Diuretics Victor Nadler Objectives By the end of

Diuretics Victor Nadler

Objectives • By the end of this class students will be able to: • Describe the mechanisms of renal ion and water reabsorption that are most relevant to diuretic action • Name the major diuretics used in clinical medicine • Describe the mechanism by which each drug increases urine formation and, in some instances, reduces blood pressure during chronic pharmacotherapy • List the major clinical uses of each drug and explain the mechanism(s) by which the drug improves each condition • Use each drug appropriately in the treatment of cardiovascular and renal disease

Diuretic A Drug That Increases Urine Volume

The Many Uses Of Diuretics • • Reduction of blood pressure Reduction of localized or generalized edema Treatment of acute and chronic congestive heart failure Improvement of renal function Reduction of aqueous humor volume Correction of specific ion imbalances Rapid elimination of toxins and drugs

Diuretics Are: • Safe: low toxicity, low incidence of side effects when used appropriately • Effective: high degree of success in accomplishing therapeutic objectives • Cheap

Proximal Tubule

Reabsorption into the Bloodstream

Proximal Tubule

Thick Ascending Limb

Distal Tubule

Collecting Duct

Collecting Duct

Mechanisms of Sodium Reabsorption • • • Diffusion through selective channels Cotransport with nutrients Na+/H+ exchange Passive diffusion through tight junctions Na+/K+/2 Cl- cotransport Na+/Cl- cotransport

Renal Handling of Potassium • Passive reabsorption (proximal tubule, thick ascending limb) • Secretion by exchange for Na+ (collecting duct)

Renal Handling of Calcium and Magnesium • Calcium • Reabsorption by parathyroid hormone and vitamin D-regulated mechanism in the distal tubule • Passive reabsorption in the thick ascending limb • Magnesium • Passive reabsorption in the thick ascending limb

Diuretics Increase Urine Volume Mainly by Increasing the Luminal Concentration of Solute

Osmotic Diuretics (Mannitol) • Molecular Mechanism • Solutes that are filtered, but not reabsorbed • Pharmacologically inert, metabolically inert, nontoxic • Physiological Mechanism • Increased osmolarity of the glomerular filtrate holds water in the renal tubules • Increased renal interstitial blood flow removes solutes from the interstitial fluid, thus inhibiting countercurrent exchange • Non-Renal Mechanism • Increased osmolarity of the plasma draws water from the eye and brain

Osmotic Diuretics (Mannitol) • Major Clinical Uses • • • Maintenance of renal function in acute renal failure Facilitation of toxin and drug excretion Resolution of cerebral edema (when there is no active bleeding) Temporary resolution of narrow angle glaucoma Reduction of bronchial mucus in cystic fibrosis

Thiazide Diuretics (Hydrochlorothiazide, Chlorthalidone) • Molecular Mechanism – Block of Na+-Cl- cotransport in the distal tubule (for diuresis) – Opening of K+ channels in vascular smooth muscle, reduced [Na+]i in vascular smooth muscle, reduced Na+ contribution to arterial and cardiac remodeling, enhanced NO production/reduced degradation (for blood pressure) • Physiological Mechanism – Transient in ECFV, followed by a small sustained ; no lasting change in cardiac output (for diuresis) – Sustained in peripheral resistance (for blood pressure)

Distal Tubule

Collecting Duct

Thiazide Diuretics (Hydrochlorothiazide, Chlorthalidone) • Molecular Mechanism – Block of Na+-Cl- cotransport in the distal tubule (for diuresis) – Opening of K+ channels in vascular smooth muscle, reduced [Na+]i in vascular smooth muscle, reduced Na+ contribution to arterial and cardiac remodeling, enhanced NO production/reduced degradation (for ↓ blood pressure) • Physiological Mechanism – Transient in ECFV, followed by a small sustained ; no lasting change in cardiac output (for diuresis) – Sustained in peripheral resistance (for ↓ blood pressure)

Arterial Smooth Muscle Cell

Mechanisms for Reduction of Peripheral Resistance by Thiazide Diuretics • Opening of K+ channels in vascular smooth muscle • Reverse Na+-induced inhibition of NO production/increased degradation • Inhibition of arterial and cardiac remodeling caused by excess Na+ • Lasting reduction (~5%) in plasma [Na+] leads to Na+ depletion in vascular smooth muscle cells, which triggers efflux of Ca 2+ via Na+/Ca 2+ exchange?

