• Urine formation starts from Glomerular Filtration.• Around 180 Liter of fluid is filtered everyday inglomerulus. All soluble constituents of blood exceptplasma proteins and lipids are filtered at glomerulus.• But more than 99% of the glomerular filtrate isreabsorbed in the tubules. So inspite of 180 literfluid filtration in glomerulus, only 1.5 liter of urine isproduced in 24 hours.• Hence, tubular reabsorption and secretion are themore effective steps than the glomerular filtrationfor the drug target, as they alter urine formation ingreater extend.
Tubular reabsorption can occur at four different sites.PROXIMAL CONVULATED TUBULE• Glucose, bicarbonate, amino acids and othermetabolites are reabsorbed.• Two-third of Na+ is reabsorbed, Chloride enters inexchange for a base anion, such as formate andoxalate.• Water follows passively to maintain iso-osmolarity.1. Direct entry of Na+ along with electrochemicalgradient.
2. Na+/ K+ pump. Transfer of Na+ and Ca++ coupled toactive reabsorption of glucose, amino acids andother organic anions & PO4-3 through specificsymporters.3. Exchange of H+:Proximal tubule cells secrete H+ with the help ofcarbonic anhydrase.4. Large amount of HCO3-,amino acid, acetate createdriving force for Cl- to diffuse through paracellularpathway.
LOOP OF HENLE(DESCENDING LOOP OF HENLE)• The filtrate entering here is isotonic due to waterreabsorption in this area.• Tubular fluid becomes concentrated (Hypertonic)(Three fold increase in salt concentration).LOOP OF HENLE(ASCENDING LOOP OF HENLE)1. ASCENDING LOOP OF HENLE (Medullary partlined by cuboidal cells).• Unique. Impermeable to water.
• Active reabsorption of Na+, K+ & Cl- is mediated bya Na+/K+/2Cl- Cotransporter.• Mg++ and Ca++ enter the interstitial fluid.• 25% to 30% of tubular NaCl returns to theinterstitial fluid (blood). So, Loop of Henle is calleddiluting region. A major site for salt reabsorption.2. ASCENDING LOOP OF HENLE (Cortical part linedby flattened cells).• Impermeable to water.• Salt reabsorption continues but through Na+-Cl-symporters.• Tubular fluid gets further diluted.
DISTAL CONVULATED TUBULE• Impermeable to water.• 10% of filtered NaCl is reabsorbed via Na+/Cl-transporter that is sensitive to Thiazidediuretics.• Calcium reabsorption mediated by Na+/Ca++exchanger into the interstitial fluid.• Ca++ excretion is regulated by parathyroidhormone in this portion of the tubule.
COLLECTING TUBULE & DUCT• Na+, K+, water reabsorption.• Na+ enters through channels to tubular cells butabsorption in blood relies on Na+/K+-ATPase.• Aldosterone receptors in tubular cells influenceNa+ reabsorption & K+ secretion.• Absorption of Na+ at this site occurs through aspecific amiloride sensitive Na+ channel &controlled by aldosterone.• ADH promotes reabsorption of water from thecollecting tubule mediated by cAMP.
Summary of sites of renal reabsorption offiltrate
Relative magnitude of Na+ reabsorption at differenttubular sites is:PT- 65-70%, Asc LH- 20-25%, DT- 8-9%, CD- 1-2%.• According to this, diuretics acting on proximaltubule should be most efficacious but it is notbecause they distort acid-base balance or they aretoo weak.• Loop diuretics have substantial effect because oflimited capacity for salt reabsorption in distaltubule and collecting duct. And that is why K+sparing diuretics produce only mild salureticactivity.• Loop > Thiazide > K+ sparing > Case inhibitors.
GFR is dependant on pumping action of heart,magnitude of renal blood flow and relativedimensions of afferent & efferent glomerularvessels.RAS with distal tubular reabsorption:-• Angiotensin2 produced in kidney has direct effect onintrarenal vascular beds as well as salt & waterreabsorption.• Sympathetic stimulation→ ↑es renin release→Tubular transport.→Directly enhance reabsorption of salt & water.• PGs→ modulates renal circulation & renin release.• PGE2→inhibits ADH & has direct effect on tubularreabsorption.
