Meloximol

Indications

• Pain and inflammation in musculoskeletal disorders
• Osteoarthritis
• Rheumatoid arthritis
• Ankylosing spondylitis

Dosage

Children: For children aged 16-17 years, the dose is 7.5 mg once daily, increased if necessary up to 15 mg once daily. For children aged 12-17

Adults: The typical adult dosage is 15 mg once daily, reduced to 7.5 mg once daily if necessary.

Mechanism of action

Meloxicam inhibits prostaglandin synthetase (cyclooxygenase 1 and 2) enzymes, resulting in decreased synthesis of prostaglandins that sensitize neuronal pain receptors. This inhibition leads to its analgesic and anti-inflammatory effects. It preferentially inhibits COX-2, which may reduce gastrointestinal irritation compared to non-selective NSAIDs.

Pharmacodynamics

Meloxicam exhibits anti-inflammatory, analgesic, and antipyretic effects. It has been shown to decrease markers of inflammation, such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), in patients with rheumatoid arthritis. While meloxicam is designed to cause less gastrointestinal irritation due to its COX-2 selectivity, it still carries risks associated with gastrointestinal symptoms, including inflammation, bleeding, and ulceration.

Pharmacokinetics

Meloxicam is well-absorbed following oral administration, with peak plasma concentrations typically reached within 4 to 5 hours. It has a half-life of approximately 15 to 20 hours, allowing for once-daily dosing. The drug is extensively metabolized in the liver, and its metabolites are primarily excreted in the urine. Patients with renal or hepatic impairment may require dose adjustments or careful monitoring due to altered pharmacokinetics.

Contra-indications

• Active gastrointestinal bleeding
• Active gastrointestinal ulceration
• History of gastrointestinal bleeding related to previous NSAID therapy
• History of significant renal impairment
• History of coronary artery bypass graft surgery
• History of hypersensitivity to aspirin or any other NSAID, including those who have experienced asthma, angioedema, urticaria, or rhinitis precipitated by these agents

Adverse effects

• Gastrointestinal discomfort
• Gastrointestinal bleeding
• Nausea
• Vomiting
• Headache
• Constipation
• Diarrhea
• Renal impairment
• Cardiovascular events
• Delayed onset of labor
• Potential exacerbation of asthma symptoms

Interactions

• Increased risk of gastrointestinal side effects when used with other NSAIDs
• May interfere with the effects of antihypertensive medications
• Caution advised with anticoagulants due to increased bleeding risk
• May reduce the effectiveness of diuretics

Precautions

• Use with caution in patients with a history of gastrointestinal disorders, such as ulcerative colitis or Crohn's disease
• Use with caution in elderly patients due to increased risk of serious side effects
• Monitor renal function in patients with renal impairment
• Long-term use may lead to decreased female fertility, which is reversible upon discontinuation

Pregnancy

Avoid unless the potential benefit outweighs the risk. Avoid during the third trimester due to risk of fetal ductus arteriosus closure and potential persistent pulmonary hypertension in the newborn.

Breast-feeding

Use with caution; present in milk in animal studies, manufacturer advises avoiding use during breastfeeding.

Storage

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

Formulations

• Meloxicam 7.5 mg oral tablets
• Meloxicam 15 mg oral tablets
• Meloxicam 500 mg oral suspension

Indications

• Bladder irrigation during urological surgery
• Irrigation for transurethral resection of the prostate gland
• Irrigation for bladder tumors

Dosage

Children: Refer to the BNF for Children for pediatric dosing guidelines.

Adults: Refer to the product literature for specific dosing information.

Mechanism of action

Glycine binds to strychnine-sensitive and strychnine-insensitive glycine receptors in the central nervous system. The strychnine-sensitive receptor is a chloride channel that enhances inhibitory neurotransmission. This action may contribute to glycine's potential antispastic effects. Additionally, glycine potentiates NMDA receptor-mediated neurotransmission, which may have implications in managing certain neurological conditions, such as neuroleptic-resistant negative symptoms in schizophrenia.

Pharmacodynamics

Glycine plays a crucial role in various biological functions, including energy metabolism and immune response. It is involved in hormone synthesis and helps in modulating neurotransmitter release, particularly in inhibitory pathways. Glycine's ability to enhance chloride conductance in neurons contributes to its antispastic properties and its potential to mitigate oxidative stress in immune responses.

