Renal Pharmacology Notes

Renal Pharmacology

The kidney is mainly a regulatory organ; it also has excretory function. The functional unit of the kidney is the nephron. Each kidney contains about 1 million nephrons. The functions of the kidney are:

1. Regulatory: Acid-base, fluid and electrolyte balance.
2. Excretory: Excretion of nitrogenous waste products.
3. Hormonal: Activation of vitamin D, production of renin and erythropoietin.

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Mechanism Of Urine Formation

It consists of the following steps:

1. Glomerular filtration
2. Tubular reabsorption
3. Active tubular secretion

Urine formation begins with glomerular filtration. The volume of fluid filtered is about 180 L/day, of which more than 99% gets reabsorbed in the renal tubules; urine output is about 1–1.5 L/day. After filtration, fluid traverses in the renal tubules. The tubular fluid contains Na⁺, K⁺, Cl^–, HCO₃^–, amino acids, glucose, etc.

1. Proximal tubule: Site 1
   
   • Most of the filtered Na⁺ is actively reabsorbed; chloride is reabsorbed passively along with sodium. Carbonic anhydrase plays an important role in Na⁺–H⁺ exchange (Na⁺–H⁺ antiporter) and helps in the reabsorption of bicarbonate and secretion of H⁺. Potassium, glucose, amino acids, etc. are also reabsorbed in the proximal convoluted tubule (PT). Proportionately, water also gets reabsorbed – so tubular fluid in the PT remains isotonic.
2. Descending limb of the loop of Henle
   • The descending limb is impermeable to Na+ and urea, and highly permeable to water. Hence, fluid in this segment becomes hypertonic.
3. Thick ascending limb of the loop of Henle: Site 2
   • The thick ascending limb is impermeable to water but highly permeable to Na⁺ and Cl^–. Active reabsorption of sodium and chloride occurs by Na⁺–K⁺–2Cl⁺ cotransporter. This is selectively blocked by loop diuretics. Ca²⁺ and Mg²⁺ are also reabsorbed at this site. The tubular fluid becomes hypotonic.
4. Early distal tubule: Site 3
   • It is impermeable to water, but sodium and chloride are reabsorbed with the help of Na⁺–Cl^– symporter. This is blocked by thiazides.
5. Late distal convoluted tubule and collecting duct: Site 4
   • Sodium is actively reabsorbed; chloride and water diffuse passively. Exchange of Na⁺– K⁺, H⁺ ions occur. The Na⁺–K⁺ exchange is under the influence of aldosterone (aldosterone promotes Na+ absorption and K⁺ depletion). The absorption of water in the collecting duct (CD) is under the influence of antidiuretic hormone (ADH). In the absence of ADH, CD becomes impermeable to water and a large amount of dilute urine is excreted. Normally, H⁺ ions present in urine convert NH₃ to NH₄⁺, which is excreted.

Diuretics

Diuretics are drugs that promote excretion of Na⁺ and water in urine.

Classification according to the primary site of action in the nephron

1. Drugs acting at PT (Site 1)
   • Carbonic anhydrase inhibitor: Acetazolamide.
2. Drugs acting at the thick ascending limb of the loop of Henle (Site 2)
   • Loop diuretics: Furosemide, bumetanide, torsemide.
3. Drugs acting at early distal tubule (Site 3)
   • Thiazides: Chlorothiazide, hydrochlorothiazide, benzthiazide, polythiazide.
   • Thiazide-related diuretics: Chlorthalidone, indapamide, metolazone.
4. Drugs acting at late distal tubule and CD (Site 4)
   • Aldosterone antagonist: Spironolactone, eplerenone
   • Direct inhibitors of renal epithelial Na+ channels: Amiloride, triamterene.
5. Drugs acting on the entire nephron (the main site of action is a loop of Henle)
   • Osmotic diuretics: Mannitol, glycerol, isosorbide.

