Transcript Drugs Affecting the Renal System

Diuretics: drugs that
affect the renal system
Learning Objectives
After studying this content, the student will be able to:
1) 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.
2) 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.
3) In general, describe the primary therapeutic uses of diuretics and the
broad types of adverse effects.
4) Describe the mechanism of action that most diuretics have in common.
5) List the four major classes of diuretics; describe mechanism / site of
action in nephron, clinical uses, side effects, and any key considerations.
6) Describe the relative efficacy of loop diuretics, thiazides, and potassiumsparing diuretics in increasing urine output.
7) Describe several ways by which renal function can be monitored.
8) Describe parameters used in monitoring patients undergoing drug
therapy with diuretics. Pay particular attention to safety considerations.
9) Highlight key considerations regarding patient education for diuretic
therapy.
Review
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 ~ 50-80 % 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+
ClBicarbonate
K+
PO4-
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
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
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
net
Opposing
forces are
equal in
magnitude
Questions?
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
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Therapeutic Uses of Diuretics

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1- *Treatment of hypertension
2- *Mobilization of edematous fluid
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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
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How do diuretics promote excretion of water?
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By reducing the amount of water reabsorbed from tubular filtrate
Let’s review function of the nephron
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
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
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
Four major classes of diuretics
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Osmotic diuretics- have a unique MOA
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Loop diuretics
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Block reabsorption of Na, Cl in the Loop of Henle
Thiazides
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Highly osmotic molecules that are freely filtered at the glomerulus,
and drag water into the filtrate too (non-reabsorbed, non-metab’d)
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
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.
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Osmotic Diuretics
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Pharmacokinetics
 Onset 1-3 hours, half-life 1-2 hours
Dosing
 Mannitol
 0.25-0.5 gm/kg IV Q4-6 hours
Adverse Effects
 Edema!

Headache
 N/V
 Fluid & Electrolyte imbalances!!! Again, use caution!
 Watch for dehydration!
Drug Specifics
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Extreme Caution if CHF, risk of pulmonary edema
Loop Diuretics
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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

Loop Diuretics
Furosemide (prototype) is most commonly prescribed
 Therapeutic uses:

Pulmonary edema
 Edematous states
 Hypertension
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
PO, IV, IM
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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)
 20-800 mg/day PO/IV (“average” dose 40-80 mg/day)
 Bumetanide 2-8mg/day PO/IV
 Torsemide 20-200mg/day PO/IV
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Adverse Effects
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Electrolyte Imbalances!
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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


Loop Diuretics
vs irreversible
Hypersensitivity
Drug Interactions- digoxin, ototoxic drugs, potassium-sparing
diuretics, lithium, anti-hypertensives, NSAIDS
Drug Specifics

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Torsemide has better absorption with GI edema
Continuous IV infusion may improve diuresis over bolus dosing
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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
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But do not cause hearing loss.
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Thiazide-induced hypokalemia is a
special problem for patients taking
digoxin
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Increase excretion of Na, Cl, K & water
Can elevate blood glucose and plasma uric
acid
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Thiazide Diuretics
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Pharmacokinetics
 Good absorption, renal elimination, onset 1-2
hours
Therapeutic uses:
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Essential hypertension
Edema
Diabetes insipidus
Dosing
 Hydrochlorothiazide 25-50mg PO Qday

Most widely used
 Chlorothiazide
250-500mg PO/IV q6-12hrs
 Metolazone 2.5-10mg PO Qday
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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 moderatesevere renal dysfunction
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Potassium Sparing Diuretics
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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
Potassium Sparing Diuretics
Therapeutic uses
 Hypertension
 Edematous states
 Heart failure (decreases mortality in severe failure)
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Primary hyperaldosteronism
Premenstrual syndrome
Polycystic ovary syndrome
Acne in young women
Potassium Sparing Diuretics:
key considerations
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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.
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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 AmilorideDosing
 Spironolactone: 25-200mg PO Qday-BID
 Triamterene: 100-300mg PO Qday-BID
 Amiloride: 5-10mg PO Qday
Potassium Sparing Diuretics
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Adverse Effects
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Electrolyte imbalances
Dehydration
Impotence
Gynecomastia- become tender/ painful (spironolactone)
Drug Specifics
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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
General Considerations of
Diuretic Therapy
Monitoring Renal Function
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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
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,
Patient Education
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Purpose
Duration
Timing- don’t take at bedtime
Symptoms
Therapeutic Adverse effects
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Dietary Considerations
Sodium
 Potassium
 Fluids
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Drug-Induced Nephrotoxicity
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Antibiotics
Aminoglycosides (gentamicin, tobramycin)
 Antifungals (Amphotericin B)
 Vancomycin
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Non-steroidal anti-inflammatory drugs
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Angiotensin converting enzyme (ACE) inhibitors
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Ibuprofen, et. al.
Captopril, Lisinopril
Hypersensitivity reactions
Cancer chemotherapy drugs
Cisplatin
 Cyclophosphamide, Ifosfamide

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.
Patient Case TR, slide 2
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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?
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.
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What diuretic would be appropriate for this patient?
Patient Case NK, slide 2
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What monitoring parameters should be
followed?
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What are some options if the patient doesn’t
respond?