The main function of the kidney is the excretion of waste products; it is also important in the regulation of the salt and water content of the body and in acid–base balance. The main active transport mechanism in the renal tubule is the sodium pump (the Na + /K + ATPase) in the basolateral membrane of the tubule cells. All the constituents of the plasma (other than protein) are filtered into the renal tubules at the glomerulus and 75% of the filtrate is reabsorbed isosmotically in the proximal tubules , bicarbonate in particular. Some organic acids and bases are secreted into the tubule. Water is absorbed in the descending limb of the medullary loop (Henle’s loop). In the thick ascending limb of the loop , which is impermeable to water, there is active reabsorption of salt via a Na + /K + /2Cl – cotransporter (a symport in which transport of one ion is coupled to that of another) in the luminal membrane. This reabsorption of salt from the filtrate into the cells and from there into the interstitium is a major factor in producing hypertonicity in the interstitium in this area. In the distal tubule , more absorption of sodium ions (Na + ) and chloride ions (Cl – ) occurs, and potassium ions (K + ) are secreted into the filtrate. The collecting tubule and collecting ducts have low permeability to both salts and water; here Na + reabsorption and K + excretion are promoted by aldosterone and passive water reabsorption promoted by the antidiuretic hormone (ADH). The hypertonicity of the interstitium produced by the reabsorption of salt in the thick ascending loop is the main factor providing the osmotic gradient for ADH-mediated water reabsorption. Normally less than 1% of filtered Na + is excreted in the urine.
Drugs Acting on the Kidney
- •
Diuretics
- •
Drugs affecting urinary pH (see lower right of Fig. 18.1 )
Fig. 18.1
Diagram of the nephron.
The movement of ions in the main parts of the tubule, the sites of action of the principal drugs, some of the main agents secreted into the proximal tubule and the range of salt concentration from cortex to inner medulla are shown.
ADH , Antidiuretic hormone; C , cotransporter; P , pump;.
- •
Drugs that can alter the excretion of organic molecules: e.g. probenecid
Diuretics
Diuretics are drugs that increase Na + (and thus water) excretion by a direct action on the kidney. They do this mainly by reducing the absorption of salt from the filtrate, the increase in water loss being secondary to the increased salt loss.
Loop diuretics
Examples: furosemide , torasemide.
Pharmacological actions
- •
Very potent diuretics causing a profuse flow of urine
- •
K + and hydrogen ion (H + ) loss
- •
Decreased excretion of uric acid
- •
Increased excretion of calcium ions (Ca 2+ ) and magnesium ions (Mg 2+ )
- •
Moderate vasodilator effect
Mechanism of the diuretic action
See Fig. 18.1 .
Pharmacokinetic aspects
Loop diuretics are given orally or intravenously (IV) and are secreted into the proximal tubule. The fraction not secreted is metabolized in the liver. Furosemide has a half-life of 90 min and a duration of action of 3–6 h. Torasemide has a longer half-life and duration of action.
Unwanted effects
The main unwanted effects of this drug class are:
- •
hypokalaemia owing to K + loss,
- •
metabolic alkalosis owing to H + loss,
- •
depletion of Ca 2+ and Mg 2+ , and
- •
depletion of the extracellular fluid volume resulting in hypotension.
High IV doses can cause deafness. Nausea and hypersensitivity reactions can occur.
Thiazides and related diuretics
Examples of thiazides: Bendroflumethiazide and hydrochlorothiazide ; examples of the related agents are chlortalidone, xipamide and adipiodone (indapamide).
Pharmacological actions of thiazides and their congeners
- •
Moderately potent diuretic effect (but in diabetes insipidus, thiazides reduce urine volume)
- •
K + and H + loss
- •
Decreased excretion of uric acid
- •
Decreased excretion of Ca 2+
- •
Increased excretion of Mg 2+
- •
Moderate vasodilator effect
Mechanism of the diuretic action
See Fig. 18.1 .
Pharmacokinetic aspects
Given orally, thiazides and related agents are secreted into the proximal tubule ( Fig. 18.1 ). With most agents, the diuresis starts within 2 h and lasts 8–12 h. Chlortalidone has a longer duration of action.
Unwanted effects of thiazides and related agents
The main unwanted effects are a result of renal actions are:
- •
hypokalaemia due to K + loss,
- •
metabolic alkalosis due to H + loss, and
- •
increased plasma uric acid (gout thus a possibility).
Other unwanted effects include possible hyperglycaemia (a problem in diabetes mellitus), increased plasma cholesterol (with long-continued use), male impotence (reversible) and allergic reactions. A rare but serious adverse effect is hyponatraemia.
Potassium-sparing diuretics
Examples: amiloride, spironolactone and triamterene.
These have only limited diuretic action and all act in the distal tubule and collecting tubules, the sites for the control of K + homeostasis.
Spironolactone is given orally and is rapidly metabolized to an active metabolite, canrenone. The onset of action is slow. It is an antagonist of aldosterone, inhibiting the Na + -retaining, K + -excreting effect of aldosterone. Eplerenone is similar but shorter acting. As these drugs are steroid-like, unwanted actions on other steroid receptors outside of the renal system can occur, resulting in gynaecomastia, testicular problems and menstrual disorders.
Triamterene and amiloride are both given orally, triamterene having a more rapid onset and shorter duration of action than amiloride. These drugs inhibit Na + reabsorption and reduce K + excretion.
Unwanted effects
All three agents can cause hyperkalaemia and may cause acidosis.
Osmotic diuretics
Osmotic diuretics (e.g. mannitol ) are drugs that pass into the tubules in the glomerulus and increase the osmotic pressure of the filtrate. They act mainly in the proximal tubule and the overall effect is to increase water excretion. They are usually given IV and the principal unwanted effects are a temporary expansion of the extracellular fluid compartment and hyponatraemia, resulting from osmotic extraction of intracellular water.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
