Entacapone, sold under the brand name Comtan among others, is a medication commonly used in combination with other medications for the treatment of
Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
.
Entacapone together with
levodopa and
carbidopa
Carbidopa (Lodosyn) is a drug given to people with Parkinson's disease in order to inhibit peripheral metabolism of levodopa. This property is significant in that it allows a greater proportion of administered levodopa to cross the blood–br ...
allows levodopa to have a longer effect in the brain and reduces Parkinson's disease
signs and symptoms for a greater length of time than levodopa and carbidopa therapy alone.
Entacapone is a selective and
reversible inhibitor
An enzyme inhibitor is a molecule that binds to an enzyme and blocks its activity. Enzymes are proteins that speed up chemical reactions necessary for life, in which substrate molecules are converted into products. An enzyme facilitates a sp ...
of the enzyme
catechol-''O''-methyltransferase (COMT).
When taken together with levodopa (
L-DOPA) and carbidopa, entacapone stops catechol-''O''-methyltransferase from breaking down and
metabolizing
Metabolism (, from el, μεταβολή ''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 cell ...
levodopa, resulting in an overall increase of levodopa remaining in the brain and body.
Carbidopa/levodopa/entacapone
Carbidopa/levodopa/entacapone, sold under the brand name Stalevo among others, is a dopaminergic fixed-dose combination medication that contains carbidopa, levodopa, and entacapone for the treatment of Parkinson's disease. It is marketed by Swis ...
(Stalevo), a medication developed by
Orion Pharma and marketed by
Novartis
Novartis AG is a Swiss-American multinational pharmaceutical corporation based in Basel, Switzerland and
Cambridge, Massachusetts, United States (global research).name="novartis.com">https://www.novartis.com/research-development/research-loc ...
, is a single tablet
formulation that contains levodopa, carbidopa, and entacapone.
Medical uses
Entacapone is used
in addition to levodopa and carbidopa for people with Parkinson's disease to treat the signs and symptoms of end-of-dose "wearing-off."
"Wearing-off" is characterized by the re-appearance of both
motor
An engine or motor is a machine designed to convert one or more forms of energy into mechanical energy.
Available energy sources include potential energy (e.g. energy of the Earth's gravitational field as exploited in hydroelectric power g ...
and
non-motor symptoms of Parkinson's disease occurring towards the end of a previous levodopa and carbidopa dose.
In clinical trials, entacapone has not been shown to slow progression or reverse Parkinson's disease.
Entacapone is an
orally active drug that can be taken with or without food.
Pregnancy and breastfeeding
Pregnancy category C: risk is not ruled out.
Although there have been animal studies that showed that entacapone was
excreted
Excretion is a process in which metabolic waste
is eliminated from an organism. In vertebrates this is primarily carried out by the lungs, kidneys, and skin. This is in contrast with secretion, where the substance may have specific tasks after lea ...
into maternal rat milk, there have been no studies with
human breast milk. Caution is advised for mothers taking entacapone while breastfeeding or during pregnancy.
Children
Entacapone safety and efficacy have not been assessed in
infants or children.
Liver problems
Biliary
A bile duct is any of a number of long tube-like structures that carry bile, and is present in most vertebrates.
Bile is required for the digestion of food and is secreted by the liver into passages that carry bile toward the hepatic duct. It ...
excretion is the major route of
excretion
Excretion is a process in which metabolic waste
is eliminated from an organism. In vertebrates this is primarily carried out by the lungs, kidneys, and skin. This is in contrast with secretion, where the substance may have specific tasks after ...
for entacapone. People with liver dysfunction may require additional caution and more frequent liver function monitoring while taking entacapone.
Kidney problems
There are no significant considerations for people with poor kidney function taking entacapone.
Contraindications
There is a high risk for allergic reactions for people who are hypersensitive to entacapone.
Potential limiting conditions to consider before starting entacapone include:
* History of
allergic reaction
Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derma ...
to entacapone
* History of
liver disease
Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common.
Signs and symptoms
Some of the si ...
,
liver dysfunction
Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common.
Signs and symptoms
Some of the s ...
, or
alcoholism
Alcoholism is, broadly, any drinking of alcohol that results in significant mental or physical health problems. Because there is disagreement on the definition of the word ''alcoholism'', it is not a recognized diagnostic entity. Predomi ...
* Current or planned
pregnancy
Pregnancy is the time during which one or more offspring develops (gestation, gestates) inside a woman, woman's uterus (womb). A multiple birth, multiple pregnancy involves more than one offspring, such as with twins.
Pregnancy usually occur ...
