Pentoxyverine ( rINN) or carbetapentane is an

antitussive Cold medicines are a group of medications taken individually or in combination as a treatment for the symptoms of the common cold and similar conditions of the upper respiratory tract. The term encompasses a broad array of drugs, including ana ...

(cough suppressant) commonly used for cough associated with illnesses like

common cold The common cold, or the cold, is a virus, viral infectious disease of the upper respiratory tract that primarily affects the Respiratory epithelium, respiratory mucosa of the human nose, nose, throat, Paranasal sinuses, sinuses, and larynx. ...

. It is sold

over-the-counter Over-the-counter (OTC) drugs are medicines sold directly to a consumer without a requirement for a prescription from a healthcare professional, as opposed to prescription drugs, which may be supplied only to consumers possessing a valid pres ...

as Solotuss, or in combination with other medications, especially

decongestant A decongestant, or nasal decongestant, is a type of pharmaceutical drug that is used to relieve nasal congestion in the upper respiratory tract. The active ingredient in most decongestants is either pseudoephedrine or phenylephrine (the latter o ...

s. One such product is ''Certuss'', a combination of

guaifenesin Guaifenesin, also known as glyceryl guaiacolate, sold under the brand name Mucinex, among others, is an expectorant medication taken by mouth and marketed as an aid to eliminate sputum from the respiratory tract. Chemically, it is an ether of ...

and pentoxyverine. The drug has been available in the form of drops, suspensions and

suppositories A suppository is a dosage form used to deliver pharmaceutical drug, medications by insertion into a body orifice (any opening in the body), where it dissolves or melts to exert local or systemic effects. There are three types of suppositories, eac ...

. It was formerly available over-the-counter in United States. However, the U.S. Food & Drug Administration ruled in 1987 that pentoxyverine was not generally recognized as safe and effective and ordered it to be removed from the over-the-counter market.

Uses

The drug is used for the treatment of dry cough associated with conditions such as common cold,

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. ...

sinusitis Sinusitis, also known as rhinosinusitis, is an inflammation of the mucous membranes that line the sinuses resulting in symptoms that may include production of thick nasal mucus, nasal congestion, facial congestion, facial pain, facial pressure ...

. Like

codeine Codeine is an opiate and prodrug of morphine mainly used to treat pain, coughing, and diarrhea. It is also commonly used as a recreational drug. It is found naturally in the sap of the opium poppy, ''Papaver somniferum''. It is typically use ...

and other antitussives, it relieves the symptom, but does not heal the illness. No controlled

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

s regarding the efficiency of pentoxyverine are available.

Pharmacologist Pharmacology is the science of drugs and medications, including a substance's origin, composition, pharmacokinetics, pharmacodynamics, therapeutic use, and toxicology. More specifically, it is the study of the interactions that occur between ...

s use the substance as a selective

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

at the

sigma-1 receptor The sigma-1 receptor (σ1R), one of two sigma receptor subtypes, is a Chaperone (protein), chaperone protein at the endoplasmic reticulum (ER) that modulates calcium signaling through the IP3 receptor. In humans, the σ1 receptor is encoded by ...

in animal and

in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...

experiments.

Contraindications

Pentoxyverine is contraindicated in persons with bronchial asthma or other kinds of

respiratory insufficiency Respiratory failure results from inadequate gas exchange by the respiratory system, meaning that the arterial oxygen, carbon dioxide, or both cannot be kept at normal levels. A drop in the oxygen carried in the blood is known as hypoxemia; a r ...

(breathing difficulties), as well as angle-closure

glaucoma Glaucoma is a group of eye diseases that can lead to damage of the optic nerve. The optic nerve transmits visual information from the eye to the brain. Glaucoma may cause vision loss if left untreated. It has been called the "silent thief of ...

. No data are available for the use of pentoxyverine during pregnancy,

lactation Lactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process naturally occurs with all sexually mature female mammals, although it may predate mammals. The process ...

, or children under two years of age, wherefore the drug must not be used under these circumstances. Antitussive drugs are not useful in patients with extensive

phlegm Phlegm (; , ''phlégma'', "inflammation", "humour caused by heat") is mucus produced by the respiratory system, excluding that produced by the throat nasal passages. It often refers to respiratory mucus expelled by coughing, otherwise known as ...

production because they prevent coughing up the phlegm.

Adverse effects

The most common side effects (seen in more than 1% of patients) are upper abdominal (belly) pain, diarrhoea, dry mouth, and nausea or vomiting.

Allergic reaction Allergies, also known as allergic diseases, are various conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include Allergic rhinitis, hay fever, Food allergy, food al ...

s of the skin like itching, rashes,

hives 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 ...

and angiooedema are rare. The same is true for anaphylactic shock and

convulsion A convulsion is a medical condition where the body muscles contract and relax rapidly and repeatedly, resulting in uncontrolled shaking. Because epileptic seizures typically include convulsions, the term ''convulsion'' is often used as a synony ...

Overdose

Overdosage leads to drowsiness, agitation, nausea and

anticholinergic Anticholinergics (anticholinergic agents) are substances that block the action of the acetylcholine (ACh) neurotransmitter at synapses in the central nervous system, central and peripheral nervous system. These agents inhibit the parasympatheti ...

effects like

tachycardia Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal ...

(high heart rate), dry mouth, blurred vision, glaucoma, or

urinary retention Urinary retention is an inability to completely empty the bladder. Onset can be sudden or gradual. When of sudden onset, symptoms include an inability to urinate and lower abdominal pain. When of gradual onset, symptoms may include urinary incont ...

