Drug tolerance or drug insensitivity is a
pharmacological
Pharmacology is the science of drugs and medications, including a substance's origin, composition, pharmacokinetics, pharmacodynamics, therapeutic use, and toxicology. More specifically, it is the study of the interactions that occur between ...
concept describing subjects' reduced reaction to a drug following its repeated use. Increasing its dosage may re-amplify the drug's effects; however, this may accelerate tolerance, further reducing the drug's effects. Drug tolerance is indicative of drug use but is not necessarily associated with
drug dependence or
addiction
Addiction is a neuropsychological disorder characterized by a persistent and intense urge to use a drug or engage in a behavior that produces natural reward, despite substantial harm and other negative consequences. Repetitive drug use can ...
. The process of tolerance development is reversible (e.g., through a
drug holiday) and can involve both
physiological
Physiology (; ) is the science, scientific study of function (biology), functions and mechanism (biology), mechanisms in a life, living system. As a branches of science, subdiscipline of biology, physiology focuses on how organisms, organ syst ...
factors and
psychological
Psychology is the scientific study of mind and behavior. Its subject matter includes the behavior of humans and nonhumans, both consciousness, conscious and Unconscious mind, unconscious phenomena, and mental processes such as thoughts, feel ...
factors.
One may also develop drug tolerance to
side effect
In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects.
A drug or procedure usually use ...
s, in which case tolerance is a desirable characteristic. A medical intervention that has an objective to increase tolerance (e.g.,
allergen immunotherapy
Allergen immunotherapy, also known as desensitization or hypo-sensitization, is a medical treatment for environmental allergies (such as insect bites) and asthma. Immunotherapy involves exposing people to larger and larger amounts of allergens ...
, in which one is exposed to larger and larger amounts of
allergen
An allergen is an otherwise harmless substance that triggers an allergic reaction in sensitive individuals by stimulating an immune response.
In technical terms, an allergen is an antigen that is capable of stimulating a type-I hypersensitivi ...
to decrease one's
allergic reactions
Allergies, also known as allergic diseases, are various conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic dermatitis, alle ...
) is called
drug desensitization.
The opposite concept to drug tolerance is
reverse tolerance, in which case the subject's reaction or effect will increase following its repeated use. The two notions are not incompatible and tolerance may sometimes lead to reverse tolerance. For example, heavy drinkers initially develop tolerance to alcohol (requiring them to drink larger amounts to achieve a similar effect) but excessive drinking can cause
liver damage, which then puts them at risk of intoxication when drinking even very small amounts of alcohol.
Drug tolerance should not be confused with
drug tolerability, which refers to the degree to which overt
adverse effect
An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. The term compli ...
s of a drug can be tolerated by a patient.
Tachyphylaxis
Tachyphylaxis is a subcategory of drug tolerance referring to cases of sudden, short-term onset of tolerance following the administration of a drug.
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
Receptor may refer to:
* Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and respond ...
, desensitizing it through constant interaction. Other possibilities include a reduction in receptor density (usually associated with receptor agonists), other mechanisms leading to changes in action potential firing rate, or alterations in protein transcription among others adaptations. Pharmacodynamic tolerance to a
receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of rec ...
involves the reverse, i.e., increased receptor firing rate, an increase in receptor density, or other mechanisms.
While most occurrences of pharmacodynamic tolerance occur after sustained exposure to a drug, instances of acute or instant tolerance (tachyphylaxis) can occur.
Pharmacokinetic (metabolic) tolerance
Pharmacokinetics refers to the absorption, distribution, metabolism, and excretion of drugs (ADME). 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 (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 e.g. CYP450 enzymes. This is most commonly seen with substances such as
ethanol
Ethanol (also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound with the chemical formula . It is an Alcohol (chemistry), alcohol, with its formula also written as , or EtOH, where Et is the ps ...
.
This type of tolerance is most evident with oral ingestion, because other routes of drug administration bypass
first-pass metabolism
The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism at a specific location in the body which leads to a reduction in the concentration of the active drug before it reaches the ...
. 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 leading to tolerance.
Behavioral tolerance
Behavioral tolerance occurs with the use of certain psychoactive drugs, where tolerance to a behavioral effect of a drug, such as increased motor activity by methamphetamine, occurs with repeated use. It may occur through drug-independent learning or as a form of pharmacodynamic tolerance in the brain; the former mechanism of behavioral tolerance occurs when one learns how to actively overcome drug-induced impairment through practice. Behavioral tolerance is often context-dependent, meaning tolerance depends on the environment in which the drug is administered, and not on the drug itself.
describes the opposite phenomenon.
See also
References
{{DEFAULTSORT:Drug Tolerance
Addiction
Pharmacodynamics
Substance dependence