Biotrim Oral Suspension

Indications

• Bacterial infections
• Urinary tract infections
• Respiratory tract infections
• Prophylaxis of recurrent urinary tract infections

Dosage

Children: For children aged 6 weeks to 5 months: 4 mg/kg twice daily (max. 200 mg). For children 6 months to 5 years: 4 mg/kg twice daily (max. 200 mg). For children 6–11 years: 4 mg/kg twice daily (max. 200 mg). For children

Adults: 200 mg twice daily.

Mechanism of action

Trimethoprim is a reversible inhibitor of dihydrofolate reductase, an enzyme that catalyzes the formation of tetrahydrofolic acid from dihydrofolic acid. By inhibiting this enzyme, trimethoprim disrupts the biosynthesis of nucleic acids and proteins in bacteria, leading to their growth inhibition. The drug has a significantly higher affinity for bacterial dihydrofolate reductase compared to the mammalian enzyme, ensuring selective antibacterial activity.

Pharmacodynamics

Trimethoprim exerts its antimicrobial effects by disrupting bacterial nucleic acid synthesis. It is effective against various gram-negative bacteria and some coagulase-negative Staphylococcus species. Resistance can develop through mechanisms such as alterations to the bacterial cell wall or overproduction of the target enzyme. Monitoring for potential blood disorders is important during therapy, as rare adverse effects can occur.

Pharmacokinetics

Trimethoprim is well absorbed from the gastrointestinal tract and reaches peak plasma concentrations within 1-4 hours post-administration. It has a volume of distribution that suggests extensive tissue penetration, including into the lungs and kidneys, and is primarily excreted unchanged in the urine. The elimination half-life is approximately 8-10 hours, and dosing adjustments may be necessary in cases of renal impairment.

Contra-indications

• Severe renal impairment
• Known hypersensitivity to trimethoprim or any component of the formulation

Adverse effects

• Diarrhoea
• Nausea
• Headache
• Dizziness
• Fatigue
• Skin reactions
• Vomiting
• Anxiety
• Agranulocytosis
• Eosinophilia
• Photosensitivity reactions
• Thrombocytopenia
• Leukopenia
• Pseudomembranous colitis

Interactions

• Increases exposure to pramipexole
• Increases exposure to treprostinil
• Increases exposure to dopaminergic receptor agonists
• Increases concentration of antiepileptics
• Increases concentration of fosphenytoin
• Increases concentration of phenytoin
• Increases risk of haematological toxicity with azathioprine in renal transplant patients
• Increases concentration of digoxin
• Increases exposure to repaglinide

Precautions

• Caution in patients with renal impairment
• Caution in elderly patients (75 years and over)
• Monitor for signs of blood disorders such as sore throat, fever, and pallor
• Consider local antimicrobial susceptibility patterns before use

Pregnancy

Manufacturer advises avoidance due to potential fetal developmental toxicity observed in animal studies.

Breast-feeding

Manufacturer advises avoidance as trimethoprim is present in milk in animal studies.

Storage

Store in a cool, dry place, away from direct sunlight. Keep out of reach of children.

Formulations

• Tablets
• Oral suspension
• Injection solution

Indications

• Bacterial infections
• Toxoplasmosis in pregnancy (in combination with pyrimethamine and folinic acid)
• Congenital toxoplasmosis (in combination with pyrimethamine and folinic acid)

Dosage

Children: For children aged 12–17 years, the recommended dose is 1 g three times a day until delivery for toxoplasmosis in pregnancy. For other specific conditions, refer to the BNF for Children for detailed dosing guidelines.

Adults: For adults, the typical dosing for bacterial infections can vary, and it is essential to refer to the BNF for specific recommendations based on the condition being treated. Generally, dosage adjustments may be necessary in renal impairment.

Mechanism of action

Sulfadiazine acts as a competitive inhibitor of the bacterial enzyme dihydropteroate synthetase, blocking the conversion of para-aminobenzoic acid (PABA) to folic acid. This inhibition is crucial for bacterial growth and reproduction, as folic acid is vital for nucleic acid synthesis.

