A drug interaction is a situation in which a substance (usually another drug) affects the activity of a drug when both are administered together. This action can be synergistic (when the drug's effect is increased) or antagonistic (when the drug's effect is decreased) or a new effect can be produced that neither produces on its own. Typically, interactions between drugs come to mind (drug-drug interaction). However, interactions may also exist between drugs and foods (drug-food interactions), as well as drugs and medicinal plants or herbs (drug-plant interactions). People taking antidepressant drugs such as monoamine oxidase inhibitors should not take food containing tyramine as hypertensive crisis may occur (an example of a drug-food interaction). These interactions may occur out of accidental misuse or due to lack of knowledge about the active ingredients involved in the relevant substances.

It is therefore easy to see the importance of these pharmacological interactions in the practice of medicine. If a patient is taking two drugs and one of them increases the effect of the other it is possible that an overdose may occur. The interaction of the two drugs may also increase the risk that side effects will occur. On the other hand, if the action of a drug is reduced it may cease to have any therapeutic use because of under dosage. Notwithstanding the above, on occasion these interactions may be sought in order to obtain an improved therapeutic effect. Examples of this include the use of codeine with paracetamol to increase its analgesic effect. Or the combination of clavulanic acid with amoxicillin in order to overcome bacterial resistance to the antibiotic. It should also be remembered that there are interactions that, from a theoretical standpoint, may occur but in clinical practice have no important repercussions.

The pharmaceutical interactions that are of special interest to the practice of medicine are primarily those that have negative effects for an organism. The risk that a pharmacological interaction will appear increases as a function of the number of drugs administered to a patient at the same time. Over a third (36%) of older adults in the U.S. regularly use 5 or more medications or supplements and 15% are potentially at risk for a major drug-drug interaction. Both the use of medications and subsequent adverse drug interactions have increased significantly between 2005-2011.

It is possible that an interaction will occur between a drug and another substance present in the organism (i.e. foods or alcohol). Or in certain specific situations a drug may even react with itself, such as occurs with dehydration. In other situations, the interaction does not involve any effect on the drug. In certain cases, the presence of a drug in an individual's blood may affect certain types of laboratory analysis (analytical interference).

It is also possible for interactions to occur outside an organism before administration of the drugs has taken place. This can occur when two drugs are mixed, for example, in a saline solution prior to intravenous injection. Some classic examples of this type of interaction include that thiopentone and suxamethonium should not be placed in the same syringe and same is true for benzylpenicillin and heparin. These situations will all be discussed under the same heading due to their conceptual similarity.

Drug interactions may be the result of various processes. These processes may include alterations in the pharmacokinetics of the drug, such as alterations in the absorption, distribution, metabolism, and excretion (ADME) of a drug. Alternatively, drug interactions may be the result of the pharmacodynamic properties of the drug, e.g. the co-administration of a receptor antagonist and an agonist for the same receptor.

Tachyphylaxis (Greek ταχύς, "tachys", "rapid", and φύλαξις, "phylaxis", "protection") is a medical term describing an acute, sudden decrease in response to a drug after its administration, i.e. a rapid and short-term onset of drug tolerance. It can occur after an initial dose or after a series of small doses. Increasing the dose of the drug may be able to restore the original response.

Tachyphylaxis is characterized by the rate sensitivity: the response of the system depends on the rate with which a stimulus is presented. To be specific, a high-intensity prolonged stimulus or often-repeated stimulus may bring about a diminished response also known as desensitization.

Drug tolerance is a pharmacological 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. The process of tolerance development is reversible (e.g., through a drug holiday) and can involve both physiological factors and psychological factors.

One may also develop drug tolerance to side effects, in which case tolerance is a desirable characteristic. A medical intervention that has for objective to increase tolerance (e.g., allergen immunotherapy, in which one is exposed to larger and larger amounts of allergen to decrease one's allergic reactions) is called drug desensitization.

The opposite concept to drug tolerance is drug reverse tolerance (or drug sensitization), 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 effects of a drug can be tolerated by a patient.

