Pharmacology of Renal System

Pharmacology of Renal System

The renal system is responsible to carry out certain significant physiological functions including; excretion of waste products (urea in mammals and uric acid in reptiles and birds), maintenance of acid-base balance (through retention and liberation of HCO^-₃ and H⁺ respectively) and regulation of systemic blood pressure (via rennin angiotensin aldosterone system). The basic structural and functional unit of renal system is called nepheron that is broadly divided into two segments; renal corpuscle (including the cup shaped structure called Bowman’s capsule and associated capillary meshwork known as glomerulus) and renal tubule (subdivided into proximal convoluted tubule (PCT), Loop of Henle (U-shaped structure that consists of thin descending and thick ascending portions), distal convoluted tubule (DCT) and terminal collecting duct (CD). The kidneys receive approximately 25% of cardiac output that is subjected to glomerular filtration (it is driven by plasma hydrostatic/osmotic pressure and normally filters almost all plasma constituents except proteins, lipids and protein-bound substances). However about 99% of this filtrate is reabsorbed by renal tubule to avoid the loss of essential components like water and nutrients. Each segment of renal tubule is provided with unique structural as well functional adaptability to ensure optimum reabsorption.

PCT: The tubular fluid (present inside tubular lumen) contains sodium, water, carbon dioxide and other filtered substances. Excess of water and carbon dioxide are reversibly converted into carbonic acid (through the catalytic action of luminal carbonic anhydrase (CA) enzyme) for the sake of excretion. Alternatively carbonic acid can give rise to water and carbon dioxide which can passively diffuse into intracellular environment where once again the same enzyme is utilized to form carbonic acid and then it is splitted to yield hydrogen and bi carbonate ions. There are two transport systems (located on basolateral membrane) for the movement of bicarbonate ions into interstitial space; Na⁺- HCO^-₃ symport system and HCO^-₃-Cl^- antiport system. Reabsorption of sodium is induced by three systems (located on luminal/apical membrane); sodium channels, Na⁺- H⁺ counter transport system (which also serves to expel H⁺ into tubular lumen) and system for the co-transport of Na⁺ with glucose/amino acids. To compensate the increased level of intracellular sodium, Na⁺/K⁺/ATP_ase pump (located on basolateral membrane) drives sodium to interstitial space whereas potassium is made to enter inside intracellular environment. PCT is the site of action of carbonic anhydrase inhibitors (like Acetazolamide), which inhibit both luminal as well as intracellular carbonic anhydrase enzymes thereby preventing the reabsorption of water, carbon dioxide and HCO^-₃ and partial inhibition of sodium reabsorption_. This results in enhanced flow of urine that is alkaline in nature. Reduced level of HCO^-₃ in plasma leads to systemic acidosis that is undesirable. CA inhibitors are primarily used to treat hydrocephalus (cerebral edema) and glaucoma. CA enzyme is present in CNS (CA inhibition causes reduction of intracranial pressure, anticonvusant effect), ciliary body (CA inhibition enhances the drainage of aqueous humor thus reducing intra-ocular pressure), kidney (CA inhibition causes diuresis) and gastric mucosa (although CA inhibition reduces gastric acid secretion however it lacks any therapeutic significance).

Descending (thin) loop of Henle: This portion (located in renal medulla) is characterized by high permeability for water and absence of solute reabsorption. Transcellular and paracellular passive transport of water takes place at this point that can be prevented through the use of osmotic diuretics (Glycerol and Mannitol). Osmotic diuretics increase the osmolarity (and associated osmotic pressure) of tubular fluid that helps to draw more water from intracellular and interstitial environments causing enhanced flow of urine. Glycerol can be given orally however sometimes it can cause vomiting. Mannitol is unable to get absorbed after oral administration therefore it should be given parentrally. Activation of rennin angiotensin aldosterone system terminates the diuresis induced by osmotic diuretics.