Carbonic Anhydrase Inhibitors

1. Mechanism of action CO₂ and H₂O from the tubular lumen diffuse into the tubular cell where H₂CO₃ is formed under the influence of carbonic anhydrase. Carbonic acid (H₂CO₃) dissociates into H⁺ and HCO₃^–. The H⁺ ions exchange with luminal Na⁺ (Na⁺–H⁺ antiporter). In the lumen, H⁺ ions combine with the filtered HCO3− to form H2CO3. The H₂CO₃ dissociates into CO₂ and H₂O with the help of carbonic anhydrase, which is present near the brush border. The main site of action of acetazolamide is the proximal tubule (Site 1); it also acts in the CD. Acetazolamide, by inhibiting the carbonic anhydrase enzyme, prevents the formation of H⁺ ions. Thus, Na⁺–H⁺ exchange is prevented. Na⁺ is excreted along with HCO₃^– in urine. In the distal tubule (DT), increased Na⁺–K⁺ exchange leads to loss of K⁺. The net effect is loss of Na⁺, K⁺ and HCO₃^– in urine, resulting in alkaline urine.
2. Acetazolamide is not used as a diuretic because of its low efficacy. It is used in the following:
   • Glaucoma: Carbonic anhydrase inhibitors decrease intraocular pressure (IOP) by reducing the formation of aqueous humour. Acetazolamide is used in acute congestive glaucoma by oral and i.v. routes. Topical carbonic anhydrase inhibitors, dorzolamide and brinzolamide are used in chronic simple glaucoma
   • To alkalinize urine in acidic drug poisoning.
   • Acute mountain sickness: Acetazolamide can be used both for symptomatic relief and prophylaxis of acute mountain sickness. The beneficial effect may be due to a decrease in pH and the formation of cerebrospinal fluid.
   • Absence seizures: As an adjuvant.
3. Adverse effects These include hypersensitivity reactions (skin rashes, fever, nephritis, etc.), headache, drowsiness, paraesthesia, hypokalaemia, metabolic acidosis and renal stones.

Osmotic Diuretics

These include mannitol, glycerol and isosorbide.

Mannitol: Mannitol is administered intravenously. It is neither metabolized in the body nor significantly reabsorbed from the renal tubules. It is pharmacologically inert and is freely filtered at the glomerulus.

Glycerol: Glycerol can be used orally to reduce IOP in acute congestive glaucoma.

1. Mechanism of action Osmotic diuretics draw water from tissues by osmotic action. This results in increased excretion of water and electrolytes. Their site of action is the loop of Henle and the proximal tubule.

1. Uses of osmotic diuretics
   • Mannitol is used to prevent acute renal shutdown in shock, cardiovascular surgery, haemolytic transfusion reactions, etc.
   • Mannitol is used to reduce elevated intracranial tension (ICT) following a head injury or tumour. It draws fluid from the brain into the circulation by osmotic effect, thus lowering ICT.
   • Mannitol 20% (i.v.), glycerol 50% (oral) and isosorbide (oral) are used to reduce the elevated IOP in acute congestive glaucoma. They draw fluid from the eye, by osmotic effect, into blood – IOP is decreased.
2. Adverse effects
   • Too rapid and too much quantity of i.v. mannitol can cause marked expansion of ECF volume, which can lead to pulmonary oedema.
   • Headache, nausea and vomiting may occur.
3. Contraindications Mannitol is contraindicated in congestive cardiac failure (CCF) and pulmonary oedema because it expands ECF volume by increasing the osmolality of the extracellular compartment and increases the load on the heart, thus aggravating the above condition. Other contraindications are chronic oedema, anuric renal disease, active intracranial bleeding and tubular necrosis.

Loop Diuretics (High-Ceiling Diuretics)

The important loop diuretics are furosemide, bumetanide and torsemide.

