Furosemide
Furosemide (INN) or frusemide (former BAN) is a loop diuretic used in the treatment of congestive heart failure and edema. It is most commonly marketed by Sanofi-Aventis under the brand name Lasix. It has also been used to prevent thoroughbred and standardbred race horses from bleeding through the nose during races.
Along with some other diuretics, furosemide is also included on the World Anti-Doping Agency'sbanned drug list due to its alleged use as a masking agent for other drugs.
Mechanism of action
Furosemide, like other loop diuretics, acts by inhibiting NKCC2, the luminal Na-K-2Cl symporterin the thick ascending limb of the loop of Henle. The action on the distal tubules is independent of any inhibitory effect on carbonic anhydrase or aldosterone; it also abolishes the corticomedullary osmotic gradient and blocks negative as well as positive free water clearance.
Due to the large NaCl absorptive capacity of the Loop of Henle, diuresis is not limited by development of acidosis, as it is with the carbonic anhydrase inhibitors.
By inhibiting the transporter, the loop diuretics reduce the reabsorption of NaCl and also diminish the lumen-positive potential that derives from K+ recycling. This electrical potential normally drives divalent cation reabsorbtion in the loop, and by reducing this potential loop diuretics cause an increase in Mg2+ and Ca2+ excretion. Prolonged use can cause significant hypomagnesemiain some patients. Since Ca2+ is actively reabsorbed in the distal convoluted tubule, loop diuretics do not generally cause hypocalcemia.
Additionally, furosemide is a noncompetitive subtype-specific blocker of GABA-A receptors. Furosemide has been reported to reversibly antagonize GABA-evoked currents of α6β2γ2 receptors at µM concentrations, but not α1β2γ2 receptors. During development, the α6β2γ2 receptor increases in expression in cerebellar granule neurons, corresponding to increased sensitivity to furosemide
Clinical use in humans
Furosemide, as a loop diuretic, is principally used in the following indications (Aventis, 1998):
§ Edema associated with heart failure, hepatic cirrhosis, renal impairment, nephrotic syndrome
§ Adjunct in cerebral/pulmonary edema where rapid diuresis is required (IV injection)
It is also sometimes used in the management of severe hypercalcemia in combination with adequate rehydration.
Although disputed, it is considered ototoxic: "usually with large parenteral doses and rapid administration and in renal impairment"
The tendency, as for all loop diuretics, to cause low potassium levels (hypokalemia) has given rise to combination products, either with potassium itself (e.g. Lasix-K) or with the potassium sparing diuretic of amiloride (Co-amilofruse).
Precautions, side-effects, and administration
Furosemide is injected either intramuscularly (IM) or intravenously (IV), usually 0.5-1.0 mg/kg 2x/day, although less before a horse is raced. As with many diuretics, it can cause dehydration and electrolyte imbalance, including loss of potassium, calcium, sodium, and magnesium. It is especially important to prevent potassium loss. Excessive use of Furosemide will most likely lead to a metabolic alkalosis due tohypochloremia and hypokalemia. The drug should therefore not be used in horses that are dehydrated or experiencing kidney failure. It should be used with caution in horses with liver problems or electrolyte abnormalities. Overdose may lead to dehydration, change in drinking patterns and urination, seizures, GI problems, kidney damage, lethargy, collapse, and coma.
Furosemide should be used with caution when combined with corticosteroids (as this increases the risk of electrolyte imbalance), aminoglycoside antibiotics (increases risk of kidney or ear damage), and trimethoprim sulfa (causes decreased platelet count). It may also cause interactions with anesthesics, so its use should be related to the veterinarian if the animal is going into surgery, and it decreases the kidney's ability to excrete aspirin, so dosages will need to be adjusted if combined with that drug
Furosemide may increase the risk of digoxin toxicity due to hypokalemia.
The drug is best not used during pregnancy or in a lactating mare, as it has been shown to be passed through the placenta and milk in studies with other species. It should not be used in horses with pituitary pars intermedia dysfunction (Cushings).
Furosemide is detectable in urine 36–72 hours following injection. Its use is prohibited by most equestrian organizations.
Drug Interactions
Furosemide has potential interactions with the following medications:
§ Aminoglycoside antibiotics such as Gentamicin
§ Aspirin and other salicylates
§ Other diuretics (e.g. ethacrynic acid, hydrochlorothiazide)
§ Lithium
§ Synergistic effects with other antihypertensives (e.g. Doxazosin)
Bumetanide
Bumetanide (trade names Bumex or Burinex) is a loop diuretic of the sulfamyl category to treat heart failure. It is often used in people in whom high doses of furosemide are ineffective. It is marketed by Hoffmann-La Roche. The main difference between the two substances is inbioavailability and pharmacodynamic potency. Furosemide is incompletely absorbed in the intestine (60%), and there is substantial inter- and intraindividual differences in bioavailability (range 10-90%). Bumetanide is almost completely absorbed (80%), and the absorption is not altered when it is taken with food. It is said to be a more predictable diuretic, meaning that the predictable absorption is reflected in a more predictable effect.
Bumetanide is 40 times more potent than furosemide (for patients with normal renal function).
In the brain, bumetanide blocks the NKCC1 cation-chloride co-transporter, and thus decreases internal chloride concentration in neurons. In turn, this concentration change makes the action ofGABA more hyperpolarizing, which may be useful for treatment of neonatal seizures, that quite often are not responsive to traditional GABA-targeted treatment, such as barbiturates. Bumetanide is therefore currently under evaluation as a prospective antiepileptic drug
TORSEMIDE
USES: Torsemide is a "water pill" (diuretic) that increases the amount of urine you make, which causes your body to get rid of excess water. This drug is used to treathigh blood pressure. Lowering high blood pressure helps prevent strokes, heart attacks, and kidney problems.This medication also reduces swelling/fluid retention (edema) which can result from conditions such as congestive heart failure, liver disease, or kidney disease. This can help to improve symptoms such as trouble breathing.