Ascending (thick) loop of Henle: This portion is completely impermeable to water but it is responsible to conduct 25-30% of total sodium reabsorption. Calcium and Mgnesium use transcellular and paracellular modes of transportation to get entry inside cellular and interstitial space. Na⁺/K⁺/2Cl symport system (located on apical membrane) drives the concerned ions into cellular environment. Remining task is performed by Na⁺/K⁺ antiport and K⁺/Cl^- co-transport systems, located on basolateral membrane. Loop diuretics (like Frusemide/Furosemide (Lasix) and Ethacrynic acid) have the potential to cause diuresis, natriuresis and kaliuresis by blocking the action Na⁺/K⁺/2Cl symport system. Although these are considered as most potent diuretics but they can cause some side effects like ototoxicity and nephrotoxicity. Therefore they should not be co-administered with other ototoxic and nephrotoxic drugs (Aminoglycosides and Cisplatin).The hypokalemia associated with loop diuretics can predispose patients to Digitalis toxicosis. Mercurial diuretics (like Marsalyl) also possess similar mode of action but they are effective only in acidic urine (therefore they cause short-term diuresis). Furthermore their excessive administration can cause mercury toxicosis (Plumbism).

DCT: Parathyroid hormone facilitates the reabsorption of calcium through calcium channels located on apical membrane. Na⁺/ Cl^- symport system is also there to conduct solute reabsorption (only 5% of total sodium reabsorption occurs here). Chloride channels (located on basolateral membrane) transport excess of Cl^- into interstitial space while sodium is removed via Na⁺/K⁺ antiport system (located on basolateral membrane). DCT and ascending loop of Henle are known as diluting segments because they are impermeable to water and execute only solute reabsorption. Thiazide diuretics (like Chlorthiazide and Hydrochlorothiazide) act here by inhibiting sodium reabsorption (through blocking Na⁺/Cl^- symport system) and improving calcium reabsorption. These drugs can cause hyperglycemia and hyperuricemia therefore they are contraindicated in gout [Fixation (ankylosis) of joints due to uric acid accumulation, patient becomes temporarily immobilized] and diabetes mellitus (insulin deficiency or insulin resistance leads to hyperglycemia and glycosuria). Udder edema in dairy calves is a common indication for the used of these diuretics.

CD: This segment of nepheron comprises of two distinct cell types; Principal cells and Intercalated cells. Principal cells are having water channels that are meant for passive reabsorption of water under the influence of vasopressin/antidiuretic hormone (ADH; released by supra-optic nuclei of posterior pituitary gland). Aldosterone-mediated influx of sodium and efflux of potassium (across the luminal membrane) is made possible by the presence of sodium and potassium channels respectively (normally excretion of potassium and reabsorption of sodium takes place). Na⁺/K⁺ antiport system is responsible for ionic transport across the basolateral membrane. Intercalated cells contain H⁺/K⁺ antiport system (at the apical membrane) that supply hydrogen ion (derived from carbonic acid) into the lumen and remove potassium ions. This site is used by potassium-sparing diuretics (cause potassium retention) to elicit their pharmacological response. Triamterone and Amiloride induce diuresis via blocking Na⁺/K⁺ antiport system (leading to natriuresis and potassium retention). These agents can be used to inhibit the loss of potassium (leading to hypokalemia) that occurs with the administration of loop diuretics and thiazide diuretics. The ability of these drugs to cause hyperkalemia indicates their contraindication in patients taking potassium supplements and ACE inhibitors. Triamterone can cause megaloblastic anemia (oversized RBC production followed by their prompt degradation by reticuloendothelial system) by inhibiting the activity of folic acid (vitamin C). Triamterone and Amiloride are primarily used to treat cerebral edema.

Aldosterone receptor antagonists: Whenever there is a need for solute reabsorption (to enhance plasma osmolarity) the hypothalamus releases corticotrophin releasing hormone (CRH) that stimulates anterior pituitary gland to liberate adrenocorticotrophic hormone (ACTH). ACTH stimulates adrenal cortex for the synthesis and subsequent release of corticosteroids (glucocorticoids and mineralocorticoids). Aldosterone is a mineralocorticoid that undergoes receptor occupancy and then enters into the nucleus of target cell. There the hormone-receptor complex attaches to specific DNA sequence and promote transcription (synthesis of mRNA synthesis. Messenger RNA diffuses into the cytoplasm (where ribosomes are present) to initiate translation (protein synthesis). As a result aldosterone-induced proteins (AIP_S) are synthesized which carry out retention of sodium and excretion of potassium in CD of nepheron. Administration of aldosterone receptor antagonists (like Spironolactone) will block this pathway and diuresis will be caused. Same steroid receptors are shared by and other steroids (that are either naturally present in the body or they are given from exogenous sources) so always there will be a competition for receptor occupancy among steroid hormones. Overdosage of Aldosterone receptor antagonists can deprive testosterone and Dihydroprogesterone (Progesterone analogue) of their receptor occupancy (disturbing the level/activity of sexual steroids) that can lead to many unwanted effects in male (like impotence (sexual dysfunction), gynecomastia) and female (estrus/menstrual irregularities) patients. Spironolactone is used for the treatment of hyperaldosteronism.

