Methenamine, also known as hexamine or hexamethylenetetramine and sold under the brand names Hiprex, Urex, and Urotropin among others, is a

urinary tract The human urinary system, also known as the urinary tract or renal system, consists of the kidneys, ureters, bladder, and the urethra. The purpose of the urinary system is to eliminate waste from the body, regulate blood volume and blood pressu ...

antiseptic An antiseptic ( and ) is an antimicrobial substance or compound that is applied to living tissue to reduce the possibility of sepsis, infection, or putrefaction. Antiseptics are generally distinguished from ''antibiotics'' by the latter's abil ...

and

antibacterial An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention ...

medication Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...

which is used in the

prevention Prevention may refer to: Health and medicine * Preventive healthcare, measures to prevent diseases or injuries rather than curing them or treating their symptoms General safety * Crime prevention, the attempt to reduce deter crime and crimin ...

of recurrent

urinary tract infection A urinary tract infection (UTI) is an infection that affects a part of the urinary tract. Lower urinary tract infections may involve the bladder (cystitis) or urethra (urethritis) while upper urinary tract infections affect the kidney (pyel ...

s (UTIs).
fda.gov] It is not an

antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting pathogenic bacteria, bacterial infections, and antibiotic medications are widely used in the therapy ...

, and unlike antibiotics, has no risk of

bacterial resistance Antimicrobial resistance (AMR or AR) occurs when microbes evolve mechanisms that protect them from antimicrobials, which are drugs used to treat infections. This resistance affects all classes of microbes, including bacteria (antibiotic resista ...

. Methenamine can reduce the risk of UTIs by 44 to 86% and has been found to be non-inferior to low-dose prophylactic antibiotics. It is taken

by mouth Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

. The drug is available both by prescription and at lower doses

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 ...

. Besides for UTI prevention, methenamine is also available in a

topical A topical medication is a medication that is applied to a particular place on or in the body. Most often topical medication means application to body surfaces such as the skin or mucous membranes to treat ailments via a large range of classes ...

form to treat

hyperhidrosis Hyperhidrosis is a medical condition in which a person exhibits excessive perspiration, sweating, more than is required for the Thermoregulation, regulation of body temperature. Although it is primarily a physical burden, hyperhidrosis can deterio ...

Side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s of methenamine are generally minor and include

upset stomach Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues. Since the abdomen contains most of the body's vital organs, it can be an indicator of a wide variety of diseases. Given th ...

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

, and

headache A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...

, among others. Methenamine is a

prodrug A prodrug is a pharmacologically inactive medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be ...

formaldehyde Formaldehyde ( , ) (systematic name methanal) is an organic compound with the chemical formula and structure , more precisely . The compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde. It is stored as ...

acid An acid is a molecule or ion capable of either donating a proton (i.e. Hydron, hydrogen cation, H+), known as a Brønsted–Lowry acid–base theory, Brønsted–Lowry acid, or forming a covalent bond with an electron pair, known as a Lewis ...

urine Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...

. Formaldehyde is a non-specific antiseptic and

bactericide A bactericide or bacteriocide, sometimes abbreviated Bcidal, is a substance which kills bacteria. Bactericides are disinfectants, antiseptics, or antibiotics. However, material surfaces can also have bactericidal properties based solely on their p ...

which works via denaturation of bacterial

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

s and

nucleic acid Nucleic acids are large biomolecules that are crucial in all cells and viruses. They are composed of nucleotides, which are the monomer components: a pentose, 5-carbon sugar, a phosphate group and a nitrogenous base. The two main classes of nuclei ...

s. Conversion of methenamine into formaldehyde only occurs in acidic environments and hence its actions show

selectivity Selectivity may refer to: Psychology and behaviour * Choice, making a selection among options * Discrimination, the ability to recognize differences * Socioemotional selectivity theory, in social psychology Engineering * Selectivity (radio), a ...

for tissues like the

bladder The bladder () is a hollow organ in humans and other vertebrates that stores urine from the kidneys. In placental mammals, urine enters the bladder via the ureters and exits via the urethra during urination. In humans, the bladder is a distens ...

and

stomach The stomach is a muscular, hollow organ in the upper gastrointestinal tract of Human, humans and many other animals, including several invertebrates. The Ancient Greek name for the stomach is ''gaster'' which is used as ''gastric'' in medical t ...

. Chemically, methenamine is a simple cyclized

hydrocarbon In organic chemistry, a hydrocarbon is an organic compound consisting entirely of hydrogen and carbon. Hydrocarbons are examples of group 14 hydrides. Hydrocarbons are generally colourless and Hydrophobe, hydrophobic; their odor is usually fain ...

and is similar in structure to

adamantane Adamantane is an organic compound with formula C10H16 or, more descriptively, (CH)4(CH2)6. Adamantane molecules can be described as the fusion of three cyclohexane rings. The molecule is both rigid and virtually stress-free. Adamantane is the mo ...

. Methenamine was discovered in 1859 and was first introduced for medical use as a urinary antiseptic in 1895. It was formally approved for medical use in the

United States The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...

in 1967. Though it became a "forgotten drug" following the discovery of antibiotics in 1928, there has been a resurgence in interest in methenamine since 2010 owing to increasing rates of bacterial resistance with antibiotics. Larger and higher-quality

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 of methenamine for UTI prevention have started to be published in the 2020s and it may soon be recommended by more

medical guideline A medical guideline (also called a clinical guideline, standard treatment guideline, or clinical practice guideline) is a document with the aim of guiding decisions and criteria regarding diagnosis, management, and treatment in specific areas of ...

s. Methenamine has been found to be more

cost-effective Cost-effectiveness analysis (CEA) is a form of economic analysis that compares the relative costs and outcomes (effects) of different courses of action. Cost-effectiveness analysis is distinct from cost–benefit analysis, which assigns a monetar ...

than low-dose prophylactic antibiotics for preventing UTIs.

Medical uses

Urinary tract infections

Methenamine is used in the treatment and

of recurrent

s (UTIs) requiring long-term therapy. It is approved and used in both adults and children at least 6years of age. The drug can also be used in special populations including older adults, people undergoing genitourinary

surgical procedures Many surgical procedure names can be broken into parts to indicate the meaning. For example, in gastrectomy, "ectomy" is a suffix meaning the removal of a part of the body. "Gastro-" means stomach. Thus, ''gastrectomy'' refers to the surgical rem ...

