1. Objectives for Lecture on Diuretics
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

2. A Drug That Increases Urine Volume
Diuretic
A Drug That Increases Urine Volume

3. 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

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

5. Proximal Tubule

6. Reabsorption into the Bloodstream

7. Proximal Tubule

8. Thick Ascending Limb

9. Distal Tubule

10. Collecting Duct

11. Collecting Duct

12. 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

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

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

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

16. 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

17. 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

18. Thiazide Diuretics (Hydrochlorothiazide, Chlorthalidone)
Molecular Mechanism
Block of Na+-Cl- cotransport in the distal tubule (for diuresis)
Opening of Ca2+-dependent K+ channel in vascular smooth muscle, reduced [Na+]i in vascular smooth muscle, reduced Na+ contribution to arterial and cardiac remodeling, enhanced NO production by endothelial cells? (for  blood pressure)
Physiological Mechanism
Transient  in ECFV, followed by a small sustained ; no lasting change in cardiac output
Sustained  in peripheral resistance

19. Distal Tubule

20. Collecting Duct

21. Thiazide Diuretics (Hydrochlorothiazide, Chlorthalidone)
Molecular Mechanism
Block of Na+-Cl- cotransport in the distal tubule
Opening of Ca2+-dependent K+ channel in vascular smooth muscle, reduced [Na+]i in vascular smooth muscle, reduced Na+ contribution to arterial and cardiac remodeling, enhanced NO production by endothelial cells?
Physiological Mechanism
Transient  in ECFV, followed by a small sustained ; no lasting change in cardiac output
Sustained  in peripheral resistance

22. Arterial Smooth Muscle Cell

23. Possible Mechanisms for Reduction of Peripheral Resistance by Thiazide Diuretics
Opening of a Ca2+-dependent K+ channel in vascular smooth muscle
Lasting reduction (~5%) in plasma [Na+] leads to Na+ depletion in vascular smooth muscle cells, which triggers efflux of Ca2+ via Na+/Ca2+ exchange
Inhibition of arterial and cardiac remodeling
Reverse Na+-induced inhibition of NO production by endothelial cells

24. Thiazide Diuretics (Hydrochlorothiazide, Chlorthalidone)
Major Clinical Use
Chronic therapy of essential hypertension
Reduce certain cardiovascular morbidities somewhat more effectively in the American population than other antihypertensive drugs (demonstrated with chlorthalidone)
Highly successful as monotherapy, especially in persons with “sodium-dependent” hypertension
African-Americans
Elderly
Obese
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

25. Hydrochlorothiazide vs Chlorthalidone
Chlorthalidone appears equal or superior to lisinopril or amlodipine with respect to cardiovascular morbidity
Hydrochlorothiazide appears inferior to lisinopril or amlodipine with respect to cardiovascular morbidity
Chlorthalidone shown to reduce cardiovascular morbidity better than hydrochlorothiazide
Chlorthalidone has a longer duration of action than hydrochlorothiazide. Possibly for that reason, it may be superior for once a day dosing. Chlorthalidone also opens K+ channels in vascular smooth muscle with greater potency
Most products that combine a thiazide diuretic with an antihypertensive drug from another class contain hydrochlorothiazide. However, combinations with chlorthalidone have begun to appear on the market.

26. Thiazide Diuretics (Hydrochlorothiazide, Chlorthalidone)
Other Effects
Ca2+-sparing
Good for individuals with osteoporosis or who are at risk of developing osteoporosis
K+, Mg2+ 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)

27. 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

28. Thick Ascending Limb

29. Collecting Duct

30. Loop Diuretics (Furosemide)
Molecular Mechanisms
Inhibition of Na+/K+/2 Cl- cotransport by NKCC2 in the thick ascending limb
Stimulation of vasodilatory prostaglandin/NO synthesis in veins (especially when administered iv) and in some arterial beds
Inhibition of NKCC1 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)

31. 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

32. 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 PGE2)
Combine with ACE inhibitor or ARB (until serum creatinine reaches 3 mg/dL)

33. Loop Diuretics (Furosemide)
Adverse Effects
K+, Mg2+, Ca2+ wasting
Use ACE inhibitor/ARB or add potassium-sparing diuretic!
May require Mg2+, not usually Ca2+, 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!

34. Collecting Duct

35. 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

36. 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)
Eplerenone is a more specific aldosterone receptor antagonist than spironolactone