Diuretics

Outline

• Introduction – 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

Objectives

To understand: 1) The therapeutic applications of diuretics

2) The role of different portions of the nephron in ion exchange

3) The sites of action and pharmacology of diuretics

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

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

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

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

Diuretics

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

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

• 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

Principles Important for Understanding Diuretics

Effects

Fluid Flow and Ion Transport in the Nephron

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!

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%)

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)

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

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

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

Na+

+

NaHCO3

CA

CA Inhibitors

• Pharmacodynamics:– 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).

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.

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. 1-1.5 hr

– Secreted by organic acid transporters (OATs) into the PT

Loop Diuretics

• Mechanism of Action:– 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

• Indications:– 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)

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)

Loop Diuretics

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.

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)

Thiazides• Mechanism of Action:

– 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

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

Thiazides

~Birkenhäger Diuretics and blood pressure reduction: physiological aspects. J. Hyperten. 1990, 8 (Suppl 2) S3-S7.

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

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

• Adverse effects: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

Thiazides

• Adverse effects continued:– Hyperuricemia

• 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

Thiazides

• Less common problems:– Hypersensitivity

• 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

Thiazides

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

K+-sparing Diuretics• Mechanism of Action:

– 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

• Adverse Effects:– Hyperkalemia– Gynecomastia– Amenorrhea (mild estrogenic activity)

• Contraindications:– Disease states that may induce hyperkalemia:

• Diabetes mellitus• Multiple myeloma• Tubulo-interstitial renal disease• Renal insufficiency

K+-sparing Diuretics

Osmotic Diuretics

Osmotic diuretics:– 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

• Pharmacokinetics:– 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

Osmotic Diuretics

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**

Structure-Activity Relationships

Aldosterone agonists and caffeine analogs

Furosemide analogs Azides

• 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)

Diuretics can make some conditions worse

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

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

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

Side effects of diureticsThe most common side effect associated with diuretics is

K+ loss (hypokalemia)

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

SummaryDiuretic 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)

Proximal tubule - 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

- increased K+ losses, because of increased Na+ delivery with increased aldosterone

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

Summary