, people with long-term

catheterization In medicine, a catheter ( ) is a thin tube made from medical grade materials serving a broad range of functions. Catheters are medical devices that can be inserted in the body to treat diseases or perform a surgical procedure. Catheters are man ...

, and

kidney transplant Kidney transplant or renal transplant is the organ transplant of a kidney into a patient with end-stage kidney disease (ESRD). Kidney transplant is typically classified as deceased-donor (formerly known as cadaveric) or living-donor transplantat ...

recipients. It has not been studied in

neonate In common terminology, a baby is the very young offspring of adult human beings, while infant (from the Latin word ''infans'', meaning 'baby' or 'child') is a formal or specialised synonym. The terms may also be used to refer to Juvenile (orga ...

s or

infant In common terminology, a baby is the very young offspring of adult human beings, while infant (from the Latin word ''infans'', meaning 'baby' or 'child') is a formal or specialised synonym. The terms may also be used to refer to juveniles of ...

s. Methenamine is employed as an alternative to

s. The drug is not used in the curative treatment of UTIs and should be started only after bacterial eradication by appropriate antimicrobial agents. As it is an

and not an antibiotic, methenamine has no risk of promoting

. Studies have administered continuous methenamine therapy usually for 12months or less, but in some studies for as long as 2 to 10years. A 2012

Cochrane review Cochrane is a British international charitable organisation formed to synthesize medical research findings to facilitate evidence-based choices about health interventions involving health professionals, patients and policy makers. It includes ...

found that methenamine was effective in the prevention of UTIs. The

relative risk The relative risk (RR) or risk ratio is the ratio of the probability of an outcome in an exposed group to the probability of an outcome in an unexposed group. Together with risk difference and odds ratio, relative risk measures the association bet ...

symptomatic Signs and symptoms are diagnostic indications of an illness, injury, or condition. Signs are objective and externally observable; symptoms are a person's reported subjective experiences. A sign for example may be a higher or lower temperature ...

UTI was 0.24 and of

bacteriuria Bacteriuria is the presence of bacteria in urine. Bacteriuria accompanied by symptoms is a urinary tract infection while that without is known as asymptomatic bacteriuria. Diagnosis is by urinalysis or urine culture. ''Escherichia coli'' is the ...

was 0.56. In the case of short-term treatment (≤1week), the relative risk of symptomatic UTI was 0.14. On the other hand, methenamine was not effective in reducing the risk of symptomatic UTI or bacteriuria in people with known renal tract abnormalities or

neurogenic bladder Neurogenic bladder dysfunction, often called by the shortened term neurogenic bladder, was technically termed neurogenic lower urinary tract dysfunction by the International Continence Society. It refers to urinary bladder problems due to disease o ...

. The

quality of evidence Evidence-based medicine (EBM) is "the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients. It means integrating individual clinical expertise with the best available exte ...

was mixed and often poor. A subsequent large

randomized controlled trial A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical ...

(RCT), the "ALternatives To prophylactic Antibiotics for the treatment of Recurrent urinary tract infection in women" (ALTAR) trial, was conducted by the

United Kingdom The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom (UK) or Britain, is a country in Northwestern Europe, off the coast of European mainland, the continental mainland. It comprises England, Scotlan ...

National Health Service The National Health Service (NHS) is the term for the publicly funded health care, publicly funded healthcare systems of the United Kingdom: the National Health Service (England), NHS Scotland, NHS Wales, and Health and Social Care (Northern ...

(NHS). This study, published in 2022, reported that methenamine (hippurate) was non-inferior to daily low-dose antibiotics for prevention of UTIs. The antibiotics used in the study included

nitrofurantoin Nitrofurantoin, sold under the brand name Macrobid among others, is an antibacterial medication of the nitrofuran class used to treat urinary tract infections (UTIs), although it is not as effective for kidney infections. It is taken by mouth ...

trimethoprim Trimethoprim (TMP) is an antibiotic used mainly in the treatment of bladder infections. Other uses include for middle ear infections and travelers' diarrhea. With sulfamethoxazole or dapsone it may be used for ''Pneumocystis'' pneumonia ...

, and

cephalexin Cefalexin, also spelled cephalexin, is an antibiotic that can treat a number of bacterial infections. It kills gram-positive bacteria, gram-positive and some gram-negative bacteria by disrupting the growth of the bacterial cell wall. Cefalexi ...

. There was a small and non-significant numerical advantage of antibiotics over methenamine in this trial (~0.5 fewer UTIs per year), but this difference was deemed of limited clinical consequence and was considered to be outweighed by the advantages of methenamine. UTI-free rates over 12months were 43% with methenamine and 54% with antibiotics. Besides effectiveness in terms of UTI prevention, methenamine demonstrated lower rates of bacterial resistance relative to antibiotic therapy in this trial and in other studies. A 2024

systematic review A systematic review is a scholarly synthesis of the evidence on a clearly presented topic using critical methods to identify, define and assess research on the topic. A systematic review extracts and interprets data from published studies on ...

found that methenamine was non-inferior to antibiotic prophylaxis in the prevention of UTIs in two comparative prospective

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

, including the ALTAR trial. Other, older studies found that methenamine was inferior to antibiotics including

trimethoprim/sulfamethoxazole Trimethoprim/sulfamethoxazole, sold under the trade names Bactrim, Cotrim (a short form of the British Approved Name, Co-trimoxazole) and Septra, among others, is a fixed-dose combination antibiotic medication used to treat a variety of bacte ...

, trimethoprim, and nitrofurantoin in preventing or suppressing current UTIs, but these studies were of lower quality. Additional large and high-quality

s of methenamine for UTI prevention are needed as of 2024. More studies are also needed in special populations like older adults. Another large RCT of methenamine for UTI prevention, the international

European European, or Europeans, may refer to: In general * ''European'', an adjective referring to something of, from, or related to Europe ** Ethnic groups in Europe ** Demographics of Europe ** European cuisine, the cuisines of Europe and other West ...

