1. Diuretics

2. Outline Introduction Diuretic pharmacology Diuretic resistance
History of diuretics
Diuretic Use
Role of the nephron
Ion transport
Diuretic pharmacology
Proximal convoluted tubule diuretics
Loop (of Henle) diuretics
Distal convoluted tubule diuretics
Collecting duct diuretics
Diuretic resistance

3. Objectives To understand: The therapeutic applications of diuretics
The role of different portions of the nephron in ion exchange
The sites of action and pharmacology of diuretics

4. History of Diuretics
Diuretics effective for the treatment of edema have been available since the 16th century
In 1930, Swartz discovered that the antimicrobial sulfanilamide could be used to treat edema in patients with CHF due to an increase in renal excretion of Na+
Except for spironolactone, diuretics were developed empirically, without knowledge of specific transport pathways in the nephron
Spironolactone is a K-sparing diuretic

5. Conditions Treated with Diuretics
In addition to edema and CHF, diuretics are used to treat the following conditions:
Hypertension
Renal insufficiency
Hepatic cirrhosis
Hypercalcemia
Nephrogenic Diabetes Insipidus (thaizide diuretics only)
Glaucoma (osmotic diuretics only)
Cerebral edema (osmotic diuretics only)
Hyperaldosteronism (K+-sparing diuretics only)
Syndrome of Inappropriate ADH Secretion (SIADH)
Polycystic ovarian syndrome
Heart failure. By flushing excess fluids from the body, diuretics can relieve the edema (swelling from excess fluids) that commonly occurs with heart failure. Specifically, spironolactone and eplerenone have been independently shown to benefit patients with heart failure and poor heart function in patients already taking loop diuretics. However, a recent study has shown that spironolactone increased the risk of high potassium levels, a condition called hyperkalemia, leading to higher rates of hospitalization and mortality. This risk was more pronounced in patients taking ACE inhibitors, as well as angiotensin II receptor blockers (ARBs) and potassium supplements.

6. History of Diuretics
Diuretics are the most commonly prescribed drugs in the United States
They can be extremely efficacious, but have an extremely wide range of adverse side effects

7. Diuretics
Perhaps no other class of drugs is so widely prescribed, yet so frequently misused:

8. Diuretic Actions
The increased urine flow flushes the following dissolved substances (solutes) from the body:
Na+
K+ (except K+-sparing diuretics)
Ca++
Mg++
Cl-
HCO3-
Phosphorus
Uric acid

9. Principles Important for Understanding Diuretics Effects
Interference with Na+ reabsorption at one nephron site interferes with other renal functions linked to it
It can also lead to increased Na+ reabsorption at more distal sites
Increased flow and Na+ delivery to the distal nephron stimulates K + (and H +) secretion – increasing their excretion as well

10. Principles Important for Understanding Diuretics Effects
Diuretics act only if Na+ reaches their site of action.
The magnitude of the diuretic effect depends on the amount of Na+ reaching that site
Diuretic actions at different nephron sites can produce synergism
All, except spironolactone, act from the lumenal side of the tubular cellular membrane

11. Fluid Flow and Ion Transport in the Nephron
Time to revisit what we learned on Monday

12. Ion Transport - Proximal Tubule
Glomerular filtrate has the same composition as the blood plasma (minus proteins) when it enters the PT
The PT determines the rate of Na+ and H2O delivery to the more distal portions of the nephron
A wide variety of transporters couple Na+ movement into the cell to the movement of amino acids, glucose, phosphate, and other solutes
Water follows salt!

13. Ion Transport – Loop of Henle
Interstitial osmotic gradient determines renal concentrating capacity
Countercurrent Exchange:
Descending limb is permeable to H2O
Ascending limb is impermeable to H2O & actively pumps Na+ out of the lumen
Osmolarity increases toward tip of loop
Major ions transported:
Na+ & Cl- (load dependent)
K+ (~20-30%)
Mg++ (~50-60%)
Ca++ (~20%)

14. Ion Transport – Distal Tubule & Collecting Duct
Main site of hormonal regulation
ADH, vasopressin
↑ H2O reabsorption
Aldosterone
↑ NaCl reabsorption
Na+/K+ ATPase drives final ion reabsorption:
Na+/Cl- symport
Na+/H+ antiport (only in late DT)

15. Clinical Correlate: Fanconi Syndrome
Fanconi syndrome is a condition in which solute reabsorption in the PT is dysfunctional.  What major changes in urine composition are expected as a result?
↑ in amino acids
↑ glucose
↑ inorganic phosphate
↑ low MW proteins
Since other nephron segments cannot compensate, there is an increase in the excretion of amino acids, glucose, inorganic phosphate, and low molecular weight proteins in the urine.