The detection of laboratory parameters is based on physicochemical reactions between the substance being measured and reagents designed for this purpose. These reactions can be altered by the presence of drugs giving rise to an over estimation or an underestimation of the real results. Levels of cholesterol and other blood lipids can be overestimated as a consequence of the presence in the blood of some psychotropic drugs. These overestimates should not be confused with the action of other drugs that actually increase blood cholesterol levels due to an interaction with its metabolism.

Most experts consider that these are not true interactions, so they will not be dealt with further in this discussion.

These chemical reactions are also known as pharmacological incompatibilities. The reactions occur when two or more drugs are mixed outside the body of the organism for the purpose of joint administration. Usually the interaction is antagonistic and it almost always affects both drugs. Examples of these types of interactions include the mixing of penicillins and aminoglycosides in the same serum bottle, which causes the formation of an insoluble precipitate, or the mixing of ciprofloxacin with furosemide. The interaction of some drugs with the transport medium can also be included here. This means that certain drugs cannot be administered in plastic bottles because they bind with the bottle's walls, reducing the drug's concentration in solution.

Many authors do not consider them to be interactions in the strictest sense of the word. An example is the database of the General Council of Official Pharmacists Colleges of Spain (Consejo General de Colegios Oficiales de Farmacéuticos de España), that does not include them among the 90,000 registered interactions.

Tachyphylaxis is a subcategory of drug tolerance referring to cases of sudden, short-term onset of tolerance following the administration of a drug.

Some fruit juices and fruits can interact with numerous drugs, in many cases causing adverse effects. The effect was first discovered by accident, when a test of drug interactions with alcohol used grapefruit juice to hide the taste of the ethanol.

It is still best-studied with grapefruit and grapefruit juice, but similar effects have more recently been seen with some (not all) other citrus fruits. One medical review advises patients to avoid all citrus juices until further research clarifies the risks. The interacting chemicals are found in many plants, and so many other foods may be affected; effects have been observed with apple juice, but their clinical significance is not yet known.

Normal amounts of food and drink, such as one whole grapefruit or a small glass () of grapefruit juice, can cause drug overdose toxicity. Fruit consumed three days before the medicine can still have an effect. The relative risks of different types of citrus fruit have not been systematically studied. Affected drugs typically have an auxiliary label saying “Do not take with grapefruit” on the container, and the interaction is elaborated on in the package insert. People are also advised to ask their physician or pharmacist about drug interactions.

The effects are caused by furanocoumarins (and, to a lesser extent, flavonoids). These chemicals inhibit key drug metabolizing enzymes, such as cytochrome P450 3A4 (CYP3A4). CYP3A4 is a metabolizing enzyme for almost 50% of drugs, and is found in the liver and small intestinal epithelial cells. As a result, many drugs are affected. Inhibition of enzymes can have two different effects, depending on whether the drug is either

1. metabolized by the enzyme to an inactive metabolite, "or"

2. activated by the enzyme to an active metabolite.

If the active drug is metabolized by the inhibited enzyme, then the fruit will stop the drug being metabolized, leaving elevated concentrations of the medication in the body, which can cause adverse effects. Conversely, if the medication is a prodrug, it needs to be metabolised to be converted to the active drug. Compromising its metabolism lowers concentrations of the active drug, reducing its therapeutic effect, and risking therapeutic failure.

Low drug concentrations can also be caused when the fruit suppresses drug absorption from the intestine.

Developmental toxicity is any structural or functional alteration, reversible or irreversible, which interferes with homeostasis, normal growth, differentiation, development or behavior, and which is caused by environmental insult (including drugs, lifestyle factors such as alcohol, diet, and environmental toxic chemicals or physical factors). It is the study of adverse effects on the development of the organism resulting from exposure to toxic agents before conception (either parent), during prenatal development, or post-natally until puberty. The substance that causes developmental toxicity from embryonic stage to birth is called teratogens. The effect of the developmental toxicants depends on the type of substance, dose and duration and time of exposure.