* Current or planned
surgeries
Side effects
The following
side effects
In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...
have been reported by people with Parkinson's disease treated with entacapone:
* Abdominal pain
* Nausea
* Vomiting
* Fatigue
* Dry mouth
* Back ache
Movement problems
The most common side effect of entacapone is movement problems, which occur in 25% of people taking entacapone.
This drug may cause or worsen
dyskinesia
Dyskinesia refers to a category of movement disorders that are characterized by involuntary muscle movements, including movements similar to tics or chorea and diminished voluntary movements. Dyskinesia can be anything from a slight tremor of ...
for people with Parkinson's disease treated together with levodopa and carbidopa.
In particular, "
peak-dose dyskinesias" may occur when levodopa levels are at its
peak concentration in the
serum plasma.
Diarrhea
10% of patients taking entacapone have been shown to experience
diarrhea
Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin w ...
.
Diarrhea may occur within 4–12 weeks of initial entacapone use but resolves after discontinuation of the drug. Use of entacapone in the presence of diarrhea can also be associated with
weight loss
Weight loss, in the context of medicine, health, or physical fitness, refers to a reduction of the total body mass, by a mean loss of fluid, body fat ( adipose tissue), or lean mass (namely bone mineral deposits, muscle, tendon, and other co ...
, low
potassium
Potassium is the chemical element with the symbol K (from Neo-Latin ''kalium'') and atomic number19. Potassium is a silvery-white metal that is soft enough to be cut with a knife with little force. Potassium metal reacts rapidly with atmosph ...
levels, and
dehydration
In physiology, dehydration is a lack of total body water, with an accompanying disruption of metabolic processes. It occurs when free water loss exceeds free water intake, usually due to exercise, disease, or high environmental temperature. Mil ...
.
In clinical studies, severe diarrhea was the most common reason for discontinuation of entacapone.
Urine color
10% of people taking entacapone experience a change in urine color to orange, red, brown, or black. This side effect is due to entacapone metabolism and excretion in the urine and shown to not be harmful.
Sudden sleep onset
People have reported
sudden sleep onset while engaging in daily activities without prior warning of drowsiness. In controlled studies, patients on entacapone had a 2% increased risk of
somnolence
Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...
compared to
placebo
A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures.
In general, placebos can af ...
.
Low blood pressure
Episodes of
orthostatic hypotension
Orthostatic hypotension, also known as postural hypotension, is a medical condition wherein a person's blood pressure drops when standing up or sitting down. Primary orthostatic hypertension is also often referred to as neurogenic orthostatic hyp ...
have been shown to be more common at the start of entacapone use due to increased levels of levodopa.
Behavior problems
Post-marketing data shows that entacapone may change or worsen
mental status
The mental status examination (MSE) is an important part of the clinical assessment process in neurological and psychiatric practice. It is a structured way of observing and describing a patient's psychological functioning at a given point in ...
, leading to behaviors such as
delusion
A delusion is a false fixed belief that is not amenable to change in light of conflicting evidence. As a pathology, it is distinct from a belief based on false or incomplete information, confabulation, dogma, illusion, hallucination, or som ...
s, agitation, confusion, and
delirium.
People taking entacapone may experience increased urges to participate in gambling, sexual activities, money spending, and other stimulating reward behaviors.
Interactions
In studies, entacapone has shown a low potential for interaction with other drugs. In theory, it could interact with
MAO inhibitor
Monoamine oxidase inhibitors (MAOIs) are a class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressants, espec ...
s,
tricyclic antidepressant
Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants, which is important for the management of depression. They are second-line drugs next to SSRIs. TCAs were discovered in the early 1950s and wer ...
s and
noradrenaline reuptake inhibitors because they also increase
catecholamine
A catecholamine (; abbreviated CA) is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine.
Catechol can be either a free molecule or a su ...
levels in the body, with drugs being metabolized by COMT (for example
methyldopa
Methyldopa, sold under the brand name Aldomet among others, is a medication used for high blood pressure. It is one of the preferred treatments for high blood pressure in pregnancy. For other types of high blood pressure including very high blo ...
,
dobutamine
Dobutamine is a medication used in the treatment of cardiogenic shock (as a result of inadequate tissue perfusion) and severe heart failure. It may also be used in certain types of cardiac stress tests. It is given by IV only, as an injection in ...
,
apomorphine
Apomorphine, sold under the brand name Apokyn among others, is a type of aporphine having activity as a non- selective dopamine agonist which activates both D2-like and, to a much lesser extent, D1-like receptors. It also acts as an antag ...
,
adrenaline
Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands an ...
, and
isoprenaline
Isoprenaline, or isoproterenol (brand name: Isoprenaline Macure), is a medication used for the treatment of bradycardia (slow heart rate), heart block, and rarely for asthma. It is a non-selective β adrenoceptor agonist that is the isopropyla ...
