Tolerance, development

Pharmocodynamic tolerance develops in response to continued application of drugs, by mechanisms that include reversible cellular adaptation processes, such as receptor desensitization, internalization and downregu-lation as well as changes in the activity and levels of other components of the receptor s signal transduction pathways. 

The regulation of receptor synthesis is a second component of receptor downregulation. It involves processes that reduce gene transcription, mRNA stability, and receptor half-life time. It should be noted that mechanisms in addition to the regulation of the receptor number may account for tolerance development. Second messenger levels and enzyme activities that participate in the signaling of a given receptor are... 

Taken together, the regulation of time course and extent of receptor desensitization and tolerance development involves complex cellular processes. Detailed understanding of the molecular mechanisms of receptor... 

DIARRHEA. When these dragp are used orally they occasionally result in excessive salivation, abdominal cramping, flatus, and sometimes diarrhea The patient is informed that these reactions will continue until tolerance develops, usually within a few weeks. Until tolerance develops, the nurse ensures that proper facilities, such as a bedside commode, bedpan, or bathroom, are readily available. The patient is encouraged to ambulate to assist the passing of flatus. If needed, a rectal tube may be used to assist in the passing of flatus. The nurse keeps a record of the fluid intake and output and tlie number, consistency, and frequency of stools if diarrhea is present. The primary health care provider is informed if diarrhea is excessive because this may be an indication of toxicity. 

When use of the CNS stimulants causes insomnia, the nurse administers the drug early in the day (when possible) to diminish sleep disturbances. The patient is encouraged not to nap during the day. Other stimulants, such as coffee, tea, or cola drinks, are avoided. In some patients, nervousness, restlessness, and palpitations may occur. The vital signs are checked every 6 to 8 hours or more often if tachycardia, hypertension, or palpitations occur. Many times these adverse reactions will diminish with continued use as tolerance develops. If tolerance develops, the dosage is not increased. 

Stimulants induce both tolerance and sensitization to their behavioral effects. Tolerance develops to the anorectic and euphoric effects of stimulants (Schuster 1981) however, chronic intermittent use of low doses of stimulants delays the development of tolerance. With the doses commonly used in clinical practice, patients treated for narcolepsy or for depressive or apathetic states find that the stimulant properties usually persist without development of tolerance however, the persistence of antidepressant effects remains a matter of controversy. Sensitization has been linked to the development of amphetamine-induced psychosis (Yui et al. 1999). Sensitization to the induction of psychosis is suggested because psychosis is induced by progressively lower doses and shorter periods of consumption of amphetamine following repeated use over time (Sato 1986). Sensitization for amphetamine-induced psychosis may persist despite long periods of abstinence. 

Dependence and withdrawal can occur with all of the stimulants. Cocaine is one of the most strongly reinforcing drugs in self-administration paradigms in animals and also has a psychological withdrawal syndrome. A typical pattern of withdrawal includes a ravenous appetite, exhaustion, and mental depression, which may last for several days after the drug is withdrawn. Because tolerance develops quickly, abusers may take large doses, compared with those used medically, for example, as anorexiants. 

GHB treatment in mice, tolerance develops to both the hypolocomotion and cataleptic effects of the drug (Itzhak and Ali 2002). There is also preclinical evidence of cross-tolerance and cross-dependence of GHB with alcohol (Colombo et al. 1995 Fadda et al. 1989). As described in the earlier section on clinical pharmacology, GHB and its analogues have been used in humans in the treatment of alcohol withdrawal. Nicholson and Balster (2001) reviewed the evidence for cross-tolerance and cross-dependence of GHB with alcohol. 

Clonazepam, a typical 1 4 benzodiazepine, is effective in absence seizures, myoclonic jerks and tonic-clonic seizures and given intravenously it attenuates status epilepticus. It is less sedative than phenobarbitone but tolerance develops and its withdrawal, as... 

Like LSD, tolerance develops very rapidly so the next day it might take twice as many liberty caps to repeat the experience and so most users only use mushrooms occasionally. Physical dependence and withdrawal symptoms do not result from regular use though some people may become psychologically dependent and feel a desire to use on a regular basis. At present there is no evidence of serious health damage from longterm use. 

Flint, B.A. and Ho, I.K. Tolerance development to phencyclidine by chronic administration. Prog Neuropsvchopharmacol 4 233-239,... 

Fischman, M.W., Schuster, C.R. Tolerance development to chronic methamphetamine intoxication in the rhesus monkey. Pharmacol. Biochem. Behav. 2 503, 1974. 

Amphetamine Clinically used for narcolepsy (sudden day-time onset sleep) and Attention Deficit Hyperactivity Disorder (ADHD) formerly used as a short-term slimming agent, as an antidepressant and to boost athletic performance recreational use widespread tolerance develops readily highly addictive regular users suffer many health problems and a reduced life expectancy amphetamine psychosis may develop, with similar symptoms to acute paranoid schizophrenia. 

Cocaine Clinically used as a local anaesthetic during eye surgery recreational use widespread tolerance develops readily highly addictive, especially crack cocaine severe potential problems similar to amphetamine users often become suspicious and paranoid, displaying antisocial and troublesome behaviour patterns. 

Since 3 agonists have few of the long-term side effects of ft agonists, 3 agonists that could overcome tolerance development may be useful drugs in the treatment of chronic pain. In fact, the non-peptide 3 selective agonist SIOM [100] did not de-... 

Like <5 selective agonists, k agonists have few of the side effects of morphine and recent studies have suggested that k selective agonists may be effective analgesics [2]. However, a limitation to the clinical use of k agonists is tolerance development. 

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