ImpresU trial in older women, which is comparing methenamine to

placebo A placebo ( ) can be roughly defined as a sham medical treatment. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures. Placebos are used in randomized clinical trials ...

instead of against antibiotics, is underway as of 2022. Methenamine is not widely recommended by

s for UTI prevention as of 2022. However, this is expected to change in the near future due to the publication of the ALTAR trial and other new high-quality clinical trials. In addition to prescription methenamine, a lower-dose combination formulation of methenamine with the

nonsteroidal anti-inflammatory drug Non-steroidal anti-inflammatory drugs (NSAID) are members of a Indication (medicine), therapeutic drug class which Analgesic, reduces pain, Anti-inflammatory, decreases inflammation, Antipyretic, decreases fever, and Antithrombotic, prevents bl ...

(NSAID)

sodium salicylate Sodium salicylate is a sodium salt of salicylic acid. It can be prepared from sodium phenolate and carbon dioxide under higher temperature and pressure. Historically, it has been synthesized by refluxing methyl salicylate (wintergreen oil) with ...

is available

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 ...

under brand names like Cystex for treatment and prevention of UTI symptoms. This formulation is much less-studied than prescription methenamine and little data are available to inform its use. Methenamine is provided mainly as methenamine hippurate (the

hippuric acid Hippuric acid (Greek language, Gr. ''hippos'', horse, ''ouron'', urine) is a carboxylic acid and organic compound. It is found in urine and is formed from the combination of benzoic acid and glycine. Levels of hippuric acid rise with the consumpt ...

salt In common usage, salt is a mineral composed primarily of sodium chloride (NaCl). When used in food, especially in granulated form, it is more formally called table salt. In the form of a natural crystalline mineral, salt is also known as r ...

) or methenamine mandelate (the

mandelic acid Mandelic acid is an aromatic alpha hydroxy acid with the molecular formula C6H5CH(OH)CO2H. It is a white crystalline solid that is soluble in water and polar organic solvents. It is a useful precursor to various drugs. The molecule is chiral. The ...

salt). The drug is taken twice daily in the case of methenamine hippurate and four times daily in the case of methenamine mandelate. Methenamine hippurate is more popular and commonly used owing to its more convenient dosing schedule. Methenamine is taken three times daily in the case of formulations in which low-dose methenamine

free base In chemistry, a free base (freebase, free-base) is a term for the neutral form of an amine or other Lewis base. The term is used in the pharmaceutical industry in contrast to salt-based formulations like hydrochlorides. The amine is often an ...

is combined with sodium salicylate. The dosing schedule of methenamine is less convenient than once-daily low-dose prophylactic antibiotics.

Other genitourinary infections

Methenamine is converted into

only in acidic environments like the urinary

and hence is not expected to be effective in the eradicative treatment of

pyelonephritis Pyelonephritis is inflammation of the kidney, typically due to a bacterial infection. Symptoms most often include fever and flank tenderness. Other symptoms may include nausea, burning with urination, and frequent urination. Complications ...

(kidney infection) or

chronic bacterial prostatitis Chronic bacterial prostatitis (CBP) is a bacterial infection of the prostate gland and a form of prostatitis (prostate inflammation). It should be distinguished from other forms of prostatitis such as acute bacterial prostatitis (ABP) and chro ...

. As a result, it is not recommended for such indications. However, methenamine may help to prevent pyelonephritis and hospitalization by preventing UTIs that can lead to these complications. In addition, in men with persistent or recurring chronic bacterial prostatitis, prophylactic methenamine may be useful as an alternative to low-dose prophylactic antibiotics in preventing prostatitis-derived UTIs and managing associated symptoms. Prophylactic low-dose methenamine combined with an

ascorbic acid Ascorbic acid is an organic compound with formula , originally called hexuronic acid. It is a white solid, but impure samples can appear yellowish. It dissolves freely in water to give mildly acidic solutions. It is a mild reducing agent. Asco ...

(vitamin C) supplement has been reported to be effective for this purpose based on

clinical experience Anecdotal evidence (or anecdata) is evidence based on descriptions and reports of individual, personal experiences, or observations, collected in a non-systematic manner. The term ''anecdotal'' encompasses a variety of forms of evidence. This w ...

. In any case, supporting data for this use are lacking as of 2020.

Excessive sweating

Methenamine, in a

cream Cream is a dairy product composed of the higher-fat layer skimmed from the top of milk before homogenization. In un-homogenized milk, the fat, which is less dense, eventually rises to the top. In the industrial production of cream, this proces ...

or gel stick formulation sold under brand names like Antihydral and Dehydral, is used in the treatment of

(excessive sweating) and has been reported to be clinically effective for this indication. The skin is slightly

ic and formaldehyde can be released from methenamine in this environment.

Available forms

Methenamine is provided in the form of 500 and 1,000mg

oral The word oral may refer to: Relating to the mouth * Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid **Oral administration of medicines ** Oral examination (also known as an oral exam or ora ...

tablets. It is available both alone and in

combination In mathematics, a combination is a selection of items from a set that has distinct members, such that the order of selection does not matter (unlike permutations). For example, given three fruits, say an apple, an orange and a pear, there are ...

with the

(NSAID)

. Other combinations with other drugs, such as

phenazopyridine Phenazopyridine is a medication which, when excreted by the kidneys into the urine, has a local analgesic effect on the urinary tract. It is often used to help with the pain, irritation, or urgency caused by urinary tract infections, surger ...

, are also available. Methenamine is provided pharmaceutically alone as the

(methenamine hippurate) and

(methenamine mandelate)

s. The

and other salts, including anhydromethylencitrate and sulfosalicylate, have also been marketed in some countries. Methenamine mandelate is provided as an enteric coated tablet and is taken four times daily, whereas methenamine hippurate is available only in non-coated tablet form and is taken twice daily. Non-coated methenamine tablets can have a chemical taste described as sweet, sour, and/or metallic. Methenamine is available both by prescription (by itself) and

(in combinations). Over-the-counter formulations in combination with sodium salicylate (162.5mg) contain a lower amount of methenamine of 162mg methenamine free base per tablet compared to prescription formulations and are taken three times daily.