Diuretic Tolerance: There are two forms of diuretic tolerance. Short-term tolerance, so-called braking, refers to a decrease in the response to a diuretic after the first dose has been administered. This can be prevented by restoring diuretic-induced loss of volume. The mechanism by which short-term tolerance occurs is unclear. It may be mediated by activation of angiotensin II or the sympathetic nervous system, but neither the inhibition of angiotensin-converting enzyme nor adrenergic blockade, separately or together, consistently prevents it. With long-term administration of a diuretic, the solute that escapes from the loop of Henle floods more distal regions of the nephron. By unknown mechanisms, increased exposure to solute causes hypertrophy of distal nephron segments, with concomitant increases in the reabsorption of sodium. Sodium that escapes from the loop of Henle is therefore reabsorbed at more distal sites, decreasing overall diuresis. The result is long-term tolerance of the loop diuretic.

Clinical indications for the use of diuretics

1. Edematous conditions:

Hepatic ascities: Hepatic necrosis (Cirrhosis) causes obstruction of portal blood flow, intense pressure is exerted (by accumulated blood) on walls of portal vasculature that favors the leakage of plasma followed by its accumulation in pericardial sac (hydropericardium occurs). Insufficient steroid (Aldosterone) metabolism as a result of cirrhosis can also promote edema by prolonging the duration of action of aldosterone.

CHF: Left-sided heart failure causes pulmonary edema while right-sided heart failure leads to peripheral edema. Diuretics (Frusemide, Acetazolamide or Thiazides) can be administered to resolve the edema.

Nephrotic syndrome: Altered glomerular filteration causes protein loss and reduced level of plasma proteins leads to hypotention that results in the activatioin of rennin angiotensin aldosterone system to induce solute and fluid reabsorption leading to edematous state. Aldosterone receptor anatagonists can be helpful to solve this problem.

Pre-menstrual edema: Hormonal imbalance (excess of estrogen) promotes the loss of fluid into extracellular space thus giving rise to edema.

Hydrocephalus (cerebral edema): Decreased osmotic pressure of CSF impairs its drainage (via crainial ventricles) and edema is developed. Osmotic diuretics and Carbonic anhydrase inhibitors are commonly used for this purpose.

Glaucoma: Overproduction or improper drainage of aqueous humor enhances the intraocular pressure and use of Carbonic anhydrase inhibitor is a good treatment option.

Udder edema: Swelling of udder that can be easily confused with mastitis (inflammation of udder).

Hydrothorax: Accumulation of fluid in thoracic cavity that can disturb normal breathing.

2. Non-edematous conditions:

Hypertension: Diuretics reduce the plasma volume and thus decrease blood pressure. Carbonic anhydrase inhibitors are commonly used for this purpose.

Hypercalcemia: Loop diuretics and others can be helpful to promote the excretion of excessive blood calcium however thiazides should not be used in this case as they facilitate calcium absorption in DCT.

Nephrogenic diabetes insipidus: This is characterized by non-responsiveness of principal cells (found in CD) to the action of ADH. The result is flow of large volume of diluted urine. Thiazide diuretics have the unique ability to undilute urine (by prmoting solute excretion) and can be used for this purpose. The 2nd type of diabetes insipidus is known as central diabetes insipidus that occurs due to congenital or acquired deficiency of ADH.

Epistaxis: It is defined as nasal bleeding (common in race horses) due to peripheral vasodilation and accumulation of blood in nasal sinuses. Diuretics facilitate the removal of excessive fluid and relieve this problem. Application of cold water on the head region is an alternate option of therapy.

Hyperaldosteronism: It is an endocrine disorder that results in excessive release of aldosterone leading to overretention of fliud and solutes thereby causing edema. Spironolactone can be used to treat this condition.