Diuretics

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

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

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

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.

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

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

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

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

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

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 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.

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 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

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

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: 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

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)

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 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: 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

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 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.

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

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

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

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

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: 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

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

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

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

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 Furosemide analogs Azides Benzene rings Aldosterone agonists and caffeine analogs

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)

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

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

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

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

Summary