16. Diuretic Classifications
Diuretics are catagorized by their site/type of action:
Carbonic Anhydrase (CA) inhibitors:
Proximal tubule
Acetazolamide
Loop-acting diuretics:
Lasix®, furosumide
Thiazide diuretics:
Late thick ascending limb & early distal convoluted tubule
Aquatensen®, metolazone.
K+-sparing diuretics:
Late distal convoluted tubule & collecting duct
Aldactone®, spironolactone
Osmotic diuretics:
Mannitol, urea

17. Proximal Tubule Diuretics – Carbonic Anhydrase (CA) Inhibitors
Mechanism of Action:
CO2 diffuses into the PT
CO2 + H2O ↔ H2CO3 ↔ H+ + HCO3-
↓ CA activity = ↓ HCO3- reabsorption
Na+ is most abundant cation present in PT fluid, thus it accompanies HCO3- through the PT
↑ HCO3-, K+, and H2O excretion CA
Na+ +
The discovery of this drug is actually an interesting story. It is a member of the sulfonamides, a group of antibacterial agents which, when intially investigated, were shown to induce a metabolic acidosis because they inhibited excretion of hydrogen ion from the kidney.
NaHCO3

18. CA Inhibitors Pharmacodynamics: Indications: Relatively weak diuretic
Well absorbed in the gut
Exert an effect within 30 min
t1/2 is approx. 13 hr
Indications:
Generally given for reasons other than diuresis:
Glaucoma
Cerebral edema
To purposely alkalinize urine (barbiturate overdose).
methamphetamine

19. CA Inhibitors Adverse Effects:
Metabolic acidosis due to urinary loss of HCO3- and hypokalemia
Effectiveness is reduced with continued therapy because plasma [HCO3-] fall, reducing the amount of HCO3- that appears in the urine.

20. Loop Diuretics Loop diuretics:
This class of diuretics are the most potent available and can cause excretion of up to 20% of the filtered Na+.
Produce the greatest increase in urine flow
May be administered I.V. to reduce edema in patients with a variety of conditions (ex: heart failure)
Most commonly used as oral medications
Rapidly absorbed from the gut & acts within 20 min
t1/2 is approx hr
Secreted by organic acid transporters (OATs) into the PT

21. Loop Diuretics Mechanism of Action: Pharmacodynamics:
Blocks the Na+/K+/2Cl- co-transporter in the apical membrane of the TAL of Henle's loop
Pharmacodynamics:
Decreases maximal urinary concentrating capacity,
Causes excretion of a high volume of dilute urine
Lowers the amount of body fluid and the blood pressure
Extensively protein bound in the plasma

22. Loop Diuretics Indications: Contraindications: Hypertension
Heat failure with pulmonary edema
Renal insufficiency
Hepatic cirrhosis
Hypercalcemia
Contraindications:
Severe liver or kidney disease
Use with caution
Hypertensive elderly who show no edema
Those susceptible to hypokalemia (digitalis users)

23. Loop Diuretics Adverse Effects:
The TAL is a major site of Ca2+ and Mg2+ reabsorption, processes that are dependent on normal Na+ and Cl- reabsorption
Therefore, loop diuretics increase urinary water, Na+, K+, Ca2+, and Mg2+ excretion
Can inhibit insulin release (hyperglycemia)
Hypokalemia (dangerous if patient using digitalis)
Hypercholesterolemia
Hyponatremia
Metabolic alkalosis
Volume contraction
Dehydration
Ototoxicity (esp. if given by rapid IV bolus)

24. Loop Diuretics Additional non-tubular effects**:
Renal Vasodilation and redistribution of blood flow
Increase in renin release
Increase in venous capacitance
**These effects mediated by release of prostaglandins from the kidney.