HOW TO USE: Take this medication by mouth with or without food, usually once a day, or as directed by your doctor. The dosage is based on your medical condition and response to therapy.If you take this drug too close to bedtime, you may need to wake up to urinate. Therefore, it is best to take this medication at least 4 hours before your bedtime. Consult your doctor or pharmacist if you have questions about your dosing schedule.Use this medication regularly in order to get the most benefit from it. Remember to use it at the same time each day as directed. It is important to continue taking this medication even if you feel well. Most people with high blood pressure do not feel sick. Generally, it may take 4-6 weeks, sometimes up to 12 weeks, before the full blood pressure-lowering effect is seen. Do not stop taking this medication without consulting your doctor.Cholestyramine and colestipol can decrease the absorption of torsemide. If you are taking either of these drugs, separate it from torsemide by at least 2 hours.If your condition persists or worsens, contact your doctor or pharmacist.
SIDE EFFECTS: Dizziness, lightheadedness, headache, blurred vision, loss of appetite, stomach upset, diarrhea, or constipation may occur as your body adjusts to the medication. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.This medication may lead to excessive loss of body water and minerals (including potassium). Tell your doctor immediately if you have any of these unlikely but serious symptoms of dehydration or mineral loss: muscle cramps or weakness, confusion, severe dizziness, drowsiness, unusual dry mouth or thirst, nausea or vomiting, fast/irregular heartbeat, unusual decrease in the amount of urine, fainting, seizures.Tell your doctor immediately if any of these unlikely but serious side effects occur: numbness/tingling of the arms/legs, ringing in the ears, hearing loss, decreased sexual ability.Tell your doctor immediately if any of these highly unlikely but very serious side effects occur: signs of infection (e.g., fever, persistent sore throat), easy bleeding or bruising, stomach/abdominal pain, persistent nausea/vomiting, yellowing of eyes/skin.A serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction include: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing
PRECAUTIONS: Before taking torsemide, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: severe kidney disease (inability to make urine or anuria).Before using this medication, tell your doctor or pharmacist your medical history, especially of: kidney disease, liver disease, untreated mineral imbalance (e.g., sodium, potassium), gout, lupus.If you have diabetes, torsemide may infrequently worsen control of blood glucose levels. Monitor your blood glucose levels regularly and inform your doctor of the results.This drug may reduce the potassium levels in your blood. Ask your doctor about adding potassium to your diet. A potassium supplement may be prescribed by your doctor.This medication may make you more sensitive to the sun. Avoid prolonged sun exposure, tanning booths or sunlamps. Use a sunscreen and wear protective clothing when outdoors.Before having surgery, tell your doctor or dentist that you are taking this medication.This drug may make you dizzy or drowsy or cause blurred vision. Do not drive, use machinery, or do any activity that requires alertness or clear vision until you are sure you can perform such activities safely. Limit alcoholic beverages.To minimize dizziness and lightheadedness, get up slowly when rising from a seated or lying position.Caution is advised when using this drug in the elderly because they may be more sensitive to its effects, especially dizziness.Torsemide should be used only when clearly needed during pregnancy. Discuss the risks and benefits with your doctor.It is unknown if this drug passes into breast milk. Consult your doctor before breast-feeding.
DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with them first.See also the How to Use section.This drug should not be used with the following medication because very serious interactions may occur: cisapride.If you are currently using this medication, tell your doctor or pharmacist before starting torsemide.Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: other drugs that can affect hearing/balance (e.g., ethacrynic acid, aminoglycoside antibiotics such as gentamicin, tobramycin), amphotericin B, cholestyramine, cisplatin, colestipol, corticosteroids (e.g., prednisone), digoxin, lithium, nonsteroidal anti-inflammatory drugs (NSAIDs such as ibuprofen, indomethacin), large doses of aspirin and aspirin-like drugs (salicylates).Check the labels on all your medicines (e.g., cough-and-cold products, diet aids, NSAIDs for pain/fever reduction) because they may contain ingredients that could increase your blood pressure or swelling (edema). Ask your pharmacist about the safe use of those products.This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.
Ethacrynic acid
Etacrynic acid (INN) or ethacrynic acid (USAN), trade name Edecrin, is a loop diuretic used to treat high blood pressure and the swelling caused by diseases like congestive heart failure,liver failure, and kidney failure.
Unlike the other loop diuretics, etacrynic acid is not a sulfonamide[1] and thus, its use is not contraindicated in those with sulfa allergies.
Etacrynic acid is a phenoxyacetic acid derivative containing a ketone and a methylene group. A cysteine adduct is formed with the methylene group and this is the active form.
Adverse effects
As a diuretic, etacrynic acid can cause frequent urination, but this usually resolves after taking the drug for a few weeks.
Etacrynic acid can also cause low potassium levels, which may manifest as muscle cramps or weakness. It has also been known to cause reversible or permanent hearing loss (ototoxicity)[2]and liver damage.[3] On oral administration, it produces diarrhea; intestinal bleeding may occur at higher doses.
Mechanism of action]
Etacrynic acid acts by inhibiting sodium-potassium-chloride cotransport in the ascending loop of Henle. Loss of potassium ions is less marked but chances of hypochloremic alkalosis are greater. The dose response curve of ethacrynic acid is steeper than that of furosemide and, in general, it is less manageable; dose range is 50-150mg.
Ethacrynic acid and its glutathione-adduct are potent inhibitors of glutathione S-transferase family members, which are enzymes involved inxenobiotic metabolism. This family of enzymes has recently been shown to have a high rate of genetic variability.
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