Cross-tolerance is a phenomenon that occurs when
tolerance to the effects of a certain drug produces tolerance to another drug. It often happens between two drugs with similar functions or effects—for example, acting on the same
cell receptor
In biochemistry and pharmacology, receptors are chemical structures, composed of protein, that receive and transduce signals that may be integrated into biological systems. These signals are typically chemical messengers which bind to a recept ...
or affecting the transmission of certain
neurotransmitters
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell.
Neur ...
. Cross-tolerance has been observed with pharmaceutical drugs such as
anti-anxiety agents and
illicit substances, and sometimes the two of them together. Often, a person who uses one drug can be tolerant to a drug that has a completely different function.
[Kolb, Bryan, and Ian Whishaw. An Introduction to Brain and Behavior. New York: Worth Publishers, 2014. Print.] This phenomenon allows one to become tolerant to a drug that they have never used before.
Drug classifications and cross-tolerance
Anxiolytics and sedatives
Excitation of the GABA receptor produces an influx of negatively charged chloride ions, which hyperpolarizes the neuron and makes it less likely to give rise to an action potential. In addition to
gamma-Aminobutyric acid (GABA) itself, the GABA
A receptor can also bind barbiturates and benzodiazepines. Benzodiazepine binding increases the binding of GABA and barbiturates maximize the time the pore is open. Both of these mechanisms allow for influx of chloride ions. When these drugs are taken together, especially with
ethanol
Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an Alcohol (chemistry), alcohol with the chemical formula . Its formula can be also written as or (an ethyl ...
(drinking alcohol), there is a disproportionate increase in toxicity because the effects of both occur simultaneously and add up since they act on the same receptor at different sites. Convergence upon the GABA
A receptor is why tolerance for one drug in the group will most likely cause cross-tolerance for the other drugs in the group.
However, the barbiturates are also
AMPA receptor
The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (also known as AMPA receptor, AMPAR, or quisqualate receptor) is an ionotropic receptor, ionotropic transmembrane receptor for glutamate (iGluR) that mediates fast synapse, synap ...
blockers, and in addition interact with the
nAChR and
voltage-gated calcium channels
Voltage-gated calcium channels (VGCCs), also known as voltage-dependent calcium channels (VDCCs), are a group of voltage-gated ion channels found in the membrane of excitable cells (''e.g.'', muscle, glial cells, neurons, etc.) with a permeabi ...
. As a result, somebody who is tolerant to benzodiazepines is more sensitive to barbiturates than vice versa.
Antipsychotics
These drugs block dopamine receptors and some also block serotonin receptors (such as
chlorpromazine
Chlorpromazine (CPZ), marketed under the brand names Thorazine and Largactil among others, is an antipsychotic medication. It is primarily used to treat psychotic disorders such as schizophrenia. Other uses include the treatment of bipolar dis ...
, the first antipsychotic used clinically). Having been on one or more antipsychotics for any appreciable amount of time results in dramatically reduced sensitivity to others with similar mechanisms of action. However, an antipsychotic with a substantial disparity in
pharmacology
Pharmacology is a branch of medicine, biology and pharmaceutical sciences concerned with drug or medication action, where a drug may be defined as any artificial, natural, or endogenous (from within the body) molecule which exerts a biochemica ...
(e.g.
haloperidol
Haloperidol, sold under the brand name Haldol among others, is a typical antipsychotic medication. Haloperidol is used in the treatment of schizophrenia, tics in Tourette syndrome, mania in bipolar disorder, delirium, agitation, acute psychosi ...
and
quetiapine
Quetiapine, sold under the brand name Seroquel among others, is an atypical antipsychotic medication used for the treatment of schizophrenia, bipolar disorder, and major depressive disorder. Despite being widely used as a sleep aid due to its ...
) may retain significant efficacy.
Antidepressants and mood stabilizers
MAO inhibitor drugs block an enzyme system resulting in increased stores of monoamine neurotransmitters. More common antidepressants such as tricyclic antidepressants and SSRIs block reuptake transporters causing increased levels of norepinephrine or serotonin in synapses.