Pharmacokinetics

Glycine is absorbed readily in the gastrointestinal tract and is utilized by the body for protein synthesis and other metabolic functions. The distribution of glycine in the body is widespread, as it is present in various tissues. Glycine is metabolized in the liver and other tissues, with excretion primarily occurring via the kidneys. The pharmacokinetics of glycine can be influenced by factors such as age, renal function, and overall health status.

Adverse effects

• Fluid overload
• Electrolyte imbalance
• Nausea
• Vomiting
• Headache
• Hypotension

Precautions

• Monitor for signs of fluid overload during irrigation
• Use caution in patients with pre-existing electrolyte imbalances
• Careful consideration in patients with renal impairment

Pregnancy

Glycine is generally considered safe for use during pregnancy when used as an irrigation solution, but risks should be discussed with a healthcare provider.

Breast-feeding

Glycine is likely safe during breastfeeding, but limited data is available. Consultation with a healthcare professional is advisable.

Storage

Store in a cool, dry place. Protect from light. Do not freeze.

Formulations

• Glycine 1.5% irrigation solution 3 litre Easyflow bags
• Glycine 1.5% irrigation solution 1 litre Flowfusor bottles
• Glycine 1.5% irrigation solution 1 litre Easyflow bags
• Glycine 1.5% irrigation solution 2 litre Flowfusor bottles

Indications

• Lead poisoning
• Mercury poisoning
• Calcium overload
• Certain diagnostic procedures involving heavy metals

Dosage

Children: Refer to the BNF for Children for appropriate dosing information tailored for paediatric patients.

Adults: Refer to the BNF for specific dosing guidelines based on the condition being treated, considering factors such as the severity of metal poisoning and renal function.

Mechanism of action

Edetate functions by forming stable complexes with divalent and trivalent metal ions, including lead and calcium, through its multiple carboxylate and amine groups. This chelation renders the metals more soluble and promotes their renal excretion, thereby reducing their toxic effects in the body.

Pharmacodynamics

The chelation of metals by edetate decreases the free metal concentration in the bloodstream, which mitigates the toxic effects associated with heavy metal accumulation. The efficacy of edetate in removing metals such as lead has been well documented, and its ability to bind calcium can influence calcium homeostasis in certain clinical scenarios.

Pharmacokinetics

Edetate is administered intravenously, with rapid distribution throughout the extracellular fluid. It is primarily excreted unchanged by the kidneys. The onset of action occurs quickly after administration, and the duration depends on the dose and the patient's renal function. The elimination half-life is approximately 1 hour but may vary based on renal clearance.

Contra-indications

• Hypersensitivity to edetate or any component of the formulation
• Severe renal impairment
• Active bleeding disorders

Adverse effects

• Hypocalcemia
• Nausea
• Vomiting
• Diarrhea
• Abdominal pain
• Headache
• Rash
• Fever

Interactions

• May enhance the effects of anticoagulants
• Concurrent use with calcium supplements may reduce effectiveness
• May interfere with the absorption of certain medications due to changes in gastrointestinal motility

Precautions

• Use with caution in patients with renal impairment
• Monitor electrolyte levels, particularly calcium, during treatment
• Assess the patient's hydration status before administration

Pregnancy

Limited data on the use of edetate in pregnancy. Use only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Caution is advised as it is not known whether edetate is excreted in human milk. Weigh the risks and benefits before use.

Storage

Store in a cool, dry place, protected from light. Do not freeze.

Formulations

• Edetate disodium injection
• Edetate calcium disodium injection

Indications

• Alcohol use disorder
• Acute alcohol intoxication
• Antiseptic for skin disinfection

Mechanism of action

Ethanol affects the brain’s neurons in several ways. It alters their membranes, ion channels, enzymes, and receptors. Ethanol binds directly to the receptors for acetylcholine, serotonin, GABA, and NMDA receptors for glutamate. The sedative effects are mediated through binding to GABA receptors and glycine receptors, while also inhibiting NMDA receptor functioning. As an anti-infective, ethanol acts as an osmolyte, disrupting the osmotic balance across cell membranes. The acute effects result from competitive inhibition of glycine binding to NMDA receptors, leading to disrupted glutamatergic neurotransmission.