Pharmacodynamics

Sulfadiazine is a synthetic bacteriostatic antibiotic effective against many gram-positive and some gram-negative organisms. It inhibits bacterial multiplication by interfering with folic acid metabolism. Resistance to sulfadiazine usually implies resistance to all sulfonamides, as they share similar mechanisms of action.

Pharmacokinetics

Sulfadiazine is well absorbed when administered orally, with high tissue distribution. It achieves significant concentrations in various bodily fluids, including pleural and synovial fluids. While it is effective, its absorption can be affected by the presence of pus, which can inhibit its antibacterial action. Renal function can influence its clearance, necessitating dose adjustments in cases of impaired renal function.

Contra-indications

• Acute porphyrias

Adverse effects

• Agranulocytosis
• Aplastic anaemia
• Haemolytic anaemia
• Decreased appetite
• Ataxia
• Back pain
• Blood disorders
• Cough
• Crystaluria
• Cyanosis
• Depression
• Diarrhoea
• Dizziness
• Drowsiness
• Dyspnoea
• Eosinophilia
• Erythema nodosum
• Fatigue
• Fever
• Haematuria
• Hallucination
• Headache
• Hepatic disorders
• Hypoglycaemia
• Neutropenia
• Oral disorders
• Pancreatitis
• Photosensitivity reaction
• Skin reactions
• Thrombocytopenia
• Tinnitus
• Vertigo
• Vomiting

Interactions

• Sulfadiazine + antiepileptics: Moderate (increases concentration)
• Sulfadiazine + fosphenytoin: Moderate (increases concentration)
• Sulfadiazine + phenytoin: Moderate (increases concentration)

Precautions

• Caution in asthma
• Caution in blood disorders
• Caution in elderly patients
• Monitor blood counts on prolonged treatment
• Plasma concentration monitoring may be required in moderate to severe renal impairment

Pregnancy

Risk of neonatal haemolysis and methaemoglobinaemia in the third trimester; fear of increased risk of kernicterus in neonates appears to be unfounded.

Breast-feeding

Small risk of kernicterus in jaundiced infants and of haemolysis in G6PD-deficient infants.

Storage

Store in a cool, dry place away from light.

Formulations

• Solution for infusion
• Oral suspension

Indications

• Dry eye syndrome
• Ocular surface disorders
• Topical lubrication
• Pharmaceutical excipients in formulations

Dosage

Children: Refer to specific product guidelines, as doses may vary by formulation and indication.

Adults: Refer to specific product guidelines, as doses may vary by formulation and indication.

Mechanism of action

Carboxymethyl cellulose acts by forming a viscous gel when it comes into contact with water. This gel-like consistency helps to retain moisture, providing lubrication and protection to ocular surfaces. The polymer's ability to bind water makes it effective at enhancing the viscosity of formulations, which can prolong the retention time of active ingredients in contact with the affected tissues.

Pharmacodynamics

Carboxymethyl cellulose exhibits its effects primarily through its physical properties rather than specific biochemical interactions. Its high viscosity contributes to a protective barrier on mucosal surfaces, aiding in the alleviation of dryness and irritation. The gel-forming property helps to maintain hydration and can facilitate the healing process of epithelial tissues.

Pharmacokinetics

Carboxymethyl cellulose is not significantly absorbed through the gastrointestinal tract or ocular surfaces. Its action is mainly local, with minimal systemic absorption. The polymer is excreted unchanged, and its viscosity and gel-forming capabilities are maintained until it is cleared from the application site through natural processes such as blinking or swallowing.

Adverse effects

• Allergic reactions
• Skin irritation
• Gastrointestinal disturbances
• Headache
• Dizziness

Precautions

• Use with caution in patients with known allergies to carboxymethyl derivatives
• Monitor for potential allergic reactions
• Consider potential interactions with other medications

Pregnancy

Safety during pregnancy has not been established. Use only if potential benefits justify the risks.

Breast-feeding

It is not known whether carboxymethyl is excreted in human milk. Caution should be exercised.

