By blocking the carbonic anhydrase, these inhibitors decrease the reabsorption of NaHCO3 by 25–30% and cause diuresis.
They have a weak natriuretic effect due to compensatory mechanisms that come into play following chronic administration [1]. The prototypical carbonic anhydrase inhibitor is acetazolamide.
13.3.1 Pharmacokinetics
The carbonic anhydrase inhibitors are well absorbed after oral administration. There is an increase in urine pH from HCO3− and diuresis is apparent within 30 min and maximal at 2 h. The effect persists for 12 h after a single dose. Excretion of the drug is by secretion in the proximal tubule S2 segment. Therefore, dosing must be reduced in renal insufficiency.
13.3.2 Uses of Carbonic Anhydrase Inhibitors
Carbonic anhydrase inhibitors are used for the following:
- 1.
Glaucoma – The reduction of aqueous humor formation by carbonic anhydrase inhibitors decreases the intraocular pressure.
- 2.
Urinary Alkalization – Uric acid and cysteine are relatively insoluble and may form stones in acidic urine. Thus by alkalization of the urine they prevent their precipitation.
- 3.
Metabolic Alkalosis: When the alkalosis is due to excessive use of diuretics, acetazolamide can be useful in correcting the alkalosis as well as producing a small additional diuresis for correction of volume overload.
- 4.
Acute Mountain Sickness: By decreasing cerebral spinal fluid (CSF) formation and by decreasing the pH of the CSF and brain, acetazolamide can increase ventilation and diminish symptoms of mountain sickness. This is also useful in the treatment of sleep apnea.
- 5.
Miscellaneous:
- 1.
Hypokalemic periodic paralysis
- 2.
CSF leak
- 3.
Severe hyperphosphatemia
- 1.
13.3.3 Side Effects
Side effects include:
- 1.
Hyperchloremic metabolic acidosis
- 2.
Renal stones. There is a higher incidence of calcium and phosphate stones as they are insoluble in an alkaline pH.
- 3.
Hypokalemia
- 4.
Drowsiness and paresthesia
- 5.
Hypersensitivity reactions (fever, rashes, bone marrow suppression, and interstitial nephritis)
13.3.4 Contraindications
Carbonic anhydrase inhibitors are contraindicated in patients with cirrhosis of liver as they may develop hyperammonemia and hepatic encephalopathy.
13.4 Sodium Glucose Cotransporter 2 Inhibitors
Inhibiting this transporter will result in glucose excretion of 30–50% of the amount filtered. Two SGLT2 inhibitors (dapagliflozin and canagliflozin) are currently available.
13.4.1 Pharmacokinetics
The SGLT2 inhibitors are rapidly absorbed by the GI tract. The elimination half-life of dapagliflozin is 10–12 h and up to 70% of the given dose is excreted in the urine. The drugs are not recommended in patients with severe renal failure or advanced liver disease.
13.4.2 Clinical Indications and Adverse Reactions
Currently, the only indication for the use of these drugs is as third-line therapy for diabetes mellitus. SGLT2 inhibitors will reduce the hemoglobin A1C by 0.5–1.0%, similar to other oral hypoglycemic agents.
SGLT2 inhibitors may also be used as an adjunct to weight loss treatment.
There is a six-fold increased incidence of genital fungal infection in women and a slightly higher risk of urinary tract infections.
13.5 Adenosine A-1 Receptor Antagonists
Adenosine A-1 receptor antagonists prevent tubuloglomerular feedback by interfering with the activation of NHE3 in the proximal convoluted tubules and the adenosine-mediated enhancement of collecting tubule K+ secretion.
Caffeine and theophylline are the prototypical agents. They exhibit a modest and nonspecific inhibition of these adenosine receptors and produce a mild diuretic effect.
13.6 Loop Diuretics
Loop diuretics act selectively on the medullary ascending portion of the thick loop of Henle’s and inhibit NaCl reabsorption. The decreased reabsorption of sodium chloride alters the tonicity of the normally hypertonic medullary interstitium and leads to a reduced urine-concentrating ability of the kidneys thus facilitating diuresis. Loop diuretics also lead to a loss of potassium and hydrogen ions.
The two drugs that were initially available were the sulfonamide derivative furosemide and phenoxyacetic acid derivative ethacrynic acid. The prototypical agents of this class are the sulfonamide derivatives furosemide, bumetanide and torasemide.
13.6.1 Pharmacokinetics
The loop diuretics are rapidly absorbed. Absorption of orally administered loop diuretics is variable. It is about 10–50% with furosemide but is about 80–90% for torasemide and bumetanide.
Approximately 90–95% of loop diuretics are bound to plasma proteins and its volume of distribution is relatively low. This protein binding is essential for the delivery of furosemide to the kidney, the site for its action [4].
Loop diuretics have to be secreted into the luminal side of the proximal tubules in order to have an effect. Medications that compete for the same weak acid secretion (NSAIDs or probenecid) may interfere with their secretion and thus make it ineffective.
