unit 5

• Diuretics


  Drugs that increase the rate of urine flow and sodium excretion, used to adjust the volume and/or composition of body fluids
• Nephron


  • The basic urine-forming unit of the kidney, consisting of a filtering apparatus (glomerulus) connected to a long tubular portion that reabsorbs and conditions the glomerular ultrafiltrate
  • Each human kidney has approximately one million nephrons

  
• Renal tubular transport


  1. Na+,K+-ATPase in basolateral membrane hydrolyzes ATP, transporting Na+ into intercellular/interstitial spaces and K+ into cell

  2. Na+ diffuses across luminal membrane via Na+ channels down electrochemical gradient

  3. Na+-linked symporters in luminal membrane cause concentration of substrates to rise in epithelial cell

  4. Accumulation of Na+ and other solutes in intercellular space creates osmotic pressure differential, driving water movement

  5. Water and solute movement into intercellular space increases hydrostatic pressure, driving bulk water flow and solute convection out of intercellular space
• Diuretic action


  Increase rate of urine flow and sodium excretion, reducing extracellular fluid volume by decreasing total-body NaCl content
• Diuretic braking mechanisms


  • Activation of sympathetic nervous system and renin-angiotensin-aldosterone axis
  • Decreased arterial blood pressure
  • Hypertrophy of renal epithelial cells
  • Increased expression of renal epithelial transporters
  • Alterations in natriuretic hormones
• Inhibitors of carbonic anhydrase

  1. Potently inhibit membrane-bound and cytoplasmic carbonic anhydrase

  2. Nearly complete abolition of NaHCO3 reabsorption in proximal tubule

  3. Inhibition of both membrane-bound and cytoplasmic carbonic anhydrase contributes to diuretic activity

  4. Also inhibit carbonic anhydrase involved in acid secretion in collecting duct
• Therapeutic uses of carbonic anhydrase inhibitors

  • Limited usefulness as single diuretic agents
  • Effective when combined with diuretics blocking Na+ reabsorption at more distal sites
  • Major indication is open-angle glaucoma
  • Also used for epilepsy, altitude sickness, familial periodic paralysis, and correcting metabolic alkalosis

  
• Osmotic diuretics

  Agents that are freely filtered at the glomerulus, undergo limited reabsorption, and increase plasma and tubular fluid osmolality
• Mechanism of osmotic diuretics

  1. Extract water from intracellular compartments, expanding extracellular fluid volume and decreasing blood viscosity

  2. Inhibit renin release, increasing renal blood flow and removing NaCl and urea from renal medulla

  3. Reduce medullary tonicity, decreasing water extraction from descending thin limb and passive NaCl reabsorption in ascending thin limb

  4. Inhibit reabsorption of Mg2+ in thick ascending limb
• Therapeutic uses of osmotic diuretics

  • Attenuate reduction in GFR in acute tubular necrosis
  • Maintain urine flow but not GFR in vascular and open-heart surgery
  • Convert oliguric to nonoliguric acute tubular necrosis in some patients
• Loop diuretics, high-ceiling diuretics

  • Inhibit Na+-K+-2Cl- symporter in thick ascending limb of loop of Henle
  • Highly efficacious due to large percentage of filtered Na+ reabsorbed in this segment and limited reabsorptive capacity of more distal nephron segments
• Mechanism of loop diuretics is binding to Cl--binding site on Na+-K+-2Cl- symporter in thick ascending limb, blocking its function
• Na+–K+–2Cl– symport inhibitors

  Also called high-ceiling diuretics, highly efficacious inhibitors of Na+–K+–2Cl– symport in the thick ascending limb of the loop of Henle
• Approximately 25% of the filtered Na+ load normally is reabsorbed by the thick ascending limb
• Nephron segments past the thick ascending limb do not possess the reabsorptive capacity to rescue the flood of rejectate exiting the thick ascending limb
• Mechanism of Na+–K+–2Cl– symport inhibitors