Certain Pathogens are also included since the toxins they secrete are known to cause adverse effects on the development of the organism when the mother or fetus is infected. Developmental toxicology is a science studying adverse developmental outcomes. This term has widely replaced the early term for the study of primarily structural congenital abnormalities, teratology, to enable inclusion of a more diverse spectrum of congenital disorders. Typical factors causing developmental toxicity are radiation, infections (e.g. rubella), maternal metabolic imbalances (e.g. alcoholism, diabetes, folic acid deficiency), drugs (e.g. anticancer drugs, tetracyclines, many hormones, thalidomide), and environmental chemicals (e.g. mercury, lead, dioxins, PBDEs, HBCD, tobacco smoke). The first-trimester exposure is considered the most potential for developmental toxicity.

Once fertilization has taken place, the toxicants in the environment can pass through the mother to the developing embryo or fetus across the placental barrier. The fetus is at greatest risk during the first 14th to 60th day of the pregnancy when the major organs are being formed. However, depending on the type of toxicant and amount of exposure, a fetus can be exposed toxicant at any time during pregnancy. For example, exposure to a particular toxicant at one time in the pregnancy may result in organ damage and at another time in the pregnancy could cause death of the fetus and miscarriage. There are a number of chemicals, biological agents (such as bacteria and viruses), and physical agents (such as radiation) used in a variety of workplaces that are known to cause developmental disorders. Developmental disorders can include a wide range of physical abnormalities, such as bone or organ deformities, or behavioral and learning problems, such as a mental retardation. Exposures to some chemicals during pregnancy can lead to the development of cancer later in the life of the child and are called transgenerational carcinogens. Exposure to toxicants during the second and the third trimester of a pregnancy can lead to slow fetal grown and result in low birth weight.

Symptom onset is usually rapid, often occurring within minutes of elevated serotonin levels. Serotonin syndrome encompasses a wide range of clinical findings. Mild symptoms may consist of increased heart rate, shivering, sweating, dilated pupils, myoclonus (intermittent jerking or twitching), as well as overresponsive reflexes. However, many of these symptoms may be side effects of the drug or drug interaction causing excessive levels of serotonin; not an effect of elevated serotonin itself. Tremor is a common side effect of MDMA's action on dopamine, whereas hyperreflexia is symptomatic of exposure to serotonin agonists. Moderate intoxication includes additional abnormalities such as hyperactive bowel sounds, high blood pressure and hyperthermia; a temperature as high as . The overactive reflexes and clonus in moderate cases may be greater in the lower limbs than in the upper limbs. Mental changes include hypervigilance or insomnia and agitation. Severe symptoms include severe increases in heart rate and blood pressure that may lead to shock. Temperature may rise to above in life-threatening cases. Other abnormalities include metabolic acidosis, rhabdomyolysis, seizures, renal failure, and disseminated intravascular coagulation; these effects usually arising as a consequence of hyperthermia.

The symptoms are often described as a clinical triad of abnormalities:

- Cognitive effects: headache, agitation, hypomania, mental confusion, hallucinations, coma

- Autonomic effects: shivering, sweating, hyperthermia, vasoconstriction, tachycardia, nausea, diarrhea.

- Somatic effects: myoclonus (muscle twitching), hyperreflexia (manifested by clonus), tremor.

Copper toxicity, also called copperiedus, refers to the consequences of an excess of copper in the body. Copperiedus can occur from eating acid foods cooked in uncoated copper cookware, or from exposure to excess copper in drinking water or other environmental sources.

Upon the discontinuation of serotonergic drugs, most cases of serotonin syndrome resolve within 24 hours, although in some cases delirium may persist for a number of days. Symptoms typically persist for a longer time frame in patients taking drugs which have a long elimination half-life, active metabolites, or a protracted duration of action.

Cases have reported muscle pain and weakness persisting for months, and antidepressant discontinuation may contribute to ongoing features. Following appropriate medical management, serotonin syndrome is generally associated with a favorable prognosis.

