Maropitant (
INN
Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...
;
trade name: Cerenia ), used as maropitant
citrate
Citric acid is an organic compound with the chemical formula HOC(CO2H)(CH2CO2H)2. It is a colorless weak organic acid. It occurs naturally in citrus fruits. In biochemistry, it is an intermediate in the citric acid cycle, which occurs in the ...
(
USAN
280px, "Samguk Sagi" Book 04. Silla's Records. In 512, Usan-guk(于山國)was Ulleungdo(鬱陵島)
Usan-guk, or the State of Usan, occupied Ulleung-do and the adjacent islands during the Korean Three Kingdoms period. According to th ...
), is a
neurokinin-1 (NK1) receptor antagonist developed by
Zoetis
Zoetis Inc. (/zō-EH-tis/) is an American drug company, the world's largest producer of medicine and vaccinations for pets and livestock. The company was a subsidiary of Pfizer, the world's largest drug maker, but with Pfizer's spinoff of its ...
specifically for the treatment of
motion sickness
Motion sickness occurs due to a difference between actual and expected motion. Symptoms commonly include nausea, vomiting, cold sweat, headache, dizziness, tiredness, loss of appetite, and increased salivation. Complications may rarely include de ...
and vomiting in dogs. It was approved by the FDA in 2007 for use in dogs
[Package Insert for Cerenia at Pfizer Animal Health (full detailed drug information)]
/ref> and in 2012 for cats.
Maropitant has mild pain-relieving, anti-anxiety
An anxiolytic (; also antipanic or antianxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxiet ...
and anti-inflammatory
Anti-inflammatory is the property of a substance or treatment that reduces inflammation or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs remedy pain by reducing inflammation as o ...
effects.
Veterinary uses
Injectable maropitant is used in dogs to treat and prevent acute vomiting
Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose.
Vomiting can be the result of ailments like food poisoning, gastroenteri ...
; tablets are used for preventing vomiting from a variety of causes, though it requires a higher dose to prevent vomiting from motion sickness
Motion sickness occurs due to a difference between actual and expected motion. Symptoms commonly include nausea, vomiting, cold sweat, headache, dizziness, tiredness, loss of appetite, and increased salivation. Complications may rarely include de ...
. The injectable version is also licensed for preventing and treating acute vomiting in cats.
Maropitant is effective in treating vomiting from a variety of causes, including gastroenteritis, chemotherapy
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemothe ...
, and kidney failure
Kidney failure, also known as end-stage kidney disease, 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 failure is classified as eit ...
; when given beforehand, it can prevent vomiting caused by using an opioid
Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid use ...
as a premedication
Premedication is using medication before some other therapy (usually surgery or chemotherapy) to prepare for that forthcoming therapy. Typical examples include premedicating with a sedative or analgesic before surgery; using prophylactic (prevent ...
. Some have claimed that maropitant is better at treating vomiting than nausea, pointing to cats with chronic kidney disease who, when receiving maropitant, had a reduction in vomiting but no corresponding increase in appetite.
Maropitant has been used in acute cases of rapid or labored breathing Labored respiration or labored breathing is an abnormal respiration characterized by evidence of increased effort to breathe, including the use of accessory muscles of respiration, stridor, grunting, or nasal flaring.
Classification
Labored breat ...
to prevent vomiting that could lead to aspiration pneumonia
Aspiration pneumonia is a type of lung infection that is due to a relatively large amount of material from the stomach or mouth entering the lungs. Signs and symptoms often include fever and cough of relatively rapid onset. Complications may inc ...
. It has been given in combination with a benzodiazepine to cats prior to stressful events (such as a veterinary visit) to possibly relieve hypersensitivity.
When compared to other antiemetic
An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer. They m ...
s, maropitant has similar or greater effectiveness to 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 di ...
and metoclopramide
Metoclopramide is a medication used for stomach and esophageal problems. It is commonly used to treat and prevent nausea and vomiting, to help with emptying of the stomach in people with delayed stomach emptying, and to help with gastroesoph ...
for centrally mediated vomiting induced by 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 ...
or xylazine
Xylazine is a pharmaceutical drug used for sedation, anesthesia, muscle relaxation, and analgesia in animals such as horses, cattle, and other non-human mammals. Veterinarians also use xylazine as an emetic, especially in cats. It is an anal ...
