Therapeutic index
Encyclopedia
The therapeutic index is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes death (in animal studies) or toxicity (in human studies).
Quantitatively, it is the ratio
given by the lethal or toxic dose divided by the therapeutic dose.
In animal studies, the therapeutic index is the lethal dose of a drug for 50% of the population (LD50
) divided by the minimum effective dose
for 50% of the population (ED50).
Lethality is not determined in human clinical trials; instead, the dose that produces a toxicity in 50% of the population (TD50) is used to calculate the therapeutic index.
While the lethal dose is important to determine in animal studies, there are usually severe toxicities that occur at sublethal doses in humans, and these toxicities often limit the maximum dose of a drug. A higher therapeutic index is preferable to a lower one: a patient would have to take a much higher dose of such a drug to reach the lethal/toxic threshold than the dose taken to elicit the therapeutic effect.
in animal studies, or for humans, 
Generally, a drug or other therapeutic agent with a narrow therapeutic range (i.e. having little difference between toxic and therapeutic doses) may have its dosage adjusted according to measurements of the actual blood levels achieved in the person taking it. This may be achieved through therapeutic drug monitoring
(TDM) protocols.
The therapeutic index varies widely among substances: most forgiving among the opioid
analgesics is remifentanyl, which offers a therapeutic index of 33,000:1; tetrahydrocannabinol
, a sedative and analgesic of herbal origin (genus Cannabis
), has a safe therapeutic index of 1000:1, while diazepam
, a benzodiazepine
sedative-hypnotic and skeletal muscle relaxant
has a less-forgiving index of 100:1 and morphine
, a sedative
, antidepressant
, and analgesic
also of herbal origin (genus Papaver
) has an index of 70:1 (which, however, is still considered very safe).
Less safe are cocaine
, a stimulant
and local anaesthetic; ethyl alcohol
, a widely available sedative
consumed world-wide: the therapeutic indices for these substances are 15:1 and 10:1 respectively. Even less safe are drugs such as digoxin
, a cardiac glycoside
; its therapeutic index is approximately 2:1. Other examples of drugs with a narrow therapeutic range, which may require drug monitoring both to achieve therapeutic levels and to minimize toxicity, include: dimercaprol
, theophylline
, warfarin
and lithium carbonate
. Some antibiotics require monitoring to balance efficacy with minimizing adverse effect
s, including: gentamicin
, vancomycin
, amphotericin B
(nicknamed 'amphoterrible' for this very reason), and polymyxin B
.
The effective therapeutic index can be affected by targeting
, in which the therapeutic agent is concentrated in its area of effect. For example, in radiation therapy for cancerous tumors, shaping the radiation beam precisely to the profile of a tumor in the "beam's eye view" can increase the delivered dose without increasing toxic effects, though such shaping might not change the therapeutic index. Similarly, chemotherapy or radiotherapy with infused or injected agents can be made more efficacious by attaching the agent to an oncophilic substance, as is done in peptide receptor radionuclide therapy for neuroendocrine tumors
and in chemoembolization or radioactive microspheres therapy for liver tumors and metastases. This concentrates the agent in the targeted tissues and lowers its concentration in others, increasing efficacy and lowering toxicity.
Sometimes the term safety ratio is used instead, particularly when referring to psychoactive drugs used for non-therapeutic (e.g. nonmedical) purposes. In such cases, the "effective" dose is that which produces the desired effect, which can vary and can be greater or less than the therapeutically effective dose.
The concept of safety ratio/TI also ignores the ease or difficulty with which a toxic or lethal dose may be reached. This is more of a consideration for recreational drug users. While heroin and common alcohol may appear similarly dangerous based on their safety ratio (6 vs 10), an inexperienced drinker will most likely vomit and fall asleep long before reaching life-threatening amounts of alcohol in their system. On the other hand, heroin users are at a much greater risk of death from a misjudged dose due to varying drug purity, individual tolerances, and influence-affected judgment.
A related concept is protective index
, which is the same except that TD50 (median toxic dose) is used in place of LD50. For many substances, toxic effects can occur at levels far below those needed to cause death, and thus the protective index (if toxicity is properly specified) is often more informative about a substance's relative safety. Nevertheless, the therapeutic index is still useful as it can be considered an upper bound
for the protective index, and the former also has the advantages of objectivity and easier comprehension.
Quantitatively, it is the ratio
Ratio
In mathematics, a ratio is a relationship between two numbers of the same kind , usually expressed as "a to b" or a:b, sometimes expressed arithmetically as a dimensionless quotient of the two which explicitly indicates how many times the first number contains the second In mathematics, a ratio is...
given by the lethal or toxic dose divided by the therapeutic dose.
In animal studies, the therapeutic index is the lethal dose of a drug for 50% of the population (LD50
LD50
In toxicology, the median lethal dose, LD50 , LC50 or LCt50 of a toxin, radiation, or pathogen is the dose required to kill half the members of a tested population after a specified test duration...