Storage

Store in a cool, dry place, away from direct sunlight. Keep out of reach of children.

Formulations

• Carboxymethyl cellulose sodium (CMC) - commonly used as a thickening agent in various formulations

Indications

• Constipation
• Dietary fiber supplementation
• Irritable bowel syndrome
• Diverticular disease
• Weight management

Dosage

Children: Refer to appropriate guidelines for specific dosage; generally taken with adequate fluid intake.

Adults: Refer to appropriate guidelines for specific dosage; generally taken with adequate fluid intake.

Mechanism of action

Cellulose acts primarily as a bulk-forming laxative. It absorbs water in the intestines, which increases stool bulk and stimulates peristalsis, thus facilitating bowel movements. Additionally, cellulose is not digestible by human enzymes, leading to fermentation by gut bacteria, which may enhance gut health and alter gut microbiota composition.

Pharmacodynamics

Cellulose increases stool weight and frequency of bowel movements. It works by retaining water in the intestines, leading to softer stools and improved passage through the gastrointestinal tract. The bulking effect of cellulose can help alleviate constipation and promote overall digestive health. It may also play a role in cholesterol reduction and glycemic control through its effects on digestion and absorption of nutrients.

Pharmacokinetics

Cellulose is not absorbed into the bloodstream due to its indigestible nature. Instead, it passes through the gastrointestinal tract, where it adds bulk to the stool. Its fermentation by colonic bacteria produces short-chain fatty acids, which may have beneficial effects on colon health. The onset of action for cellulose as a laxative can vary but is generally within 24 to 72 hours after ingestion.

Adverse effects

• Bloating
• Flatulence
• Diarrhea
• Abdominal discomfort

Precautions

• Use with caution in patients with a history of gastrointestinal disorders.
• Monitor for potential allergic reactions in sensitive individuals.

Pregnancy

Cellulose is generally considered safe during pregnancy as it is a non-toxic, indigestible fiber.

Breast-feeding

Cellulose is also considered safe during breastfeeding; it is excreted in breast milk in negligible amounts.

Storage

Store in a cool, dry place away from direct sunlight.

Formulations

• Powder
• Capsules
• Tablets
• Granules

Indications

• Hypovolemic shock
• Severe burns
• Postoperative fluid replacement
• Sepsis
• Trauma management

Dosage

Children: Refer to established guidelines for specific dosing, as it varies based on the type of colloidal solution used and the clinical condition being treated.

Adults: Refer to established guidelines for specific dosing, as it varies based on the type of colloidal solution used and the clinical condition being treated.

Mechanism of action

Colloidal solutions work by maintaining oncotic pressure in the blood, thus helping to retain fluid within the vascular system. This is primarily due to the large molecular weight of the colloidal particles, which cannot easily pass through capillary walls. The presence of colloids in the blood helps to draw water into the circulation, increasing blood volume and improving tissue perfusion.

Pharmacodynamics

The pharmacodynamics of colloidal solutions are centered on their ability to exert osmotic pressure, which helps maintain blood volume and pressure. This effect is particularly important in conditions such as hypovolemia and shock, where fluid replacement is necessary to restore hemodynamic stability. The efficacy of colloidal solutions can vary depending on the type of colloid used, as well as the underlying clinical condition being treated.

Pharmacokinetics

Colloidal solutions are typically administered intravenously and their pharmacokinetics can vary based on the specific formulation. Generally, colloids are distributed throughout the vascular compartment and have a longer duration of action compared to crystalloids, as they remain in circulation longer. The elimination of colloids is primarily through the reticuloendothelial system, where they are metabolized or eliminated by the liver and spleen. Factors such as particle size and composition can influence their distribution and clearance.

Adverse effects

• Allergic reactions
• Injection site reactions
• Nausea
• Vomiting
• Headache
• Fever

Precautions

• Use with caution in patients with known allergies to any component of the formulation
• Monitor for signs of hypersensitivity during administration
• Consider volume overload in patients with cardiac or renal impairment

Pregnancy

The safety of colloidal solutions during pregnancy has not been established. Use only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is not known whether colloidal solutions are excreted in human milk. Caution should be exercised when administering to breastfeeding mothers.

