The presence of anion and cation transporters is essential for most highly protein-bound diuretic drugs to gain access to their site of action, the lumen of the renal tubule. Loop and thiazide diuretics and carbonic anhydrase inhibitors are secreted through the organic acid pathway, and amiloride and triamterene via an organic base transporter (Brater, 1998). Renal insufficiency accompanied by reduced creatinine clearance decreases delivery of diuretic drugs to their secretory site and hence to their site of action. Accumulation of endogenous organic acids during chronic renal failure may result in competition with diuretics for transport at proximal tubule secretion sites (Brater, 1993). Other transporters, including the p-glycoprotein efflux pump, breast cancer resistance protein (BRCP), multidrug and toxin extrusion proteins (MATE1, MATE2-K), and multidrug resistance proteins (MRP2, MRP4), are located in the proximal tubule that contribute to transport of drug into the urine functioning as a mechanism of drug clearance (2013).

The most common indication for diuretic use is removal of tissue edema. Understanding the physiological principles underlying edema formation depends upon an understanding of net capillary filtration. Similar to net filtration pressure in the glomeruli, net capillary filtration, or fluid flux out of a capillary, is dependent upon the plasma colloidal osmotic pressure retaining fluid, and hydrostatic pressure in the arterial capillary forcing fluid out of the capillary through fenestrations and pores. Since the arterial capillary hydrostatic pressure is greater than the plasma colloidal osmotic pressure in most tissues, a small amount of fluid moves from the vasculature into the interstitial space. However, on the venous capillary side, plasma osmotic pressure is greater than the venous hydrostatic pressure and fluid is reabsorbed from the interstitial space into the venous capillary in most tissues, resulting in little net fluid loss into the interstitial space. The lymphatics contribute to fluid absorption from the interstitial space, ensuring no accumulation of fluid in the interstitial space in healthy tissues.

If the fluid movement out of the capillaries exceeds absorption of fluid by venous capillaries and lymphatics, edema results. There can be numerous causes of edema including: lymphatic obstruction (i.e., neoplasia), decreased plasma osmotic pressure (i.e., hypoalbuminemia), and increased venous hydrostatic pressure (i.e., decreased cardiac contractility, excessive intravascular fluid volume). Additionally, the loss of capillary integrity (i.e., inflammation, neurogenic) can result in tissue edema and noncardiogenic pulmonary edema due to head trauma, seizures, and electrocution that occur as a result of poorly understood mechanisms. Therefore the cause of the edema should be identified prior to any therapy, including diuretics.

Congestive heart failure (CHF) is a complex pathophysiological process that begins with decreased cardiac output. The decreased cardiac output and decreased renal blood flow leads to activation of the renin–angiotensin–aldosterone system followed by renal retention of salt and water. High baroreceptor activity causes increased peripheral vascular resistance and increased ADH, which lead to further salt and water retention by the kidneys. Increased central venous pressure caused by increased left ventricular end-diastolic pressures cause increased capillary hydrostatic pressure. All of these factors lead to greater fluid flux out of vessels, resulting in edema related to cardiac disease.

This class of drugs was discovered as a result of the observation that sulfanilamide chemotherapeutic agents were capable of causing metabolic acidosis by inhibition of carbonic anhydrase (CA). Screening of sulfanilamides resulted in identification of compounds whose predominant mechanism of action was CA inhibition. These drugs have been used sparingly in veterinary medicine as diuretics and are more commonly used for ophthalmic purposes as topical formulations. The prototype drug in this class, acetazolamide (Diamox^®, Dazamide^®), is available in tablets (125 and 250 mg), extended-release capsules (500 mg), and injectable (500 mg per vial). Other CA inhibitors include preparations for oral use, dichlorphenamide (Daranide^®) and methazolamide (Neptazane^®), and a topical drug, dorzolamide (Trusopt^®), for ophthalmic use.

Limited information is available regarding pharmacokinetics of CA inhibitors in animals. The pharmacokinetics of acetazolamide in dogs administered an extended release product produced an approximately 7-hour half-life with a T_MAX at 3 hours (Li et al., 2014). Acetazolamide gains access to the renal tubules via the organic acid secretion pathway. A dose of 22 mg/kg is reported to have an onset of action of 30 minutes, maximal effects in 2–4 hours, and a duration of action of 4–6 hours in small animals (Roberts, 1985). Oral absorption of drugs in this class is appears to be good in dogs. The oral bioavailability of acetazolamide is 25% in horses, with a terminal half-life of 7 hours (Alberts et al., 2000). Acetazolamide is eliminated primarily through the kidneys. The pharmacokinetics of methazolamide has not been reported in dogs, cats, or horses.