Thiazide Diuretics (Hydrochlorothiazide, Chlorthalidone) • Major Clinical Use • Chronic therapy of essential hypertension • Reduce certain cardiovascular morbidities more effectively in the American population than other antihypertensive drugs (demonstrated with chlorthalidone) • Highly successful as monotherapy, especially in persons with “sodiumdependent” hypertension (salt-sensitive blood pressure) § African-Americans § Elderly § Chronic kidney disease, diabetes, metabolic syndrome • Also used frequently in combination with calcium channel blocker or ACE inhibitor/ARB; additive effect with calcium channel blocker, additive or synergistic effect with ACE inhibitor or ARB

Hydrochlorothiazide vs Chlorthalidone • Chlorthalidone better inhibits progression to symptomatic cardiovascular disease. • Chlorthalidone has a longer duration of action. It better maintains therapeutic plasma concentration for a full 24 hr and therefore may be superior for once a day dosing. • Chlorthalidone opens K+ channels in vascular smooth muscle with greater potency. • Current recommendations prefer chlorthalidone for monotherapy. • Most products that combine a thiazide diuretic with an antihypertensive drug from another class contain hydrochlorothiazide. Combinations with chlorthalidone have begun to appear on the market, but are still few in number.

Thiazide Diuretics (Hydrochlorothiazide, Chlorthalidone) • Other Effects • Ca 2+-sparing • Good for individuals with osteoporosis or who are at risk of developing osteoporosis • K+, Mg 2+ wasting • Can predispose to ventricular arrythmias • Use low dose, add K+-sparing diuretic, or add ACE inhibitor/ARB • Some insulin resistance (but still beneficial in persons with diabetes)

Thiazide Diuretics (Hydrochlorothiazide, Chlorthalidone) • Possible synergism between thiazide diuretics and ACE inhibitors/ARBs • Renin secretion is a major compensatory response of the body to administration of a diuretic. This limits the drop in blood pressure that a diuretic can produce. • ACE inhibitors (e. g. , lisinopril) and ARBs (e. g. , candesartan) block the ability of renin to increase production of angiotensin II (ACEI) or block the action of angiotensin II (ARB) and thus enhance the efficacy of diuretics. • ACE inhibitors/ARBs also reduce aldosterone secretion somewhat. This effect counteracts the K+ wasting effect of diuretics. • Especially useful in hypertension + diabetes or chronic kidney disease, Stage 2 hypertension • Synergism observed primarily in salt-sensitive individuals, additivity in others

Thick Ascending Limb

Collecting Duct

Loop Diuretics (Furosemide) • Molecular Mechanisms • Inhibition of Na+/K+/2 Cl- cotransport by NKCC 2 in the thick ascending limb • Stimulation of vasodilatory prostaglandin/NO synthesis in veins (especially when administered iv) and in some arterial beds • Inhibition of NKCC 1 in vascular smooth muscle • Physiological Mechanisms • Effects on extracellular fluid volume and total body sodium similar to those of thiazide diuretics, but much larger • Increased systemic venous capacitance and renal blood flow • Sustained decrease in peripheral resistance (no greater than with thiazide diuretic)

Loop Diuretics (Furosemide) • Major Clinical Use - Acute Condition • Treatment of acute decompensated congestive heart failure/pulmonary edema • Immediate: prostaglandin/NO synthesis dilates veins, reducing preload and facilitating return of edema fluid from the lungs to the circulation • Delayed: Diuresis eliminates the mobilized edema fluid from the body

Loop Diuretics (Furosemide) • Major Clinical Uses - Chronic Conditions • Not generally used for essential hypertension; efficacy similar to thiazide diuretics, but more difficult to manage • Chronic congestive heart failure • Relieves the congestion (i. e. , pulmonary edema) and peripheral edema • Combine with ACE inhibitor or ARB and other drugs • Chronic renal insufficiency • Assures high urine volume and reduces oxygen demand of the kidney (dilate the afferent arteriole by increasing PGE 2) • Combine with ACE inhibitor or ARB (until serum creatinine reaches 3 mg/d. L)

Loop Diuretics (Furosemide) • Adverse Effects • K+, Mg 2+, Ca 2+ wasting • Use ACE inhibitor/ARB or add potassium-sparing diuretic! • May require Mg 2+, not usually Ca 2+, supplement • Inability to either concentrate or dilute the urine (dilutional hyponatremia, dehydration) • Regulate fluid intake! • Do not let these possible adverse effects deter you from using a loop diuretic when it is indicated. Monitor!

Collecting Duct

K+-sparing Diuretics (Spironolactone, Eplerenone, Triamterene, Amiloride) • Molecular Mechanisms • Competitive antagonism of aldosterone (spironolactone, eplerenone) • Block of Na+ channels in the collecting duct (triamterene, amiloride) • Na+/K+ exchange in the collecting duct (all) • Physiological Mechanisms • Effects on extracellular fluid volume and total body Na+ similar to those of thiazide diuretics, but smaller • K+ retention

K+-sparing Diuretics (Spironolactone, Eplerenone, Triamterene, Amiloride) • Major Clinical Uses • To compensate for K+ loss caused by thiazide and loop diuretics • To combat excessive levels of aldosterone (spironolactone, eplerenone; congestive heart failure, cirrhosis/hepatitis) • Add on for treatment of resistant hypertension • Eplerenone is a more specific aldosterone receptor antagonist than spironolactone