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█ Loop diuretics (Furosemide, torsemide, bumetanide , and ethacrynic acid) Pharmacokinetics  They are absorbed from the GIT and secreted into the lumen of the PCT by an organic acid excretory system.  The absorption of furosemide is erratic but bumetanide is...

█ Loop diuretics (Furosemide, torsemide, bumetanide , and ethacrynic acid) Pharmacokinetics  They are absorbed from the GIT and secreted into the lumen of the PCT by an organic acid excretory system.  The absorption of furosemide is erratic but bumetanide is complete.  Diuresis occurs within 5 minutes after i.v. administration and within 30 minutes of oral administration. Mechanism and pharmacological effects  Loop diuretics inhibit Na+/K+/2Cl― co-transport system in the thick ascending limb of LOH leading to inhibition of the active reabsorption Na+, Cl―, and K+. These ions are excreted with equiosmotic amount of water. – They also increase excretion of Ca2+, Mg2+, halides and H+. – Na+ and water loss at this segment is high, so they are potent (or high ceiling) diuretics (i.e., up to 25% of the filtered Na+ load).  They ↑ renal PGE2 and PGI2 production leading to VD and ↑ RBF and GFR. – Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit PG synthesis and antagonize this effect of loop diuretics. – VD of pulmonary vascular bed also occurs due to ↑ PG formation. Therapeutic uses Edematous conditions: e.g. CHF, nephrotic syndrome, etc. – Many patients require fluid and sodium restriction to have the best results. – Diuretics are not used to treat edema due to lymphatic obstruction (lymphedema) or inflammatory edema (localized edema with high protein content is difficult to be resolved by diuretics). Acute pulmonary edema: loop diuretic ↓ pulmonary congestion by: – They cause venodilatation → ↓ venous return. – They cause VD of pulmonary vascular bed even before diuresis occurs. Acute renal failure: to maintain adequate GFR and enhance K+ excretion. Acute hypercalcemia and acute hyperkalemia: saline should be given to compensate for Na+ and water loss. Hypertensive emergencies: i.v. furosemide is usually given in emergencies: – Loop diuretics ↓ plasma volume. – They cause peripheral VD due to ↑ PGs production in many vascular beds. – Hyponatremia ↓↓ sensitivity of the vascular smooth muscles to circulating catecholamines. 90 Adverse effects – Hypovolemia and hypotension. – Electrolyte disturbances: Hyponatremia, hypokalemia, hypomagnesemia, and hypocalcemia (all need to be properly replaced). – Hypokalemic metabolic alkalosis: due to ↑ tubular secretion of K+ and H+. – Hyperuricemia and precipitation of acute gout: This is caused by: – Increased uric acid reabsorption in the PCT as a result of hypovolemia (It may be prevented by using lower doses to avoid hypovolemia). – Competition with uric acid excretion at the organic acid excretory system in the PCT. – Ototoxicity: – It is reversible hearing loss. It occurs with very high doses. – It may be due impairment of ion transport in the stria vascularis (inner ear). – Occurs more frequent with:  Patients with impaired renal function.  Ethacrynic acid.  Concomitant use of other ototoxic drugs e.g. aminoglycosides. – Allergic reactions: all loop diuretics (except ethacrynic acid) are derivatives of sulfonamides; they cause occasional skin rash, eosinophilia, and less often, interstitial nephritis. █ Thiazide diuretics Classification  True thiazides (they are derivatives of sulfonamides): hydrochlorothiazide, bendroflumethiazide.  Thiazide-like diuretics: metalozone, indapamide, chlorthalidone. Pharmacokinetics  Thiazide diuretics are absorbed from the GIT. They are secreted into the lumen of the PCT by an organic acid excretory system.  They produce diuresis within 1–2 hours. Mechanism and pharmacological effects  Thiazides inhibit Na+/Cl― co-transport system in the proximal part of DCT leading to inhibition of the active reabsorption Na+, Cl―. These ions are excreted with equiosmotic amount of water. – Excess Na+ reaching the DCT is reabsorbed in exchange with K+ (→ K+ loss). 