Introduction of diuretics

Diuretics (natriuretics) are drugs that cause a net loss of Na+ and water in urine. The application or uses of diuretics in the management of hypertension has outstripped their use in edema.

Classification of diuretics

1.High efficacy diuretics (Inhibitors of Na+- K+-2Cl¯ cotransport)- Sulphamoyl derivatives: (@BTF)

• Furosemide.
• Bumetanide.
• Torasemide.

2.Medium efficacy diuretics (Inhibitors of Na+-Cl¯ symport):

• Benzothiadiazines (thiazides): (@H2B2):

• • Hydrochlorothiazide.
  • Benzthiazide.
  • Hydroflumethiazide.
  • Bendroflumethiazide.

• Thiazide like (related heterocyclics) (@ CC MIX):

• • Chlorthalidone.
  • Metolazone.
  • Xipamide.
  • Indapamide.
  • Clopamide.

3.Weak or adjunctive diuretics (@ A SETA MIG):

• Carbonic anhydrase inhibitors:

• • Acetazolamide.

• Potassium-sparing diuretics:

• • Aldosterone antagonist:

• • • Spironolactone.
    • Eplerenone.

• • Inhibitors of renal epithelial Na+ channel:

• • • Triamterene.
    • Amiloride.

• • Osmotic diuretics:

• • • Mannitol.
    • Isosorbide.
    • Glycerol.

High Ceiling (Loop) Diuretic drugs (Inhibitors of Na+-K+-2Cl¯ Co-transport)

High efficacy diuretics . 25% of Na reabsorbed in the thick ascending loop (TAL). Past the thick ascending loop (TAL) does not possess the resorptive capacity.

Mechanism of action:

It inhibits Na+-K+-2Cl¯ Cotransport from the luminal side of the thick ascending limb of the loop of Henle. Decreased absorption of Na+ and Cl¯. High amounts of Na+ and water excreted in the urine. K+ excretion increased due to exchanged with Na+ in the distal tubule. Enhance excretion of Ca2+  and Mg2+  by abolishing the transepithelial potential difference in the thick ascending loop (TAL).

Other action: Inhibits carbonic anhydrase enzymes in the proximal tubule (PT) and increases HCO₃– excretion.

Pharmacokinetics of furosemide:

Furosemide is a rapidly orally absorbed drug but its bioavailability is about 60%. Severe CHF oral bioavailability may be markedly lessened or reduced necessitating parenteral administration. Low lipid solubility and highly bound to plasma proteins.

It is partially or partly conjugated with glucuronic acid and majorly excreted unchanged by glomerular filtration as well as tubular secretion. Plasma t½ averages 1–2 hours but is prolonged in patients with pulmonary edema, renal and hepatic insufficiency.

Bumetanide:

It is almost similar to furosemide in all respects but is 40 times more potent. It induces very rapid diuresis and is highly effective in pulmonary edema. Bumetanide is more lipid-soluble; oral bioavailability is 80–100%.

It is generally preferred for oral use in severe CHF due to the fact that its bioavailability is impaired to a lesser extent than that of furosemide. Extensively bound to plasma proteins, partly metabolized and partly excreted unchanged in urine and plasma t½ ~60 min.

Torasemide (Torsemide):

It is a high ceiling diuretic with properties similar to furosemide but 3 times more potent than furosemide. Oral absorption is more rapid and more complete. The elimination t½ (about 3.5 hours) and duration of action (about the range is 4–8 hours) are longer.

Use of high ceiling diuretics:

1. Edema: Diuretics agents are preferred in CHF for rapid mobilization of edema fluid in the body. For nephrotic and other forms of resistant edema, high ceiling diuretics are effective and are the drugs of choice.
2. Acute pulmonary edema (acute LVF, following MI): Increase PG synthesis →venodilation → shift of blood from pulmonary to the systemic circulation.
3. Cerebral edema:  Along with osmotic diuretics are primarily used to lower intracranial pressure by withdrawing water, furosemide may be combined to improve efficacy.
4. Hypertension: Only in the case of the presence of renal insufficiency, CHF, or in resistant cases and in hypertensive emergencies.
5. Forced diuresis: Poisoning due to drugs like barbiturates, salicylates.
6. Hypercalcemia of malignancy: Along with saline infusion.
7. Blood transfusion: To avoid volume overload.