Although CA inhibitors are sulfonamide derivatives, side effects commonly associated with sulfonamides are not reported or expected (Trepanier, 2004). CNS drowsiness and disorientation may occur as a result of inhibition of CA in the CNS. Because CA inhibitors decrease ammonia excretion, the severity of preexisting hepatic disease may be worsened and hepatic encephalopathy can be induced. Use is also contraindicated in patients with certain electrolyte disturbances (due to K⁺ and Na⁺ wasting) and those with metabolic or respiratory acidosis. Use in patients with severe pulmonary disease who cannot respond to drug-induced metabolic acidosis with respiratory compensation is also contraindicated. Because CA inhibitors alkalinize the urine, calcium phosphate calculi formation is enhanced, and excretion of weak organic bases is reduced. Rare blood dyscrasias associated with CA inhibitors have also been reported in the human, but not in the veterinary literature.

The primary indication for use of CA inhibitors is to inhibit production of aqueous humor and reduce intraocular pressure. Topical application of dorzolamide (q 8–12 h) produced similar reductions in intraocular pressure compared to oral methazolamide (5 mg/kg q 12 h) or the combination of topical and oral therapy (Gelatt and MacKay, 2001). The topical CA inhibitors therapy is preferred due to equivalent efficacy, lower potential for adverse effects, and lower cost than systemic administration. Acetazolamide (5–10 mg/kg PO q 8 h) and methazolamide (5 mg/kg PO q 12 h given two to three times daily) have been used previously in dogs for management of glaucoma. CA inhibitors have been administered to patients with hydrocephalus for short-term medical management, often in combination with furosemide, but long-term management with diuretics, in people, is often not successful (Thomas, 2010).

In human medicine, CA inhibitors have been used as an adjunctive therapy for epilepsy and in management of acute mountain (high-altitude) sickness. In both human and veterinary medicine, the use of CA inhibitors as diuretics has limited effectiveness due to the rapid development of tolerance. Theoretically, acetazolamide could be used to manage metabolic alkalosis, but this is not a typical clinical practice in veterinary medicine.

Osmotic diuretics contain simple solutes of low molecular weight that are typically freely filtered by the glomerulus, undergo limited tubular reabsorption, and are pharmacologically inert. They increase serum and tubular fluid osmolarity resulting in fluid shifts. The most common osmotic diuretic is mannitol, a six-carbon nonmetabolized polyalcohol with a molecular weight of 182. Other agents include glycerin, isosorbide, urea, and hypertonic saline solutions. Because mannitol is the most commonly used osmotic diuretic in both human and veterinary medicine, subsequent discussion will focus primarily on this drug. Concentrated mannitol (15–25%) may crystallize at cooler temperatures, in which case the drug can often be resolubilized by warming the solution. Prior to administration, the solution should be cooled and any remaining crystals removed using an in-line intravenous (IV) filter. There are no veterinary-approved mannitol formulations available. For IV use in animals, the human formulations are used. Human products (Osmitrol^®, Resectisol^®) range from 5% (275 mOsm/l) to 25% (1375 mOsm/l) and are available for IV administration.

Hyperosmolar solutions exert part of their effects by establishing an osmotic gradient between plasma and extravascular fluid compartments resulting in fluid movement into the plasma. Acute effects of this gradient include decreases in hematocrit, blood viscosity, plasma sodium, plasma pH, and, to some degree, the volume of solid organs. Hence, parenchymal dehydration and acute hemodilution are theoretically related as long as the osmotically active particles are effectively separated by a relatively solute-impermeable barrier.

Mannitol is not metabolized and is handled as an inert substance by the body. Studies in dogs and humans indicate that mannitol distribution and elimination follow a two-compartment model (Cloyd et al., 1986; Rudehill et al., 1993). The distribution half-life of intravenously administered mannitol is measured in minutes. Elimination half-life is dose dependent and ranges from 0.5 to 1.5 hours for doses between 0.25 and 1.5 g/kg. Mannitol is eliminated rapidly by the kidneys unless renal function is impaired. As a result, penetration of mannitol into tissues is limited by rapidly falling plasma concentrations. Mannitol is administered intravenously in a slow bolus over 15–30 minutes. Glycerin and isosorbide are administered orally. Of the available osmotic diuretics, only glycerin is eliminated by biotransformation.