Mechanism of action The Site of action is the thick ascending limb of the loop of Henle (Site 2)
Loop diuretics bind to the luminal side of Na⁺–K⁺–2Cl^– cotransporter and block its function. There is an increased excretion of Na⁺ and Cl^– in urine. The tubular fluid reaching DT contains a large amount of Na⁺. Hence, more Na+ exchanges with K⁺, leading to K⁺ loss. Furosemide has weak carbonic anhydrase inhibiting activity, hence increasing the excretion of HCO₃^–. Loop diuretics also increase the excretion of Ca²⁺ and Mg²⁺.

1. • Loop diuretics are called high-ceiling diuretics because they are highly efficacious – have maximal Na⁺ excreting capacity when compared to thiazides and potassium-sparing diuretics. Loop diuretics are rapidly absorbed through the gastrointestinal tract.
   • Furosemide and bumetanide are administered orally, i.v. and i.m. routes. Torsemide is given orally and intramuscularly. Furosemide has a rapid onset of action – within 2–5 min of i.v., 10– 20 min after i.m. and 30–40 min after oral administration. The duration of action of furosemide is short (2–4 h).
2. Bumetanide and torsemide
   • Can be administered orally and parenterally.
   • Are more potent than furosemide.
   • Have better oral bioavailability than furosemide.
   • Torsemide has a longer half-life than others.
3. Therapeutic uses of loop diuretics
   • During the initial stages of renal and cardiac oedema, loop diuretics are preferred. They are also useful in hepatic oedema – vigorous diuresis should be avoided to prevent hepatic coma.
   • Intravenous furosemide is used in hypercalcaemia, as it promotes excretion of Ca²⁺ in urine.
   • Acute pulmonary oedema–loop diuretics act in the following way:
   • Loop diuretics may be used in cerebral oedema, but i.v. mannitol is the preferred drug.
   • Hypertension: Loop diuretics can be used in hypertension associated with CCF/renal failure and in hypertensive emergencies. Furosemide is not preferred in uncomplicated primary hypertension because of its short duration of action.
   • To prevent volume overload, furosemide is administered during blood transfusion.

1. Adverse effects of loop diuretics
   • Electrolyte disturbances are the common adverse effects seen with loop diuretics. They are:
     • Hypokalaemia: It is the most important adverse effect. It can cause fatigue, muscular weakness and cardiac arrhythmias. Hypokalaemia can be prevented by using a combination of a loop diuretic with a potassium-sparing diuretic. It can be treated by K+ supplementation.
     • Hyponatraemia: Loop diuretics can cause depletion of sodium from the body.
     • Hypocalcaemia and hypomagnesaemia: These are due to the increased urinary excretion of Ca²⁺ and Mg²⁺, respectively.
   • The metabolic disturbances include:
     • Hyperglycaemia: This can occur due to decreased insulin secretion.
     • Hyperuricaemia: These drugs decrease renal excretion of uric acid and may precipitate attacks of gout.
     • Hyperlipidaemia: They increase plasma triglycerides and LDL cholesterol levels.
   • Ototoxicity manifests as deafness, vertigo and tinnitus. Symptoms are usually reversible on the stoppage of therapy. The risk of ototoxicity is increased in patients with renal impairment and in those receiving other ototoxic drugs like cyclosporine and aminoglycosides.
   • Hypersensitivity: Skin rashes, eosinophilia, photosensitivity, etc. may occur.
2. Drug interactions
   • Furosemide/thiazides × digoxin: These diuretics cause hypokalaemia which increases the binding of digoxin to Na⁺K⁺-ATPase leading to digoxin toxicity.
   • Furosemide × aminoglycosides: Both are ototoxic drugs and cause enhanced toxicity when used together.
   • Furosemide × nonsteroidal anti-inflammatory drugs (NSAIDs): NSAIDs inhibit prostaglandin (PG) synthesis and block PG-mediated haemodynamic changes of loop diuretics. Chronic use of NSAIDs leads to Na⁺ and H₂O retention and diminish the antihypertensive effect of loop diuretics/thiazides.
   • Furosemide/chlorthalidone × amiloride: Furosemide/chlorthalidone causes hypokalaemia, whereas amiloride conserves potassium. The combination of these diuretics does not alter plasma potassium levels; also improves diuretic response – synergistic effect.