Contraindications

The

safety Safety is the state of being protected from harm or other danger. Safety can also refer to the control of recognized hazards in order to achieve an acceptable level of risk. Meanings The word 'safety' entered the English language in the 1 ...

of methenamine in people with

renal impairment 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 ...

is unknown and it is considered to be

contraindicated In medicine, a contraindication is a condition (a situation or factor) that serves as a reason not to take a certain medical treatment due to the harm that it would cause the patient. Contraindication is the opposite of indication, which is a rea ...

in this context. Other contraindications include severe

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. Liver diseases File:Ground gla ...

or hepatic impairment, known

hypersensitivity Hypersensitivity (also called hypersensitivity reaction or intolerance) is an abnormal physiological condition in which there is an undesirable and adverse immune response to an antigen. It is an abnormality in the immune system that causes Imm ...

to methenamine or the drug formulation's components, severe

dehydration In physiology, dehydration is a lack of total body water that disrupts metabolic processes. It occurs when free water loss exceeds intake, often resulting from excessive sweating, health conditions, or inadequate consumption of water. Mild deh ...

hyperphosphatemia Hyperphosphatemia is an electrolyte disorder in which there is an elevated level of phosphate in the blood. Most people have no symptoms while others develop calcium deposits in the soft tissue. The disorder is often accompanied by low calci ...

, and use of

sulfonamide In organic chemistry, the sulfonamide functional group (also spelled sulphonamide) is an organosulfur group with the Chemical structure, structure . It consists of a sulfonyl group () connected to an amine group (). Relatively speaking this gro ...

s. Caution is also advised in people with

gout Gout ( ) is a form of inflammatory arthritis characterized by recurrent attacks of pain in a red, tender, hot, and Joint effusion, swollen joint, caused by the deposition of needle-like crystals of uric acid known as monosodium urate crysta ...

. Its safety during

pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...

is unclear and it is known to enter the

placenta The placenta (: placentas or placentae) is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas, and waste exchange between ...

amniotic fluid The amniotic fluid is the protective liquid contained by the amniotic sac of a gravid amniote. This fluid serves as a cushion for the growing fetus, but also serves to facilitate the exchange of nutrients, water, and biochemical products betwee ...

, and

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 ...

. As such, discontinuation of methenamine is recommended during

breastfeeding Breastfeeding, also known as nursing, is the process where breast milk is fed to a child. Infants may suck the milk directly from the breast, or milk may be extracted with a Breast pump, pump and then fed to the infant. The World Health Orga ...

. No teratogenic effects with methenamine in animals have been observed. Although the preceding contraindications of methenamine have been specified, they are not well-defined and may not be absolute contraindications in all cases.

Side effects

s of methenamine are minor and infrequent, reportedly occurring in fewer than 4% of individuals. They include

dyspepsia Indigestion, also known as dyspepsia or upset stomach, is a condition of impaired digestion. Symptoms may include upper abdominal fullness, heartburn, nausea, belching, or upper abdominal pain. People may also experience feeling full earlier ...

(upset stomach),

abdominal pain Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues. Since the abdomen contains most of the body's vital organs, it can be an indicator of a wide variety of diseases. Given th ...

dysuria Dysuria refers to painful or uncomfortable urination. It is one of a constellation of ''irritative'' bladder symptoms (also sometimes referred to as lower urinary tract symptoms), which includes nocturia and urinary frequency. Diagnosis The cl ...

(painful or uncomfortable urination),

vomiting Vomiting (also known as emesis, puking and throwing up) is the 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, gastroenteritis, pre ...

diarrhea Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...

rash A rash is a change of the skin that affects its color, appearance, or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cracke ...

, and

pruritus An itch (also known as pruritus) is a sensation that causes a strong desire or reflex to scratch. Itches have resisted many attempts to be classified as any one type of sensory experience. Itches have many similarities to pain, and while both ...

(itching). The drug is generally very well-tolerated. Rarely, reversibly

elevated liver enzymes In medicine Medicine is the science and Praxis (process), practice of caring for patients, managing the Medical diagnosis, diagnosis, prognosis, Preventive medicine, prevention, therapy, treatment, Palliative care, palliation of their injur ...

, including of

alanine aminotransferase Alanine aminotransferase (ALT or ALAT), formerly alanine transaminase (ALT), and even earlier referred to as serum glutamate-pyruvate transaminase (GPT) or serum glutamic-pyruvic transaminase (SGPT), is a transaminase enzyme () that was first ch ...

(ALT) and

aspartate aminotransferase Aspartate transaminase (AST) or aspartate aminotransferase, also known as AspAT/ASAT/AAT or (serum) glutamic oxaloacetic transaminase (GOT, SGOT), is a pyridoxal phosphate (PLP)-dependent transaminase enzyme () that was first described by Arthur ...

(AST), have been reported. Normalization of liver enzymes has occurred with discontinuation or continuation of methenamine.

Hypersensitivity reaction Hypersensitivity (also called hypersensitivity reaction or intolerance) is an abnormal physiological condition in which there is an undesirable and adverse immune response to an antigen. It is an abnormality in the immune system that causes im ...

s have also rarely been reported. It has been said that methenamine, overall, is very

safe A safe (also called a strongbox or coffer) is a secure lockable enclosure used for securing valuable objects against theft or fire. A safe is usually a hollow cuboid or cylinder, with one face being removable or hinged to form a door. The body ...

Formaldehyde Formaldehyde ( , ) (systematic name methanal) is an organic compound with the chemical formula and structure , more precisely . The compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde. It is stored as ...

is a known

carcinogen A carcinogen () is any agent that promotes the development of cancer. Carcinogens can include synthetic chemicals, naturally occurring substances, physical agents such as ionizing and non-ionizing radiation, and biologic agents such as viruse ...

, for instance being associated with

nasopharyngeal cancer Nasopharyngeal carcinoma (NPC), or nasopharynx cancer, is the most common cancer originating in the nasopharynx, most commonly in the postero-lateral nasopharynx or pharyngeal recess ( fossa of Rosenmüller), accounting for 50% of cases. NPC occur ...

and

leukemia Leukemia ( also spelled leukaemia; pronounced ) is a group of blood cancers that usually begin in the bone marrow and produce high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or '' ...

. This compound also occurs in small amounts as a contaminant in

alcoholic beverage Drinks containing alcohol (drug), alcohol are typically divided into three classes—beers, wines, and Distilled beverage, spirits—with alcohol content typically between 3% and 50%. Drinks with less than 0.5% are sometimes considered Non-al ...

s, and is chemically similar to the carcinogenic

ethanol Ethanol (also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound with the chemical formula . It is an Alcohol (chemistry), alcohol, with its formula also written as , or EtOH, where Et is the ps ...