Pharmacodynamics

Ethanol produces cellular injury through dehydration and precipitation of cytoplasm, contributing to its bactericidal and antifungal actions. It can lead to neuritis and nerve degeneration when injected near nerve tissues. Up to 98% of ethanol in the body is oxidized, primarily by the hepatic enzyme alcohol dehydrogenase. Its modulation of neurotransmitter receptors, particularly GABA and NMDA, leads to its sedative properties and potential for developing tolerance with chronic use.

Pharmacokinetics

Ethanol is readily absorbed from the gastrointestinal tract and distributed throughout the body. It has a volume of distribution of approximately 0.5 to 0.6 L/kg. Ethanol is metabolized predominantly in the liver by alcohol dehydrogenase to acetaldehyde, which is further oxidized to acetic acid by aldehyde dehydrogenase. The elimination half-life of ethanol varies but is generally around 4 to 5 hours. Factors such as age, sex, body weight, and genetic variability can influence ethanol metabolism.

Contra-indications

• Hypersensitivity to ethanol
• Acute alcohol intoxication
• Severe liver disease
• Pregnancy (in non-medicinal use)
• Severe pancreatitis
• Severe head injury or intracranial bleeding

Adverse effects

• Dizziness
• Nausea
• Vomiting
• Headache
• Sedation
• Cognitive impairment
• Respiratory depression
• Hypotension
• Gastrointestinal bleeding
• Alcohol withdrawal syndrome

Interactions

• CNS depressants (e.g., benzodiazepines, opioids) may enhance sedative effects
• Disulfiram may cause unpleasant reactions when taken with ethanol
• Acetaminophen may increase hepatic toxicity when used with ethanol
• Warfarin may have altered effects when used with ethanol

Precautions

• Caution in patients with a history of alcohol abuse
• Use with caution in patients with hepatic impairment
• Monitor for signs of respiratory depression
• Consider potential for addiction and withdrawal symptoms
• Use in moderation in older adults due to increased sensitivity

Pregnancy

Ethanol should be avoided during pregnancy due to the risk of fetal alcohol spectrum disorders.

Breast-feeding

Ethanol can pass into breast milk; breastfeeding should be avoided for a minimum of 2 hours after consumption.

Storage

Store in a cool, dry place away from light. Keep tightly closed and out of reach of children.

Formulations

• Oral solutions
• Topical antiseptics
• Intravenous formulations
• Medicinal tinctures

Indications

• Adjustment of pH in pharmaceutical formulations
• Facilitation of drug absorption
• Used in sterile preparations

Dosage

Children: Refer to specific product guidelines for dosing information, as hydrochloric acid is typically used in a controlled setting based on formulation requirements.

Adults: Refer to specific product guidelines for dosing information, as hydrochloric acid is typically used in a controlled setting based on formulation requirements.

Mechanism of action

Hydrochloric acid dissociates in aqueous solution to release hydrogen ions (H+), leading to a decrease in pH. This acidic environment promotes the activation of pepsinogen to pepsin, an enzyme essential for protein digestion. Additionally, the acidity aids in the absorption of certain minerals and drugs that require an acidic environment for optimal bioavailability.

Pharmacodynamics

The primary pharmacodynamic action of hydrochloric acid is the maintenance of gastric acidity, which is essential for normal digestive processes. The acidic environment helps in denaturing proteins, activating digestive enzymes, and providing a barrier against pathogenic microorganisms. Its effects can influence the absorption and efficacy of various medications, particularly those that are pH-dependent.

Pharmacokinetics

Hydrochloric acid does not undergo significant systemic absorption when used in its normal contexts, as it acts locally within the gastrointestinal tract. The amount of hydrochloric acid produced by the stomach varies with food intake and physiological needs. It is secreted by parietal cells in the gastric mucosa, and its secretion is regulated by neural, hormonal, and local factors. The half-life of hydrochloric acid is not applicable as it is continuously produced and neutralized within the gastrointestinal tract.

Contra-indications

• Hypersensitivity to hydrochloric acid or any of its components
• Severe renal impairment
• Active gastrointestinal bleeding

Adverse effects

• Abdominal pain
• Diarrhea
• Nausea
• Vomiting
• Esophageal irritation
• Gastric mucosal irritation
• Electrolyte imbalances

Interactions

• May interact with alkaline substances, potentially neutralizing hydrochloric acid
• Caution with antacids as they may affect the efficacy of hydrochloric acid

Precautions

• Use with caution in patients with a history of gastritis or gastric ulcers
• Monitor electrolytes in prolonged use
• Use cautiously in patients with respiratory conditions due to potential aspiration risks

Pregnancy

Hydrochloric acid is classified as a category C drug. Use during pregnancy only if clearly needed and the potential benefits justify the risks to the fetus.