Thirty percent of the drug is metabolized and excreted via the gastrointestinal tract. It is primarily eliminated by the kidney by glomerular filtration and tubular secretion. Half-life varies from 1 to 3 h and depends on renal function and the dose has to be adjusted in patients with renal failure.
The diuresis lasts for 2–3 h following an oral dose of furosemide but lasts for about 4–6 h following use of torasemide.
13.6.2 Pharmacodynamics
Loop diuretics inhibit the luminal Na+/K+/2Cl− transporter in the thick ascending loop of Henle. They thus reduce the reabsorption of NaCl.
Loop diuretics increase the excretion of water, Na, K, Cl, phosphate, Mg, and Ca. In normal circumstances, this increased loss of calcium is counter-balanced by increased intestinal absorption and parathyroid hormone-induced renal reabsorption of Ca2+ and hypocalcemia does not develop.
Loop diuretics have also been shown to increase synthesis of prostaglandins. This increases renal blood flow and decreases the peripheral vascular tone. The latter reduces pulmonary congestion and left ventricular filling pressures in the presence of heart failure.
13.6.3 Uses of Loop Diuretics
Loop diuretics are used in treatments for the following [1]:
- 1.
Hyperkalemia
- 2.
Acute pulmonary edema
- 3.
Increased intracranial pressure: they can be used even in the presence of disrupted blood-brain barrier.
- 4.
Acute renal failure
- 5.
Edematous conditions
- 1.
Congestive failure
- 2.
Cirrhotic ascites
- 3.
Nephrotic syndrome
- 1.
- 6.
Hypercalcemia
- 7.
Hyponatremia
- 8.
Toxicity due to ingestion of bromide, fluoride and iodide.
13.6.4 Side Effects
Side effects include [1]:
- 1.
Hyponatremia
- 2.
Hypokalemic metabolic alkalosis
- 3.
Hypomagnesemia
- 4.
Hyperuricemia
- 5.
Hypercalciuria, which can lead to mild hypocalcemia and secondary hyperparathyroidism
- 6.
Hypercalcemia in volume-depleted patients with metastatic breast or squamous cell lung carcinoma
- 7.
Dehydration
- 8.
Ototoxicity: dose-related hearing loss that is usually reversible
- 9.
Furosemide may increase the toxicity of aminoglycosides and cephalosporins.
- 10.
Allergic reactions: skin rash, eosinophilia, and less often, interstitial nephritis. Allergic reactions are much less common with ethacrynic acid.
- 11.
Direct toxic action resulting in interstitial nephritis
13.6.5 Contraindications
Furosemide, bumetanide, and torasemide may exhibit allergic cross-reactivity in patients who are sensitive to other sulfonamides, but this appears to be very rare.
Use with caution in patients with hepatic cirrhosis, borderline renal failure, or heart failure.
13.6.6 Furosemide
Furosemide can be administered orally (0.75–3 mg kg–1) or intravenously (0.1–1 mg kg–1). Absorption is variable after an oral dose and ranges from 0–100% (mean of 50%). The peak effect is seen 60–90 min after an oral dose. Approximately 90% of the drug is bound to plasma proteins and its volume of distribution is relatively low.
About 30% of the elimination is via the GI tract while the rest is excreted unchanged by the kidneys by glomerular filtration and tubular secretion. The elimination half-life of furosemide is 60–90 min.
Furosemide increases renal artery blood flow if the intravascular fluid volume is maintained. It increases the blood flow to the inner cortex and medullary regions. This is mediated through release of prostaglandins.
Loop diuretics have a high ceiling effect (i.e., increasing doses lead to increasing diuresis).
13.6.7 Bumetanide
The mechanism of action and its effects are similar to those of furosemide. Bumetanide is absorbed completely after oral administration. Its rate of elimination is less dependent on renal function. Ototoxicity may be slightly less frequent than with furosemide, but renal toxicity is more of a problem. Because it is more potent, smaller doses are required.
13.7 Thiazides
The thiazide diuretics are chemically related to carbonic anhydrase inhibitors. These agents inhibit the NaCl, rather than NaHCO3 transportation. They have their predominant site of action at the distal convoluted tubule and have some effect on the collecting ducts.
13.7.1 Pharmacokinetics
Thiazides can be administered orally. They are highly protein bound like the loop diuretics. Also like the loop diuretics, they are secreted by the organic acid secretory system in the proximal tubule and compete with the secretion of uric acid by that system. Hence, this might result in hyperuricemia.
13.7.2 Pharmacodynamics
Thiazides inhibit NaCl reabsorption from the luminal side of epithelial cells in the distal convoluted tubules by blocking the Na+/Cl− transporter. They increase the excretion of Na, K, Cl, HCO3, phosphate, and urate.
Thiazides actually enhance Ca2+ reabsorption. This effect can be helpful in some patients to prevent calcium stones in patients with hypercalciuria.
13.7.3 Uses of Thiazide Diuretics
Thiazides are used to treat the following:
- 1.
Hypertension
- 2.
Heart failure
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