(alcohol)

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

acetaldehyde Acetaldehyde (IUPAC systematic name ethanal) is an organic compound, organic chemical compound with the chemical formula, formula , sometimes abbreviated as . It is a colorless liquid or gas, boiling near room temperature. It is one of the most ...

. Because of the formaldehyde exposure with methenamine, there have been concerns about methenamine's potential carcinogenicity and the possibility that it might increase the risk of

cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

, for instance

stomach cancer Stomach cancer, also known as gastric cancer, is a malignant tumor of the stomach. It is a cancer that develops in the Gastric mucosa, lining of the stomach. Most cases of stomach cancers are gastric carcinomas, which can be divided into a numb ...

. No clinical studies have looked directly at the long-term effects of methenamine in this regard. However, there are no published

case report In medicine, a case report is a detailed report of the symptoms, signs, diagnosis, treatment, and follow-up of an individual patient. Case reports may contain a demographic profile of the patient, but usually describe an unusual or novel occurrenc ...

s documenting incidence of cancer with methenamine as of 2023. Moreover,

animal studies Animal studies is a recently recognised field in which animals are studied in a variety of cross-disciplinary ways. Scholars who engage in animal studies may be formally trained in a number of diverse fields, including art history, anthropology ...

have found no evidence of long-term carcinogenicity with oral methenamine. On the other hand, the findings of animal studies of methenamine and carcinogenicity have also been questioned by some authors, though this topic is controversial. Antibiotics are known to disrupt the gut,

, and

vagina In mammals and other animals, the vagina (: vaginas or vaginae) is the elastic, muscular sex organ, reproductive organ of the female genital tract. In humans, it extends from the vulval vestibule to the cervix (neck of the uterus). The #Vag ...

microbiota Microbiota are the range of microorganisms that may be commensal, mutualistic, or pathogenic found in and on all multicellular organisms, including plants. Microbiota include bacteria, archaea, protists, fungi, and viruses, and have been found ...

. This has been associated with increased risk of recurrent UTIs. Methenamine has been limitedly studied in this regard, but was found in one small study to preserve urinary microbial diversity. However, more studies are needed to assess the influence of methenamine on the host microbiome, both in the urinary tract and elsewhere in the body. Side effects of the

form of methenamine for

include

dry skin Xeroderma, xerosis or xerosis cutis, or simply dry skin, is a skin condition characterized by excessively dry skin. The term derives . In most cases, dry skin can safely be treated with moisturizers (also called emollients). Xeroderma occurs ...

, among others.

Overdose

Doses of methenamine much higher than usual have been clinically studied and found to produce significant

toxicity Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacteria, bacterium, or plant, as well as the effect o ...

. More specifically, doses of 8g per day (4–8-fold usual doses) for 3 to 4weeks resulted in bladder irritation, painful and frequent urination,

albuminuria Albuminuria is a pathological condition of elevated albumin protein in the urine (often measured as urine albumin-to-creatinine ratio of >30 milligrams of albumin per 1 gram of creatinine per day). It is a type of proteinuria, and is the most com ...

(

albumin Albumin is a family of globular proteins, the most common of which are the serum albumins. All of the proteins of the albumin family are water- soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Alb ...

in urine),

crystalluria Crystalluria refers to crystals found in the urine when performing a urine test. Crystalluria is considered often as a benign condition and as one of the side effects of sulfonamides and penicillins. The main reason for the identification of urin ...

(

crystal A crystal or crystalline solid is a solid material whose constituents (such as atoms, molecules, or ions) are arranged in a highly ordered microscopic structure, forming a crystal lattice that extends in all directions. In addition, macros ...

s in urine), and

hematuria Hematuria or haematuria is defined as the presence of blood or red blood cells in the urine. "Gross hematuria" occurs when urine appears red, brown, or tea-colored due to the presence of blood. Hematuria may also be subtle and only detectable with ...

(

blood Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood is com ...

in urine). Some of these side effects are thought to be due to high levels of

in the bladder and consequent irritation. Doses of methenamine of up to 10 to 20g/day have also been studied and found to be tolerable without major toxicity. When methenamine was first introduced in the late 1800s and early 1900s, doses of 15 to 30g per day were commonly employed and doses of up to 60 to 180g per day were tried in some cases. Toxic effects of such high doses included urinary tract and bladder irritation, frequent urination,

strangury Strangury (or stranguria) is the symptom characterized by painful, frequent urination of small volumes that are expelled slowly only by straining and despite a severe sense of urgency, usually with the residual feeling of incomplete emptying. The ...

, and hematuria.

Animal studies Animal studies is a recently recognised field in which animals are studied in a variety of cross-disciplinary ways. Scholars who engage in animal studies may be formally trained in a number of diverse fields, including art history, anthropology ...

employing double the modern human dosage of methenamine for 6 to 12months found no adverse effects.

Interactions

Concomitant use of methenamine and

s can result in

insoluble In chemistry, solubility is the ability of a substance, the solute, to form a solution with another substance, the solvent. Insolubility is the opposite property, the inability of the solute to form such a solution. The extent of the solub ...

methenamine

s precipitating in

and hence is not recommended. Urinary

alkalinizing agent Alkalinizing agents are drugs used to manage disorders associated with low pH. For example, they may be used to treat acidosis due to kidney failure. Used for oral or parenteral therapy, sodium bicarbonate is the commonly preferred alkalinizing ...

s, such as

antacid An antacid is a substance which neutralization (chemistry), neutralizes gastric acid, stomach acidity and is used to relieve heartburn, indigestion, or an upset stomach. Some antacids have been used in the treatment of constipation and diarrhe ...

carbonic anhydrase inhibitor Carbonic anhydrase inhibitors are a class of pharmaceuticals that suppress the activity of carbonic anhydrase. Their clinical use has been established as anti-glaucoma agents, diuretics, antiepileptics, in the management of mountain sickness, g ...

s, and certain

food Food is any substance consumed by an organism for Nutrient, nutritional support. Food is usually of plant, animal, or Fungus, fungal origin and contains essential nutrients such as carbohydrates, fats, protein (nutrient), proteins, vitamins, ...

s, may diminish the effectiveness of methenamine by making the urine more

alkaline In chemistry, an alkali (; from the Arabic word , ) is a basic salt of an alkali metal or an alkaline earth metal. An alkali can also be defined as a base that dissolves in water. A solution of a soluble base has a pH greater than 7.0. The ...

and thereby preventing the

hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...

of methenamine into

. Conversely, urinary acidifying agents, like

(vitamin C), sodium acid phosphate, and

ammonium chloride Ammonium chloride is an inorganic chemical compound with the chemical formula , also written as . It is an ammonium salt of hydrogen chloride. It consists of ammonium cations and chloride anions . It is a white crystalline salt (chemistry), sal ...