Storage

Store at room temperature, protect from light, and do not freeze. Keep out of reach of children.

Formulations

• Colloidal silver
• Colloidal gold
• Colloidal iron
• Other metal colloids

Dosage

Children: There are no defined pediatric dosages for diethanolamine, and its use in children is not recommended due to potential developmental risks.

Adults: There is no established adult dosage for diethanolamine as it is primarily used in industrial applications and consumer products rather than as a therapeutic agent.

Mechanism of action

Diethanolamine acts by inhibiting choline transport into neural precursor cells, resulting in decreased intracellular concentrations of choline and phosphocholine. This inhibition leads to reduced cell proliferation and increased apoptosis in exposed cells. The compound can also be phosphorylated to phospho-DEA, which may alter choline metabolism further, possibly impacting brain development and liver health.

Pharmacodynamics

DEA has been shown to affect cellular functions such as proliferation and apoptosis. In studies, exposure to DEA resulted in diminished cell growth and increased programmed cell death in neural precursor cells, indicating a significant impact on cell viability and metabolism, particularly in the context of prenatal exposure.

Pharmacokinetics

The pharmacokinetics of diethanolamine are not well-documented in the available literature. Its absorption, distribution, metabolism, and excretion (ADME) properties in humans and animals remain largely unexplored. However, studies suggest that DEA can have systemic effects upon dermal absorption, particularly influencing liver and brain development.

Adverse effects

• Increased apoptosis
• Altered brain development
• Diminished intracellular concentrations of choline and phosphocholine
• Increased incidence and multiplicity of liver tumors in mice

Precautions

• Use with caution in pregnant individuals due to potential effects on fetal brain development
• Consider potential for reduced choline uptake in neural precursor cells

Pregnancy

Diethanolamine may have detrimental effects on fetal brain development as indicated by studies in mice.

Storage

Store in a cool, dry place away from direct sunlight and out of reach of children.

Indications

• Monitoring respiratory function
• Assessment of metabolic status
• Management of respiratory acidosis
• Management of respiratory alkalosis

Dosage

Children: Dosing for interventions related to carbon dioxide levels in pediatric patients should be guided by clinical protocols and the BNF for Children.

Adults: Dosing for interventions related to carbon dioxide levels is typically based on clinical assessment and individual patient needs. Refer to clinical guidelines for specific scenarios.

Mechanism of action

Carbon dioxide acts primarily as a signaling molecule in the body, influencing respiratory drive and blood pH. It is produced during cellular respiration and is a critical component of the bicarbonate buffering system, which helps maintain acid-base homeostasis. Elevated levels of CO2 in the blood stimulate ventilation in the lungs, increasing the rate of gas exchange and facilitating the removal of excess CO2.

Pharmacodynamics

The pharmacodynamic effects of dioxides, particularly carbon dioxide, are closely related to its concentration in the blood. As CO2 levels increase, it leads to respiratory acidosis, which can stimulate the respiratory centers in the brain to increase ventilation. Conversely, low levels of CO2 can cause respiratory alkalosis, potentially leading to decreased respiratory drive. CO2 also plays a role in vasodilation and can affect blood flow and pressure through its influence on smooth muscle tone.

Pharmacokinetics

Carbon dioxide is produced endogenously during metabolic processes and is transported in the bloodstream primarily in three forms: dissolved in plasma, as bicarbonate ions (HCO3-), and bound to hemoglobin. The half-life of CO2 in the bloodstream is very short due to its rapid exchange with alveolar gas in the lungs. The elimination of CO2 occurs through exhalation, making it a dynamic component of respiratory physiology.

Pregnancy

Data on the effects of dioxide during pregnancy are limited. Caution is advised due to potential risks associated with exposure.

Breast-feeding

Limited data are available regarding the excretion of dioxide in human milk. Caution is recommended.

Storage

Store in a cool, dry place, away from direct sunlight and moisture.