Chronic exposure to excessive manganese levels can lead to a variety of psychiatric and motor disturbances, termed manganism. Generally, exposure to ambient manganese air concentrations in excess of 5 micrograms Mn/m can lead to Mn-induced symptoms.

In initial stages of manganism, neurological symptoms consist of reduced response speed, irritability, mood changes, and compulsive behaviors. Upon protracted exposure symptoms are more prominent and resemble those of idiopathic Parkinson's disease, as which it is often misdiagnosed, although there are particular differences in both the symptoms (nature of tremors, for example), response to drugs such as levodopa, and affected portion of the basal ganglia. Symptoms are also similar to Lou Gehrig's disease and multiple sclerosis.

ICD-9-CM code 985.8 "Toxic effect of other specified metals" includes acute & chronic copper poisoning (or other toxic effect) whether intentional, accidental, industrial etc.

- In addition, it includes poisoning and toxic effects of other metals including tin, selenium nickel, iron, heavy metals, thallium, silver, lithium, cobalt, aluminum and bismuth. Some poisonings, e.g. zinc phosphide, would/could also be included as well as under 989.4 Poisoning due to other pesticides, etc.

- Excluded are toxic effects of mercury, arsenic, manganese, beryllium, antimony, cadmium, and chromium.

Manganism or manganese poisoning is a toxic condition resulting from chronic exposure to manganese. It was first identified in 1837 by James Couper.

Tardive Dysmentia is a rarely used term introduced in a 1983 paper to describe "changes in affect, activation level, and interpersonal interaction", and hypothesized to be caused by long-term exposure to neuroleptic drugs in the same way as the much better known syndrome of tardive dyskinesia. Several papers in the following years discussed the validity of the concept, and this small literature was reviewed in a 1993 publication by M. S. Myslobodsky, who drew attention to the "possibility that the syndrome of dysmentia is occasional excessive emotional reactivity, enhanced responsiveness to environmental stimuli, and indifference to or reduced awareness of the patient's abnormal involuntary movements", but concluded that the pathophysiology is uncertain. Since then, the term has fallen into disuse, receiving at most only passing mentions in the literature.

Symptoms

- Pain right hypochondrium referred to right shoulder

- Pyrexia (100.4 F)

- Profuse sweating and rigors

- Loss of weight

- Earthy complexion

Signs

- Pallor

- Tenderness and rigidity in right hypochondrium

- Palpable liver

- tenderness

- Basal lung signs

PRS symptoms have common characteristics with many other psychiatric disorders. However, none of the present DSM diagnoses can account for the full scope of symptoms seen in PRS, and refusal to eat, weight loss, social withdrawal and school refusal can be considered as the main distinctive features. Any system may be involved, however some more commonly engaged than others.

Gastrointestinal:

- recurring pain

- nausea

- loss of appetite

Neurological:

- headache

- seizure

- motor dysfunction

- sensory dysfunction

- fatigue

- altered consciousness

Musculoskeletal:

- joint pains

- muscle weakness

The effect of grapefruit juice with regard to drug absorption was originally discovered in 1989. The first published report on grapefruit drug interactions was in 1991 in the Lancet entitled "Interactions of Citrus Juices with Felodipine and Nifedipine," and was the first reported food-drug interaction clinically. However, the effect only became well-publicized after being responsible for a number of bad interactions with medication.

The most distinctive feature of PEPD is episodic burning pain of the rectum, ocular, and mandibular regions. It should be stressed that while pain often originates or is centered in these areas it can also spread or be diffuse in nature. Pain experienced by patients with this disorder should not be underestimated as women with the disorder who have also given birth describe PEPD pain as worse than labor pain. Concomitant with this pain is typically flushing, often in an area associated with the pain.

During attacks in infants, the child often looks startled or terrified and can scream inconsolably. These attacks can be precipitated by injections, defecation, wiping of the perineum, eating, or the consumption of oral medication. When attacks occur due to such precipitation, pain and flushing are often present in the area of attack precipitation, though symptoms may also be diffuse in nature.