. It works better than chlorpromazine and metoclopramide for vomiting peripherally induced induced with syrup of ipecac
Syrup of ipecac (), or simply ipecac, is a drug that was once widely used as an expectorant (in low doses) and a rapid-acting emetic (in higher doses). It is obtained from the dried rhizome and roots of the ipecacuanha plant ('' Carapichea ipec ...
. Unlike dimenhydrinate
Dimenhydrinate, sold under the brand name Dramamine, among others, is an over-the-counter drug used to treat motion sickness and nausea. Dimenhydrinate is a theoclate salt composed of diphenhydramine, an ethanolamine derivative, and 8-chloroth ...
and acepromazine
Acepromazine, acetopromazine, or acetylpromazine (commonly known as ACP, Ace, or by the trade names Atravet or Acezine 2, number depending on mg/ml dose) is a phenothiazine derivative antipsychotic drug. It was used in humans during the 1950s a ...
, which are used for motion sickness, maropitant does not cause sedation.
Maropitant has been used as an adjunct treatment in severe bronchitis
Bronchitis is inflammation of the bronchi (large and medium-sized airways) in the lungs that causes coughing. Bronchitis usually begins as an infection in the nose, ears, throat, or sinuses. The infection then makes its way down to the bronchi. ...
due to its weak anti-inflammatory effects m. It alleviates visceral pain Visceral pain is pain that results from the activation of nociceptors of the thoracic, pelvic, or abdominal viscera (organs). Visceral structures are highly sensitive to distension (stretch), ischemia and inflammation, but relatively insensitive to ...
and has been found to reduce the amount of needed general anesthesia (both sevoflurane
Sevoflurane, sold under the brand name Sevorane, among others, is a sweet-smelling, nonflammable, highly fluorinated methyl isopropyl ether used as an inhalational anaesthetic for induction and maintenance of general anesthesia. After desflura ...
and isoflurane
Isoflurane, sold under the brand name Forane among others, is a general anesthetic. It can be used to start or maintain anesthesia; however, other medications are often used to start anesthesia rather than isoflurane, due to airway irritation w ...
) needed in some operations.
Some believe that maropitant can be used in rabbits and guinea pigs
The guinea pig or domestic guinea pig (''Cavia porcellus''), also known as the cavy or domestic cavy (), is a species of rodent belonging to the genus '' Cavia'' in the family Caviidae. Breeders tend to use the word ''cavy'' to describe the a ...
to relieve pain caused by ileus
Ileus is a disruption of the normal propulsive ability of the intestine. It can be caused by lack of peristalsis or by mechanical obstruction.
The word 'ileus' is from Ancient Greek ''eileós'' (, "intestinal obstruction"). The term 'subileus' ref ...
(impaired bowel movements), though it lacks antiemetic effects in rabbits, who cannot vomit.
Maropitant is given orally, subcutaneously
The subcutaneous tissue (), also called the hypodermis, hypoderm (), subcutis, superficial fascia, is the lowermost layer of the integumentary system in vertebrates. The types of cells found in the layer are fibroblasts, adipose cells, and macro ...
, and intravenously
Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...
.
Contraindications
Maropitant is only indicated for dogs at least 16 weeks old, as some very young puppies suffered bone marrow hypoplasia (incomplete development ). It should also not be used in animals with suspected GI obstruction or toxin ingestion.
It is not recommended to give maropitant for more than five consecutive days, as it tends to accumulate in the body due to one of the liver enzymes responsible for its metabolism, CYP2D15, becoming saturated. However, there have been studies where beagles
The beagle is a breed of small scent hound, similar in appearance to the much larger foxhound. The beagle was developed primarily for hunting hare, known as beagling. Possessing a great sense of smell and superior tracking instincts, the b ...
who were given maropitant for two weeks in a row showed no signs of toxicity.