Dosage

Children: Refer to specific guidelines for pediatric dosing; consult the BNF for Children for accurate dosage information.

Adults: Refer to specific guidelines for use; dosage may vary based on the context of use.

Mechanism of action

Hydroxide ions act primarily as bases, neutralizing acids to form water and salts. They participate in various biochemical pathways, including selenium metabolism and the degradation of reactive oxygen species. Hydroxide can influence enzyme activity and stability by altering the pH of the environment, thereby affecting metabolic reactions.

Pharmacodynamics

Hydroxide ions can impact biological processes by changing the local pH, which influences enzyme activity, ion transport, and the solubility of other compounds. Their ability to neutralize acids can help regulate physiological pH, contributing to homeostasis in living organisms.

Pharmacokinetics

As an inorganic ion, hydroxide does not undergo traditional pharmacokinetic processes like absorption, distribution, metabolism, or excretion. Instead, it is rapidly equilibrated in biological fluids and participates in acid-base reactions, having immediate effects on the local environment.

Pregnancy

There is limited information regarding the use of hydroxide during pregnancy. Consult a healthcare professional for advice.

Breast-feeding

Limited data is available on the excretion of hydroxide in breast milk. Consult a healthcare professional before use.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Indications

• Emulsifying agent in drug formulations
• Stabilizer for parenteral preparations
• Solubilizer for hydrophobic drug compounds
• Ingredient in topical formulations

Dosage

Children: Refer to specific product guidelines, as dosing varies based on formulation and intended use.

Adults: Refer to specific product guidelines, as dosing varies based on formulation and intended use.

Mechanism of action

Polysorbate functions primarily as an emulsifying agent. It reduces the surface tension between immiscible liquids, allowing them to mix more easily. This property is particularly useful in stabilizing emulsions and suspensions, facilitating the delivery of active pharmaceutical ingredients in various formulations.

Pharmacodynamics

Polysorbate does not exert pharmacological effects in the traditional sense, as it does not bind to specific receptors to elicit a physiological response. Instead, it plays a crucial role in modifying the physical properties of drug formulations, thereby enhancing drug delivery and absorption. Its ability to solubilize drugs enhances their bioavailability, particularly for poorly soluble compounds.

Pharmacokinetics

Polysorbate is generally considered to be non-toxic and is not absorbed to a significant extent when administered orally. It is metabolized by the liver and excreted primarily through the gastrointestinal tract. The pharmacokinetic profile may vary depending on the route of administration and the specific formulation in which it is used.

Adverse effects

• Allergic reactions
• Skin irritation
• Gastrointestinal disturbances

Precautions

• Use cautiously in patients with known allergies to polysorbates or related compounds
• Monitor for allergic reactions in susceptible individuals

Pregnancy

Polysorbate is generally considered safe for use during pregnancy, but consult with a healthcare provider for specific cases.

Breast-feeding

Polysorbate is considered safe during breastfeeding, but consult with a healthcare provider for individual advice.

Storage

Store at room temperature, away from direct sunlight and moisture.

Formulations

• Polysorbate 20
• Polysorbate 80

Dosage

Children: Refer to specific drug formulations and product labels as purified substances can vary widely in their use and dosing.

Adults: Refer to specific drug formulations and product labels as purified substances can vary widely in their use and dosing.

Mechanism of action

The mechanism of action for purified compounds varies widely depending on the specific substance. Generally, purified drugs exert their effects by interacting with specific biological targets, such as receptors, enzymes, or ion channels, leading to a desired therapeutic effect. This interaction can involve binding to receptors to activate or inhibit signaling pathways, modulating enzymatic activity, or altering physiological processes.

Pharmacodynamics

Pharmacodynamics describes the effects of a drug on the body and the relationship between drug concentration and effect. For purified drugs, this can involve dose-response relationships and the time course of their action. The purified form often enhances potency and reduces variability in response among patients, which can lead to more predictable therapeutic outcomes. The overall effect is determined by the drug's affinity for its target, the efficacy of the drug-receptor interaction, and the downstream signaling pathways activated as a result of this interaction.

