INTRODUCTION
- Besides the lung, the skin and the intestines, the kidneys are the most important excretory organs within the human body. It is the most important Homeostatic organ of the body.
- The kidneys control the salt and mineral contents, regulate the fluid balance and thus participate in the acid and base balance of the body. The main function of the kidneys is to maintain the balance of the normal composition of the blood and all other body fluids.
- Through the blood, all cell metabolic waste products are transported to the kidneys, where they are then filtered out of the blood plasma and passed out of the body.
- Excretion takes place through the urine. It is produced in the nephrons, functional unit of kidney of which over a million are to be found in the kidneys. Following several filtrations at different points, the urine eventually leaves the body via the ureter, the bladder and the urethra.
PHYSIOLOGY OF URINE FORMATION
Nephron: According to their function and structure, two parts of the nephron are distinguished:
- – Renal corpuscle or malphigian body (corpusculum renal).
- – Uriniferous tubule or renal tubule (tubulus renalis).
- An aggregation of very fine capillaries (glomerulum) is enclosed by a watertight capsule (capsula glomeruli or Bowman's capsule) (Fig. 6.1.1).
- In the glomerulus the blood is filtered through pores of the vessels and cell clefts into the Bowman's capsule (Fig. 6.1.2). Very less substances, such as minerals, urea, creatinine (a metabolic product of the muscle tissues) and glucose, pass through the filter. The kidney receives about 25% of total CO.
- Blood cells and protein molecules are too big for the openings of the filter and remain in the blood. When, for example, due to infections, the openings of the filter extend, these substances get in the filtrate and can be detected in the urine.
- The filtered fluid, the primary urine, is collected by the Bowman's capsule and conducted to the adjacent uriniferous tubules. 125 ml (0.03 gal) of primary urine are produced per minute which makes 170–180 (37.4– 39.6 gal) liters in 24 hours.
- The uriniferous tubules, also called renal tubules, extend from the renal cortex into the renal medulla. It is their task to recover those substances dissolved in the primary urine that are indispensable to the body (reabsorption).
- The renal tubules first proceed in a loop-like fashion and then pass down, up, and downwards again. Due to different morphological structures, the individual sections (main tubule, descending limb, middle piece and collecting tubule) take over different tasks in the reabsorption process.
Proximal tubule: Sodium bicarbonate, sodium chloride, amino acids and glucose are re-absorbed in the proximal tubule along with water by specific transport mechanisms. Osmotic diuretics act here.
Henle's loop: In the thin descending limb of the loop of Henle, Water is reabsorbed by osmotic forces. Hence osmotic diuretics are acting here too. The thick ascending limb actively reabsorbs sodium chloride from the lumen (but is impermeable to water) by Na+/K+/ 2Cl− co-transporter. ‘Loop diuretics’ selectively block this transporter (Fig. 6.1.3).
Distal convoluted tubule: In the early distal tubule, sodium chloride is reabsorbed by an electrically neutral Na+ and Cl− transporter. This transporter is blocked by thiazide diuretics.
Collecting tubule: In the late distal tubule and collecting duct, NaCl− is actively reabsorbed, in exchange for K+ and H+ to maintain the ionic balance-regulated by aldosterone. Absorption of water is under the control of antidiuretic hormone (ADH).
- The resorption of substances is a complicated procedure accomplished, on the one hand, under the influence of physical processes and on the other, hormonally, controlled by the endocrine system.
- Everyday 99% of primary urine is reabsorbed. Thus, within 24 hours approximately 1.5 liters (0.33 gal) of urine are produced that are excreted by the body. The quantity of urine varies according to the external influences like the intake of fluids and physical stress.
- Natriuresis: Increase in renal sodium excretion.
- Salturesis: Increase in ranal salt excretion.
DIURETICS
Diuretic is an agent which increases urine and solute excretion.
Classification
- Ceiling or high efficacy diuretics: Furosemide, Ethacrynic acid, Bumetanide, Piretanide, Torsemide.
- Moderate efficacy diuretics:
- Thiazides diuretics: Benzothiadiazines like Chlorothiazide, Hydrochlorothiazide, Polythiazide.