25. Distal Convoluted Tubule Diuretics
Thiazide (or thiazide-like) diuretics:
Increase the excretion of both Na+ and Cl- into the urine by inhibiting Na+ and Cl- transport in the cortical TAL and early DT
Milder diuretic action compared to loop diuretics
They are either prescribed alone or in conjunction with a K+-sparing version (for heart patients)

26. Thiazides Mechanism of Action: Pharmacodynamics:
Secreted into the tubular lumen by OATs in the PT
Acts on the DT to inhibit Na+ and Cl- transport
Pharmacodynamics:
Results in a modest diuresis
Increases renal excretion of K+, & Mg++
Reduces Ca++ and urate excretion
Not effective at low glomerular filtration rates
Impairs maximal diluting but not maximal concentrating ability

27. Thiazides Indications: Hypertension:
Reduce blood pressure and associated risk of CV aneurism and MI
Should be considered first-line therapy in hypertension (effective, safe and cheap)
Mechanism of action in hypertension is uncertain – involves vasodilation that is not a direct effect but a consequence of the diuretic/natriuretic effect

28. Thiazides
Schematic drawing of temporal changes in mean arterial pressure (MAP), total peripheral vascular resistance (TPR), cardiac output (CO) and plasma volume (PV) during thiazide treatment of a hypertensive subject
~Birkenhäger Diuretics and blood pressure reduction: physiological aspects. J. Hyperten. 1990, 8 (Suppl 2) S3-S7.

29. Thiazides Indications continued: Edema (cardiac, liver, renal)
Idiopathic hypercalciuria:
Condition characterized by recurrent stone formation in the kidneys due to excess Ca++ excretion
Used to prevent Ca++ loss and protect the kidneys
Diabetes Insipidus:
Malfunction of AQ2 water channels in CD
Used to concentrate urine

30. Thiazides Adverse effects: Among them are: Hypokalemia
Initially, were used at high doses, causing many adverse effects. Lower doses now used cause fewer side effects.
Among them are:
Hypokalemia
Dehydration (esp. in elderly)
Leads to postural hypotension
Hyperglycemia
Impaired insulin release secondary to hypokalemia

31. Thiazides Adverse effects continued: Hyperuricemia Hyperlipidemia
Thiazides compete with urate for tubular secretion
Hyperlipidemia
Mechanism unknown, but cholesterol increase is trivial (1%)
Impotence
Hyponatremia
Thirst, Na+ loss, SIADH
Usually occurs after prolonged use

32. Thiazides Less common problems: Hypersensitivity Metabolic Alkalosis
May manifest as interstitial nephritis, pancreatitis, rashes, or blood dyscrasias (all very rare)
Metabolic Alkalosis
Due to increased Na+ load at DT → increased Na+/H+ exchanger activity
Hypercalcemia

33. Collecting Duct Diuretics
Potassium-sparing diuretics:
Spironolactone, Amiloride, Triamterene
Used to protect from excess K+ loss, which can occur with loop and thiazide diuretics
Far less potent, K+-sparing diuretics are commonly used in conjunction with other diuretics
Frequently used in patients with liver disease and ascites (fluid build-up in the abdomen due to liver damage)
Occasionally used to treat hypertension and hypokalemia

34. K+-sparing Diuretics Mechanism of Action: Pharmacodynamics:
Acts on the late DT & CD to block aldosterone-stimulated Na+ reabsorption and K+ and H+ excretion
Pharmacodynamics:
Spironolactone:
Competitive aldosterone antagonist
↓ aldosterone-stimulated ammoniagenesis throughout nephron
Amiloride & Triamterene
Inhibits Na+ channels in the apical membrane of the late DT & CD
K+ & H+ secretion in this segment is driven by the electrochemical Na+ gradient
Results in decreased K+ & H+ secretion into the urine

35. K+-sparing Diuretics Adverse Effects: Contraindications: Hyperkalemia
Gynecomastia
Amenorrhea (mild estrogenic activity)
Contraindications:
Disease states that may induce hyperkalemia:
Diabetes mellitus
Multiple myeloma
Tubulo-interstitial renal disease
Renal insufficiency

36. Osmotic Diuretics Osmotic diuretics: Mechanism of Action:
Mannitol, glycerin, isosorbide, urea
Least used form of diuretics
Mechanism of Action:
Filtered at glomerulus where it markedly increases tubular fluid osmolality
Inhibits the reabsorption of water and dissolved substances, and causing an increase in urine flow

