Furozyd

Indications

• Oedema associated with congestive heart failure
• Oedema due to hepatic cirrhosis
• Nephrotic syndrome

Mechanism of action

Furosemide promotes diuresis by blocking tubular reabsorption of sodium and chloride in the proximal and distal tubules, as well as in the thick ascending loop of Henle. This is achieved through competitive inhibition of sodium-potassium-chloride cotransporters (NKCC2), preventing sodium reabsorption and consequently increasing the excretion of water, sodium, chloride, magnesium, calcium, hydrogen, and potassium ions. Furosemide also exerts direct vasodilatory effects, which contribute to its effectiveness in treating acute pulmonary edema.

Pharmacodynamics

Furosemide effectively manages hypertension and edema associated with congestive heart failure, cirrhosis, and renal disorders, including nephrotic syndrome. It enhances renal excretion of sodium and water by inhibiting their reabsorption from the nephron, resulting in increased urine production. The diuretic effect begins within 1 to 1.5 hours after oral administration, with peak effects occurring within 2 hours and lasting 4 to 6 hours. Intravenous administration leads to rapid effects, with onset within 5 minutes and peak effects at 30 minutes.

Pharmacokinetics

Furosemide is well-absorbed when given orally, with a bioavailability of approximately 50-70%. It is extensively protein-bound (approximately 95-98%) and is secreted via active transport mechanisms in the kidneys. The elimination half-life is about 1-2 hours in healthy individuals, but this can be prolonged in patients with renal impairment. Furosemide is excreted primarily through the kidneys, with a significant portion undergoing hepatic metabolism. Monitoring of electrolytes is necessary due to the risk of hypokalemia and other electrolyte imbalances.

Contra-indications

• Addison's disease
• anuria
• comatose or pre-comatose states associated with liver cirrhosis
• dehydration
• hyperkalaemia
• hypovolaemia
• resistant oedema
• hypotension
• impaired micturition
• prostatic enlargement

Adverse effects

• agranulocytosis
• aplastic anaemia
• dehydration
• hypotension
• malaise
• mucosal reaction
• nephritis
• tubulointerstitial nephritis
• pancreatitis
• acute kidney injury
• hepatic disorders
• skin eruption
• tetany
• vasculitis
• hearing impairment
• gastrointestinal discomfort
• gynaecomastia
• musculoskeletal pain
• hyperglycaemia
• hyperuricaemia
• muscle cramps

Interactions

• aliskiren + furosemide: Unknown (decreases exposure)
• leflunomide + furosemide: Unknown (increases exposure)
• nitisinone + furosemide: Unknown (increases exposure)
• teriflunomide + furosemide: Unknown (increases exposure)

Precautions

• Caution in patients with hepatorenal syndrome
• Caution in patients with hypoproteinaemia as it may reduce diuretic effect and increase risk of side effects
• Should correct hypovolaemia before initiation of treatment
• Monitor plasma-potassium concentration
• Monitor electrolytes

Pregnancy

Furosemide should not be used to treat gestational hypertension because of the maternal hypovolaemia associated with this condition.

Breast-feeding

Manufacturers advise avoiding use during breastfeeding as furosemide may inhibit lactation; however, the amount in milk is too small to be harmful.

Storage

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

Formulations

• Tablets
• Oral suspension
• Oral solution

Indications

• Skin disinfection
• Preparation of skin before injections
• Cleansing minor wounds

Dosage

Children: Apply to the skin as required; consult product literature for specific guidance.

Adults: Apply to the skin as required for disinfection.

Mechanism of action

Alcohol exerts its antiseptic effect by denaturing proteins, disrupting cell membranes, and dehydrating microbial cells, leading to cell lysis and death.

Pharmacodynamics

Alcohol has broad-spectrum antimicrobial activity, effective against bacteria, fungi, and viruses. Its efficacy is influenced by concentration, with higher concentrations generally being more effective.

Pharmacokinetics

Alcohol is rapidly absorbed through the skin and mucous membranes. It is metabolized primarily in the liver, with a half-life that varies based on the individual's metabolic rate and the amount consumed.