Adverse effects:

A. Electrolyte disturbance (more common adverse effects).

• Hypokalemia:  Most common and it can cause fatigue, muscle weakness, and cardiac arrhythmias. Hypokalemia can be prevented by using a combination of loop diuretics with potassium-sparing diuretics. It can also be treated by K+ supplementation.

• Hyponatremia: Loop diuretics can cause the depletion of sodium from the body.

• Hypocalcemia and hypomagnesemia:  If chronic use of these drugs due to the increased urinary excretion of Ca²⁺  and Mg ²⁺  respectively. Hypomagnesaemia can predispose to arrhythmias.

B. Metabolic disturbance:

• Hyperglycaemia: can occur due to decreased insulin secretion.

• Hyperuricaemia: Drugs decrease the renal excretion of uric acid and may precipitate an attack of gout.

• Hyperlipidemia: Increased plasma triglycerides and LDL cholesterol level.

C. Ototoxicity: Deafness, vertigo, and tinnitus due to direct damage to hair cells in the inner ear. Symptoms are generally reversible on the stoppage of therapy. Note: Drugs contraindicated with drugs like cyclosporine, aminoglycosides, etc.

D. Hypersensitivity: Skin rashes, eosinophilia, photosensitivity, etc. may occur.

Interactions:

1. Aminoglycosides (synergism of ototoxicity).
2. Lithium (Increased plasma levels of Li+).
3. Digitalis glycosides (increased digitalis-induced arrhythmias).
4. NSAIDs (blunted diuretic response).
5. Thiazide diuretics (show synergism of diuretic activity of both drugs).

Medium efficacy diuretic drugs (Thiazides and related diuretics)

Medium efficacy; 90% Na+ already absorbed.

Mechanism of action:

Inhibits NaCl reabsorption from the luminal side of epithelium cells in the distal convoluting tubules (DCT) by blocking the Na+-Cl¯ cotransporter. K+ Excretion increased due to change with Na+ in the distal tubule. Enhanced reabsorption of Ca²⁺  due to enhancement of Na+/ Ca²⁺  pump.

Other action: inhibits carbonic anhydrase enzyme in PT and increases HCO₃– excretion.

Pharmacokinetics:

It is well absorbed orally and more lipid-soluble agents have larger volumes of distribution (some are also bound in tissues), lower rates of renal clearance, and are longer acting.

• T½ of hydrochlorothiazide is 3–6 hours, but action persists longer (6–12 hours).
• Chlorthalidone: long-acting compound with a t½ 40–50 hours, used exclusively as antihypertensive.
• Metolazone:  t½  12–24 hours.
• Xipamide:  t½  12 hours.
• Indapamide: t½  12–24 hours.
• Clopamide: t½  12–18 hours.

Uses:

1. Edema: for maintenance therapy.
2. Hypertension: Especially chlorthalidone is one of the first-line drugs.
3. Hypercalciuria: Renal calcium stones in the kidney. Thiazides act by reducing Ca2+ excretion.
4. Diabetes insipidus: Reduction in blood/ECF volume→ reduction in GFR → increased reabsorption of NaCl and water from proximal tubule (compensatory) →less delivery of NaCl and water to the distal tubule → decreased diuresis.

Adverse effects:

• Hypokalaemia and metabolic alkalosis: Weakness, fatigue, muscle cramps; cardiac arrhythmias are serious complications. Hypokalaemia can be prevented and treated by:

• •  High dietary K+ intake or

• •   Supplements of KCl (24–72 mEq/day) or

• •  Concurrent use of K+ sparing diuretics.

• Acute saline depletion.

• Dilutional hyponatremia.

• GIT and CNS disturbances: nausea, vomiting, and diarrhea, Headache, giddiness, weakness, paresthesias, impotence, etc.

• Hearing loss: Increased salt content of endolymph and direct toxic action on the hair cells in the internal ear.

• Allergic manifestations:  Rashes, photosensitivity.

• Hyperuricaemia (long-term use of higher dose).

• Hyperglycaemia and hyperlipidemia.

• Hypocalcemia.

• Hypomagnesaemia.

• Aggravated renal insufficiency, probably by reducing GFR.