Pharmacokinetics

Pharmacokinetics involves the absorption, distribution, metabolism, and excretion (ADME) of a drug. For purified substances, absorption can be more efficient due to the absence of impurities that may affect solubility or stability. Distribution may also be enhanced, leading to higher bioavailability. Metabolism can be influenced by the structure of the purified compound, as it may be metabolized more readily by liver enzymes. Excretion typically occurs through the kidneys or liver, depending on the molecular characteristics of the purified drug.

Pregnancy

Consult with a healthcare professional, as the safety of purified forms of medications during pregnancy may vary depending on the specific substance.

Breast-feeding

Consult with a healthcare professional, as the safety of purified forms of medications during breastfeeding may vary depending on the specific substance.

Storage

Store in a cool, dry place, away from light and moisture, and keep out of reach of children.

Dosage

Children: Refer to the specific drug's dosing guidelines for children.

Adults: Refer to the specific drug's dosing guidelines for adults.

Pregnancy

Consult with a healthcare provider, as safety data may vary depending on the specific drug and its classification.

Breast-feeding

Consult with a healthcare provider, as safety data may vary depending on the specific drug and its classification.

Storage

Store in a cool, dry place away from direct sunlight and moisture. Keep out of reach of children.

Indications

• Potential role in bone health
• Support for connective tissue formation
• May aid in mineral metabolism

Dosage

Children: There is no established clinical dosage for silicon in paediatric populations, as it is not classified as an essential nutrient.

Adults: There is no established clinical dosage for silicon in adults, as it is not classified as an essential nutrient.

Mechanism of action

Silicon is believed to enhance the synthesis of glycosaminoglycans and collagen, which are important for the structural integrity of connective tissues. It may also influence the activity of certain enzymes involved in bone mineralization, thus playing a role in maintaining bone density and health.

Pharmacodynamics

The pharmacodynamics of silicon is not fully elucidated; however, it is thought to involve the modulation of bone metabolism and the promotion of connective tissue health. Silicon may have a synergistic effect with other minerals, such as calcium and magnesium, aiding in their utilization and metabolism in the body.

Pharmacokinetics

The pharmacokinetics of silicon is complex, as it is not absorbed through typical gastrointestinal pathways. Instead, silicon is thought to be taken up in the form of silicates and then distributed throughout the body, particularly in connective tissues. The elimination of silicon occurs primarily through renal excretion, with some variations depending on dietary intake and individual metabolism.

Pregnancy

Silicon is generally considered safe during pregnancy, as it is a naturally occurring element in the human body. However, specific recommendations regarding supplementation should be followed based on the advice of a healthcare provider.

Breast-feeding

Silicon is present in breast milk in small amounts. Its safety during breastfeeding is generally regarded as acceptable, although supplementation should be approached with caution and under medical advice.

Storage

Silicon should be stored in a cool, dry place, protected from light and moisture. Follow specific storage recommendations provided by the manufacturer if available.

Dosage

Children: Refer to specific drug guidelines in the BNF for Children for appropriate dosing information.

Adults: Refer to specific drug guidelines in the BNF for appropriate dosing information.

Mechanism of action

The mechanism of action will vary significantly depending on the specific drug referred to as 'sufficient.' Generally, mechanisms of action may include receptor agonism or antagonism, enzyme inhibition, or modulation of signaling pathways within cells. Understanding the specific drug's pharmacodynamics is crucial for determining its therapeutic efficacy.

Pharmacodynamics

Pharmacodynamics involves the study of the biochemical and physiological effects of drugs and their mechanisms of action. It encompasses the interactions between drug molecules and target receptors, the resulting cellular responses, and the overall therapeutic effects observed in patients. The relationship between drug concentration and effect is fundamental to understanding drug efficacy and safety.

Pharmacokinetics

Pharmacokinetics describes how a drug is absorbed, distributed, metabolized, and excreted in the body. Key parameters include bioavailability, volume of distribution, clearance, and half-life. These factors influence dosing regimens and the timing of therapeutic effects. Individual patient characteristics, such as age, sex, organ function, and genetic factors, can also impact pharmacokinetic profiles.

