Other Diuretics

Mannitol

Mannitol is a white, crystalline organic compound with the formula (C₆H₈(OH)₆). This polyol is used as an osmotic diuretic agent and a weak renal vasodilator. It was originally isolated from the secretions of the flowering ash, called manna after their resemblance to the Biblical food, and is also referred to as mannite and manna sugar.In plants, it is used to induce osmotic stress.

Uses

Medical applications

Mannitol is used clinically in osmotherapy to reduce acutely raised intracranial pressure until more definitive treatment can be applied, e.g., after head trauma. It is also used to treat patients with oliguric renal failure. It is administered intravenously, and is filtered by the glomeruli of the kidney, but is incapable of being resorbed from the renal tubule, resulting in decreased water and Na⁺ reabsorption via its osmotic effect. Consequently, mannitol increases water and Na⁺ excretion, thereby decreasing extracellular fluid volume.

Mannitol can also be used as a facilitating agent for the transportation of pharmaceuticals directly into the brain. The arteries of the blood-brain barrier are much more selective than normal arteries. Normally, molecules can diffuse into tissues through gaps between the endothelial cells of the blood vessels. However, what enters the brain must be much more rigorously controlled. The endothelial cells of the blood-brain barrier are connected by tight junctions, and simple diffusion through them is impossible. Rather, active transport is necessary, requiring energy, and only transporting molecules that the arterial endothelial cells have receptor signals for. Mannitol is capable of opening this barrier by temporarily shrinking the endothelial cells, simultaneously stretching the tight junctions between them.^[  An intracarotid injection of high molarity mannitol (1.4-1.6M), causes the contents of the artery to be hyperosmotic to the cell. Water leaves the cell and enters the artery in order to recreate an osmotic equilibrium. This loss of water causes the cells to shrivel and shrink, stretching the tight junctions between the cells. The newly formed gap reaches its peak width five minutes after mannitol injection, and stays widely open for thirty minutes. During this timespan, drugs injected into the artery can easily diffuse though the gaps between cells directly into the brain. This makes mannitol indispensable for delivering various drugs directly to the brain (e.g., in the treatment of Alzheimer's disease, or in chemotherapy for brain tumors

Mannitol is commonly used in the circuit prime of a heart lung machine during cardiopulmonary bypass. The presence of mannitol preserves renal function during the times of low blood flow and pressure, while the patient is on bypass. The solution prevents the swelling of endothelial cells in the kidney, which may have otherwise reduced blood flow to this area and resulted in cell damage.

Mannitol is also being developed by an Australian pharmaceutical company as a treatment for cystic fibrosis and bronchiectasis and as a diagnostic test for airway hyperresponsiveness. The mannitol is orally inhaled as a dry powder through what is known as an osmohaler and osmotically draws water into the lungs to thin the thick, sticky mucus characteristic of cystic fibrosis. This is intended to make it easier for the sufferer to cough the mucus up during physiotherapy. The critical characteristic of the mannitol is its particle size distribution.

Mannitol is also the first drug of choice for the treatment of acute glaucoma in veterinary medicine. It is administered as a 20% solution IV. It dehydrates the vitreous humor and, thus, lowers the intraocular pressure. However, it requires an intact blood-ocular barrier to work.

Mannitol can also be used to temporarily encapsulate a sharp object (such as a helix on a lead for an artificial pacemaker) while it is passed through the venous system. Because the mannitol dissolves readily in blood, the sharp point will become exposed at its destination.

Mannitol may be administered in cases of severe Ciguatera poisoning. Severe ciguatoxin, or "tropical fish poisoning" can produce stroke-like symptoms.

Mannitol is the primary ingredient of Mannitol Salt Agar, a bacterial growth medium, and is used in others.

In oral doses larger than 20 g, mannitol acts as an osmotic laxative, and is sometimes sold as a laxative for children

In foods

Mannitol does not stimulate an increase in blood glucose, and is therefore used as a sweetener for people with diabetes, and in chewing gums. It also has a low glycemic index, making it a low carb food. Although mannitol has a higher heat of solution than most sugar alcohols, its comparatively low solubility reduces the cooling effect usually found in mint candies and gums. However, when mannitol is completely dissolved in a product, it induces a strong cooling effect.  Also, it has a very low hygroscopicity- it does not pick up water from the air until the humidity level is 98%. This makes mannitol very useful as a coating for hard candies, dried fruits, and chewing gums, and it is often included as an ingredient in candies and gum. The pleasant taste and mouthfeel of mannitol also makes it a popular excipient for chewable tablets.