Classification of Diuretics(According to the site of action)DRUGS USED IN RENAL DISORDERSDrugs that modify Drugs that modifysalt excretion water excretionPCT TAL DCT CCT Osmotic diuretics ADH ADHagonist antagonistK+-sparingdiureticsThiazidesLoopdiureticsCarbonicanhydraseinhibitors
Loop Diuretics (High ceiling diuretics)• Inhibitors of Na+ K+ 2Cl- Cotransporter. Inhibit Na+& Cl- reabsorption.• Also produce venodilator action, directly orindirectly by releasing renal factor.• Increased H+ & K+ loss. Thus may producemetabolic alkalosis.• Increase in Ca++ & Mg++ concentration &decreased excretion of uric acid.• They also potentiate the action of Thiazides.• The excretion of Na+ continues even if ECF is less& hence may result into dehydration &hypotension.
• Therapeutic Uses:Diuretic actions of Loop Diuretics:1. Oedema due to cardiac failure, hepatic disease,nephrotic syndrome.2. Acute pulmonary edema & cerebral edema,pregnancy & idiopathic edema.3. Acute chronic renal failure.4. Barbiturate poisoning, salicylate poisoning.Nondiuretic action of Loop Diuretics:1. As an antihypertensive.2. Idiopathic calcium urolithiasis.3. In Hypocalcaemia.4. Diabetes insipidus.5. Hyponatremic states due to water retention.
6. Glaucoma• Adverse effects:1. Hypokalemia, So used with potassium sparingdiuretics.2. Hyponatremia, dehydration & metabolic acidosis.3. Hyperglycemia, hyperuricemia.4. Weakness, fatigue, dizziness, cramps & myalgia.5. Prostatic hypertrophy, ototoxicity, cardiac arrestafter IV injection.6. Hepatic insufficiency, gastric upset.7. Orthostatic hypotension.
1) Furosemide• Potent, oral, diuretic, possessing halogenatedsalfamoyl benzene ring common to Thiazidediuretics.• Thick ascending loop of Henle. Blocks Na+-K+-2Cl-symport.• IV administration increases the renal blood flow.It increases PGE2 synthesis in the kidneys, whichhas a locally protective, vasodilator effect.• In physiological or pharmacological stress, itcounters the intrarenal vasoconstriction.• Furosemide attaches to the Cl- binding site ofprotein (Na+ K+ 2Cl-) to inhibit its transportfunction.
Pharmacological actions:-• Kidneys:- Excretion of Na+, K+, Cl-, PO4-2.Excessive chloride loss →hypochloremic alkalosis.K+ loss→ Hypokalemia.( Less marked withFurosemide than Thiazides).Little change in Urine pH. Potent renin releasers.• Blood vessels & BP:- IV furosemide dilatesperipheral vasculature, Lowers the arterialBP, rapid venous pooling of blood, reducingcardiac preload & afterload.• Metabolic actions:- ↑sed blood uric acid &disturbances of glucose tolerance, ↑sed bloodurea. Ca++ & Mg++ excretion also ↑ses.
Pharmacokinetics:-• Absorbed orally, Bioavailability 60-100%.• Lipid solubility is low, Food reduces bioavailability.• Excreted within 4 hours. Onset of action is quick& short.• 50% excreted unchanged, rest conjugated withglucuronide in kidney.Dose:-20-80 mg once in morning. Upto 200mg in renalinsufficiency every 6 hrs by IM/IV. In pulmonaryedema 40-80 mg IV.→LASIX 40 mg tab., 20 mg/2ml inj., SALINEX 40 mgtab., FRUSENEX 40 mg, 100 mg tab.
2) Torsemide• 3 times more potent than furosemide.• Oral absorption more rapid and complete. 80%metabolized in liver.• t1/2= 3.5 hrs. Duration of action= 4-8 hrs.• Used in hypertension & edema.Dose:-2.5 mg OD in hypertension, 5-20 mg/day inedema, 100 mg BD in renal failure.→DIURETOR 10,20 mg tabs., DYTOR 10,20,100 mgtabs.
3) Bumetanide• 40 times more potent than furosemide.• Onset & duration and its effect on electrolyteexcretion are similar to furosemide.• 80% absorption. It is metabolized in liver & itshalf life is not prolonged in renal insufficiency.Dose:-1-5 mg oral OD in the morning, 2-4 mg IM/IV,(Max 15 mg/day in renal failure).→BUMET 1mg tab., 0.25 mg/ml inj.Axosemide, Tripamide, Piretanide are otherdiuretics belonging to the furosemide group.