Pregnancy

Consult with a healthcare provider before use. Insufficient data on safety.

Breast-feeding

Consult with a healthcare provider before use. Insufficient data on safety.

Storage

Store in a cool, dry place away from direct sunlight.

Mechanism of action

Sulfadiazine is a competitive inhibitor of the bacterial enzyme dihydropteroate synthetase. This enzyme is needed for the proper processing of para-aminobenzoic acid (PABA) which is essential for folic acid synthesis. The inhibited reaction is necessary in these organisms for the synthesis of folic acid.

Pharmacodynamics

Sulfadiazine is a sulfonamide antibiotic. The sulfonamides are synthetic bacteriostatic antibiotics with a wide spectrum against most gram-positive and many gram-negative organisms. However, many strains of an individual species may be resistant. Sulfonamides inhibit multiplication of bacteria by acting as competitive inhibitors of <i>p</i>-aminobenzoic acid in the folic acid metabolism cycle. Bacterial sensitivity is the same for the various sulfonamides, and resistance to one sulfonamide indicates resistance to all. Most sulfonamides are readily absorbed orally. However, parenteral administration is difficult, since the soluble sulfonamide salts are highly alkaline and irritating to the tissues. The sulfonamides are widely distributed throughout all tissues. High levels are achieved in pleural, peritoneal, synovial, and ocular fluids. Although these drugs are no longer used to treat meningitis, CSF levels are high in meningeal infections. Their antibacterial action is inhibited by pus.

Mechanism of action

Trimethoprim is a reversible inhibitor of dihydrofolate reductase, one of the principal enzymes catalyzing the formation of tetrahydrofolic acid (THF) from dihydrofolic acid (DHF). Tetrahydrofolic acid is necessary for the biosynthesis of bacterial nucleic acids and proteins and ultimately for continued bacterial survival - inhibiting its synthesis, then, results in bactericidal activity. Trimethoprim binds with a much stronger affinity to bacterial dihydrofolate reductase as compared to its mammalian counterpart, allowing trimethoprim to selectively interfere with bacterial biosynthetic processes. Trimethoprim is often given in combination with sulfamethoxazole, which inhibits the preceding step in bacterial protein synthesis - given together, sulfamethoxazole and trimethoprim inhibit two consecutive steps in the biosynthesis of bacterial nucleic acids and proteins. As a monotherapy trimethoprim is considered bacteriostatic, but in combination with sulfamethoxazole is thought to exert bactericidal activity. Trimethoprim is a bacteriostatic lipophilic weak base structurally related to pyrimethamine. It binds to and reversibly inhibits the bacterial enzyme dihydrofolate reductase, selectively blocking conversion of dihydrofolic acid to its functional form, tetrahydrofolic acid. This depletes folate, an essential cofactor in the biosynthesis of nucleic acids, resulting in interference with bacterial nucleic acid and protein production. Bacterial dihydrofolate reductase is approximately 50,000 to 60,000 times more tightly bound by trimethoprim than is the corresponding mammalian enzyme. To determine the incidence & severity of hyperkalemia during trimethoprim therapy, 30 consecutive patients with acquired immunodeficiency syndrome receiving high-dose (20 mg/kg/day) trimethoprim were studied; in addition, the mechanism of trimethoprim-induced hyperkalemia was investigated in rats. Trimethoprim increased serum potassium concn by 0.6 mmol/l despite normal adrenocortical function & glomerular filtration rate. Serum potassium levels >5 mmol/l were observed during trimethoprim treatment in 15 of 30 patients. In rats, iv trimethoprim inhibited renal potassium excretion by 40% & increased sodium excretion by 46%. It was concluded that trimethoprim blocks apical membrane sodium channels in the mammalian distal nephron. As a consequence, the transepithelial voltage is reduced & potassium secretion is inhibited. Decreased renal potassium excretion secondary to these direct effects on kidney tubules leads to hyperkalemia in a substantial number of patients being treated with trimethoprim-containing drugs.