In illicit drugs

Mannitol is sometimes used as an adulterant or cutting agent for heroin, methamphetamines or other illicit drugs. In popular culture, when it is used in this manner, it is often referred to as baby laxative.^[

Controversy

The three studies that initially found that high-dose mannitol was effective in cases of severe head injury have been the subject of a recent investigation. Although several authors are listed with Dr. Julio Cruz, it is unclear whether the authors had knowledge of how the patients were recruited. Further, the Federal University of São Paulo, which Dr. Cruz gave as his affiliation, has never employed him. Currently, therefore, the Cochrane review recommending high-dose mannitol^[ has been withdrawn pending re-evaluation, as there is some evidence that mannitol may worsen cerebral edema.

Toxicology

Mannitol is contraindicated in patients with anuria and congestive heart failure

Acetazolamide

Acetazolamide, sold under the trade name Diamox, is a carbonic anhydrase inhibitor that is used to treat glaucoma, epileptic seizures, benign intracranial hypertension (pseudotumor cerebri), altitude sickness, cystinuria, and dural ectasia. Acetazolamide is available as a generic drug and is also used as a diuretic.

Mechanism of action

Acetazolamide is a carbonic anhydrase inhibitor; medically it may be used to treat conditions of moderate to severe metabolic alkalosis. It does this by interfering with bicarbonate (HCO₃^-) resorption in the kidneys, thereby re-acidifying the blood.

Carbonic anhydrase (CA) catalyzes the first part of the following reversible reaction, in which carbon dioxide (CO₂) and water (H₂O) are converted to carbonic acid (H₂CO₃) and vice-versa:

CO₂ + H₂O <--^CA--> H₂CO₃ <--> H⁺ + HCO₃^-

In the kidney tubules, locally secreted hydrogen ions normally combine with filtered bicarbonate (HCO₃^-) to form carbonic acid (H₂CO₃). Carbonic acid in turn is normally acted upon by carbonic anhydrase, leading to formation of CO₂. As CO₂ rapidly leaves the tubules by diffusing across cell membranes, the above reaction normally runs shifted strongly to the left (i.e. reversed), and more bicarbonate can be continuously reabsorbed from the serum. However, in the presence of acetazolamide, carbonic anhydrase is inhibited and carbonic acid levels build up. The inhibition of carbonic anhydrase in turn leads to a slowing of the reverse reaction and a decrease in the body's ability to reabsorb serum bicarbonate, resulting in urinary bicarbonate wasting. By contrast, the H⁺ that is also present in the lumen is reabsorbed via an alternative pathway along with Cl^-; it then passes into the bloodstream, leading to hyperchloremic metabolic acidosis.^[ This effect can also be used for therapeutic correction of alkalosis seen in altitude sickness or other forms of respiratory alkalosis.

Uses

Acetazolamide is often used in the treatment of various diseases.

Glaucoma

It has been used for glaucoma sufferers. The drug decreases fluid formation in the eye resulting in lower intraocular pressure.

Neurologic

In epilepsy, its main use is in absence seizures and myoclonic seizures. It can be used in both episodic ataxia types 1 and 2 (although the mechanisms are presumed to be different between the two).

In catamential epilepsy, an increase in seizure frequency around menses, acetazolamide can be an adjunct to an anti-seizure medication regimen to aid in decreasing seizure frequency around menses.

It is also used to decrease generation of cerebrospinal fluid in idiopathic intracranial hypertension^[4] and has shown efficacy in some forms ofperiodic paralysis.

Marfan syndrome

It's been demonstrated in drug trials to relieve symptoms associated with dural ectasia in individuals with Marfan Syndrome.

Sleep apnea

Off-label uses include acetazolamide as a conjunction drug to merely assist patients with central sleep apnea by lowering blood pH and encourage respiration.

Acute mountain sickness

To reduce the incidence of Acute Mountain Sickness acetazolamide is sometimes taken prophylactically, anywhere between 125 milligrams (mg) to 1000 mg per day, starting a few days before going to higher altitudes. Such use is recommended for those ascending from sea level to 3000 meters (9800 feet) in one day, or for those ascending more than 600 meters (2000 feet) per day once above an altitude of 2500 meters (8200 feet). Also, prophylactic use is recommended for those with a significant history of acute mountain sickness.

The drug forces the kidneys to excrete bicarbonate, the conjugate base of carbonic acid. By increasing the amount of bicarbonate excreted in the urine, the blood becomes more acidic. Acidifying the blood stimulates ventilation, which increases the amount of oxygen in the blood. At high altitudes, climbers hyperventilate in response to lower oxygen levels. The hyperventilation results in reduced carbon dioxide (an acid) and a respiratory alkalosis. The normal physiologic response to a respiratory alkalosis is for the kidneys to increase excretion of bicarbonate (a base) to compensate for the loss of carbon dioxide. This kidney response takes a few days, however acetazolamide in a sense accelerates this process by leading to a more rapid renal bicarbonate loss (metabolic acidosis).