, may enhance the effectiveness of methenamine by making the urine more

ic and thereby facilitating its hydrolysis into formaldehyde. Formaldehyde has been found ''

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 ...

'' to react with

hydrochloric acid Hydrochloric acid, also known as muriatic acid or spirits of salt, is an aqueous solution of hydrogen chloride (HCl). It is a colorless solution with a distinctive pungency, pungent smell. It is classified as a acid strength, strong acid. It is ...

to form the highly

ic compound

bis(chloromethyl) ether Bis(chloromethyl) ether is an organic compound with the chemical formula (ClCH2)2O. It is a colourless liquid with an unpleasant suffocating odour and it is one of the chloroalkyl ethers. Bis(chloromethyl) ether was once produced on a large scale ...

and it may be conceivable that this might likewise occur in the

Pharmacology

Pharmacodynamics

Methenamine has non-specific

and

properties in

ic environments via

into

. Formaldehyde is an

aldehyde In organic chemistry, an aldehyde () (lat. ''al''cohol ''dehyd''rogenatum, dehydrogenated alcohol) is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred ...

and is highly

reactive Reactive may refer to: *Generally, capable of having a reaction (disambiguation) *An adjective abbreviation denoting a bowling ball coverstock made of reactive resin *Reactivity (chemistry) *Reactive mind *Reactive programming See also *Reactanc ...

and thereby

bactericidal A bactericide or bacteriocide, sometimes abbreviated Bcidal, is a substance which kills bacteria. Bactericides are disinfectants, antiseptics, or antibiotics. However, material surfaces can also have bactericidal properties based solely on their p ...

. It acts by binding to and denaturing

bacterial Bacteria (; : bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among the ...

s and

s. Methenamine is almost completely inactive as an antibacterial in

environments, in which it is not degraded into formaldehyde. The drug's spectrum of antibacterial activity includes all urinary tract

pathogen In biology, a pathogen (, "suffering", "passion" and , "producer of"), in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a Germ theory of d ...

s. It is specifically effective against common UTI-causing bacteria including ''

Staphylococcus saprophyticus ''Staphylococcus saprophyticus'' is a Gram-positive coccus belonging to the genus ''Staphylococcus''. ''S. saprophyticus'' is a common cause of community-acquired urinary tract infections. History ''Staphylococcus saprophyticus'' was not recogni ...

'', ''

Escherichia coli ''Escherichia coli'' ( )Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. is a gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus '' Escherichia'' that is commonly fo ...

'', ''

Enterococcus faecalis ''Enterococcus faecalis'' – formerly classified as part of the group D '' Streptococcus,'' is a Gram-positive, commensal bacterium naturally inhabiting the gastrointestinal tracts of humans. Like other species in the genus '' Enterococcus'', ' ...

'', and ''

Enterococcus faecium ''Enterococcus faecium'' is a Gram-positive, gamma-hemolytic or non-hemolytic bacterium in the genus ''Enterococcus''. It can be commensal (innocuous, coexisting organism) in the gastrointestinal tract of humans and animals, but it may also be ...

''. However, ''

Klebsiella aerogenes ''Klebsiella aerogenes'', previously known as ''Enterobacter aerogenes'', is a Gram-negative, oxidase-negative, catalase-positive, citrate-positive, indole-negative, rod-shaped bacterium. Capable of motility via peritrichous flagella, it is appr ...

'' (''Enterobacter aerogenes'') has been said to generally be resistant to methenamine, although the mechanism and rationale supporting this resistance have not been described. In addition, certain

urea Urea, also called carbamide (because it is a diamide of carbonic acid), is an organic compound with chemical formula . This amide has two Amine, amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest am ...

-splitting bacteria, such as ''

Proteus In Greek mythology, Proteus ( ; ) is an early prophetic sea god or god of rivers and oceanic bodies of water, one of several deities whom Homer calls the "Old Man of the Sea" (''hálios gérôn''). Some who ascribe a specific domain to Prote ...

'' and ''

Pseudomonas ''Pseudomonas'' is a genus of Gram-negative bacteria belonging to the family Pseudomonadaceae in the class Gammaproteobacteria. The 348 members of the genus demonstrate a great deal of metabolic diversity and consequently are able to colonize a ...

'' species, can make the urine more alkaline, thereby potentially inhibiting the antibacterial effects of methenamine. '' Providencia'' and '' Morganella'' species are also urea-splitting and might likewise be resistant to methenamine, although this topic requires more research. Methenamine is provided medically as the

, and the acid salt component plays a key role in helping to make the urine more acidic such that the activity of methenamine is optimized.

Ascorbic acid Ascorbic acid is an organic compound with formula , originally called hexuronic acid. It is a white solid, but impure samples can appear yellowish. It dissolves freely in water to give mildly acidic solutions. It is a mild reducing agent. Asco ...

(vitamin C), sodium acid phosphate, or

can also be supplemented to further acidify the urine. However, it is unclear whether this actually improves treatment effectiveness or not.

Pharmacokinetics

Absorption

Methenamine is rapidly absorbed from the

gastrointestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the Digestion, digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascula ...

with

oral administration Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

. Its 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%. H ...

is high (≥70%).

Distribution

The drug is

distributed 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 ...

widely throughout the body, including in

saliva Saliva (commonly referred as spit or drool) is an extracellular fluid produced and secreted by salivary glands in the mouth. In humans, saliva is around 99% water, plus electrolytes, mucus, white blood cells, epithelial cells (from which ...

bile Bile (from Latin ''bilis''), also known as gall, is a yellow-green/misty green fluid produced by the liver of most vertebrates that aids the digestion of lipids in the small intestine. In humans, bile is primarily composed of water, is pro ...

cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless Extracellular fluid#Transcellular fluid, transcellular body fluid found within the meninges, meningeal tissue that surrounds the vertebrate brain and spinal cord, and in the ventricular system, ven ...

synovial fluid Synovial fluid, also called synovia, elp 1/sup> is a viscous, non-Newtonian fluid found in the cavities of synovial joints. With its egg white–like consistency, the principal role of synovial fluid is to reduce friction between the articul ...

s, and

pleural effusion A pleural effusion is accumulation of excessive fluid in the pleural space, the potential space that surrounds each lung. Under normal conditions, pleural fluid is secreted by the parietal pleural capillaries at a rate of 0.6 millilitre per kilog ...

s. In accordance with its presence in cerebrospinal fluid, methenamine is known to cross the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

and enter 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 ...

