1. Diuretics: drugs that affect the renal system

2. Learning Objectives
After studying this content, the student will be able to:
Review normal distribution of water/fluid volume in the human body. Review capillary forces (hydrostatic and oncotic pressure) that determine filtration vs. reabsorption in capillaries under normal, healthy conditions.
Review the major functions of the kidneys; the functionally distinct sections of the renal nephron; and describe how water is reabsorbed from the tubular fluid.
In general, describe the primary therapeutic uses of diuretics and the broad types of adverse effects.
Describe the mechanism of action that most diuretics have in common.
List the four major classes of diuretics; describe mechanism / site of action in nephron, clinical uses, side effects, and any key considerations.
Describe the relative efficacy of loop diuretics, thiazides, and potassium-sparing diuretics in increasing urine output.
Describe several ways by which renal function can be monitored.
Describe parameters used in monitoring patients undergoing drug therapy with diuretics. Pay particular attention to safety considerations.
Highlight key considerations regarding patient education for diuretic therapy.

3. Review

4. Normal Distribution of Water in the Human Body
Under normal healthy conditions, total body water is properly distributed between body compartments
Total body water comprises ~ % of body weight
How is TBW distributed?
Intracellular fluid (ICF) = 66% of total body water
Extracellular fluid (ECF) =
33% of total body water
Interstitial fluid 75% of ECF
Plasma 25% of ECF
Na+
Cl-
Bicarbonate K+
PO4-

5. Distribution of body water depends on forces acting on the water molecules and on the permeability of tissues
Vocabulary:
Hydrostatic pressure
Oncotic pressure
Capillary permeability
“Net” force
Filtration
Reabsorption

6. Hydrostatic Pressure and Oncotic Pressure
Hydrostatic pressure refers to the pressure that a fluid exerts on the walls of its container (think of a balloon filled with water.) The main cause of hydrostatic pressure in the circulatory system is the force of blood on the blood vessel walls (ie “Blood pressure”)
Oncotic pressure is a form of osmotic pressure exerted by proteins (notably albumin), typically in the blood plasma
Capillary permeability can be thought of as the “leakiness” of the capillary endothelium; ie the capacity of the microvasculature to allow small molecules (eg ions, water, nutrients) or even whole cells (eg lymphocytes on their way to the site of inflammation) to flow out of, or into, a capillary

7. Hydrostatic and Oncotic Pressure
Hydrostatic pressure and oncotic pressure are opposing forces in blood vessels.
Under normal conditions, hydrostatic pressure tends to “push” fluid out of the capillary (filtration) whereas oncotic pressure tends to “pull” fluid into the capillary (reabsorption)
The “net force” determines whether filtration or reabsorption occurs at any single location along the capillary microvasculature
net
Opposing forces are equal in magnitude
net

8. Questions?

9. Kidneys and Diuretics The kidneys have three basic functions:
Maintain plasma (ECF) volume and composition
Maintenance of acid-base balance
Excretion of metabolic wastes and foreign substances
Diuretics are used primarily to decrease plasma fluid volume:
Diuretics promote excretion of water
To do this, diuretics must interfere with the normal operation of the kidney
 Adverse effects of diuretics may include:
Hypovolemia
Acid-base imbalance
Altered electrolyte levels 9

10. Therapeutic Uses of Diuretics
1- *Treatment of hypertension
2- *Mobilization of edematous fluid
eg heart failure, liver failure, kidney disease, other
There are many causes of edematous states, but they share the common characteristic in that the normal distribution of body water is altered
3- used to prevent renal failure
How do diuretics promote excretion of water?
By reducing the amount of water reabsorbed from tubular filtrate
Let’s review function of the nephron

11. Basic Nephron Anatomy The nephron is the functional unit of kidney
Each kidney has about one million nephrons
Nephron micro-anatomy
Glomerulus
Proximal convoluted tubule
Loop of Henle
Descending
Ascending
Distal convoluted tubule
Collecting duct

12. Basic nephron processes
Filtration:~ 20% of the plasma that flows through the glomerular capillaries gets filtered into Bowman’s Capsule (180 liters filtrate produced daily)
Occurs only at glomerulus
Reabsorption: more than 99% of the water, nutrients and ions get reabsorbed.
Na reabsorption creates osmotic gradient.
Cl may be co-absorbed or passively follow the sodium
“Water follows salt.”
By reabsorbing sodium from the tubular fluid, water also gets reabsorbed from tubular fluid.
Occurs at several highly specific locations in nephron
Active secretion: various wastes, drugs and toxins
Occurs at PCT
Net result: 1.5 – 2 liters of urine produced daily