Contra-indications

• Concomitant use with lithium
• Regular use in neonates
• Patients with severe burns when diathermy has been preceded by application of alcoholic skin disinfectants

Adverse effects

• Eye erythema
• Punctate keratitis
• Cytotoxicity
• Eye discolouration

Interactions

• Increases risk of visual disturbances with antiepileptics
• Increases concentration with methylphenidate
• Increases risk of facial flushing and skin irritation with topical pimecrolimus
• Increases concentration with retinoids
• Increases concentration with acitretin
• Increases risk of facial flushing and skin irritation with topical tacrolimus
• Decreases antidiuretic effect with vasopressin

Precautions

• Avoid regular application to inflamed or broken skin or mucosa
• Avoid broken skin
• Flammable

Pregnancy

Sufficient iodine may be absorbed to affect the fetal thyroid in the second and third trimester.

Breast-feeding

Avoid regular or excessive use.

Storage

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

Formulations

• Betadine 2.5% dry powder spray
• Industrial methylated spirit
• Povidone-Iodine 25 mg per 1 gram

Indications

• Bacterial infections
• Pneumonia
• Meningitis
• Syphilis
• Endocarditis
• Skin and soft tissue infections

Dosage

Children: Paediatric dosing for benzylpenicillin is determined by the child's weight and the severity of the infection. Refer to the BNF for Children for specific dosing guidelines.

Adults: The usual adult dose for benzylpenicillin varies based on the type and severity of the infection. It is generally administered via intramuscular or intravenous routes. For severe infections, doses may range from 1 to 4 million units every 4 to 6 hours.

Mechanism of action

Benzylpenicillin exerts its antibacterial effects by inhibiting the synthesis of bacterial cell walls. It binds to penicillin-binding proteins (PBPs) located inside the bacterial cell wall, disrupting the transpeptidation process, which is crucial for cross-linking peptidoglycan layers. This inhibition leads to cell lysis and death of the bacteria.

Pharmacodynamics

Benzylpenicillin demonstrates time-dependent bactericidal activity, meaning its effectiveness is related to the duration of time the drug concentration remains above the minimum inhibitory concentration (MIC) for the target bacteria. It has a narrow spectrum of activity, primarily targeting Gram-positive cocci and some Gram-negative rods.

Pharmacokinetics

Benzylpenicillin is typically administered parenterally due to poor oral absorption. It is rapidly distributed throughout the body and can penetrate various tissues, including the central nervous system during inflammation. The drug is primarily eliminated by renal excretion, with a half-life of approximately 30 minutes to 1 hour in healthy individuals. Dosage adjustments may be necessary in patients with renal impairment.

Interactions

• leflunomide+benzylpenicillin: Unknown (increases exposure)
• nitisinone+benzylpenicillin: Unknown (increases exposure)
• teriflunomide+benzylpenicillin: Unknown (increases exposure)

Pregnancy

Benzylpenicillin is generally considered safe to use during pregnancy, as it is a penicillin antibiotic and has a long history of use.

Breast-feeding

Benzylpenicillin is excreted in breast milk in small amounts, but it is not expected to have adverse effects on a nursing infant.

Storage

Store in a cool, dry place, protected from light. Reconstituted solutions should be used promptly or stored in a refrigerator and used within a limited time frame.

Formulations

• Benzylpenicillin injection

Indications

• Electrolyte replacement
• Volume expansion in hypovolemic patients
• Management of hyponatremia
• Support in intravenous fluid therapy

Dosage

Children: Refer to the BNF for Children for appropriate dosing in paediatric patients, as dosages may vary based on the formulation and clinical condition.

Adults: Refer to specific product information or clinical guidelines for dosage recommendations, as disodium is often part of combination products.

Mechanism of action

Disodium compounds often function by providing sodium ions that are essential for various physiological processes. Sodium ions play a critical role in maintaining osmotic balance, nerve impulse transmission, and muscle contraction. In the context of intravenous solutions, disodium helps to restore electrolyte balance in patients.

Pharmacodynamics

The pharmacodynamics of disodium is primarily related to its role in electrolyte balance and fluid homeostasis. Sodium ions are vital for the function of excitable tissues, including neurons and muscle cells. Changes in sodium levels can affect blood pressure, hydration status, and overall cellular function.

Pharmacokinetics

The pharmacokinetics of disodium compounds depend on their specific formulation and route of administration. When administered intravenously, disodium is rapidly distributed in the extracellular fluid, where it helps to maintain osmotic pressure. Sodium is primarily excreted by the kidneys, and its levels can be influenced by fluid intake, dietary sodium, and renal function.