Note that acetazolamide is not an immediate fix for acute mountain sickness; it speeds up part of the acclimatization process which in turn helps to relieve symptoms. This may take up to a day or two, and requires waiting without any further rapid ascent. It is often advisable to descend if even mild acute mountain sickness is experienced. If serious sickness is encountered, descent is considered mandatory unless other circumstances present greater danger.

Side-effects

Common side effects of using this drug include numbness and tingling in the fingers and toes, and taste alterations (parageusia), especially for carbonated drinks. Some may also experience blurred vision but this usually disappears shortly after stopping the medication. Acetazolamide also increases the risk of developing calcium oxalate and calcium phosphate kidney stones. Everyone will experience more frequent urination as a result of using acetazolamide. One should drink more fluids than usual to prevent dehydration and headaches. Acetazolamide prolongs the effects of amphetamines and related drugs. Acetazolamide also causes metabolic acidosis.

Contraindications

Acetazolamide should not be taken by individuals if:

§                     They have sickle cell anemia

§                     They are allergic to sulfa medications

§                     They are allergic to any carbonic anhydrase inhibitor

§                     They have liver or kidney disease

§                     They have adrenal gland failure (i.e. Addison's disease)

§                     They are pregnant or nursing mothers

Dorzolamide

Dorzolamide (trade name Trusopt) is a carbonic anhydrase inhibitor. It is an anti-glaucoma agent and topically applied in the form of eye drops. This drug, developed by Merck, was the first drug in human therapy (market introduction 1995) which resulted from structure-based drug design. Dorzolamide hydrochloride is used to lower increased intraocular pressure in open-angleglaucoma and ocular hypertension.

The combination of dorzolamide with timolol is marketed under the trade name Cosopt.

Brinzolamide

rinzolamide  is a carbonic anhydrase inhibitorused to lower intraocular pressure in patients with open-angle glaucoma or ocular hypertension.

Chemistry

Brinzolamide is a carbonic anhydrase inhibitor (specifically, carbonic anhydrase II). Carbonic anhydrase is found primarily in erythrocytes (but also in other tissues including the eye). It exists as a number of isoenzymes, the most active of which is carbonic anhydrase II (CA-II).
Indications

Use for the treatment of open-angle glaucoma and raised intraocular pressure due to excess aqueous humor production.
Pharmacodynamics

Inhibition of carbonic anhydrase in the ciliary processes of the eye decreases aqueous humor secretion and thus lowers the intraocular pressure in the anterior chamber, presumably by reducing the rate of formation of bicarbonate ions with subsequent reduction in sodium and fluid transport; this alleviates the effects of open-angle glaucoma.
Pharmacokinetics
Absorption

The recommended frequency for topical application is three times per day. Following ocular instillation, the suspension is systemically absorbed to some degree; however the plasma concentrations are low and generally below the limits of detection (less than 10 ng/mL) due to extensive binding by tissues and erythrocytes. Oral administration is less-favored due to variable absorption from the stomach mucosa and an increased side-effect profile versus ophthalmic administration.
Distribution

The compound is fairly well protein-bound (60%), but adheres extensively to the carbonic anhydrase-containing erythrocytes. Due to the abundance of readily-bound erythrocytes and minimal known metabolism, Brinzolamide's whole blood half-life is very long (111 days).
Metabolism

While definitive sites of metabolism have not been firmly established, there are several metabolites worthy of note. N-Desethylbrinzolamide is an active metabolite of the parent compound, and thus exhibits carbonic anhydrase inhibitory activity (largely carbonic anhydrase-I, when in the presence of Brinzolamide) and also accumulates in the erythrocytes. However, Brinzolamide's other known metabolites (N-Desmethoxypropylbrinzolamide and O-Desmethylbrinzolamide) either have no activity or their activity is currently unknown.
Excretion

Brinzolamide is excreted primarily unchanged (60%) in the urine, although the renal clearance rate has not been definitively determined. N-Desethylbrinzolamide is also found in the urine along with lower concentrations of the inactive metabolites, N-Desmethoxypropylbrinzolamide and O-Desmethylbrinzolamide; exact levels have not been definitively determined.

Side effects

§                     Common, but mild: Blurred vision; bitter, sour, or unusual taste; itching, pain, watering, or dryness of the eyes; feeling that something is in the eye; headache; runny nose

§                     Rare, but serious: Fast or irregular heartbeat; fainting; skin rash, hives, or itching; severe eye irritation, redness, or swelling; swelling in the face, lips, or throat; wheezing or trouble breathing
Precautions

§                     Hypersensitivity to other sulfonamides

§                     Acute angle-closure glaucoma

§                     Concomitant administration of oral carbonic anhydrase inhibitors

§                     Moderate-to-severe renal or hepatic insufficiency
Combination with timolol

The combination of brinzolamide with timolol is marketed under the trade name Azarga. Clinical studies have shown this combination to be more effective than either of the medications taken as monotherapy.