. Especially in children, pentoxyverine can cause

hypoventilation Hypoventilation (also known as respiratory depression) occurs when ventilation is inadequate (''hypo'' meaning "below") to perform needed respiratory gas exchange. By definition it causes an increased concentration of carbon dioxide ( hypercap ...

, but much more seldom than codeine and other

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, ...

antitussives. The treatment of overdosage aims at the symptoms; there are no specific

antidote An antidote is a substance that can counteract a form of poisoning. The term ultimately derives from the Greek term φάρμακον ἀντίδοτον ''(pharmakon antidoton)'', "(medicine) given as a remedy". An older term in English which is ...

s available.

Interactions

No interactions have been described at usual doses. It is possible that pentoxyverine can increase the potency of sedative drugs like

benzodiazepine Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...

s, some

anticonvulsant Anticonvulsants (also known as antiepileptic drugs, antiseizure drugs, or anti-seizure medications (ASM)) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also used in the treatme ...

s and

antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...

s, and alcohol. Likewise, some consumer informations warn patients from taking the drug in combination with or up to two weeks after

monoamine oxidase inhibitor Monoamine oxidase inhibitors (MAOIs) are a drug class, 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 antidepressa ...

s, which are known to cause potentially fatal reactions in combination with the (chemically only distantly related) antitussive

dextromethorphan Dextromethorphan, sold under the brand name Robitussin among others, is a cough suppressant used in many cough and Common cold, cold medicines. In 2022, the US Food and Drug Administration (FDA) approved the combination dextromethorphan/bupropi ...

Mechanism of action

Pentoxyverine is believed to suppress the

cough reflex The cough reflex occurs when stimulation of cough receptors in the respiratory tract by dust or other foreign particles produces a cough, which causes rapidly moving air which usually remove the foreign material before it reaches the lungs. This ...

in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

, but the exact mechanism of action is not known with certainty. The drug acts as an

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.muscarinic receptors Muscarinic acetylcholine receptors (mAChRs) are acetylcholine receptors that form G protein-coupled receptor complexes in the cell membranes of certain neurons and other cells. They play several roles, including acting as the main end-recep ...

(subtype M₁) and as an agonist at

sigma receptor Sigma receptors (σ-receptors) are protein receptors that bind ligands such as 4-PPBP (4-phenyl-1-(4-phenylbutyl) piperidine), SA 4503 (cutamesine), ditolylguanidine, dimethyltryptamine, and siramesine. There are two subtypes, sigma-1 rec ...

s (subtype σ₁) with an IC₅₀ of 9 nM. Its

properties can theoretically relax the

pulmonary alveoli A pulmonary alveolus (; ), also called an air sac or air space, is one of millions of hollow, distensible cup-shaped cavities in the lungs where pulmonary gas exchange takes place. Oxygen is exchanged for carbon dioxide at the blood–air bar ...

and reduce phlegm production. Spasmolytic and local anaesthetic properties have also been described. The clinical relevance of these mechanisms is uncertain.

Pharmacokinetics

The substance is absorbed quickly from the gut and reaches its maximum plasma concentration (C_max) after about two hours. If applied rectally, C_max is reached after four hours. The

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%. H ...

of the suppositories, measured as area under the curve (AUC), is about twofold that of oral formulations, due to a

first pass effect The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism at a specific location in the body which leads to a reduction in the concentration of the active drug before it reaches the ...

of over 50%. By far the most important metabolisation reaction is ester hydrolysis, which accounts for 26.3% of the total clearance through the kidneys. Only 0.37% are cleared in form of the original substance. The plasma half life is 2.3 hours for oral formulations and three to 3.5 hours for suppositories. Pentoxyverine is also excreted into the

breast milk Breast milk (sometimes spelled as breastmilk) or mother's milk is milk produced by the mammary glands in the breasts of women. Breast milk is the primary source of nutrition for newborn infants, comprising fats, proteins, carbohydrates, and a var ...

Chemical properties

Pentoxyverine dihydrogen

citrate Citric acid is an organic compound with the formula . It is a colorless weak organic acid. It occurs naturally in citrus fruits. In biochemistry Biochemistry, or biological chemistry, is the study of chemical processes within and relati ...

, the salt that is commonly used for oral preparations, is a white to off-white, crystalline powder. It dissolves easily in water or

chloroform Chloroform, or trichloromethane (often abbreviated as TCM), is an organochloride with the formula and a common solvent. It is a volatile, colorless, sweet-smelling, dense liquid produced on a large scale as a precursor to refrigerants and po ...

, but not in

benzene Benzene is an Organic compound, organic chemical compound with the Chemical formula#Molecular formula, molecular formula C6H6. The benzene molecule is composed of six carbon atoms joined in a planar hexagonal Ring (chemistry), ring with one hyd ...

diethyl ether Diethyl ether, or simply ether, is an organic compound with the chemical formula , sometimes abbreviated as . It is a colourless, highly Volatility (chemistry), volatile, sweet-smelling ("ethereal odour"), extremely flammable liquid. It belongs ...

, or

petroleum ether Petroleum ether is the petroleum fraction consisting of aliphatic hydrocarbons and boiling in the range 35–60 °C, and commonly used as a laboratory solvent. Despite the name, petroleum ether is not an ether; the term is used only figurativ ...

. It melts at . Other orally available salts are the

hydrochloride In chemistry, a hydrochloride is an acid salt resulting, or regarded as resulting, from the reaction of hydrochloric acid with an organic base (e.g. an amine). An alternative name is chlorhydrate, which comes from French. An archaic alternati ...

and the tannate; suppositories contain the free base.

References

{{Sigma receptor modulators Antitussives Carboxylate esters Ethers Diethylamino compounds Sigma agonists Cyclopentanes