. 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 ...

and

plasma protein binding Plasma protein binding refers to the degree to which medications attach to blood proteins within the blood plasma. A drug's efficacy may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse o ...

of methenamine are unknown.

Metabolism

In terms of

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 ...

, methenamine is

hydrolyzed Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysi ...

to form

and

ammonium Ammonium is a modified form of ammonia that has an extra hydrogen atom. It is a positively charged (cationic) polyatomic ion, molecular ion with the chemical formula or . It is formed by the protonation, addition of a proton (a hydrogen nucleu ...

( pH < 6). More specifically, a single molecule of methenamine decomposes into six equivalents of formaldehyde and four ammonia molecules. The drug may be degraded 10 to 30% in the acidic environment of the

prior to absorption. This can be avoided with enteric coated tablets. In terms of pH, there is minimal hydrolysis at a pH of 7.4, 6% at a pH of 6, and 20% at a pH of 5. The hydrolysis of methenamine occurs slowly and gradually, with approximately 3hours required for 90% decomposition into formaldehyde. As breakdown of methenamine only occurs in acidic environments like the bladder and stomach, the activation of methenamine into formaldehyde in the body is

tissue-selective Tissue selectivity is a topic in distribution (pharmacology) and property of some drugs. It refers to when a drug occurs in disproportionate concentrations and/or has disproportionate effects in specific tissues relative to other tissues. An examp ...

. Following its formation, formaldehyde is rapidly metabolized into

formic acid Formic acid (), systematically named methanoic acid, is the simplest carboxylic acid. It has the chemical formula HCOOH and structure . This acid is an important intermediate in chemical synthesis and occurs naturally, most notably in some an ...

(formate) in the body.

Elimination

The drug is eliminated mainly by the

kidney In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...

s. A single oral dose of methenamine is

excreted Excretion is elimination of metabolic waste, which is an essential process in all organisms. 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 ...

70 to 90% in urine unchanged within 24hours. The

onset of action Onset of action is the duration of time it takes for a drug's effects to come to prominence upon administration. With oral administration, it typically ranges anywhere from 20 minutes to over an hour, depending on the drug in question. Other meth ...

of the urinary antibacterial effects of methenamine is within 30minutes. A urinary formaldehyde concentration of 18 to 60μg/mL can be achieved with a typical therapeutic dosage of methenamine and these concentrations of formaldehyde can inhibit almost all urinary pathogens. The

elimination half-life Biological half-life (elimination half-life, pharmacological half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the blood plasma. ...

of methenamine is 2 to 6hours.

Chemistry

Methenamine, also known as 1,3,5,7-tetraazaadamantane, is a simple

cyclic Cycle, cycles, or cyclic may refer to: Anthropology and social sciences * Cyclic history, a theory of history * Cyclical theory, a theory of American political history associated with Arthur Schlesinger, Sr. * Social cycle, various cycles in s ...

with a cage-like

structure A structure is an arrangement and organization of interrelated elements in a material object or system, or the object or system so organized. Material structures include man-made objects such as buildings and machines and natural objects such as ...

and is similar in structure to

(tricyclo .3.1.1^3,7ecane). It is specifically the analogue of adamantane in which the

carbon Carbon () is a chemical element; it has chemical symbol, symbol C and atomic number 6. It is nonmetallic and tetravalence, tetravalent—meaning that its atoms are able to form up to four covalent bonds due to its valence shell exhibiting 4 ...

atom Atoms are the basic particles of the chemical elements. An atom consists of a atomic nucleus, nucleus of protons and generally neutrons, surrounded by an electromagnetically bound swarm of electrons. The chemical elements are distinguished fr ...

s at the 1, 3, 4, and 7 positions have been replaced with

nitrogen Nitrogen is a chemical element; it has Symbol (chemistry), symbol N and atomic number 7. Nitrogen is a Nonmetal (chemistry), nonmetal and the lightest member of pnictogen, group 15 of the periodic table, often called the Pnictogen, pnictogens. ...

atoms. The drug is a white or colorless and odorless

crystalline A crystal or crystalline solid is a solid material whose constituents (such as atoms, molecules, or ions) are arranged in a highly ordered microscopic structure, forming a crystal lattice that extends in all directions. In addition, macrosc ...

compound Compound may refer to: Architecture and built environments * Compound (enclosure), a cluster of buildings having a shared purpose, usually inside a fence or wall ** Compound (fortification), a version of the above fortified with defensive struc ...

with a sweet, sour, and/or metallic taste. It is a

hydrophilic A hydrophile is a molecule or other molecular entity that is attracted to water molecules and tends to be dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clarendon Press. In contrast, hydrophobes are n ...

compound with a predicted

log P Log most often refers to: * Trunk (botany), the stem and main wooden axis of a tree, called logs when cut ** Logging, cutting down trees for logs ** Firewood, logs used for fuel ** Lumber or timber, converted from wood logs * Logarithm, in mathem ...

( XLogP3) of 0.3. Methenamine is usually provided medically as the

. Methenamine is the

cation An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...

and hippuric acid or mandelic acid is the

anion An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conven ...

History

Methenamine was first discovered as a

chemical compound A chemical compound is a chemical substance composed of many identical molecules (or molecular entities) containing atoms from more than one chemical element held together by chemical bonds. A molecule consisting of atoms of only one element ...

in 1859. It was introduced for medical use as a

urinary The human urinary system, also known as the urinary tract or renal system, consists of the kidneys, ureters, bladder, and the urethra. The purpose of the urinary system is to eliminate waste from the body, regulate blood volume and blood pressu ...

under the name ''Urotropin'' in 1895. The drug was described as rapidly sterilizing and thereby restoring

putrid Putrefaction is the fifth stage of death, following pallor mortis, livor mortis, algor mortis, and rigor mortis. This process references the breaking down of a body of an animal post-mortem. In broad terms, it can be viewed as the decomposi ...

and

pus Pus is an exudate, typically white-yellow, yellow, or yellow-brown, formed at the site of inflammation during infections, regardless of cause. An accumulation of pus in an enclosed tissue space is known as an abscess, whereas a visible collect ...