- Thiazide related agents: Clopamide, Indapamide, Chlorthalidone, Metolazone, Xipamide.
- Low efficacy diuretics:
- Carbonic anhydrase inhibitors: Acetazolamide.
- Potassium sparing diuretics: Triamterene, Amiloride, Spironolactone.
- Osmotic diuretics: Mannitol, Urea, isosorbide, Glycerol.
- Methylxanthines: Theophylline.
High Ceiling or Loop Diuretics
Frusemide (Furosemide): It is a sulfonamide derivative. It is the most popular loop diuretic (Fig. 6.1.4). Given intravenously it acts in 2–5 minutes, while following oral use, it takes 20–40 minutes; duration of action is 3–6 hours.
Mechanism of Action
- Inhibition of electrolyte absorption: Loop diuretics inhibit electrolyte reabsorption (Na+, K+, 2Cl−, and co-transport mechanism) in the thick ascending limb of the loop of Henle. (thats why they are called loop diuretics) Because they act at the luminal surface of the nephron, they must reach the urine to exert a diuretic effect.
- Inhibition of carbonic anhydrase
- Furosemide, bumetanide, and toresemide are weak inhibitors of carbonic anhydrase, probably as a result of the substituted sulfonamide side chain.
- Ethacrynic acid lacks a sulfonamyl group and does not inhibit carbonic anhydrase.
Pharmacological Effects
- Cl− excretion is greater than Na+ excretion. Hypochloramic alkalosis can occur, but it does not produce a refractory state.
- These diuretics increases renal blood flow without increasing the glomerular filtration rate.
- Large doses inhibits uric acid excretion (Secretion) therefore may it induce gout.
- Loop diuretics also enhance the excretion of K+, Ca++, and Mg++ (But Ca++ is reabsorbed in the distal tubulehence no hypocalcemia).
- They also alter renal hemodynamics to reduce fluid and electrolyte reabsorption in the proximal tubule.
- IV furosemide relieves pulmonary congestion and reduces left ventricular filling pressure by causing venodilation in congestive heart failure.
Pharmacokinetics
- Furosemide, bumetanide, and toresemide are usually administered orally in a single dose once or twice daily. Both also can be administered intramuscularly or (more frequently) intravenously. Oral bioavailability is about 60–80%. T1/2 = 1–2 hrs.
- Ethacrynic acid is administered orally or intravenously once or twice daily. One of the main differences between furosemide and ethacrynic acid is that the former has a broader dose-reponse curve, i.e. DRC of ethacrynic acid is steeper.
Therapeutic Uses
- Edema: Frusemide is highly effective for the relief of edema of all origins like cardiac, hepatic, pulmonary and renal edema.
- Acute pulmonary edema is relieved by IV frusemide due to its immediate vasodilator effect and then by diuretic action, e.g. LVF (acute) following MI.
- In cerebral edema, frusemide is used as alternative to osmotic diuretics.
- Forced diuresis: In poisoning due to drugs like barbiturates and salicylates, frusemide is used with IV fluids.
- Hypertension: With renal impairment may be treated with loop diuretics.
- Hypercalcemia and hyperkalemia: Loop diuretics enhance excretion of Ca++ and K+. But Na+ and Cl− should be replaced to avoid hyponatremia and hypochloremia.
Adverse Effects of Loop Diuretics
- GIT disturbances like nausea, vomiting and diarrhea are common with ethacrynic acid.
- Hypokalemia and metabolic alkalosis is dose dependent and can be corrected by K+ replacement and correction of hypokalemia.
- Hyperuricemia may precipitate acute attacks of gout.
- Hypocalcemia and hypomagnesemia After prolonged use this may result in osteoporosis.
- Hyponatremia, dehydration and hypovolemia should be treated with saline infusion.
- Hyperglycemia and hyperlipidemia are mild in therapeutic does.
- Ototoxicity: Loop diureties cause hearing loss by a toxic effect on the hair cells in the interal ear-more common with ethacrynic acid. It is dose-related and generally reversible. Concurrent use of other ototoxic durgs should be avoided.