37. Osmotic Diuretics Pharmacokinetics: Indications: Contraindications:
Given only IV
Acts within 10 min
Indications:
protection against renal dysfunction
Glaucoma
Cerebral edema
Contraindications:
CHF
Chronic renal failure
Not metabolized therefore patients with renal failure will not have the ability to clear mannitol

38. Diuretic Resistance Compensatory Mechanisms (RAS, SNS)
Failure to reach tubular site of action
Decreased G.I. absorption
Decreased secretion into tubular lumen
(e.g. uremia, decreased kidney perfusion, volume depletion)
Decreased availability in tubular lumen
(e.g. nephrotic syndrome)
Interference by other drugs (e.g. NSAID’s)
Tubular adaptation (chronic Loop diuretic use)
Incomplete treatment of the primary disorder
Continuation of high Na+ intake
Patient noncompliance
**Can Use Combination of Diuretics to Induce a Synergistic Effect**

39. Structure-Activity Relationships
Furosemide analogs
Azides
Benzene rings
Aldosterone agonists and caffeine analogs

40. Diuretics can make some conditions worse
Gout (thiazides and loop diuretics)
A painful inflammation of the joint caused by an excessive amount of uric acid in the blood and deposits of urates in and around joints
Hearing problems
Lupus (thiazides)
Pancreatitis (loop diuretics)
Inflammation of the pancreas
Menstrual problems or breast enlargement (K+-sparing diuretics only)

41. Interactions
If diuretics are prescribed, the doctor should be made aware of any other drug, vitamin, mineral or herbal supplement the patient is taking, especially:
Antidepressants, particularly when taking thiazide or loop-acting diuretics
Clyclosporine, particularly if taking a K+-sparing diuretic
Digitalis, particularly for patients with low K+ levels
Lithium
Other blood pressure medications

42. Drug & other interactions
Substances that can influence the effects of diuretics include the following:
Antihypertensives (esp. ACE inhibitors)
Although commonly prescribed with diabetics, these can strengthen the effects of diuretics and potentially lead to hypotension
Psychiatric medications
Some diuretics can cause a build-up of these medications in the blood, increasing the chance of side effects.
Licorice
Eating certain types of licorice while taking diuretics may cause excessive K+ loss.
Alcohol use
Heat exposure
Prolonged standing

43. Side effects of diuretics
The most common side effect associated with diuretics is K+ loss (hypokalemia)
Other Side effects include:
Dry mouth
Increased thirst
Arrhythmia
Confusion, mental changes or moodiness
Muscle cramps or pain
Numbness or tingling in the hands and feet
Nausea or vomiting
Unusual tiredness or weakness
Weak pulse
Heaviness or weakness of the legs
Dizziness or lightheadedness, especially after getting up from a sitting or lying position

44. Less common side effects
Allergic reaction
Fainting (syncope)
Increased sensitivity to sunlight, causing severe sunburn or rash
Blurred vision
Confusion or nervousness
Diarrhea, stomach cramps or pain
Loss of appetite
Difficult or painful urination
Muscle twitches or spasms
Joint pain
Fever or chills
Erectile dysfunction (impotence) or decreased desire for sex
Headache or ringing in ears
Unusual bleeding or bruising
Jaundice (yellow tint to the skin or eyes)
Mood change
Weight changes

45. Predictable Side Effects
Summary
Diuretic
Site of Action
Mechanisms of Action
Predictable Side Effects
Osmotic diuretics
Proximal tubule
- impedes water reabsorption and indirectly impedes Na+ reabsorption by blocking the convective movement of Na+
- volume contraction often with increased serum osmolality
(e.g., mannitol)
Thin descending limb
Distal tubule and collecting ducts
CA inhibitors
(e.g., acetazolamide)
- impedes HCO3-, H+, Na+ reabsorption
- HCO3- loss, .: acidosis
Loop diuretics
Thick ascending limb
- blocks Cl-, Na+ and K+ reabsorption (via Na+/K+/2Cl- pump)
- increased K+ losses, because of increased Na+ delivery with increased aldosterone
(e.g. furosemide)
Thiazides
(e.g., metolazone)
Early distal tubule
- blocks Cl- reabsorption, creating intraluminal negative charge which impedes Na+ reabsorption
K+-sparing
(e.g. spironolactone)
Late distal tubule
- blocks Na+/K+ antiports, impeding Na+ reabsorption and K+ secretion (K+-sparing effect)
- increased plasma [K+]
Early collecting ducts

46. Summary