• Mental disturbances and hepatic coma.

Interactions:

• Digitalis glycosides (increased digitalis-induced arrhythmias).
• Sulfonylurea (Reduced action).
• Cotrimoxazole (higher incidence of thrombocytopenia).
• NSAIDs (blunted diuretic response).

Weak or adjunctive diuretic drugs

Carbonic anhydrase inhibitors:

• Acetazolamide.

• • Reversible but non-competitive inhibitors of carbonic anhydrases.

Mechanism of action:

Inhibits carbonic anhydrases (CAs) enzymes at multiple sites,

1. Type II  in cells of proximal tubules (PT) resulting in slowing of hydration of CO2 →decreased availability of H+ to exchange with luminal Na+ through the Na+-H+ antiporter.
2. Inhibition of brush border Carbonic anhydrases type IV retards or delays dehydration of H2CO3 in the tubular fluid so that less CO2 diffuses back into the cells. Inhibition of Na+ and HCO3 reabsorption in proximal tubule due to Na+ gets absorbed in exchange with K+ in distal tubule(DT), collecting duct (CD), and HCO3- lost in excess in urine.
3. Present in intercalated cells of DT and CD due to less H+ available for secretion by H+ -ATPase and decrease Na+ reabsorption.

Extra-renal actions of acetazolamide:

(i) Lowering of intraocular tension due to decreased formation of aqueous humor (aqueous is rich in HCO3 ¯).

(ii) Gastric HCl decreases & pancreatic NaHCO3 secretion: This activity requires very high doses—not significant at clinically used doses.

(iii) Raised level of CO2 in brain and lowering of pH→ sedation and elevation of seizure threshold.

(iv) Alteration of CO2 transport in the lungs and tissues. These actions are masked by compensatory mechanisms.

Pharmacokinetics:

Well absorbed orally and excreted unchanged in urine and plasma t½: 8–12 hours.

Uses:

1. Glaucoma: Carbonic anhydrase mediates the formation of HCO3- in aqueous humor. Inhibition of carbonic anhydrase →decreases the rate of formation of aqueous humor →reduced intraocular pressure.
2. Acute mountain sickness: Development of alkalosis, hypoxia, and hyperventilation responses to decreased O2 tension. Acetazolamide affords relief by inducing metabolic acidosis and also decreases the pH and quantity of CSF and affords the relief.
3. To alkaline urine: Overdose of acidic drugs.
4. Epilepsy and periodic paralysis: Due to lowering of pH.

Adverse effects:

• Metabolic acidosis.
• Hypokalaemia.
• Drowsiness.
• Paresthesias.
• Fatigue.
• Abdominal discomfort.
• Hypersensitivity reactions—fever, rashes.
• Renal stone due to hypercalciuria.

Contraindications:

• Liver failure.
• COPD.

Potassium-sparing diuretics

Aldosterone antagonist: Spironolactone & Eplerenone.

Aldosterone:

The aldosterone regulates Na+ reabsorption & K+ and H+ secretion in collecting tubule and collecting duct. Enters cells and binds to the mineralocorticoid receptor (MR)→Aldosterone MR complex moves to the nucleus →direct synthesis of aldosterone-induced proteins (AIPs) → increases expression and function of Na+ channel and Na+/K+ pump.

Spironolactone:

Mechanism of action:

• It acts from the interstitial side or area of the tubular cells & combines with mineralocorticoid receptor (MR) and competitively inhibits the binding of aldosterone to the mineralocorticoid receptor (MR).
• mineralocorticoid receptor (MR)-Spironolactone complex not able to induce the synthesis of aldosterone-induced proteins’ (AIPs).
• It has no effect on Na+ and K+ transport due to the absence of aldosterone, while under normal circumstances, it increases Na+ and decreases K+ excretion.
• Also increases Ca2+ excretion by a direct action on renal tubules.

Pharmacokinetics:

The oral bioavailability of spironolactone from microfine powder tablets is about 75%. Highly bound to plasma proteins and completely metabolized in the liver and plasma t½-1-2 hours.

Use:

It is used only in combination with other more efficacious diuretics agents.