Because maropitant is metabolized by the liver, caution should be taken when giving it to dogs with 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 ...
. Caution should also be taken when giving it with other drugs that are also highly protein-bound, such as NSAIDs, anticonvulsants, and some behavior-modifying drugs; such drugs compete with maropitant for binding to plasma proteins, increasing the concentration of unbound maropitant in the blood. Maropitant should also not be used with calcium channel antagonists (used to treat high blood pressure) or in animals with heart disease, as it has a slight affinity for calcium
Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar t ...
and potassium channels
Potassium channels are the most widely distributed type of ion channel found in virtually all organisms. They form potassium-selective pores that span cell membranes. Potassium channels are found in most cell types and control a wide variety of cel ...
.
Side effects
Maropitant is safer than other antiemetics used in veterinary medicine, in part because of its high specificity for its target and thus not binding to other receptors in the central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
. Side effects in dogs and cats include hypersalivation
Hypersalivation, or ptyalism, also known as sialorrhea or hypersialosis is the excessive production of saliva. It has also been defined as increased amount of saliva in the mouth, which may also be caused by decreased clearance of saliva.Medscape ...
, 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 ...
, loss of appetite
Anorexia is a medical term for a loss of appetite. While the term in non-scientific publications is often used interchangeably with anorexia nervosa, many possible causes exist for a loss of appetite, some of which may be harmless, while others i ...
, and vomiting
Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose.
Vomiting can be the result of ailments like food poisoning, gastroenteri ...
. Eight percent of dogs taking maropitant at doses meant to prevent motion sickness vomited right after, likely due to the local effects maropitant had on the gastrointestinal tract. Small amounts of food beforehand can prevent such post-administration vomiting.
One of the most common side effects of subcutaneous administration is moderate to severe pain at the injection site. Although the manufacturer recommends keeping maropitant at room temperature, many people have noted that keeping it in the fridge reduces the sting upon injection. Only unbound maropitant causes pain – it is normally formulated with beta-cyclodextrin to increase solubility; at cooler temperatures, more of the maropitant remains bound to the cyclodextrin, leaving less maropitant unbound.
While there is no pain related to the intravenous administration of maropitant, pushing a dose in too quickly can temporarily reduce blood pressure.
Fewer than 1 in 10,000 dogs and cats experience anaphylactic reactions.
Overdose
Signs of maropitant overdose include lethargy
Lethargy is a state of tiredness, sleepiness, weariness, fatigue, sluggishness or lack of energy. It can be accompanied by depression, decreased motivation, or apathy. Lethargy can be a normal response to inadequate sleep, overexertion, overwo ...
, irregular or labored breathing, lack of muscle coordination, and tremors. Overdose of the oral formulation can cause salivation and nasal discharge, while overdose of intravenous maropitant can sometimes lead to reddish urine. The LD50 is high, being over 2,000 mg/kg for oral maropitant in rats.
Pharmacology
Mechanism of action
Vomiting is caused when impulses from the chemoreceptor trigger zone
The chemoreceptor trigger zone (CTZ) is an area of the medulla oblongata that receives inputs from blood-borne drugs or hormones, and communicates with other structures in the vomiting center to initiate vomiting. The CTZ is located within the area ...
(CRTZ) in the brain are sent to the vomiting center
The area postrema, a paired structure in the medulla oblongata of the brainstem, is a circumventricular organ having permeable capillaries and sensory neurons that enable its dual role to detect circulating chemical messengers in the blood and ...
in the medulla
Medulla or Medullary may refer to:
Science
* Medulla oblongata, a part of the brain stem
* Renal medulla, a part of the kidney
* Adrenal medulla, a part of the adrenal gland
* Medulla of ovary, a stroma in the center of the ovary
* Medulla of t ...
. Motion sickness specifically occurs when signals to the CRTZ originate from the inner ear: motion is sensed by the fluid of the semicircular canals
The semicircular canals or semicircular ducts are three semicircular, interconnected tubes located in the innermost part of each ear, the inner ear. The three canals are the horizontal, superior and posterior semicircular canals.
