that zaleplon provides effective treatment of insomnia with a favorable safety profile. 

Tolerance also has a metabolic effect commonly referred to as pharmacologic tolerance. Prolonged exposure to a drug increases the excretion of the drug from the body. This means there is a lower concentration of the drug in plasma that is distributed throughout the body. 

Ease of use, tolerability second-generation HI antihistamines are better tolerated by patients compared to first-generation HI antihistamines because they are less sedating and have fewer side effects. Although there is no pharmacological tolerance to antihistamines, some first-generation HI antihistamines have been drugs of abuse. 

Pharmacological tolerance of analgesic effects, symptoms of withdrawal, opioid-induced hyperalgesia, and psychological factors have been reported as contributing... 

Time course Rifampicin induces CYP3A4 at about 15 days, and interaction studies have generally started treatment with protease inhibitors within 15 days of the start of rifampicin therapy. Furthermore, pharmacological tolerance to effects can occur. The problems of variations in pharmacokinetics with time have been illustrated by a study of the effects of rifampicin on the pharmacokinetics of nevirapine in 16 patients coinfected with HTV-1 and tuberculosis [39"]. They took standard antituberculosis therapy and a fixed-dose combination of stavudine, lamivudine, and nevirapine. The median AUC of nevirapine was reduced by rifampicin by 26% at 4 weeks, but by only 7.5% at 10 weeks. The median Crm was reduced by 20% at 4 weeks and by 7.1% at 10 weeks. The authors concluded that the effect of rifampicin on the pharmacokinetics of nevirapine substantially decreases over time. 

Thadani, U., Maranda, C.R., Amsterdam, E., Spaccavento, L., Friedman, R.G., Chemoff, R., Zellner, S., Gorwit, J., and Hinderaker, RH. (1994). Lack of pharmacologic tolerance and rebound angina pectoris during twice-daily therapy with isosorbide-5-mononitrate. Ann. Intern. Med. 120, 353-359. 

---