13. Diuretic Agents
MOA: most diuretics block reabsorption of sodium and chloride from the tubular fluid
Specific diuretics block reabsorption of sodium and chloride at specific locations in the nephron. See next slide for locations where the four major classes of diuretics work
By blocking the reabsorption of sodium and chloride, osmotic pressure is developed within the tubules: this osmotic pressure holds water within the tubules… resulting in this fluid being eliminated from the body in urine

15. Four major classes of diuretics
Osmotic diuretics- have a unique MOA
Highly osmotic molecules that are freely filtered at the glomerulus, and drag water into the filtrate too (non-reabsorbed, non-metab’d)
Loop diuretics-
Block reabsorption of Na, Cl in the Loop of Henle
Thiazides-
Block reabsorption of Na, Cl in the early Distal Convoluted Tubule
Potassium-sparing diuretics
Block reabsorption of sodium and prevent the excretion of potassium in the collecting duct

16. Osmotic Diuretics Mannitol = caution! Must be used with CAUTION!
Mannitol is a highly osmotic molecule (draws water to it)
Mannitol cannot cross BBB, but CAN leave vascular system at all other capillaries (risk of edema!)
Used mainly in acute settings for very specific indications such as
to reduce intracranial pressure (eg head injuries)
reduce intraocular pressure
Mechanism & Site of Action: filtered at glomerulus, pulling water along with it. Not reabsorbed, not metabolized. Increases osmotic gradient in lumen of nephron. Results in increased urine production.

17. Osmotic Diuretics Pharmacokinetics
Onset 1-3 hours, half-life 1-2 hours
Dosing
Mannitol
gm/kg IV Q4-6 hours
Adverse Effects
Edema!
Extreme Caution if CHF, risk of pulmonary edema
Headache
N/V
Fluid & Electrolyte imbalances!!! Again, use caution!
Watch for dehydration!
Drug Specifics

18. Loop Diuretics
Loop diuretics are the MOST EFFECTIVE diuretic available!
And result in more fluid and electrolyte loss than any other diuretic!
Effective even when the glomerular filtration rate (GFR) is low (ie, when urine output is decreased)
Mechanism and Site of Action
Inhibit sodium and chloride reabsorption in the ascending limb of the Loop of Henle
Avoid when less efficacious agents will suffice

19. Loop Diuretics Furosemide (prototype) is most commonly prescribed
Therapeutic uses:
Pulmonary edema
Edematous states
Hypertension
PO, IV, IM
IV route for emergency use (eg pulmonary edema) that requires immediate mobilization of fluid; ICU setting- continuous infusion
Pharmacokinetics
Rapid absorption, GI edema may impair, highly protein bound, hepatic metabolism, renal elimination
Dosing: Furosemide (Lasix)
mg/day PO/IV (“average” dose mg/day)
Bumetanide 2-8mg/day PO/IV
Torsemide mg/day PO/IV

20. Loop Diuretics Adverse Effects
Electrolyte Imbalances!
Hyponatremia, hypochloremia!
Hypokalemia- is especially problematic for patients taking digoxin
Hypotension
Dehydration- sequellae include falls, venous thrombosis
Signs of dehydration? DVT? Electrolyte abnormalities?
Hyperglycemia; Hyperuricemia; Use in pregnancy
Impact on lipids, calcium, and magnesium
Ototoxicity- rare: hearing loss is usually transient
vs irreversible
Hypersensitivity
Drug Interactions- digoxin, ototoxic drugs, potassium-sparing diuretics, lithium, anti-hypertensives, NSAIDS
Drug Specifics
Torsemide has better absorption with GI edema
Continuous IV infusion may improve diuresis over bolus dosing

21. Thiazides and related Diuretics
Mechanism and Site of Action
Prevent sodium resorption in the distal convoluted tubule
Thiazide diuretics produce less diuresis than loop diuretics
Thiazide diuretics are ineffective when the GFR is low, ↓urine output
Risk of dehydration and hypokalemia
But do not cause hearing loss.
Thiazide-induced hypokalemia is a special problem for patients taking digoxin
Increase excretion of Na, Cl, K & water
Can elevate blood glucose and plasma uric acid

22. Thiazide Diuretics Pharmacokinetics
Good absorption, renal elimination, onset 1-2 hours
Therapeutic uses:
Essential hypertension
Edema
Diabetes insipidus
Dosing
Hydrochlorothiazide 25-50mg PO Qday
Most widely used
Chlorothiazide mg PO/IV q6-12hrs
Metolazone mg PO Qday