  They bind to the Na+–K+–2Cl– symporter in the thick ascending limb and block its function, bringing salt transport in this segment of the nephron to a virtual standstill
• The molecular mechanism by which Na+–K+–2Cl– symport inhibitors block the Na+–K+–2Cl– symporter is unknown, but evidence suggests that these drugs attach to the Cl–-binding site located in the symporter's transmembrane domain
• Na+–K+–2Cl– symport inhibitors also inhibit Ca2+ and Mg2+ reabsorption in the thick ascending limb by abolishing the transepithelial potential difference that is the dominant driving force for reabsorption of these cations
• Controlled clinical trials demonstrating reduced morbidity and mortality have been conducted with Na+–Cl– symport (thiazides and thiazidelike diuretics) but not Na+–K+–2Cl– symport inhibitors
• Na+–K+–2Cl– symport inhibitors appear to lower blood pressure as effectively as Na+–Cl– symport inhibitors while causing smaller perturbations in the lipid profile

  
• Benzothiadiazides

  Synthetic compounds that inhibit Na+–Cl– symport, found to predominantly increase NaCl excretion, an effect independent of carbonic anhydrase inhibition
• Mechanism of thiazide diuretics

  They inhibit the Na+–Cl– symporter, and Na+ or Cl– binding to the Na+–Cl– symporter modifies thiazide-induced inhibition of the symporter, suggesting the thiazide-binding site is shared or altered by both Na+ and Cl–
• Thiazide diuretics are ineffective when the GFR is less than 30 to 40 ml/min, with possible exceptions of metolazone and indapamide
• Thiazide diuretics decrease blood pressure in hypertensive patients by increasing the slope of the renal pressure–natriuresis relationship

  
• Thiazide diuretics are inexpensive, as efficacious as other classes of antihypertensive agents, and well tolerated
• Thiazides can be administered once daily, do not require dose titration, and have few contraindications
• Thiazides have additive or synergistic effects when combined with other classes of antihypertensive agents
• Thiazides may increase the risk of sudden death and renal cell carcinoma marginally, but in general, these agents are safe and reduce cardiovascular morbidity and mortality in hypertensive patients
• Only low doses of thiazides should be prescribed for hypertension, as adverse effects increase progressively in severity at doses higher than maximally effective antihypertensive doses

  
• A common dose for hypertension is 25 mg/day of hydrochlorothiazide or the dose equivalent of another thiazide

  
• Angina pectoris

  The primary symptom of ischemic heart disease, caused by transient episodes of myocardial ischemia due to an imbalance in the myocardial oxygen supply–demand relationship
• Anginal symptoms may occur without any increase in myocardial oxygen demand but rather as a consequence of abrupt reduction in blood flow, as might result from coronary thrombosis (unstable angina) or vasospasm (variant or Prinzmetal angina)
• In most patients with typical angina, whose symptoms are provoked by exertion, the symptoms are relieved by rest or by administration of sublingual nitroglycerin
• Drugs used in typical angina function principally by reducing myocardial oxygen demand by decreasing heart rate, myocardial contractility, and/or ventricular wall stress
• The principal therapeutic goal in unstable angina is to increase myocardial blood flow, using strategies like antiplatelet agents, heparin, coronary stents, or coronary bypass surgery
• The therapeutic aim in variant or Prinzmetal angina is to prevent coronary vasoplasm
• Organic nitrates

  Prodrugs that are sources of nitric oxide (NO), which activates guanylyl cyclase to increase intracellular cyclic GMP and promote smooth muscle relaxation
• Mechanism of organic nitrates

  They lead to the formation of the reactive free radical NO, which can activate guanylyl cyclase, increase cyclic GMP, activate PKG, and modulate phosphodiesterase activities, resulting in smooth muscle relaxation
• The enzyme mitochondrial aldehyde dehydrogenase catalyzes the reduction of nitroglycerin to yield bioactive NO metabolites, providing a potentially important clue to the biotransformation of organic nitrates in intact tissues
• Cardiovascular effects of organic nitrates

  • They promote vascular smooth muscle relaxation, with low concentrations preferentially dilating the veins more than the arterioles, decreasing ventricular chamber size and end-diastolic pressures with little change in systemic vascular resistance