Other symptoms may include hypersalivation when attacks are localized in the mandibular region, or leg weakness after foot trauma. A prominent non-physical symptom are tonic non-epileptic seizures. Such seizures are more common in infancy and childhood than during adulthood. In older children, inconsolable screaming usually precedes such attack, followed by apnea, paleness, and stiffness. Such stiffness can last from seconds to a few minutes.

Attack precipitants are usually physical in nature, such as defecation, eating, or taking medicine. Some less common precipitants are micturition, coitus, and painful stimuli. There are also non-physical precipitants, such as the thought or sight of food. In general attacks tend to occur in the precipitated area, though this is not always the case. While some individuals have described a build-up to attacks, in general they tend to be abrupt. The duration of these attacks can be from a few seconds to two hours.

Patients are largely normal between attacks. The only notable interictal problem is constipation, likely due to apprehension of precipitating an attack. This symptom often decreases with age, likely due to coping mechanisms such as the use of stool softeners.

Berserk llama syndrome or berserk male syndrome (as it is more pronounced in males) is a psychological condition suffered by human-raised llamas and alpacas that can cause them to exhibit dangerously aggressive behavior toward humans. The term has been overused, however, and is sometimes inappropriately applied to llamas with aggressive personalities that are not truly "berserk".

The condition is a result of the llama imprinting on its human handlers to such a degree that it considers them to be fellow llamas. Imprinting can be caused by bottle feeding and by isolation from other llamas. Adult male inter-llama interaction can be rough, including chest-ramming and biting, and they are strongly territorial. Male llamas suffering from this condition become dangerous when this behavior is directed toward humans and they usually have to be euthanised. Female llamas can also suffer from berserk llama syndrome but their behavior is usually limited to spitting and difficult handling.

Berserk llama syndrome can be prevented in males through castration before puberty.

Pervasive refusal syndrome (PRS), now referred to as pervasive arousal withdrawal syndrome (PAWS), is a rare but serious child psychiatric disorder that was first described by Bryan Lask and colleagues in 1991. As of 2011, it is not included in the standard psychiatric classification systems. PRS is the name allotted to a disorder in which children have abandoned their involvement in all phases of their life. It's characterized by refusal to eat, drink, talk, walk or self-care, and a firm resistance to treatment. PRS is very rare and its cause is unclear, but its severity makes it life-threatening. The disorder usually begins with a 'virus', or the child having a 'pain', that results in the need for consulting a doctor or going to the hospital, even though no substantial cause can be found. PRS starts slowly, but the child then worsens quickly becoming reluctant or not capable to do anything for themselves. They originally refuse to accept others caring for them, or helping them eat, and are very depressed and distraught. It is not guaranteed that recovery will take place, and it is a lengthy and complex process, involving specialist medical care. Nevertheless, once the patient is healthy, relapse is very infrequent.

A family with a psychiatric history or environmental stress factors can also play a role. Hospitalization is almost always necessary and the recovery period is lengthy; typically 12.8 months. During the recovery period symptoms disappear in the opposite order they appear. About 67% of the cases show complete recovery.

PRS may be linked to learned helplessness, and so it can be important for the patient to be able to manage the rate of their recovery. Music therapy may help in this regard as it provides empowerment by giving the patient choice and control, while allowing for improvisation can result in a sense of affirmation and validation; all important for a successful recovery.

