Drug tolerance & Intolerance

Has information about - Drug tolerance - definition, types, sub-types, it's examples; cross tolerance; tachyphylaxis; Drug intolerance - examples; analgesics tolerance

1. DRUG TOLERANCE & IN TOLERANCE SUBJECT : PHARMACEUTICAL BIOCHEMISTRY BY S.DASH

2. DRUG TOLERANCE Drug tolerance is a pharmacological concept describing subject’s reduced reaction to a drug following it’s repeated use. Increasing the drug dosage may re-amplify the drug’s effects; however, this may accelerate tolerance, further reducing the drug’s effects. The process of tolerance development is reversible (e.g., through a drug holiday) and can involve both physiological and psychological factors. Drug tolerance may be of two types :- Natural Acquired

3. NATURAL DRUG TOLERANCE The species/individual is inherently less sensitive to the drug. Examples : Rabbits are tolerant to atropine. Black races are tolerant to mydriatics. Certain individuals in any population are hyporesponders to certain drugs. Eg . β- adrenergic blockers

4. ACQUIRED DRUG TOLERANCE This occurs by repeated use of a drug in an individual who was initially responsive. Body is capable of developing tolerance to most drugs, but the phenomenon is very easily recognized in the case of CNS depressants. An uninterrupted presence of the drug in the body favours development of tolerance. Majorly there are three mechanisms by which drug tolerance can be developed, they are :- PHARMACODYNAMIC TOLERANCE PHARMACOKINETIC (METABOLIC) TOLERANCE BEHAVIORAL TOLERANCE

5. PHARMACODYNAMIC TOLERANCE Pharmacodynamic tolerance begins when the cellular response to a substance is reduced with repeated use. A common cause of pharmacodynamic tolerance is high concentrations of a substance constantly binding with the receptor, desensitizing it through constant interaction. Other possibilities include a reduction in receptor density (usually associated with receptor agonists), or other mechanisms leading to changes in action potential firing rate.

6. PHARMACOKINETIC TOLERANCE Pharmacokinetic tolerance also known as dispositional 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. Eg ., CYP450 enzymes. This is most commonly seen with substances such as ethanol. This type of drug tolerance is most evident with oral ingestion, because other routes od drug administration bypass first-pass metabolism. Enzyme induction is partly responsible for the phenomenon of tolerance, in which repeated use of drug leads to a reduction of the drug’s effect.

7. BEHAVIORAL TOLERANCE Behavioural tolerance occurs with the use of certain psychoactive drugs, where tolerance to a behavioural effect of a drug, such as increased motor activity by methamphetamine, occurs with repeated use. It may occur through drug-independent learning or a form of pharmacodynamic tolerance in the brain; the former mechanism of behavioural tolerance occurs when one learns how to actively overcome drug-induced impairment through practice. Behavioural tolerance is often context dependent, meaning tolerance depends on the environment in which the drug is administered, and not on the drug itself.

8. FEW OTHER TERMS… CROSS TOLERANCE It is the development of tolerance to pharmacologically related drugs. Example : Alcoholics are relatively tolerant to barbiturates and general anaesthetics. Closer the two drugs, more stronger is the cross tolerance between them. Example : There is partial cross tolerance between morphine and barbiturates but complete cross tolerance between morphine and pethidine. TACHYPHYLAXIS It is the subcategory of drug tolerance referring to cases of sudden, short-term onset of tolerance following the administration of a drug.

9. DRUG INTOLERANCE Drug intolerance or drug sensitivity refers to an inability to tolerate the adverse effects of a medication, generally at therapeutic or subtherapeutic doses. Some instances of drug intolerance are known to result from genetic variations in drug metabolism. EXAMPLES : Triflupromazine (single dose) Muscular dystonias in some individuals Carbamazepine (few doses) Ataxia in some individuals Chloroquine (single tablet) Vomiting and abdominal pain in some individuals.

10. ANALGESICS INTOLERANCE Intolerance to analgesics, particularly NSAIDs is relatively common. It is thought that a variation in the metabolism of arachidonic acid is responsible for the intolerance. Symptoms include chronic rhinosinusitis with nasal polyps, asthma, angioedema, urticaria and gastrointestinal ulcers.

11. REFERENCES: Schoneberg , Torsten (2008) “Tolerance and desensitization”. Encyclopedia of Molecular Pharmacology. DOI : 10.1007/978-3-540-38918-7-140 Essentials of Medical Pharmacology. By Tripathi (6 th Edition) Textbook of Clinical Pharmacology by Bennett and Brown. (9 th Edition) www.Wikipedia.com

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