Ethacrynic acid• An unsaturated ketone derivatives ofPhenoxyacetic acid, is a potent oral diuretic likefurosemide.• Chemically unrelated to diuretic drugs but sameeffects as of furosemide.• Max. diuresis within 2-3 hrs after giving orally.• It can be used in edematous states, especially inpatients allergic to sulphonamides.• Less used because prone to cause adverse effectswhich are similar to those of furosemide.
Interactions1. Potentiate all other antihypertensives. Thisinteraction is intentionally employed intherapeutics.2. Hypokalaemia induced by these diuretics:• Enhances digitalis toxicity.• Produces polymorphic ventricular tachycardia withquinidine and other antiarrhythmics.• Potentiates competitive neuromuscular blockersand reduces sulfonylurea action.3. Loop diuretics + aminoglycoside antibiotics – bothototoxic and nephrotoxic → additive toxicity.4. Cotrimoxazole + loop diuretics- thrombocytopenia.
5. Indomethacin/ NSAIDs + Loop diuretics- diminishesdiuretic and antihypertensive effect of loopdiuretics.6. Probenecid + furosemide and thiazides-competitively inhibits tubular secretion offurosemide and thiazides,decreases their action byreducing the concentration in the tubular fluid,while diuretics diminish uricosuric action ofprobenecid.7. Serum lithium level rises when diuretic therapy isinstituted. This is due to enhanced reabsorption ofLi+ (and Na+) in PT.8. Furosemide and warfarin/ Clofibrates:Displacement of plasma protein binding of warfarin
Resistance to high ceiling diuretics1. Renal insufficiency .• Decreased access of diuretics to its site of action due to lowg.f.r and low proximal tubular secretion.2. Nephrotic syndrome.• Binding of diuretic to urinary protein, otherpharmacodynamic causes.3. Cirrhosis of liver.• Abnormal pharmacodynamic hyperaldosteronism;mechanism not clear.4. CHF.• lmpaired oral absorption due to intestinal congestion,decreased renal blood flow and glomerular filtration,lncreased salt reabsorption in PT.
POTASSIUM SPARING DIURETICS• These are either aldosterone antagonist ordirectly inhibit Na+ channels in DT and CD cells toindirectly conserve K+.→Spironolactone and Eplerenone• Slow onsets and duration of action (24-72 hrs)• Steroid derivatives• Pharmacologic antagonists of aldosterone in thecollecting tubules• Combine and block intracellular aldosteronereceptor → reduce expression of genescontrolling synthesis of sodium ion channelsand Na+/K+ ATPase.
→Amiloride and Triamterene• Block sodium channels in the same portion of thenephron.• Duration of action: 12—24 hours.• Increase sodium clearance and decrease K+ & H+excretion.• May cause hyperkalemic metabolic acidosis.• Amiloride blocks entry of Li+ through Na+channels in the CD cells and mitigates diabetesinsipidus induced by lithium.• Given as an aerosol it affords symptomaticimprovement in cystic fibrosis by increasingfluidity of respiratory secretions.
Therapeutic uses:-• Treatment of potassium wasting caused bychronic therapy with loop and thiazide diuretics(combination in a single pill).• Treatment of aldosteronism in cirrhosis and heartfailure.Adverse effects:-• Hyperkalemia is the most important toxicity.• Can cause endocrine abnormalities(gynecomastia and antiandrogenic effects).
Interactions:-• Given together with K+ supplements-dangeroushyperkalaemia can occur.• Aspirin blocks spironolactone action by inhibitingtubular secretion of canrenone.• More pronounced hyperkalaemia can occur inpatients receiving ACE inhibitors/ angiotensinreceptor blockers (ARBs).• Spironolactone increases plasma digoxinconcentration.
Recent advancements• CRE 10904 [2-(p-fluorophenoxy), 1-(o-hydroxyphenyl)-ethane, the leading compound of a new family of loopdiuretic and antihypertensive agents: 1-aryl, 2-aryloxy-ethanes] induced high-ceiling natriuretic action in dogsand rats, but was completely inactive in pigs.• A series of sulphonylthioureas related to Torsemide, ahigh ceiling loop diuretic, were synthesized. The fourmost active compounds were examined for their dose-dependent diuresis. Three of them showed a potency,water and electrolyte excretion similar to Torsemide. Thefourth molecule, a sulphonylthiourea (BM 20), exhibitedrelative potassium-sparing properties and a minimaldiuretic dose of 0·001 mg kg−1, 200 times lower thanTorsemide.
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