) divided by the minimum effective dose
Effective dose (pharmacology)
An effective dose in pharmacology is the dose or amount of drug that produces a therapeutic response or desired effect in some fraction of the subjects taking it....
for 50% of the population (ED50).
Lethality is not determined in human clinical trials; instead, the dose that produces a toxicity in 50% of the population (TD50) is used to calculate the therapeutic index.
While the lethal dose is important to determine in animal studies, there are usually severe toxicities that occur at sublethal doses in humans, and these toxicities often limit the maximum dose of a drug. A higher therapeutic index is preferable to a lower one: a patient would have to take a much higher dose of such a drug to reach the lethal/toxic threshold than the dose taken to elicit the therapeutic effect.
in animal studies, or for humans, Generally, a drug or other therapeutic agent with a narrow therapeutic range (i.e. having little difference between toxic and therapeutic doses) may have its dosage adjusted according to measurements of the actual blood levels achieved in the person taking it. This may be achieved through therapeutic drug monitoring
Therapeutic drug monitoring
- Background :Therapeutic drug monitoring is a branch of clinical chemistry and clinical pharmacology that specializes in the measurement of medication concentrations in blood. Its main focus is on drugs with a narrow therapeutic range, i.e. drugs that can easily be under- or overdosed...
(TDM) protocols.
The therapeutic index varies widely among substances: most forgiving among the opioid
Opioid
An opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...
analgesics is remifentanyl, which offers a therapeutic index of 33,000:1; tetrahydrocannabinol
Tetrahydrocannabinol
Tetrahydrocannabinol , also known as delta-9-tetrahydrocannabinol , Δ1-THC , or dronabinol, is the main chemical psychoactive substance found in the cannabis plant. It was first isolated in 1964. In pure form, it is a glassy solid when cold, and becomes viscous and sticky if warmed...
, a sedative and analgesic of herbal origin (genus Cannabis
Cannabis
Cannabis is a genus of flowering plants that includes three putative species, Cannabis sativa, Cannabis indica, and Cannabis ruderalis. These three taxa are indigenous to Central Asia, and South Asia. Cannabis has long been used for fibre , for seed and seed oils, for medicinal purposes, and as a...
), has a safe therapeutic index of 1000:1, while diazepam
Diazepam
Diazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...
, a benzodiazepine
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
sedative-hypnotic and skeletal muscle relaxant
Muscle relaxant
A muscle relaxant is a drug which affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therapeutic groups: neuromuscular blockers and spasmolytics...
has a less-forgiving index of 100:1 and morphine
Morphine
Morphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...
, a sedative
Sedative
A sedative or tranquilizer is a substance that induces sedation by reducing irritability or excitement....
, antidepressant
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
, and analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
also of herbal origin (genus Papaver
Papaver
Papaver is a genus of 70-100 species of frost-tolerant annuals, biennials, and perennials native to temperate and cold regions of Eurasia, Africa and North America. It is the type genus of the poppy family, Papaveraceae.-Description:...
) has an index of 70:1 (which, however, is still considered very safe).
Less safe are cocaine
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...
, a stimulant
Stimulant
Stimulants are psychoactive drugs which induce temporary improvements in either mental or physical function or both. Examples of these kinds of effects may include enhanced alertness, wakefulness, and locomotion, among others...
and local anaesthetic; ethyl alcohol
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
, a widely available sedative
Sedative
A sedative or tranquilizer is a substance that induces sedation by reducing irritability or excitement....
consumed world-wide: the therapeutic indices for these substances are 15:1 and 10:1 respectively. Even less safe are drugs such as digoxin
Digoxin
Digoxin INN , also known as digitalis, is a purified cardiac glycoside and extracted from the foxglove plant, Digitalis lanata. Its corresponding aglycone is digoxigenin, and its acetyl derivative is acetyldigoxin...
, a cardiac glycoside
Cardiac glycoside
Cardiac glycosides are drugs used in the treatment of congestive heart failure and cardiac arrhythmia. These glycosides are found as secondary metabolites in several plants, but also in some animals, such as the milkweed butterflies. -Function:...
; its therapeutic index is approximately 2:1. Other examples of drugs with a narrow therapeutic range, which may require drug monitoring both to achieve therapeutic levels and to minimize toxicity, include: dimercaprol
Dimercaprol
Dimercaprol or British anti-Lewisite , is a compound developed by British biochemists at Oxford University during World War II. It was developed secretly as an antidote for lewisite, the now-obsolete arsenic-based chemical warfare agent. Today, it is used medically in treatment of arsenic,...
, theophylline
Theophylline
Theophylline, also known as dimethylxanthine, is a methylxanthine drug used in therapy for respiratory diseases such as COPD and asthma under a variety of brand names. Because of its numerous side-effects, the drug is now rarely administered for clinical use. As a member of the xanthine family, it...
, warfarin
Warfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...
and lithium carbonate
Lithium carbonate
Lithium carbonate is a chemical compound of lithium, carbon, and oxygen with the formula Li2CO3. This colorless salt is widely used in the processing of metal oxides and has received attention for its use in psychiatry. It is found in nature as the rare mineral zabuyelite.-Properties:Like almost...