), with iron because it could form
chelate
Chelation is a type of bonding of ions and molecules to metal ions. It involves the formation or presence of two or more separate coordinate bonds between a polydentate (multiple bonded) ligand and a single central metal atom. These ligands are ...
s, with substances binding to the same
albumin
Albumin is a family of globular proteins, the most common of which are the serum albumins. All the proteins of the albumin family are water-soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Albumins ...
site in the blood plasma (for example
diazepam
Diazepam, first marketed as Valium, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is commonly used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, insomnia, ...
and
ibuprofen), and with drugs being metabolized by the liver enzyme
CYP2C9
Cytochrome P450 family 2 subfamily C member 9 (abbreviated CYP2C9) is an enzyme protein. The enzyme is involved in metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, the prote ...
(for example
warfarin
Warfarin, sold under the brand name Coumadin among others, is a medication that is used as an anticoagulant (blood thinner). It is commonly used to prevent blood clots such as deep vein thrombosis and pulmonary embolism, and to prevent st ...
). None of the medications tested in studies have shown clinically relevant interactions, except perhaps warfarin for which a 13% (
CI90: 6–19%) increase in
INR was seen when combined with entacapone.
Pharmacology
Mechanism of action
Entacapone is a selective and reversible
inhibitor of catechol-''O''-methyltransferase (COMT).
COMT eliminates biologically active
catechol
Catechol ( or ), also known as pyrocatechol or 1,2-dihydroxybenzene, is a toxic organic compound with the molecular formula . It is the ''ortho'' isomer of the three isomeric benzenediols. This colorless compound occurs naturally in trace amoun ...
s present in
catecholamine
A catecholamine (; abbreviated CA) is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine.
Catechol can be either a free molecule or a su ...
s (
dopamine,
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' ...
, and
epinephrine) and their
hydroxylated
In chemistry, hydroxylation can refer to:
*(i) most commonly, hydroxylation describes a chemistry, chemical process that introduces a hydroxyl group () into an organic compound.
*(ii) the ''degree of hydroxylation'' refers to the number of OH gr ...
metabolites. When administered with a
decarboxylase inhibitor, COMT acts as the major metabolizing enzyme for levodopa and metabolizes it to
3-methoxy-4-hydroxy-L-phenylalanine (3-OMD) in the brain and in the
periphery
Periphery or peripheral may refer to:
Music
*Periphery (band), American progressive metal band
* ''Periphery'' (album), released in 2010 by Periphery
* "Periphery", a song from Fiona Apple's album '' The Idler Wheel...''
Gaming and entertainm ...
.
For the treatment of Parkinson's disease, entacapone is given as an adjunct to levodopa and an aromatic amino acid decarboxylase inhibitor,
carbidopa
Carbidopa (Lodosyn) is a drug given to people with Parkinson's disease in order to inhibit peripheral metabolism of levodopa. This property is significant in that it allows a greater proportion of administered levodopa to cross the blood–br ...
. Entacapone inhibits COMT in the periphery (but not, or at most marginally, in the brain
) and the metabolism of levodopa, thus increasing plasma levels of levodopa and causing more constant dopaminergic stimulation in order to reduce the
signs and symptoms presented in the disease.
Pharmacokinetics
Absorption
The time to highest blood plasma concentrations is approximately one hour. The substance undergoes extensive
first-pass metabolism
The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism whereby the concentration of a drug, specifically when administered orally, is greatly reduced before it reaches the system ...
. Absolute oral
bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation.
By definition, when a medication is administered intravenously, its bioavailability is 100%. Ho ...
(''F'') is 35%.
Distribution
The
volume of distribution
In pharmacology, the volume of distribution (VD, also known as apparent volume of distribution, literally, ''volume of dilution'') is the theoretical volume that would be necessary to contain the total amount of an administered drug at the same c ...
(V
d) after
intravenous injection is approximately 20 liters. 98% of the circulating entacapone is bound to serum
albumin
Albumin is a family of globular proteins, the most common of which are the serum albumins. All the proteins of the albumin family are water-soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Albumins ...
, which limits its
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 vari ...
into
tissues.
Metabolism and elimination
Entacapone is primarily metabolized to its
glucuronide
A glucuronide, also known as glucuronoside, is any substance produced by linking glucuronic acid to another substance via a glycosidic bond. The glucuronides belong to the glycosides.
Glucuronidation, the conversion of chemical compounds to glucu ...
in the liver, and 5% are converted into the
''Z''-isomer.
It has a
half-life
Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable at ...
of approximately 0.3–0.7 hours, with only 0.2% being excreted unchanged in the urine.
References
External links
*
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