23. Thiazide Diuretics Adverse Effects
Electrolyte imbalances- hyponatremia, hypochloremia, hypokalemia
Dehydration
Use in pregnancy and lactation
Hyperglycemia; Hyperuricemia;
Impact on lipids, calcium, and magnesium
May precipitate gout
Drug interactions- like loop diuretics
Drug Specifics
Chlorothiazide the only IV thiazide
Metolazone only thiazide to work in patients with moderate-severe renal dysfunction
HCTZ= Drug interactions
Digoxin
Augments effects of hypertensive medications
Can reduce renal excretion of lithium (leading to accumulation)
NSAIDs may blunt diuretic effect
Can be combined with ototoxic agents without increased risk of hearing loss

24. Potassium Sparing Diuretics
Produce only a modest increase in urine production, but a substantial decrease in potassium excretion
 Often used in conjunction with a loop or thiazide diuretic, to counteract losses of potassium
Mechanism and Site of Action
Decrease sodium absorption in distal convoluted tubule
Results in K+ absorption, and excretion of sodium

25. Potassium Sparing Diuretics
Therapeutic uses
Hypertension
Edematous states
Heart failure (decreases mortality in severe failure)
Primary hyperaldosteronism
Premenstrual syndrome
Polycystic ovary syndrome
Acne in young women

26. Potassium Sparing Diuretics: key considerations
The principal adverse effect of potassium-sparing diuretics is hyperkalemia.
Potassium-sparing diuretics should not be combined with one another or with potassium supplements
They should be used cautiously in patients taking angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers, or direct renin inhibitors.

27. Potassium Sparing Diuretics
Oral agents
Spironolactone- delayed effects (up to 48 hours);
used for HTN, edema
Reduces mortality and hospital admissions in CHF pts
Risk of hyperkalemia
Endocrine effects include gynecomastia, menstrual irregularities, impotence hirsutism, deepening of the voice
Triamterene-
Amiloride-
Dosing
Spironolactone: mg PO Qday-BID
Triamterene: mg PO Qday-BID
Amiloride: mg PO Qday

28. Potassium Sparing Diuretics
Adverse Effects
Electrolyte imbalances
Dehydration
Impotence
Gynecomastia- become tender/ painful (spironolactone)
Drug Specifics
Weak diuretic effect
Most often used in combination w/ thiazides
Spironolactone useful in patients with liver failure and ascites (high aldosterone levels)
avoid concomitant use with other agents that can raise potassium levels

29. General Considerations of Diuretic Therapy

30. Monitoring Renal Function
Creatinine Clearance
Cockcroft-Gault Equation-
has an adjustment for age, as well as gender-based differences in serum creatinine levels
Urine Output:
0.5-1 mL/kg/hr
Intake and Output
Electrolytes
Sodium

31. Monitoring Parameters
Therapeutic
Urine Output
Daily weights-
same time every day
usually right after the first morning void
Laboratory
Na, Hct
Other- K, Ca, Mg
Adverse Effects
Electrolytes
Hemodynamics- fluid volume, blood pressure,

32. Patient Education Purpose Duration Timing- don’t take at bedtime
Symptoms
Therapeutic-
Adverse effects
Dietary Considerations
Sodium
Potassium
Fluids

33. Drug-Induced Nephrotoxicity
Antibiotics
Aminoglycosides (gentamicin, tobramycin)
Antifungals (Amphotericin B)
Vancomycin
Non-steroidal anti-inflammatory drugs
Ibuprofen, et. al.
Angiotensin converting enzyme (ACE) inhibitors
Captopril, Lisinopril
Hypersensitivity reactions
Cancer chemotherapy drugs
Cisplatin
Cyclophosphamide, Ifosfamide

34. Patient Case TR, slide 1
TR is a 62 YO WM who presents in clinic complaining of some difficulty breathing while lying down at night, and increased swelling in his feet and ankles. He is diagnosed with mild congestive heart failure secondary to ischemic heart disease, and is placed on hydrochlorothiazide 50mg PO QD.

35. Patient Case TR, slide 2
What do you think is probably causing this patient’s symptoms?
What parameters are important to monitor in this patient with respect to:
Therapeutic effect?
Adverse effects?
What instructions does this patient need to ensure appropriate therapy?

36. Patient Case NK, slide 1
NK is a 74 YO WM, POD 6 from CABG surgery. He is on 3L O2, with bilateral crackles in the bases. Weight is 104.4kg (preop 98kg). His renal function is mildly impaired, with a creatinine of 1.9 mg/dl.
What diuretic would be appropriate for this patient?

37. Patient Case NK, slide 2
What monitoring parameters should be followed?
What are some options if the patient doesn’t respond?