Breast-feeding

There is limited data on the excretion of hydrochloric acid in human milk. Use with caution during breastfeeding.

Storage

Store in a cool, dry place away from direct sunlight and heat. Ensure the container is tightly closed.

Formulations

• Oral solutions
• Injectable forms
• Tablets

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

• Constipation
• Bowel preparation for diagnostic procedures (e.g., colonoscopy)

Dosage

Children: For children, macrogol is typically used at a dose of 0.5 to 1 g/kg per day, not exceeding 17 g per day, depending on the child's age and condition. Refer to the BNF for Children for detailed pediatric dosing guidance.

Adults: Typical adult dosing for constipation is 8.4 grams of macrogol powder dissolved in water, taken once daily. For bowel preparation, specific dosing regimens may vary, and it is essential to follow product instructions or medical advice.

Mechanism of action

Macrogol works as an osmotic agent, drawing water into the bowel lumen through osmosis. This increased water content softens the stool, making it easier to pass. The presence of macrogol in the intestine increases the volume and viscosity of the stool, stimulating peristalsis and facilitating bowel evacuation.

Pharmacodynamics

Macrogol's laxative effect is dose-dependent, with higher doses generally resulting in more significant bowel movement stimulation. It is not absorbed systemically, which minimizes potential side effects and interactions. The osmotic effect leads to an increase in intraluminal pressure and stool volume, contributing to effective evacuation.

Pharmacokinetics

Macrogol is largely non-absorbed in the gastrointestinal tract, which allows it to exert its effects locally within the bowel. Due to its high molecular weight, it remains in the intestinal lumen, where it facilitates water retention. Elimination occurs through feces, as it is not metabolized by the body.

Pregnancy

Macrogol can be used during pregnancy if necessary, but caution should be exercised and medical advice sought.

Breast-feeding

Macrogol is generally considered safe to use during breastfeeding.

Storage

Store in a cool, dry place, protected from light. Keep out of reach of children.

Indications

• Used as a solubilizing agent in pharmaceutical preparations
• Used in radiographic contrast media formulations

Dosage

Children: Refer to specific formulations for paediatric dosing instructions as it varies depending on the application.

Adults: Refer to specific formulations for adult dosing instructions as it varies depending on the application.

Mechanism of action

Meglumine acts by enhancing the solubility and stability of drugs in solution, particularly in radiographic contrast agents. It is involved in purinergic signaling pathways, which are essential for various physiological processes, including neurotransmission and inflammation.

Pharmacodynamics

The pharmacodynamic profile of meglumine is largely influenced by its role as a solubilizing agent. It does not exhibit direct pharmacological effects on its own but rather facilitates the action of other active ingredients in formulations. Its impact on purinergic signaling may contribute to modulating physiological responses in the body.

Pharmacokinetics

Meglumine is rapidly absorbed when administered, with its pharmacokinetics closely tied to the properties of the drugs it accompanies. The distribution, metabolism, and excretion of meglumine are not well-defined as it typically functions as an excipient rather than an active therapeutic agent. Its elimination from the body is primarily via renal pathways.

Pregnancy

There is insufficient data on the use of meglumine in pregnancy, therefore it should only be used if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Caution is advised when administering meglumine to breastfeeding women, as its effects on infants are not well studied.

Storage

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

Indications

• Topical drug delivery
• Emulsifying agent in pharmaceutical formulations
• Stabilizing agent in aqueous solutions
• Controlled drug release systems

Dosage

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

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

Mechanism of action

Poloxamer acts primarily by reducing the surface tension at the interface between different phases, such as oil and water. This property allows it to stabilize emulsions and improve the solubility of poorly soluble drugs. Additionally, poloxamer can form micelles in solution, encapsulating hydrophobic drugs and facilitating their delivery in the body.

Pharmacodynamics

Poloxamer exhibits surfactant properties that can enhance drug absorption and bioavailability by altering the permeability of biological membranes. Its action as a solubilizing agent can improve the pharmacological effects of drugs by ensuring they remain in a bioavailable form longer. The polymeric nature of poloxamer can also lead to sustained release of encapsulated drugs, prolonging their therapeutic effect.