Thiazides (Benzothiadiazides) And Thiazide-Related Diuretics

Thiazides are medium-efficacy diuretics.

1. Mechanism of action Thiazides inhibit Na⁺–Cl^– symport in early distal tubule (Site 3) and increase Na⁺ and Cl^– excretion. There is increased delivery of Na⁺ to the late distal tubule. Hence, there is an increased exchange of Na⁺–K⁺, which results in K⁺ loss. Some of the thiazides also have weak carbonic anhydrase inhibitory action and increase  HCO₃^– loss. Therefore, there is a net loss of Na⁺, K⁺, Cl^–, and HCO₃^– in urine. Unlike loop diuretics, thiazides decrease Ca²⁺ excretion.

1. Pharmacokinetics Thiazides are administered orally. They have a long duration of action and are excreted in urine.
2. Uses
   • Hypertension: Thiazides are used in the treatment of essential hypertension.
   • Heart failure: Thiazides are used in combination with loop diuretics in severe CHF.
   • Hypercalciuria: Thiazides are used in calcium nephrolithiasis, as they reduce the urinary excretion of calcium.
   • Diabetes insipidus
3. Adverse effects
   • Thiazides cause electrolyte disturbances, which include hypokalaemia, hyponatraemia, hypomagnesaemia and hypercalcaemia.
     • Hypokalaemia is more common with thiazides than loop diuretics because of their long duration of action.
     • Hypercalcaemia is due to decreased urinary excretion of calcium.
   • The metabolic disturbances are similar to those of loop diuretics – hyperglycaemia, hyperlipidaemia and hyperuricaemia.
   • They may cause impotence; hence, thiazides are not the preferred antihypertensives in young males.
   • Others: Skin rashes, hypersensitivity, gastrointestinal disturbances like nausea, vomiting and diarrhoea can occur.
4. Thiazide-related diuretics Chlorthalidone is a frequently used thiazide-related diuretic in hypertension, as it has a long duration of action. Indapamide and metolazone are longer acting than thiazides. They are used in hypertension.

Potassium-Sparing Diuretics

1. Spironolactone (aldosterone antagonist) Spironolactone is an aldosterone antagonist. It is a synthetic steroid and structurally related to aldosterone. Aldosterone enters the cell and binds to the specific mineralocorticoid receptors (MR) in the cytoplasm of the late distal tubule and CD cells (Site 4). The hormone–receptor complex (MR–AL) enters the cell nucleus, where it induces the synthesis of aldosterone-induced proteins (AIPs). The net effect of AIPs is to retain sodium and excrete potassium. Spironolactone competitively blocks the MR and prevents the formation of AIPs. Therefore, spironolactone promotes Na⁺ excretion and K⁺ retention. Spironolactone is most effective when circulating aldosterone levels are high. It also increases Ca²⁺ excretion.
   • Pharmacokinetics Spironolactone is administered orally, gets partly absorbed and is highly bound to plasma proteins; extensively metabolized in the liver and forms an active metabolite, canrenone, which has a long plasma half-life.
   • Uses
     • In oedematous conditions associated with secondary hyperaldosteronism (CCF, hepatic cirrhosis and nephrotic syndrome).
     • Spironolactone is often used with thiazides/loop diuretics to compensate K+ loss.
     • Resistant hypertension due to primary hyperaldosteronism (Conn’s syndrome).
     • CCF: Spironolactone is used in moderate-severe heart failure because it blocks the effect of aldosterone. It prevents hypokalemia, ventricular remodelling, and retards the progression of the disease.
   • Adverse effects Hyperkalaemia is the major adverse effect of aldosterone antagonists. The risk is greater in patients with renal disease or in those receiving ACE inhibitors, ARBs, β-blockers, NSAIDs, etc. Other adverse effects include nausea, vomiting, diarrhoea, peptic ulcer, drowsiness, mental confusion, menstrual disturbances, gynecomastia, decreased libido and impotence.
   • Drug interaction ACE inhibitors × spironolactone: Dangerous hyperkalaemia can occur. Eplerenone, an aldosterone antagonist, is more selective for MR. Hence, it is less likely to cause gynecomastia. Its therapeutic uses include hypertension and chronic heart failure.
2. Amiloride and triamterene (directly acting drugs) Both are directly acting potassium-sparing diuretics. They directly block the Na⁺ channels in the luminal membrane of the cells of the late distal tubule and CD. The net effect of these drugs is to increase Na⁺ excretion and retain potassium; hence, these are called K⁺-sparing diuretics. They are administered orally. Both are low-efficacy diuretics. Triamterene is extensively metabolized, while amiloride is excreted unchanged in urine.
   • Potassium-sparing diuretics are used with thiazides/loop diuretics for the treatment of hypertension. The combination therapy increases the diuretic and antihypertensive effects of thiazides/loop diuretics. They also correct hypokalaemia due to thiazides/loop diuretics.
   • Adverse effects These include hyperkalaemia, nausea, vomiting, diarrhoea, headache, dizziness and muscle cramps. Various diuretics with their site and mechanism of action are shown in Table.

