diuretics. outline introduction –history of diuretics –diuretic use –role of the nephron ion...
TRANSCRIPT
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Diuretics
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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
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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
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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
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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
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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
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Perhaps no other class of drugs is so widely prescribed, yet so frequently misused:
Diuretics
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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
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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
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• 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
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Fluid Flow and Ion Transport in the Nephron
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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!
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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%)
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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)
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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
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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
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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
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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).
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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.
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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
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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
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• 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
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• 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
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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.
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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)
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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
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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
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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
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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
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• 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
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• 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
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• 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
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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
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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
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• 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
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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
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• 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
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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**
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Structure-Activity Relationships
Aldosterone agonists and caffeine analogs
Furosemide analogs Azides
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• 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
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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
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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
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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)
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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
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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
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Summary