Pharmacokinetics

Poloxamer is poorly absorbed when administered orally and is primarily excreted unchanged in the feces. Its absorption through the skin is minimal, making it more suitable for topical applications. The pharmacokinetics can vary based on the formulation and route of administration, with its action typically being localized rather than systemic.

Adverse effects

• Skin irritation
• Allergic reactions
• Gastrointestinal disturbances
• Headache

Precautions

• Use with caution in patients with known allergies to surfactants
• Assess for skin sensitivity before use
• Monitor for adverse reactions during therapy

Pregnancy

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

Breast-feeding

It is not known whether poloxamer is excreted in human milk. Caution is advised when administering to nursing mothers.

Storage

Store at room temperature, away from moisture and heat. Keep container tightly closed.

Formulations

• Poloxamer 188 (used as a surfactant in various formulations)
• Poloxamer 407 (used in pharmaceutical formulations and drug delivery systems)

Mechanism of action

In the CNS, there exist strychnine-sensitive glycine binding sites as well as strychnine-insensitive glycine binding sites. The strychnine-insensitive glycine-binding site is located on the NMDA receptor complex. The strychnine-sensitive glycine receptor complex is comprised of a chloride channel and is a member of the ligand-gated ion channel superfamily. The putative antispastic activity of supplemental glycine could be mediated by glycine's binding to strychnine-sensitive binding sites in the spinal cord. This would result in increased chloride conductance and consequent enhancement of inhibitory neurotransmission. The ability of glycine to potentiate NMDA receptor-mediated neurotransmission raised the possibility of its use in the management of neuroleptic-resistant negative symptoms in schizophrenia. Animal studies indicate that supplemental glycine protects against endotoxin-induced lethality, hypoxia-reperfusion injury after liver transplantation, and D-galactosamine-mediated liver injury. Neutrophils are thought to participate in these pathologic processes via invasion of tissue and releasing such reactive oxygen species as superoxide. In vitro studies have shown that neutrophils contain a glycine-gated chloride channel that can attenuate increases in intracellular calcium and diminsh neutrophil oxidant production. This research is ealy-stage, but suggests that supplementary glycine may turn out to be useful in processes where neutrophil infiltration contributes to toxicity, such as ARDS. HYPERPOLARIZATION OF MOTONEURONS PRODUCED BY IONTOPHORETIC APPLICATION OF GLYCINE IS RELATIVELY TRANSIENT BUT APPROACHES THE EQUILIBRIUM POTENTIAL FOR THE INDIRECTLY ACTIVATED INHIBITORY POSTSYNAPTIC POTENTIAL...TESTS WITH GABA... INDICATE SIMILAR ELECTROPHYSIOLOGICAL EFFECTS & SIMILAR INCR IN CL- CONDUCTANCE. MAJOR EVIDENCE THAT FAVORS GLYCINE AS MEDIATOR OF INTRASPINAL POSTSYNAPTIC INHIBITION IS THE SELECTIVE ANTAGONISM OF ITS EFFECTS BY STRYCHNINE. ... GLYCINE ALSO APPEARS TO BE MOST LIKELY TRANSMITTER FOR INHIBITORY INTERNEURONS IN RETICULAR FORMATION BUT NOT IN CUNEATE NUCLEUS.

Pharmacodynamics

Helps trigger the release of oxygen to the energy requiring cell-making process; Important in the manufacturing of hormones responsible for a strong immune system.