Diuretics with Their Site and Mechanism of Action

Antidiuretics

Vasopressin

Vasopressin (AVP or arginine vasopressin; ADH) is a peptide hormone synthesized in the supraoptic and paraventricular nuclei of the hypothalamus and stored in the posterior pituitary.

Synthetic AVP is a peptide hormone; hence, it is not effective orally. It is administered by i.v., i.m., s.c. or intranasal routes and has a short duration of action.

Vasopressin Analogues

1. Desmopressin: It is a selective V₂-receptor agonist and is more potent than vasopressin as an antidiuretic. It has negligible vasoconstrictor action. It is administered by oral, nasal and parenteral routes.
2. Lypressin: It acts on both V₁– and V₂ receptors. It is less potent but longer acting than vasopressin. It is administered parenterally.
3. Terlipressin: It is a prodrug of vasopressin with selective V₁ action. It is administered intravenously.
4. Felypressin: It is a synthetic analogue of vasopressin. It is mainly used for its vasoconstrictor (V₁) action along with local anaesthetics to prolong the duration of action. Felypressin should be avoided in pregnancy because of its oxytocic (uterine stimulant) activity.
   • Uses of vasopressin analogues
     • Due to V₁-receptor-mediated actions
       • For emergency control of bleeding oesophageal varices: Terlipressin controls bleeding by constricting mesenteric blood vessels.
     • Due to V₂-receptor-mediated actions
       • Neurogenic diabetes insipidus (DI): Desmopressin is the drug of choice.
       • Diabetes insipidus (DI) is a condition characterized by the excretion of a large volume of dilute urine either due to decreased secretion of ADH from the neurohypophysis (neurogenic DI) or due to an inadequate renal tubular response to ADH (nephrogenic DI).
         1. Thiazides are useful for both central and nephrogenic DI.
         2. Amiloride is used for the treatment of lithium-induced nephrogenic DI.
       • Haemophilia and von Willebrand’s disease: Desmopressin, administered intravenously, controls bleeding by promoting the release of factor 8 and von Willebrand’s factor.
       • Primary nocturnal enuresis: Administration of desmopressin at bedtime reduces nocturnal urine volume.
   • Adverse effects
     • Nausea, vomiting, diarrhoea, belching and abdominal cramps.
     • Backache is due to uterine contraction.
     • Intranasal administration may cause local irritation and ulceration.
     • Fluid retention and hyponatraemia can occur.
     • Vasopressin can precipitate an attack of angina by constricting the coronary blood vessels. Hence, it is contraindicated in patients with hypertension and coronary artery disease.