91  – They also increase excretion of halides and H+. – They ↓ Ca2+ excretion and enhance its reabsorption. – Thiazides have moderate efficacy (i.e., maximum excretion of filtered Na+ load is only 5-7%). – Most thiazides are ineffective if the GFR is < 30-40 ml/min (so it is not useful, or even harmful, in presence of renal failure).  The action of thiazides also depends on renal PGs like loop diuretics but to much less extent. Therapeutic uses Mild edematous states: cardiac, hepatic, or renal (same as loop diuretics). Essential hypertension (mild to moderate): – They have the same mechanisms like loop diuretics (mention them). – They are often combined with other antihypertensive drugs to enhance their blood pressure-lowering effects. Hypercalcuria and renal Ca2+ stones: to ↓ urinary Ca2+ excretion. Nephrogenic diabetes inspipidus (DI): – Thiazides can reduce urine volume in some cases of DI. This is called “paradoxical antidiuretic action” and it is not clearly understood. It may be due to improvement of ADH receptor sensitivity in the renal collecting tubules. Adverse effects – Hypovolemia and hypotension. – Electrolyte disturbances: Hyponatremia and hypokalemia. – Hypokalemic metabolic alkalosis: due to ↑ tubular secretion of K+ and H+. – Hyperuricemia the same as with loop diuretics. – Hyperglycemia: due to both ↓ pancreatic release of insulin and ↓ tissue utilization of glucose. – Hyperlipidemia: due to ↑ cholesterol and LDL (by 5-15%). – Allergic reactions: thiazides are derivatives of sulfonamides; they cause occasional skin rash, dermatitis, and less often, thrombocytopenia. █ Potassium-sparing diuretics (Spironolactone – triameterine – amiloride)  Spironolactone is a steroid congener of aldosterone.  Triamterene and amiloride are synthetic drugs but not steroids. Pharmacokinetics 92  All a are absorb bed from thhe GIT.  Spironolactonne and triamterene a re metaboolized by th he liver  Amiloride is excreted e unnchanged in the urine e.  Theey have slo ow onset (days). ( anism and pharmac Mecha cological e effects  Site n: the disttal part of the DCT where e of action w Na+ is reabbsorbed (2–5%) ( in exchang e with K+ under the t influ uence of aldosterone.  Spironolacto one is a compe etitive an ntagonist of aldo osterone at a its recep ptor site att the distall part of DCT ding to ↑ Na lead + N excretio on (with exxcretion of equiosmo otic + amoount of waater) and K retention.  Tria amterene and amilo hibitors off Na+ channnels in the distal oride are direct inh partt of DCT leading to ↑ Na+ exccretion (witth excretio on of equio osmotic am mount of + water) and K retention.  The e net effec ct is: – Mild d Na+ and water loss s (i.e., max imum excrretion of filtered Na+ is only 2-5 5%) – Hypperkalemiaa: due to ↓ K excretio + + on (K will be retained in blood)). – Mettabolic acidosis: duee to ↓ H io n excretion + n (H+ will be retained in blood). Therap peutic use es All c cases of edema e due to hyperraldostero onism: – Primary hyyperaldoste eronism: e e.g. Conn’s s disease. – S Secondaryy hyperaldoosteronism m: e.g. in liv ver cirrhos sis or nephhrotic syndrome. Use ed in comb bination with w loop d diuretics or o thiazide es in orderr to: – T To minimizze the risk of electrollyte imbala ance: Loop diuretics cause hypo okalemia while K+ sparing diuretics cause hyperkalem mia. Their combinati on can minimize elec ctrolyte dissturbance.. – T To minimizze the risk of acid-ba ase imbala ance: Loop diuretics caus se metabo sis while K+ sparing olic alkalos g diuretics s cause metabolic acidosis. Their T comb bination caan minimiz ze acid-basse imbalan nce. – T To make synergism s in cases o f refractory y (resistantt) edema. Treatment off female pattern haiir loss: Spirronolacton ne is a weak compe etitive inhib ndrogens aat their receptors bitor of an d ↓ synthesis of testtosterone (antianderrogenic efffect). Som and me dermatoologists use e this feature to stop androgen--related fro ontal hair lo oss in wom men. 93