. Some antibiotics require monitoring to balance efficacy with minimizing adverse effect
Adverse effect
In medicine, an adverse effect is a harmful and undesired 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. If it results from an unsuitable or incorrect dosage or...
s, including: gentamicin
Gentamicin
Gentamicin is an aminoglycoside antibiotic, used to treat many types of bacterial infections, particularly those caused by Gram-negative organisms. However, gentamicin is not used for Neisseria gonorrhoeae, Neisseria meningitidis or Legionella pneumophila...
, vancomycin
Vancomycin
Vancomycin INN is a glycopeptide antibiotic used in the prophylaxis and treatment of infections caused by Gram-positive bacteria. It has traditionally been reserved as a drug of "last resort", used only after treatment with other antibiotics had failed, although the emergence of...
, amphotericin B
Amphotericin B
Amphotericin B is a polyene antifungal drug, often used intravenously for systemic fungal infections...
(nicknamed 'amphoterrible' for this very reason), and polymyxin B
Polymyxin B
Polymyxin B is an antibiotic primarily used for resistant gram-negative infections. It is derived from the bacterium Bacillus polymyxa. Polymyxin B is a mixture of two closely related compounds, polymyxin B1 and polymyxin B2. It has a bactericidal action against almost all gram-negative bacilli...
.
The effective therapeutic index can be affected by targeting
Targeted drug delivery
Targeted drug delivery, sometimes called smart drug delivery, is a method of delivering medication to a patient in a manner that increases the concentration of the medication in some parts of the body relative to others. The goal of a targeted drug delivery system is to prolong, localize, target...
, in which the therapeutic agent is concentrated in its area of effect. For example, in radiation therapy for cancerous tumors, shaping the radiation beam precisely to the profile of a tumor in the "beam's eye view" can increase the delivered dose without increasing toxic effects, though such shaping might not change the therapeutic index. Similarly, chemotherapy or radiotherapy with infused or injected agents can be made more efficacious by attaching the agent to an oncophilic substance, as is done in peptide receptor radionuclide therapy for neuroendocrine tumors
Neuroendocrine tumors
Neuroendocrine tumors are neoplasms that arise from cells of the endocrine and nervous systems. Many are benign, while some are cancers...
and in chemoembolization or radioactive microspheres therapy for liver tumors and metastases. This concentrates the agent in the targeted tissues and lowers its concentration in others, increasing efficacy and lowering toxicity.
Sometimes the term safety ratio is used instead, particularly when referring to psychoactive drugs used for non-therapeutic (e.g. nonmedical) purposes. In such cases, the "effective" dose is that which produces the desired effect, which can vary and can be greater or less than the therapeutically effective dose.
The concept of safety ratio/TI also ignores the ease or difficulty with which a toxic or lethal dose may be reached. This is more of a consideration for recreational drug users. While heroin and common alcohol may appear similarly dangerous based on their safety ratio (6 vs 10), an inexperienced drinker will most likely vomit and fall asleep long before reaching life-threatening amounts of alcohol in their system. On the other hand, heroin users are at a much greater risk of death from a misjudged dose due to varying drug purity, individual tolerances, and influence-affected judgment.
A related concept is protective index
Protective index
The protective index is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxicity. Quantitatively, it is the ratio given by the toxic dose divided by the therapeutic dose. A protective index is the toxic dose of a drug for 50% of the...
, which is the same except that TD50 (median toxic dose) is used in place of LD50. For many substances, toxic effects can occur at levels far below those needed to cause death, and thus the protective index (if toxicity is properly specified) is often more informative about a substance's relative safety. Nevertheless, the therapeutic index is still useful as it can be considered an upper bound
Upper bound
In mathematics, especially in order theory, an upper bound of a subset S of some partially ordered set is an element of P which is greater than or equal to every element of S. The term lower bound is defined dually as an element of P which is lesser than or equal to every element of S...
for the protective index, and the former also has the advantages of objectivity and easier comprehension.
See also
- Certain safety factorCertain safety factorThe Certain Safety Factor is the ratio of the lethal dose to 1% of population to the effective dose to 99% of the population . This is a better safety index than the LD50 for materials that have both desirable and undesirable effects, because it factors in the ends of the spectrum where doses may...
- Effective doseEffective doseEffective dose may refer to:*Effective dose the dose of pharmacologic agent which will have a therapeutic effect in some fraction of the population receiving the drug...
- EC50EC50The term half maximal effective concentration refers to the concentration of a drug, antibody or toxicant which induces a response halfway between the baseline and maximum after some specified exposure time...
- IC50IC50The half maximal inhibitory concentration is a measure of the effectiveness of a compound in inhibiting biological or biochemical function. This quantitative measure indicates how much of a particular drug or other substance is needed to inhibit a given biological process by half...
- Therapeutic windowTherapeutic windowThe Therapeutic window of a drug is the range of drug dosages which can treat disease effectively while staying within the safety range. In other words, it is the dosages of a medication between the amount that gives an effect and the amount that gives more adverse effects than desired effects...