Pregnancy

Use with caution. Consult a healthcare provider for specific guidance.

Breast-feeding

Use with caution. Consult a healthcare provider for specific guidance.

Storage

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

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

• 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.

Dosage

Children: Refer to specific product guidelines for dosing information, as monoethanolamine is primarily used in industrial applications and as a chemical intermediate rather than a therapeutic agent.

Adults: Refer to specific product guidelines for dosing information, as monoethanolamine is primarily used in industrial applications and as a chemical intermediate rather than a therapeutic agent.

Mechanism of action

Monoethanolamine acts by participating in the biosynthesis of phospholipids. It is involved in the formation of phosphatidylethanolamine and other phospholipids that are crucial for maintaining cell membrane integrity and function. This compound's role in lipid metabolism indicates its significance in cellular signaling and membrane fluidity.

Pharmacodynamics

Monoethanolamine's pharmacodynamic properties are linked to its function as a precursor in the synthesis of phospholipids. These phospholipids play critical roles in cell membrane structure, signaling pathways, and cellular communication. The modulation of phospholipid composition can influence cellular responses to various stimuli, highlighting the compound's importance in cell biology.

Pharmacokinetics

The pharmacokinetics of monoethanolamine are not well-documented in the available literature. However, as a small molecule, it is likely to be absorbed readily and distributed throughout the body. Its metabolic pathways involve conversion into various phospholipids, and it may be excreted as part of these metabolites. Additional studies would be needed to detail its absorption, distribution, metabolism, and excretion (ADME) characteristics.

Pregnancy

There is insufficient data on the use of monoethanolamine in pregnancy. Caution is advised.

Breast-feeding

There is limited information on the effects of monoethanolamine during breastfeeding. Caution is recommended if used.

Storage

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

Dosage

Children: Refer to specific product information for dosing instructions.

Adults: Refer to specific product information for dosing instructions.

Pregnancy

Consult with a healthcare provider for risk assessment and recommendations during pregnancy.

Breast-feeding

Consult with a healthcare provider to determine safety and necessity of medication while breastfeeding.

Storage

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

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.

Indications

• Preservative in food and beverages
• Antioxidant agent
• Treatment of certain types of sulfite sensitivity

Dosage

Children: Refer to the BNF for Children for appropriate dosing information.

Adults: Refer to the specific product guidelines, as dosages may vary depending on the formulation and intended use.

Mechanism of action

Sulphite acts through various biochemical pathways, including the degradation of sulfoacetaldehyde and thiosulfate metabolism. It participates in the dissimilatory sulfate reduction process, converting sulfate to hydrogen sulfide, which is integral to sulfur cycling in the environment. Additionally, sulphites are involved in the degradation of tetrachloroethene and hypotaurine, highlighting their versatility in metabolic pathways.

Pharmacodynamics

The pharmacodynamics of sulphite involves its reactivity as a reducing agent and its ability to form complexes with various organic molecules. This property allows sulphite to function as an antioxidant, scavenging free radicals and preventing oxidative damage. However, excessive exposure to sulphite can lead to adverse effects, particularly in susceptible individuals, where it may provoke hypersensitivity reactions.

Pharmacokinetics

The pharmacokinetics of sulphite in humans are not extensively characterized, but it is known to be rapidly absorbed and metabolized. Once ingested, sulphite can be oxidized to sulfate, which is then excreted in urine. The metabolism and elimination of sulphite are influenced by factors such as liver function, individual susceptibility, and dietary intake. The half-life of sulphite in the body is relatively short, necessitating regular intake for sustained effects.

Pregnancy

There is limited data on the safety of sulphites in pregnancy. Caution is advised.

Breast-feeding

Limited data available; consult a healthcare provider for specific advice regarding breastfeeding.