Mechanism of action

Meloxicam inhibits prostaglandin synthetase (cylooxygenase 1 and 2) enzymes leading to a decreased synthesis of prostaglandins, which normally mediate painful inflammatory symptoms. As prostaglandins sensitize neuronal pain receptors, inhibition of their synthesis leads to analgesic and inflammatory effects. Meloxicam preferentially inhibits COX-2, but also exerts some activity against COX-1, causing gastrointestinal irritation. Meloxicam, an oxicam derivative that is structurally related to piroxicam, is a nonsteroidal anti-inflammatory agent (NSAIA) exhibiting analgesic, antipyretic, and anti-inflammatory actions. In vitro and in vivo studies indicate that meloxicam inhibits the cyclooxygenase-2 (COX-2) isoform of prostaglandin endoperoxide synthase (prostaglandin G/H synthase [PGHS]) to a greater extent than the COX-1 isoform. However, meloxicam's COX-2 selectivity is dose dependent and is diminished at higher dosages. Therefore meloxicam sometimes has been referred to as a "preferential" rather than "selective" COX-2 inhibitor. To investigate the effect of meloxicam on human polymorphonuclear leukocyte (PMN) adhesion to human synovial cell (HSC), and to explore its mechanism. MTT colorimetry was used to determine the adhesion effect of PMN to HSC. Cell-ELISA and RT-PCR methods were used to determine the expression of ICAM-1 and VCAM-1. Nuclear transcription factor-kappa B (NF-kappa B) was measured by electrophoretic mobility shift assay (EMSA) method. Meloxicam was found to effectively inhibit TNF-alpha (50 u.mL-1 for 12 hr) and IL-1 beta (50 u.mL-1 for 12 hr)-induced adhesion of PMN to HSC (IC50 3.38 X 10(-7) mol.L-1 and 3.56 X 10(-6) mol.L-1, respectively) in a concentration-dependent manner. ICAM-1 protein and mRNA expression induced by TNF-alpha (50 u.mL-1) were inhibited by meloxicam at 1 X 10(-6)-1 X 10(-5) mol.L-1. The activation of NF-kappa B was also inhibited by meloxicam at 1 X 10(-6)-1 X 10(-5) mol.L-1. These results suggest that meloxicam inhibit TNF-alpha stimulated PMN-HSC adhesion and expression of ICAM-1 by suppressing the activity of NF-kappa B. /Investigators/ compared the effects of therapeutically equivalent doses of meloxicam and indomethacin, a preferential inhibitor of the constitutive cyclooxygenase (COX-1), on platelet aggregation and platelet thromboxane formation, which are exclusively COX-1 dependent, physiological renal, and total body prostaglandin E2 (PGE2) production. In a randomized cross-over design, 14 healthy female volunteers received meloxicam 7.5 mg per day for 6 days or indomethacin 25 mg three times per day for 3 days; the wash-out period was 5 days, and drug intake was adapted to the menstrual cycle. On the day before treatment and on the last day of each treatment period the following parameters were evaluated: maximum platelet aggregation and thromboxane B2 (TXB2) formation in response to 1.0 mmol/L arachidonic acid; 24-hour urinary excretion of PGE2 and 7 alpha-hydroxy-5, 11-diketo-tetranor-prosta-1, 16-dionic acid (PGE-M), the index metabolites of renal and total body PGE2 synthesis, respectively, were assessed by gas chromatography/tandem mass spectrometry. Maximum platelet aggregation and TXB2 formation were almost completely inhibited by indomethacin (-87% and -99%, respectively; p < 0.001, each) as compared to control (100%), but remained unaffected by meloxicam (-1% and +4%, respectively). Meloxicam showed no significant effects on urinary PGE2 excretion (-13%) and only slight effects on PGE-M excretion (-22%; p < 0.05), whereas indomethacin reduced urinary PGE2 excretion (-43%; p < 0.05) as well as PGE-M excretion (-36%; p < 0.001). /This/ data shows, that meloxicam 7.5 mg per day is COX-1 sparing in humans in vivo.

Pharmacodynamics

Meloxicam is an anti-inflammatory, analgesic analgesic with antipyretic effects in fever. Prostaglandins are substances that contribute to inflammation. This drug also exerts preferential actions against COX-2, which may reduce the possible gastrointestinal effects of this drug. In humans, meloxicam has demonstrated the ability to decrease erythrocyte sedimentation rate(ESR) in patients with rheumatoid arthritis, and to decrease ESR, C-reactive protein (CRP), as well as aquaporin-1 expression. As with other NSAIDS, prolonged use of meloxicum can result in renal or cardiovascular impairment or thrombotic cardiovascular events. A note on gastrointestinal effects As meloxicam preferentially inhibits COX-2, it is thought to cause less gastrointestinal irritation compared to other NSAIDS. Despite this, it still carries a risk of gastric inflammation, bleeding and ulceration. In one study, patients on meloxicam suffered from gastrointestinal symptoms at a rate of 13% compared to 19% of those on [diclofenac]. GI events were found to be less severe in the meloxicam-treated patients.