- Allergic reaction like skin rashes are more common with sulfonamide derivatives.
Thiazides and Thiazide-like Diuretics
Chemistry: All thiazides have a sulfonamide group. Chlorthiazide was the first thiazide to be synthesized.
Mechanism of actions (Fig. 6.1.5)
- This group of drugs block Na+/Cl− co-transport in the early distal tubule (site 3).
- They also inhibit carbonic anyhydrase activity. Increase in dose does not increase the response.
- Thiazides also enhance excretion of Mg+ and K+ (in distal segments, Na+ in the lumen is exchange for K+ which is then excreted).
- But they also inhibit urinary excreion of Ca++ and uric acid.
Pharmacokinetics: Thiazides are well-absorbed orally and are rapid acting. Duration varies from 6–48 hours. They are excreted by the kidney.
Therapeutic uses
- Hypertension: Thiazides are first line drugs.
- Edema: Thiazides may be tried in hepatic or renal edema.
- Congestive heart failure: Thiazides are the first line drugs in the management of edema due to mild to moderate CHF.
- Renal stones: Hypercalciuria with renal stones can be treated with thiazides which reduce calcium excretion.
- Diabetes insipidus: Thiazides reduce plasma volume and GFR and benefit such patients.
Adverse effects
- Hypokalemia, metabolic alkalosis, hyperuricemia, hypovolemia, dehydration, hyponatremia, hypercalcemia, and hyperlipidemia are similar to that seen with loop diuretics.
- Hyperglycemia induced by thiazides may precipitate diabetes mellitus probably by inhibition of insulin secretion. It is more common when long-acting thiazides are used for a long time.
- Weakness, fatigue and allergic reactions like rashes and photosensitivity can be seen.
Potassium Sparing Diuretics: Spironolactone
Mechanism of action
- Spironolactone, a competitive antagonist of the mineralocorticoid aldosterone, interferes with aldosterone-mediated Na+-K+ exchange, increasing Na+ loss at the distal tubular site while decreasing K+ loss (Fig. 6.1.6).
- It is most effective when circulating aldosterone levels are high.
Route of administration
- Spironolactone is usually given orally four times daily.
Therapeutic uses
- Spironolactone is often used as an adjunct to other diuretics to reduce the loss of K+ in the management of refractory edema, such as that associated with Laennec's cirrhosis.
- It also used when adrenal gland tumors result in increased aldosterone levels.
- It can be used for edema resulting from congestives heart failure, although other diuretic agents are more effective.
Adverse effects
- Hyperkalemia can occur or be exacerbated, especially in patients with impaired renal function. Spironolactone is contraindicated in patients with acute renal insufficiency or hyperkalemia and is not given in combination with another K+-sparing diuretic.
- Gastrointestinal disturbances include diarrhea.
- Androgenic side effects include menstrual irregularities and hirsutism.
- CNS disturbances include lethargy and menal confusion.
Amiloride and Triamterene
They are directly acting agents which enhance Na+ excretion and reduce K+ loss by acting on ion channels in the distal tubule and collecting duct as shown in figure.
They block the Na+ transport through ion-channels in the luminal membrane. Since K+ secretion is dependent on Na+ entry, these drugs reduce K+ excretion.165
Uses
- With thiazides and loop diuretics to prevent postassium loss.
- Edema: In cirrhosis and renal edema where aldosterone levels may be high.
- Hypretension: Along with thiazides to avoid hypokalemia and for additive effect.
- Primary or secondary aldosteronidm: Spironolactone is used.
Adverse effects are gastrointestinal disturbances, hyperkalemia and metabolic acidosis.
Carbonic Anhydrase lnhibitors
Mechanism of action (Fig. 6.1.7)
- Carbonic anhydrase is an enzyme that catalyses the formation of carbonic acid which spontaneously ionises to H+ and HCO3−. This HCO3− combines with Na+ and is reabsorbed.
- Carbonic anhydrase inhibitors block sodium bicarbonate rabsorption and cause HCO3− diuresis.
- Carbonic anhydrase is present in the nephron, eyes, gastric mucosa, pancreas and other sites.