Storage

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

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

Furosemide promotes diuresis by blocking tubular reabsorption of sodium and chloride in the proximal and distal tubules, as well as in the thick ascending loop of Henle. This diuretic effect is achieved through the competitive inhibition of sodium-potassium-chloride cotransporters (NKCC2) expressed along these tubules in the nephron, preventing the transport of sodium ions from the lumenal side into the basolateral side for reabsorption. This inhibition results in increased excretion of water along with sodium, chloride, magnesium, calcium, hydrogen, and potassium ions. As with other loop diuretics, furosemide decreases the excretion of uric acid. Furosemide exerts direct vasodilatory effects, which results in its therapeutic effectiveness in the treatment of acute pulmonary edema. Vasodilation leads to reduced responsiveness to vasoconstrictors, such as angiotensin II and noradrenaline, and decreased production of endogenous natriuretic hormones with vasoconstricting properties. It also leads to increased production of prostaglandins with vasodilating properties. Furosemide may also open potassium channels in resistance arteries. The main mechanism of action of furosemide is independent of its inhibitory effect on carbonic anhydrase and aldosterone. Though both in vivo and in vitro studies have demonstrated an anticonvulsant effect of the loop diuretic furosemide, the precise mechanism behind this effect is still debated. The current study investigates the effect of furosemide on Cs-induced epileptiform activity (Cs-FP) evoked in area CA1 of rat hippocampal slices in the presence of Cs(+) (5mM) and ionotropic glutamatergic and GABAergic receptor antagonists. As this model diverges in several respects from other epilepsy models it can offer new insight into the mechanism behind the anticonvulsive effect of furosemide. The present study shows that furosemide suppresses the Cs-FP in a dose-dependent manner with a near complete block at concentrations = 1.25 mM. Because furosemide targets several types of ion transporters we examined the effect of more selective antagonists. Bumetanide (20 uM), which selectively inhibits the Na-K-2Cl co-transporter (NKCC1), had no significant effect on the Cs-FP. VU0240551 (10 uM), a selective antagonist of the K-Cl co-transporter (KCC2), reduced the ictal-like phase by 51.73 +/- 8.5% without affecting the interictal-like phase of the Cs-FP. DIDS (50 uM), a nonselective antagonist of Cl(-)/HCO3(-)-exchangers, Na(+)-HCO3(-)-cotransporters, chloride channels and KCC2, suppressed the ictal-like phase by 60.8 +/- 8.1% without affecting the interictal-like phase. At 500 uM, DIDS completely suppressed the Cs-FP. Based on these results we propose that the anticonvulsant action of furosemide in the Cs(+)-model is exerted through blockade of the neuronal KCC2 and Na(+)-independent Cl(-)/HCO3(-)-exchanger (AE3) leading to stabilization of the activity-induced intracellular acidification in CA1 pyramidal neurons. Sodium chloride reabsorption in the thick ascending limb of the loop of Henle is mediated by the Na(+)-K(+)-2Cl(-) cotransporter (NKCC2). The loop diuretic furosemide is a potent inhibitor of NKCC2. However, less is known about the mechanism regulating the electrolyte transporter. Considering the well-established effects of nitric oxide on NKCC2 activity, cGMP is likely involved in this regulation. cGMP-dependent protein kinase I (cGKI; PKGI) is a cGMP target protein that phosphorylates different substrates after activation through cGMP. We investigated the potential correlation between the cGMP/cGKI pathway and NKCC2 regulation. We treated wild-type (wt) and cGKIa-rescue mice with furosemide. cGKIa-rescue mice expressed cGKIa only under the control of the smooth muscle-specific transgelin (SM22) promoter in a cGKI deficient background. Furosemide treatment increased the urine excretion of sodium and chloride in cGKIa-rescue mice compared to that in wt mice. We analyzed the phosphorylation of NKC

Pharmacodynamics

Furosemide manages hypertension and edema associated with congestive heart failure, cirrhosis, and renal disease, including the nephrotic syndrome. Furosemide is a potent loop diuretic that works to increase the excretion of Na+ and water by the kidneys by inhibiting their reabsorption from the proximal and distal tubules, as well as the loop of Henle. It works directly acts on the cells of the nephron and indirectly modifies the content of the renal filtrate. Ultimately, furosemide increases the urine output by the kidney. Protein-bound furosemide is delivered to its site of action in the kidneys and secreted via active secretion by nonspecific organic transporters expressed at the luminal site of action. Following oral administration, the onset of the diuretic effect is about 1 and 1.5 hours, and the peak effect is reached within the first 2 hours. The duration of effect following oral administration is about 4-6 hours but may last up to 8 hours. Following intravenous administration, the onset of effect is within 5 minutes, and the peak effect is reached within 30 minutes. The duration of action following intravenous administration is approximately 2 hours. Following intramuscular administration, the onset of action is somewhat delayed.