Structure
The ...
, which causes overstimulation. The signal travels to the brain's vestibular nuclei
The vestibular nuclei (VN) are the cranial nuclei for the vestibular nerve located in the brainstem.
In Terminologia Anatomica they are grouped in both the pons and the medulla in the brainstem.
Structure Path
The fibers of the vestibular n ...
, then to the CRTZ, and finally to the vomiting center.
Maropitant has a similar structure to substance P
Substance P (SP) is an undecapeptide (a peptide composed of a chain of 11 amino acid residues) and a member of the tachykinin neuropeptide family. It is a neuropeptide, acting as a neurotransmitter and as a neuromodulator. Substance P and its clo ...
, the key neurotransmitter in causing vomiting, which allows it to act as an antagonist and bind to the substance P receptor neurokinin 1
The tachykinin receptor 1 (TACR1) also known as neurokinin 1 receptor (NK1R) or substance P receptor (SPR) is a G protein coupled receptor found in the central nervous system and peripheral nervous system. The endogenous ligand for this receptor ...
(NK1). It is highly selective for NK1 over NK2 and NK3. Maropitant binds to the neurokinin receptors in the vagus nerves leaving the GI tract, as well as to receptors in the CRTZ and the vomiting center. By virtue of working at the last step in triggering vomiting, it can prevent a broader range of stimuli than most antiemetics can. It is effective against emetogens that act at the central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
(such as 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 ...
in dogs and xylazine
Xylazine is a pharmaceutical drug used for sedation, anesthesia, muscle relaxation, and analgesia in animals such as horses, cattle, and other non-human mammals. Veterinarians also use xylazine as an emetic, especially in cats. It is an anal ...
in cats), those that act in the periphery (e.g. syrup of ipecac
Syrup of ipecac (), or simply ipecac, is a drug that was once widely used as an expectorant (in low doses) and a rapid-acting emetic (in higher doses). It is obtained from the dried rhizome and roots of the ipecacuanha plant ('' Carapichea ipec ...
), and those that act in both (e.g. cisplatin
Cisplatin is a chemotherapy medication used to treat a number of cancers. These include testicular cancer, ovarian cancer, cervical cancer, breast cancer, bladder cancer, head and neck cancer, esophageal cancer, lung cancer, mesothelioma, ...
).
Pharmacokinetics
Maropitant's 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 ...
is unaffected by the presence of food. Bioavailability is 91% at the standard subcutaneous dose but 24% at the standard oral dose; the standard oral dose is higher to partially compensate for incomplete bioavailability. It binds to plasma proteins at a rate of 99.5%; it has a low volume of distribution (9 L/kg) and is thus not extensively absorbed. Subcutaneously administered maropitant had peak plasma concentration around half an hour after administration; the mean half-life is 6–8 hours, and a single dose lasts 24 hours in dogs. Orally administered maropitant reached its peak plasma concentration within two hours.
Maropitant undergoes 1st-pass metabolism by liver enzymes, mainly CYP2D15 (which has high affinity for maropitant and clears over 90% of it) but also by the lower-affinity CYP3A12. Repeat dosing of maropitant eventually saturates CYP2D15, causing the drug to accumulate due to reduced clearance. Thus, it is recommended to not use maropitant for more than five days straight, and to have a two-day rest period to allow maropitant to clear the body to prevent accumulation. Maropitant has over 21 metabolites, though its major one (produced by hydroxylation) is CJ-18,518.
Maropitant clearance is slower in cats.
See also
* Ezlopitant (isopropyl instead of ''tert''-butyl)
References
External links
*
Cerenia: Product Information at Vet Label
FDA: Adverse Drug Experience (ADE) Reports: See Maropitant (multiple sections, p. 121-152)
{{Neurokinin receptor modulators
Cat medications
Dog medications
NK1 receptor antagonists
Phenol ethers
Quinuclidines
Tert-butyl compounds