Diuretic Agents and Volume Balance PDF

– 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 < 30-4...

– 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  Advers se effects – Hyp a due to ↓ K+ excreti on. perkalemia – Hyp c metabolic acidos perkalemic sis: due to ↓ K+ andd ↓ H+ excreetion. – Spirronolactonee has antiandrog a genic efffects (gyn necomastia a and impottence in ma ales). Contra aindication ns All c mia: espec cases of hyperkalem h cially in the e following g conditionns: – Patients with w chronic c renal failu ure. – W With drugss that caus se hyperka alemia e.g. ACEIs. Spironolacto one shou uld not be give en with carbenoxxolone because b carbbenoxolonne has ald dosterone--like action n and can n antagonnize the effect of spirronolactone. Spironolac S ctone Triamtere ene - amiloride Structu ure Synthetic S ssteroid Synthetic non-stero oids Metabo olism Extensive E m metabolism m in the Amiloride is excrete ed liiver unchangeed in urine Mecha anism of action a Competitiv C ve antagonism N + Direct inh ibition of Na with w aldostterone at itts channels at the distal part receptor sitte in the DCT D of DCT Antiand derogenic efcts Gynecoma G astia & impotence Not preseent █ Osm motic diuretics: Mannitol,, Glycerol They arre chemica ubstances given by i.v. ally inert su on in emerrgency con i infusio nditions Mecha anism of action a  Firsst, they ↑ osmotic o pressure off plasma leading to withdrawaal of transscellular fluid d (e.g. aqueous humo or, excesssive CSF, etc). e  Sec cond, they are freely filtered byy the glom merulus and ↑ osmottic pressure of the tubu eading to ↓ water reab ular fluid le bsorption by b renal tub bules. Therap peutic use es Acute congestiv ve glauco oma and a acute rise cranial prressure: th e in intrac hey are given b apid ↑ drain by i.v. infussion for ra nage of off aqueous humor or CSF respectively by increasing thee osmotic pressure p o f the plasm ma before diuresis beegins. se effects:: dehydration with hyypernatrem Advers mia is the main m adverrse effect. 94 95