Mood stabilizers include lithium and many
anticonvulsants
Anticonvulsants (also known as antiepileptic drugs or recently as antiseizure drugs) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of b ...
, such as
carbamazepine
Carbamazepine (CBZ), sold under the trade name Tegretol among others, is an anticonvulsant medication used primarily in the treatment of epilepsy and neuropathic pain. It is used as an adjunctive treatment in schizophrenia along with other m ...
and
lamotrigine
Lamotrigine, sold under the brand name Lamictal among others, is a medication used to treat epilepsy and stabilize mood in bipolar disorder. For epilepsy, this includes focal seizures, tonic-clonic seizures, and seizures in Lennox-Gastaut synd ...
are also used for mood disorders. This would demonstrate little to zero cross-tolerance with serotonergic or
lithium
Lithium (from el, λίθος, lithos, lit=stone) is a chemical element with the symbol Li and atomic number 3. It is a soft, silvery-white alkali metal. Under standard conditions, it is the least dense metal and the least dense solid el ...
treatment.
Opioid analgesics
These drugs mimic three classes of endorphins, such as endomorphins, enkephalins, and dynorphins. All three of these classes each have their own receptor-mu, kappa, and delta. Opioids will bind to the receptor for the endorphin they are most chemically similar to. Tolerance to some effects occurs with regular use, a result of the downregulation of the stimulated opioid receptors. Cross tolerance to analgesia may develop incompletely and less rapidly, allowing rotation between opioid medications be used to compensate somewhat for tolerance. This phenomenon is called ''incomplete cross-tolerance''.
Stimulants
Cocaine, amphetamines, methylphenidate and ephedrine block the reuptake of dopamine and
norepinephrine
Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad'', ...
. With increasing doses, amphetamines also cause the direct release of these neurotransmitters.
Psychedelics
Serotonergic psychedelic
Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary states of consciousness (known as psychedelic experiences or "trips").Pollan, Michael (2018). ''How to Change Your Mind: What the New Science of ...
s act through modulation of serotonin receptors. Most of these drugs share a high affinity for the
5-HT2A receptor subtype, known to result in their common perceptual and psychological effects.
Cross-tolerance between drugs of different classifications
Sometimes cross-tolerance occurs between two drugs that do not share mechanisms of action or classification. For example, in rats some amphetamine-like stimulants have been shown to exhibit cross-tolerance with
caffeine
Caffeine is a central nervous system (CNS) stimulant of the methylxanthine class. It is mainly used recreationally as a cognitive enhancer, increasing alertness and attentional performance. Caffeine acts by blocking binding of adenosine t ...
, though this effect was not observed with amphetamine itself. It is likely that this mechanism of cross-tolerance involves the
dopamine receptor D1. Amphetamines also have cross-tolerance with
pseudoephedrine
Pseudoephedrine (PSE) is a sympathomimetic drug of the phenethylamine and amphetamine chemical classes. It may be used as a nasal/sinus decongestant, as a stimulant, or as a wakefulness-promoting agent in higher doses.
It was first characteri ...
, as pseudoephedrine can block dopamine uptake in the same manner that amphetamines do, but less potently.
Alcohol is another substance that often cross-tolerates with other drugs. Findings of cross-tolerance with nicotine in animal models suggest that it is also possible in humans, and may explain why the two drugs are often used together. Numerous studies have also suggested the possibility of cross-tolerance between alcohol and cannabis.
Cigarette smoking
Tobacco smoking is the practice of burning tobacco and ingesting the resulting smoke. The smoke may be inhaled, as is done with cigarettes, or simply released from the mouth, as is generally done with pipes and cigars. The practice is believed ...
produces increased metabolic tolerance to caffeine due to upregulation of the CYP1A enzyme family (see
aryl hydrocarbon receptor
The aryl hydrocarbon receptor (also known as AhR, AHR, ahr, ahR, or dioxin receptor) is a protein that in humans is encoded by the AHR gene. The aryl hydrocarbon receptor is a transcription factor that regulates gene expression. It was originall ...
).
References
{{DEFAULTSORT:Cross-Tolerance
Pharmacodynamics
fr:Accoutumance#Tolérance croisée