Mechanism of action

Ethanol affects the brain’s neurons in several ways. It alters their membranes as well as their ion channels, enzymes, and receptors. Alcohol also binds directly to the receptors for acetylcholine, serotonin, GABA, and the NMDA receptors for glutamate. The sedative effects of ethanol are mediated through binding to GABA receptors and glycine receptors (alpha 1 and alpha 2 subunits). It also inhibits NMDA receptor functioning. In its role as an anti-infective, ethanol acts as an osmolyte or dehydrating agent that disrupts the osmotic balance across cell membranes. ... Ethanol is known to affect a large number of membrane proteins that participate in signaling pathways such as neurotransmitter receptors, enzymes, and ion channels, and there is extensive evidence that ethanol interacts with a variety of neurotransmitters. The major actions of ethanol involve enhancing the inhibitory effects of gamma-aminobutyric acid (GABA) at GABAa receptors and blockade of the N-methyl-D-aspartate (NMDA) subtype of glutamate, an excitatory amine acid (EAA) receptor. Animal studies indicate that the acute effects of ethanol result from competitive inhibition of glycine binding to NMDA receptor and disruption of glutamatergic neurotransmission by inhibiting the response of the NMDA receptor. Persistent glycine antagonism and attenuation of glutamatergic neurotransmission by chronic ethanol exposure results in tolerance to ethanol by enhancing EAA neurotransmission and NMDA receptor upregulation. The latter appears to involve selective increases in NMDA R2B subunit concentrations and other molecular changes in specific brain loci. The abrupt withdrawal of ethanol thus produces a hyperexcitable state that leads to the ethanol withdrawal syndrome and excitotoxic neuronal death. GABA-mediated inhibition, which normally acts to limit excitation, is eliminated during ethanol withdrawal syndrome and further intensifies this excitation. In addition, NMDA receptors function to inhibit the release of dopamine in the nucleus accumbens and mesolimbic structures, which modulate the reinforcing action of addictive xenobiotics such as ethanol. By inhibiting NMDA receptor activity, ethanol could increase dopamine release from the nucleus accumbens and ventral tegmental area and could thus create dependence. Chronic ethanol administration also results in tolerance, dependence, and an ethanol withdrawal syndrome, mediated, in part, by desensitization and or downregulation of GABAa receptors. The development of alcoholic ketoacidosis (AKA) requires that a combination of physical and physiologic events occur. The normal response to starvation and depletion of hepatic glycogen stores is for amino acids to be converted to pyruvate. Pyruvate can serve as a substrate for gluconeogenesis, be converted to acetyl-CoA, which can enter the Krebs cycle or can be utilized in various biosynthetic pathways (eg, fatty acid, ketone bodies, cholesterol, and acetylcholine) ... Ethanol metabolism generates NADH, resulting in an excess of reducing potential. This high redox state favors the conversion of pyruvate to lactate, diverting pyruvate from being a substrate for gluconeogenesis. To compensate for the lack of normal metabolic substrates, the body mobilizes fat from adipose tissue and increased fatty acid metabolism as an alternative source of energy. This response is mediated by a decrease in insulin and an increased secretion of glucagon, catecholamines, growth hormone, and cortisol. Fatty acid metabolism results in the formation of acetyl-CoA and it combines with the excess acetate that is generated from ethanol metabolism to form acetoacetate. Most of the acetoacetate is reduced to beta-hydroxybutyrate due to the excess reducing potential or high redox state of the cell. Volume depletion interferes with the renal elimination of acetoacetate and beta-hydroxybutyrate, and contributes to the acidosis. An elevated lactate concentration may result from shunting from pyruvate or

Pharmacodynamics

Alcohol produces injury to cells by dehydration and precipitation of the cytoplasm or protoplasm. This accounts for its bacteriocidal and antifungal action. When alcohol is injected in close proximity to nerve tissues, it produces neuritis and nerve degeneration (neurolysis). Ninety to 98% of ethanol that enters the body is completely oxidized. Ethanol is also used as a cosolvent to dissolve many insoluble drugs and to serve as a mild sedative in some medicinal formulations. Ethanol also binds to GABA, glycine, NMDA receptors and modulates their effects. Ethanol is also metabolised by the hepatic enzyme alcohol dehydrogenase.

Mechanism of action

Ethylene glycol is metabolized by alcohol dehydrogenase to glycoaldehyde, which is then metabolized to glycolic, glyoxylic, and oxalic acids. These acids, along with excess lactic acid are responsible for the anion gap metabolic acidosis. Oxalic acid readily precipitates with calcium to form insoluble calcium oxalate crystals. Tissue injury is caused by widespread deposition of oxalate crystals and the toxic effects of glycolic and glyoxylic acids.