Acetazolamide: A sulfonamide derivative is a carbonic anhydrase inhibitor and enhances excretion of sodium, postassium, bicarbonate and water. The loss of bicarbonate leads to metabolic acidosis.
Other action
- Brain: Bicarbonate is secreted into CSF and carbonic anhydrase inhibition reduces the formation of CSF.
- Eye: The ciliary body of the eye secretes bicarbonate into the aqueous humor. Carbonic anhydrase inhibition results in decreased formation of aqueous humor and thereby reduces intraocular pressure.
Adverse effects
- Hypokalemia, drowsiness and allergic reactions can occur.
- Metabolic acidosis due to HCO3− loss.
- Renal stones – Ca++ is lost with HCO3− resulting in hypercalciuria. This excess Ca++ may precipitate resulting in the formation of renal stones.
Therapeutic uses
- Glaucoma: IOP is decreased by acetazolamide; it is given orally.
- Alkalinization of urine: As required in overdosage of acidic drugs. Also, uric acid and cysteine excretion can be enhanced as these are soluble in alkaline urine. Also used in UTI and renal stones.
- Mountain sickness: In mountain climbers who rapidly ascend great heights severe pulmonary edema or cerebral edema may occur. Acetazolamide may help by reducing CSF formation.
- Epilepsy: Acetazolamide is used as an adjuvant as it increases the seizure threshold.
Osmotic Diuretics (Mannitol)
Mechanism of action
- Osmotic diuretics are filtered at the glomerulus but are poorly reabsorbed because of their molecular size. The presence of these unresorbed solutes in the proximal tubule decreases reabsorption of Na+ and water, resulting in a large volume of urine.
- Mannitol causes an increase in renal medullary blood flow via a prostaglandin-mediated mechanism.
Pharmacologic effects: Osmotic diuretics do not markedly influence Na+ and Cl− excretion.
Route of administration
- Mannitol is a six-carbon sugar alcohol that is administered intravenously because it is not absorbed well from the gastrointestinal tract. It is not metabolized and may cause osmotic diarrhea.
- Urea is the least used osmotic diuretic. It can be given orally, but, because of its bitter taste, it is generally administered intravenously.
- Isosorbide is used orally for ophthalmologic emergencies such as acute angle-closure glaucoma.
Therapeutic uses
- The osmotic diuretics are used to reduce cerebrospinal fluid pressure.
- They transiently reduce intraocular fluid pressure.
- They are used as an adjunct in the prevention or treatment of oliguria and anuria.
- The osmotic diuretics, especially mannitol, are used prophylactically for acute renal failure in situations such as cardiovascular operations, treatment with nephrotoxic anticancer agents, severe traumatic injury, and management of hemolytic transfusion reactions.
- Forced diuresis in hypnotic or other substance poisoning.
Adverse effects
- Because they do not penetrate cells and their mode of excretion is by glomerular filtration, osmotic diuretics increase blood volume, which can cause decompensation in patients with congestive heart failure.
- When osmotic diuretics are used for the treatment of renal failure or cirrhotic disease, hyperosmolality and hyponatremia can occur.
Glycerol is effective orally—reduces intraocular and intracranial pressure.
Methylxanthines like theophylline have mild diuretic effect.
Diuretics and Drug lnteractions with other drugs
- Other ototoxic drugs like aminoglycosides should not be used with loop diuretics to avoid enhanced toxicity.
- NSAIDs blunt the effect of diuretics as they cause salt and water retention.
- Frusemide and ethacrynic acid are highly protein bound and may compete with drugs like warfarin and clofibrate for protein binding sites.
- Hypokalemia induced by diuretics enhance digitalis toxicity.
- Diuretics enhance lithium toxicity by reducing renal excretion of lithium.
- Other drugs that cause hyperkalemia (ACE inhibitors) and oral K+ supplements should be avoided with K+ sparing diuretics as together they can cause severe hyperkalemia.
The dose and duration of action of some commonly used diuretic agents are described in Table 6.1.1, while their adverse effects are described in Table 6.1.2.
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