1. To counteract K+ loss due to the fact that thiazide and loop diuretics.
2. Edema: cirrhotic and nephrotic edema in which aldosterone levels are generally high.
3. Hypertension: Drugs are given along with thiazides to avoid hypokalaemia and for additive effect.
4. CHF: Retard disease progression and lower mortality.
5. Resistant hypertension with primary hyperaldosteronism.

Adverse effects:

• Hyperkalaemia.
• Gynecomastia, loss of libido, and erectile dysfunction in males.
• Menstrual irregularities in females.
• Gastric ulcer.
• Drowsiness, ataxia.
• Mental confusion.
• Epigastric distress.
• Loose motions.

Interactions

1. Given together with K+ supplements compounds dangerous hyperkalemia can occur.
2. Aspirin blocks spironolactone action via. inhibiting the tubular secretion of its active metabolite called canrenone.
3. More pronounced hyperkalemia can occur in patients receiving ACE inhibitors/ARBs.
4. Spironolactone increases plasma digoxin concentration.

Eplerenone

A newer and more selective aldosterone antagonist has a much lower affinity for other steroidal receptors. Eplerenone is well absorbed orally, inactivated in the liver by CYP3A4, and excreted in urine well as feces and plasma t½ is 4–6 hours.

Inhibitors of renal epithelial Na+ channel (such as Triamterene and amiloride):

Mechanism of action:

Block the renal epithelial Na+ channels (ENaCs) in the luminal membrane of principal cells in late distal tubules and collecting ducts and increase Na+ excretion and decrease K+ and H+ excretion (acidosis).

Triamterene:

It is incompletely or partially absorbed orally and partly or partially bound to plasma proteins, largely metabolized in the liver to an active metabolite, and excreted in the urine. Plasma t½ is 4 hours.

Side effects: nausea, dizziness, muscle cramps and rise in blood urea, Impaired glucose tolerance, and photosensitivity.

Amiloride:

It is 10 times more potent than triamterene. At higher doses, it also inhibits Na+ reabsorption in proximal tubules (PT), but this is clinically insignificant. It decreases or reduces Ca2+ and Mg2+ excretion but increases urate excretion. The only ¼ of an oral dose is absorbed. Not bound to plasma proteins and not metabolized. Plasma t½ (20 hours) and duration of action are longer than triamterene.

Side effects: nausea, diarrhea, and headache.

Blocks entry of Li+ ion through Na+ channels in the CD cells & mitigates or reduced diabetes insipidus induced by lithium.

Uses:

• In combination with loop and thiazide diuretics: to avoid hypokalemia and for additive effect in hypertension.
• Amiloride: lithium-induced Diabetes insipidus-block the entry of Li+.
• Amiloride: Aerosol in cystic fibrosis increase fluidity of respiratory secretions.

Osmotic diuretics (Mannitol, isosorbide, glycerol):

Mannitol: pharmacologically inert and given IV.

Mechanism of action:

Site: In proximal tubule (PT) and loop of Henle.

In proximal tubule (PT): limit the osmosis of water into the interstitial space & lessen the luminal Na+ concentration and oppose the Na+ reabsorption.

Increases osmotic pressure – removes excess water from cells-increases blood flow and GFR.

An increase in renal medullary blood flow→removes NaCl and urea from the renal medulla → reduce medullary hypertonicity → decrease in the extraction of water from the descending thin limb → limits the concentration of NaCl in the tubular fluid entering the ascending thin limb (ATL) → diminishes the passive reabsorption of NaCl in the ATL.

Along with water, excretion of all cations (Na+, K+, Ca2+, Mg2+, and anions (Cl-, HCO3-, PO₄³⁻) is also enhanced.

Uses:

1. Acute congestive glaucoma, head injury condition: Encourages movement of water from brain parenchyma region, CSF, and aqueous humor.
2. To maintain pr regulates GFR & urine flow in impending acute renal failure. E.g. in shock, severe trauma, cardiac surgery, hemolytic reactions.
3. To counteract low osmolality of plasm/ECF due to rapid dialysis.

Adverse effects:

• Pulmonary edema.
• Headache.
• Nausea, vomiting.

Contraindications:

• Acute renal failure.
• Congestive heart failure (CHF).
• Active cranial bleeding.

Isosorbide and glycerol:

Orally active osmotic diuretics may be used to reduce intraocular or intracranial tension. Intravenous glycerol can cause hemolysis.