Developmental toxicity is the alterations of the developmental processes (organogenesis, morphogenesis) rather than functional alterations of already developed organs. The effects of the toxicants depends on the dose, threshold and duration. The effects of toxicity are:

1. Minor structural deformities - e.g. Anticonvulsant drugs, Warfarin, Retinoic Acid derivatives

2. Major structural deformities - e.g. DES (diethylstilbestrol), cigarette smoking

3. Growth Retardation - e.g. Alcohol, Polychlorinated Biphenyls

4. Functional alterations - e.g. Retinoic Acid derivatives, Polychlorinated Biphenyls, Phenobarbitol, Lead

5. Death- e.g. Rubella, ACE inhibitors

The DSM definition of addiction can be boiled down to compulsive use of a substance (or engagement in an activity) despite ongoing negative consequences. The medical community makes a distinction between physical dependence (characterized by symptoms of physical withdrawal symptoms, like tremors and sweating) and psychological dependence (emotional-motivational withdrawal symptoms). Physical dependence is simply needing a substance to function. Humans are all physically dependent upon oxygen, food and water. A drug can cause physical dependence and not psychological dependence (for example, some blood pressure medications, which can produce fatal withdrawal symptoms if not tapered) and some can cause psychological dependence without physical dependence (the withdrawal symptoms associated with cocaine are all psychological, there is no associated vomiting or diarrhea as there is with opiate withdrawal).

There are several different screening tools that have been validated for use with adolescents such as the CRAFFT and adults such as the CAGE.

Physical dependence on a substance is defined by the appearance of characteristic physical withdrawal symptoms when the substance is suddenly discontinued. Opiates, benzodiazepines, barbiturates, alcohol and nicotine induce physical dependence. On the other hand, some categories of substances share this property and are still not considered addictive: cortisone, beta blockers and most antidepressants are examples.

Some substances induce physical dependence or physiological tolerance - but not addiction — for example many laxatives, which are not psychoactive; nasal decongestants, which can cause rebound congestion if used for more than a few days in a row; and some antidepressants, most notably venlafaxine, paroxetine and sertraline, as they have quite short half-lives, so stopping them abruptly causes a more rapid change in the neurotransmitter balance in the brain than many other antidepressants. Many non-addictive prescription drugs should not be suddenly stopped, so a doctor should be consulted before abruptly discontinuing them.

The speed with which a given individual becomes addicted to various substances varies with the substance, the frequency of use, the means of ingestion, the intensity of pleasure or euphoria, and the individual's genetic and psychological susceptibility. Some people may exhibit alcoholic tendencies from the moment of first intoxication, while most people can drink socially without ever becoming addicted. Opioid dependent individuals have different responses to even low doses of opioids than the majority of people, although this may be due to a variety of other factors, as opioid use heavily stimulates pleasure-inducing neurotransmitters in the brain. Nonetheless, because of these variations, in addition to the adoption and twin studies that have been well replicated, much of the medical community is satisfied that addiction is in part genetically moderated. That is, one's genetic makeup may regulate how susceptible one is to a substance and how easily one may become attached to a pleasurable routine.

Eating disorders are complicated pathological mental illnesses and thus are not the same as addictions described in this article. Eating disorders, which some argue are not addictions at all, are driven by a multitude of factors, most of which are highly different from the factors behind addictions described in this article. It has been reported, however, that patients with eating disorders can successfully be treated with the same non-pharmacological protocols used in patients with chemical addiction disorders.

Gambling is another potentially addictive behavior with some biological overlap. Conversely gambling urges have emerged with the administration of Mirapex (pramipexole), a dopamine agonist.

The obsolete term physical addiction is deprecated, because of its connotations. In modern pain management with opioids physical dependence is nearly universal. High-quality, long-term studies are needed to better delineate the risks and benefits of chronic opiate use.

Paroxysmal extreme pain disorder (PEPD), originally named familial rectal pain syndrome, is a rare disorder whose most notable features are pain in the mandibular, ocular and rectal areas as well as flushing. PEPD often first manifests at the beginning of life, perhaps even "in utero", with symptoms persisting throughout life. PEPD symptoms are reminiscent of primary erythromelalgia, as both result in flushing and episodic pain, though pain is typically present in the extremities for primary erythromelalgia. Both of these disorders have recently been shown to be allelic, both caused by mutations in the voltage-gated sodium channel Na1.7 encoded by the gene "SCN9A". A different mutation in "SCN9A" causes congenital insensitivity to pain.