Drug Tolerance

Mithridatism

Physiological tolerance or drug tolerance is commonly encountered in pharmacology, when a subject’s reaction to a specific drug and concentration of the drug is progressively reduced, requiring an increase in concentration to achieve the desired effect. Drug tolerance can involve both psychological drug tolerance and physiological factors.

Tolerance rate depends on the particular drug, dosage and frequency of use, though it is typically reversible. Physiological tolerance also occurs when an organism builds up a resistance to the effects of a substance after repeated exposure. This can occur with environmental substances, such as salt or pesticides. A rapid drug tolerance is termed tachyphylaxis.

Dispositional tolerance is tolerance due to genetic factors. Some people may be born with more drug-metabolizing enzymes in the liver, or have more of a certain type of receptor in the brain, compared to other people. Previous drug exposure is not required for this type of tolerance. For example men generally have greater dispositional tolerance to alcohol than women do, because men are born with higher levels of alcohol-metabolizing enzymes in their liver than women. Behavioral tolerance is learned tolerance. A widely accepted mechanism of behavioral tolerance is when people learn how to actively overcome drug-induced impairments through practice. This type of tolerance can only develop when there is active practice of a particular skill when under the influence of the drug. An example of displayed behavioral tolerance can be seen in driving simulator studies that reveal experienced marijuana smokers usually perform better than novice smokers at the same level of intoxication.

Pharmacokinetic (metabolic) tolerance results from somatic mechanisms for absorption, distribution, metabolism, and excretion of drugs. All psychoactive drugs are first absorbed into the bloodstream, carried in the blood to various parts of the body including the site of action (distribution), broken down in some fashion (metabolism), and ultimately removed from the body (excretion). All of these factors are very important determinants of crucial pharmacological properties of a drug, including its potency, side effects, and duration of action. Pharmacokinetic tolerance occurs because of a decreased quantity of the substance reaching the site it affects. This may be caused by an increase in induction of the enzymes required for degradation of the drug. This is most commonly seen with substances such as ethanol. This type of tolerance is most evident with oral ingestion, because other routes of drug administration bypass first-pass metabolism. Enzyme induction is partly responsible for the phenomenon of tolerance, in which repeated use of a drug leads to a reduction of the drug’s effect. However, it is only one of several mechanisms of tolerance

Pharmacodynamic tolerance is a reduced response to repeated administration of the same dose or increase in the dose are required to produce the same magnitude of response. Liver damage can lead to dramatic loss of drug tolerance. For example chronic alcoholics at a late stage of alcoholism can get drunk on just a few drinks due to death of liver cells. Pharmacodynamic tolerance (reduced responsiveness) is the consequence of impaired cellular mechanisms. This may be caused by a reduced receptor response to receptor agonists (receptor desensitization), a reduction in receptor density (usually associated with receptor agonists), or other mechanisms leading to changes in action potential firing rate.

Tolerance is mediated by neural changes at the synaptic level that are induced by frequent drug use. These may include changes in number of postsynaptic receptors, receptor desensitization, or depletion of neurotransmitters. For example chronic ingestion of alcohol (a GABA agonist) eventually leads to down-regulation of inhibitory GABA receptors, as postsynaptic cells compensate for too much GABA-receptor-mediated inhibition. This process is called neural adaptation and it is also the basis of the withdrawal symptoms that can occur in chronic alcoholics and heroin addicts. One example of pharmacodynamic tolerance occurs with cocaine. Heavy use of cocaine temporarily depletes axon terminals of neurotransmitters such as dopamine and serotonin, thus cocaine has much less of a mood-elevating effect after several successive doses than it did initially.

Opioid tolerance has been particularly well studied. Tolerance to the analgesic effects of morphine is fairly rapid. There are several hypotheses about how tolerance develops, including opioid receptor phosphorylation (which would change the receptor conformation), functional decoupling of receptors from G-proteins (leading to receptor desensitization), mu-opioid receptor internalization and/or receptor down-regulation (reducing the number of available receptors for morphine to act on), and upregulation of the cAMP pathway (a counterregulatory mechanism to opioid effects). Cholecystokinin (CCK, a peptide hormone responsible for stimulating the digestion of fat and protein) might mediate some counter-regulatory pathways responsible for opioid tolerance. CCK-antagonist drugs (specifically proglumide which reduces gastric secretions) have been shown to slow the development of tolerance to morphine or any other kind of drug, including alcohol.

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