Drug intolerance or drug sensitivity refers to an inability to tolerate the

adverse effects 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 complic ...

of a medication, generally at therapeutic or subtherapeutic doses. Conversely, a patient is said to be "tolerating" a drug when they can tolerate its adverse effects. Some instances of drug intolerance are known to result from genetic variations in

drug metabolism Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. More generally, xenobiotic metabolism (from the Greek xenos "stranger" and biotic "related to living beings") is the set o ...

Pathophysiology

Drugs in systemic circulation have a certain concentration in the blood, which serves as a surrogate marker for how much drug will be delivered throughout the body (how much drug the rest of the body will "see"). There exists a minimum concentration of drug within the blood that will give rise to the intended therapeutic effect ( minimum effective concentration, MEC), as well as a minimum concentration of drug that will give rise to an unintended adverse drug event (minimum toxic concentration, MTC). The difference between these two values is generally referred to as the

therapeutic window The therapeutic index (TI; also referred to as therapeutic ratio) is a quantitative measurement of the relative safety of a drug with regard to risk of overdose. It is a comparison of the amount of a therapeutic agent that causes toxicity to the ...

. Different drugs have different therapeutic windows, and different people will have different MECs and MTCs for a given drug. If someone has a very low MTC for a drug, they are likely to experience adverse effects at drug concentrations lower than what it would take to produce the same adverse effects in the general populace; thus, the individual will experience significant toxicity at a dose that is otherwise considered "normal" for the average person. This individual will be considered "intolerant" to that drug. There are a variety of factors that can affect the MTC, which is often the subject of clinical

pharmacokinetics Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to describing how the body affects a specific su ...

. Variations in MTC can occur at any point in the

ADME ADME is the four-letter abbreviation (acronym) for absorption (pharmacokinetics), ''absorption'', distribution (pharmacology), ''distribution'', ''metabolism'', and ''excretion'', and is mainly used in fields such as pharmacokinetics and pharmacol ...

(

absorption Absorption may refer to: Chemistry and biology *Absorption (biology), digestion **Absorption (small intestine) *Absorption (chemistry), diffusion of particles of gas or liquid into liquid or solid materials *Absorption (skin), a route by which su ...

distribution Distribution may refer to: Mathematics *Distribution (mathematics), generalized functions used to formulate solutions of partial differential equations *Probability distribution, the probability of a particular value or value range of a varia ...

metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

, and

excretion Excretion is elimination of metabolic waste, which is an essential process in all organisms. In vertebrates, this is primarily carried out by the lungs, Kidney (vertebrates), kidneys, and skin. This is in contrast with secretion, where the substa ...

) process. For example, a patient could possess a genetic defect in a drug metabolizing enzyme in the

cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

superfamily. While most individuals will possess the effective metabolizing machinery, a person with a defect will have a difficult time trying to clear the drug from their system. Thus, the drug will accumulate within the blood to higher-than-expected concentrations, reaching a MTC at a dose that would otherwise be considered normal for the average person. In other words, in a person that is intolerant to a medication, it is possible for a dose of 10 mg to "feel" like a dose of 100 mg, resulting in an overdose—a "normal" dose can be a "toxic" dose in these individuals, leading to clinically significant effects. There is also an aspect of drug intolerance that is subjective. Just as different people have different pain tolerances, so too do people have different tolerances for dealing with the adverse effects from their medications. For example, while opioid-induced constipation may be tolerable to some individuals, other people may stop taking an

opioid Opioids are a class of Drug, drugs that derive from, or mimic, natural substances found in the Papaver somniferum, opium poppy plant. Opioids work on opioid receptors in the brain and other organs to produce a variety of morphine-like effects, ...

due to the unpleasantness of the constipation even if it brings them significant pain relief.

Examples of drug sensitivity

Tinnitus Tinnitus is a condition when a person hears a ringing sound or a different variety of sound when no corresponding external sound is present and other people cannot hear it. Nearly everyone experiences faint "normal tinnitus" in a completely ...

after a normal dose of

aspirin Aspirin () is the genericized trademark for acetylsalicylic acid (ASA), a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and inflammation, and as an antithrombotic. Specific inflammatory conditions that aspirin is ...

Aspirin-exacerbated respiratory disease Aspirin-exacerbated respiratory disease (AERD), also called NSAID-exacerbated respiratory disease (N-ERD) or historically aspirin-induced asthma and Samter's Triad, is a long-term disease defined by three simultaneous symptoms: asthma, chronic ...

Liver failure Liver failure is the inability of the liver to perform its normal synthetic and metabolic functions as part of normal physiology. Two forms are recognised, acute and chronic (cirrhosis). Recently, a third form of liver failure known as acute- ...

(possibly also

kidney failure Kidney failure, also known as renal failure or end-stage renal disease (ESRD), is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney fa ...

) after a normal dose of

acetaminophen Paracetamol, or acetaminophen, is a non-opioid analgesic and antipyretic agent used to treat fever and mild to moderate pain. It is a widely available over-the-counter drug sold under various brand names, including Tylenol and Panadol. Parac ...

* Muscle pain or weakness due to

statin Statins (or HMG-CoA reductase inhibitors) are a class of medications that lower cholesterol. They are prescribed typically to people who are at high risk of cardiovascular disease. Low-density lipoprotein (LDL) carriers of cholesterol play ...

therapy

Analgesic intolerance

Intolerance to

analgesic An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in s ...

s, particularly

NSAID Non-steroidal anti-inflammatory drugs (NSAID) are members of a therapeutic drug class which reduces pain, decreases inflammation, decreases fever, and prevents blood clots. Side effects depend on the specific drug, its dose and duration of ...

s, is relatively common. It is thought that a variation in the metabolism of

arachidonic acid Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega−6 fatty acid 20:4(ω−6), or 20:4(5,8,11,14). It is a precursor in the formation of leukotrienes, prostaglandins, and thromboxanes. Together with omega−3 fatty acids an ...

is responsible for the intolerance. Symptoms include chronic rhinosinusitis with

nasal polyp Nasal is an adjective referring to the nose, part of human or animal anatomy. It may also be shorthand for the following uses in combination: * With reference to the human nose: ** Nasal administration, a method of pharmaceutical drug delivery ...

asthma Asthma is a common long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wh ...

, gastrointestinal ulcers,

angioedema Angioedema is an area of swelling (edema) of the lower layer of skin and tissue just under the skin or mucous membranes. The swelling may occur in the face, tongue, larynx, abdomen, or arms and legs. Often it is associated with hives, which are ...

, and

urticaria Hives, also known as urticaria, is a kind of skin rash with red or flesh-colored, raised, itchy bumps. Hives may burn or sting. The patches of rash may appear on different body parts, with variable duration from minutes to days, and typically ...

References

{{reflist Pharmacodynamics Sensitivities nl:Intolerantie (Geneeskunde)

Pathophysiology

Examples of drug sensitivity

Analgesic intolerance

See also

References