-filled urine to a normal appearance and constitution. A

of methenamine with

salicylic acid Salicylic acid is an organic compound with the formula HOC6H4COOH. A colorless (or white), bitter-tasting solid, it is a precursor to and a active metabolite, metabolite of acetylsalicylic acid (aspirin). It is a plant hormone, and has been lis ...

was also developed and introduced the same year. Methenamine was only used as a urinary antiseptic in cases of

acidic An acid is a molecule or ion capable of either donating a proton (i.e. hydrogen cation, H+), known as a Brønsted–Lowry acid, or forming a covalent bond with an electron pair, known as a Lewis acid. The first category of acids are the ...

urine, whereas

boric acid Boric acid, more specifically orthoboric acid, is a compound of boron, oxygen, and hydrogen with formula . It may also be called hydrogen orthoborate, trihydroxidoboron or boracic acid. It is usually encountered as colorless crystals or a white ...

was used to treat UTIs with

urine. The drug name ''methenamine'', a contraction of the chemical or scientific name ''hexamethylenetetramine'', was formally introduced and designated by the ''

United States Pharmacopeia The ''United States Pharmacopeia'' (''USP'') is a pharmacopeia (compendium of drug information) for the United States published annually by the over 200-year old United States Pharmacopeial Convention (usually also called the USP), a nonprofi ...

'' (USP) by 1925 and replaced the prior name of the drug that was being used of ''hexamethylenamine''. The alternative drug name ''hexamine'' was introduced in the ''

British Pharmacopoeia The ''British Pharmacopoeia'' (''BP'') is the national pharmacopoeia of the United Kingdom. It is an annually published collection of quality standards for medicinal substances in the UK, which is used by individuals and organisations involve ...

'' (BP) by 1914 to be used instead of the commercial name ''Urotropin''. Interest in methenamine declined after the discovery of the

penicillin Penicillins (P, PCN or PEN) are a group of beta-lactam antibiotic, β-lactam antibiotics originally obtained from ''Penicillium'' Mold (fungus), moulds, principally ''Penicillium chrysogenum, P. chrysogenum'' and ''Penicillium rubens, P. ru ...

in 1928 and it has been described as a "forgotten drug". However, there was a surge of interest in methenamine from the 1950s to the 1980s. The drug was formally approved by the

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) for medical use in the United States in 1967. The

form of methenamine for treatment of hyperhidrosis was introduced around 1965. Subsequently, there was another decline in interest in methenamine from 1980 until 2010. However, there has been another resurgence in interest in methenamine for recurrent UTI prevention since 2010 owing to increasing rates of

with antibiotics. Larger and higher-quality

s of methenamine for UTI prevention, such as the

ALTAR trial, have started to be published in the 2020s, and additional trials, such as the international

ImpresU trial, are also underway as of 2024.

Society and culture

Names

''Methenamine'' is the generic name of the drug and its , , and , while ''hexamine'' is its and . Brand names of methenamine include ''Aminoform'', ''Antihydral'', ''Dehydral'', ''Formamine'', ''Formin'', ''Hexamine'', ''Hiprex'', ''Hyophen'', ''Mandelamine'', ''Metenamine'', ''Phosphasal'', ''Urelle'', ''Urex'', ''Uribel'', ''Urimar'', ''Urin DS'', ''Urogesic Blue'', ''Urotropin'', and ''Ustell'', among numerous others.

Availability

Methenamine is approved and available in the

. Only methenamine hippurate, the twice-daily formulation, is available as a

prescription drug A prescription drug (also prescription medication, prescription medicine or prescription-only medication) is a pharmaceutical drug that is permitted to be dispensed only to those with a medical prescription. In contrast, over-the-counter drugs c ...

in the United States. Of 38countries that were surveyed in one study, methenamine was available in seven of them. In any case, methenamine was marketed as a

widely throughout the world in 2004. The

form of methenamine for

has been marketed only in certain countries, including

Austria Austria, formally the Republic of Austria, is a landlocked country in Central Europe, lying in the Eastern Alps. It is a federation of nine Federal states of Austria, states, of which the capital Vienna is the List of largest cities in Aust ...

Canada Canada is a country in North America. Its Provinces and territories of Canada, ten provinces and three territories extend from the Atlantic Ocean to the Pacific Ocean and northward into the Arctic Ocean, making it the world's List of coun ...

Germany Germany, officially the Federal Republic of Germany, is a country in Central Europe. It lies between the Baltic Sea and the North Sea to the north and the Alps to the south. Its sixteen States of Germany, constituent states have a total popu ...

Luxembourg Luxembourg, officially the Grand Duchy of Luxembourg, is a landlocked country in Western Europe. It is bordered by Belgium to the west and north, Germany to the east, and France on the south. Its capital and most populous city, Luxembour ...

, and

Switzerland Switzerland, officially the Swiss Confederation, is a landlocked country located in west-central Europe. It is bordered by Italy to the south, France to the west, Germany to the north, and Austria and Liechtenstein to the east. Switzerland ...

Cost effectiveness

The costs of methenamine for long-term UTI prophylaxis can be significant. However, a 2024 study found that methenamine was more

than low-dose prophylactic antibiotics for prevention of UTIs.

Research

Methenamine might be useful in the treatment of ''

Helicobacter pylori ''Helicobacter pylori'', previously known as ''Campylobacter pylori'', is a gram-negative, Flagellum#bacterial, flagellated, Bacterial cellular morphologies#Helical, helical bacterium. Mutants can have a rod or curved rod shape that exhibits l ...

'' infections as it is activated in the acidic environment of the

. The drug can safely be used

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 nutr ...

and might be useful in the treatment of

infection An infection is the invasion of tissue (biology), tissues by pathogens, their multiplication, and the reaction of host (biology), host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmis ...

s as well as certain

References

{{Portal bar , Medicine Adamantane-like molecules Antimicrobials Antiseptics Bactericides Heterocyclic compounds with 3 rings Nitrogen heterocycles Prodrugs Tertiary amines