Pharmacodynamics

Trimethoprim exerts its antimicrobial effects by inhibiting an essential step in the synthesis of bacterial nucleic acids and proteins. It has shown activity against several species of gram-negative bacteria, as well as coagulase-negative _Staphylococcus_ species. Resistance to trimethoprim may arise via a variety of mechanisms, including alterations to the bacterial cell wall, overproduction of dihydrofolate reductase, or production of resistant dihydrofolate reductase. Rarely, trimethoprim can precipitate the development of blood disorders (e.g. thrombocytopenia, leukopenia, etc.) which may be preceded by symptoms such as sore throat, fever, pallor, and or purpura - patients should be monitored closely for the development of these symptoms throught the course of therapy. As antimicrobial susceptibility patterns are geographically distinct, local antibiograms should be consulted to ensure adequate coverage of relevant pathogens prior to use.

Mechanism of action

Diethanolamine (DEA) is a widely used ingredient in many consumer products and in a number of industrial applications. It has been previously reported that dermal administration of DEA to mice diminished hepatic stores of choline and altered brain development in the fetus. The aim of this study was to use mouse neural precursor cells in vitro to assess the mechanism underlying the effects of DEA. Cells exposed to DEA treatment (3mM) proliferated less (by 5-bromo-2-deoxyuridine incorporation) at 48 hr (24% of control [CT]), and had increased apoptosis at 72 hr (308% of CT). Uptake of choline into cells was reduced by DEA treatment (to 52% of CT), resulting in diminished intracellular concentrations of choline and phosphocholine (55 and 12% of CT, respectively). When choline concentration in the growth medium was increased threefold (to 210 uM), the effects of DEA exposure on cell proliferation and apoptosis were prevented, however, intracellular phosphocholine concentrations remained low. In choline kinase assays, we observed that DEA can be phosphorylated to phospho-DEA at the expense of choline. Thus, the effects of DEA are likely mediated by inhibition of choline transport into neural precursor cells and by altered metabolism of choline. /This/ study/ suggests that prenatal exposure to DEA may have a detrimental effect on brain development. Diethanolamine increased the incidence and multiplicity of liver tumors in the mouse following chronic exposure. Diethanolamine is known to inhibit cellular choline uptake. Since choline deficiency produces tumors in rodents, diethanolamine, through choline depletion, may result in tumor development in rodents. The potential for diethanolamine to function through this mode of action in humans is not known. The present studies examined the effect of diethanolamine (0-500 mug/mL) and choline depletion on DNA synthesis and changes in expression of genes involved in cell growth pathways in primary cultures of mouse, rat, and human hepatocytes. In mouse and rat hepatocytes DNA synthesis was increased following treatment with 10 mug/mL diethanolamine and higher (3- to 4-fold over control). In contrast, diethanolamine failed to increase DNA synthesis in human hepatocytes. Incubation of hepatocytes in medium containing reduced choline (1/10 to 1/100 of normal medium; 0.898 to 0.0898 mg/L vs. 8.98 mg/L) increased DNA synthesis (1.6- and 1.8-fold of control in mouse and rat hepatocytes, respectively); however, choline depletion did not induce DNA synthesis in human hepatocytes. Mouse and rat hepatocytes incubated in medium supplemented with 2- to 50-fold excess choline reduced diethanolamine-induced DNA synthesis to control levels or below. Gene expression analysis of mouse and rat hepatocytes following diethanolamine treatment showed increases in genes associated with cell growth and decreases in expression of genes involved in apoptotic pathways. These results support the hypothesis that choline depletion is central to the mode of action for the induction of rodent hepatic neoplasia by diethanolamine. Furthermore, since diethanolamine treatment or choline depletion failed to induce DNA synthesis in human hepatocytes, these results suggest that humans may not be at risk from the carcinogenic effects of diethanolamine. Diethanolamine which interferes with phospholipid metab produced a loss of mitochondrial integrity after subacute admin to Sprague-Dawley rats. Diethanolamine inhibited in vitro synthesis of phosphatidyl choline and phosphatidyl ethanolamine in rat liver tissue.