Clinical pharmacology of drugs used to affect renal function by Marc Imhotep Cray, M.D.

Photo: Scanning electron micrograph of the glomerulus in a human kidney. From: Widmaier EP. Vanderâ&#x20AC;&#x2122;s Human Physiology: The Mechanisms Of Body Function, 13th Ed. New York, NY: McGraw-Hill Companies, Inc., 2014: 490

Learning Objectives: 1. List major types of diuretics and relate them to their sites of action. 2. List the major applications, toxicities, and the efficacy of thiazides, loop diuretics and potassium-sparing diuretics. 3. Describe two drugs that reduce potassium loss during diuresis. 4. Describe a therapy that will reduce calcium excretion in patients who have recurrent urinary stones. 5. Discuss the principle of force diuresis. 6. Describe drugs for reducing urine volume in nephrogenic diabetes insipidus. 7. Understand the usefulness of altering urine pH by drugs. 8. Discuss the mechanisms by which drugs and chemicals damage the kidney. 9. Understand how to select and prescribe drugs for patients with renal impairment. Companion: Renal Pharmacology eNotes Marc Imhotep Cray, M.D.

Some Relevant Drugs: A. Carbonic Anhydrase Inhibitors Acetazolamide dichlorphenamide methazolamide dorzolamide B. Osmotic Diuretics mannitol C. Loop Diuretics furosemide bumetanide torsemide ethacrynic acid Marc Imhotep Cray, M.D.

D. Thiazides chlorthalidone chlorothiazide hydrochlorothiazide metolazone indapamide E. Potassium-sparing diuretics spironolactone eplerenone triamterene amiloride

F. ADH antagonists demeclocycline lithium lixivaptan tolvaptan conivaptan

Topical Outline: o Role of Renal System 

Volume Homeostasis

o Pharmacology Diuretic Drugs (Overview) o Individual Agents/Classes     

High-efficacy (loop) diuretics Moderate-efficacy diuretics Low-efficacy diuretics Osmotic diuretics Carbonic Anhydrase Inhibitors

o Adverse effects of diuretics and Drug-Drug Interactions o Alteration of Urine pH o ADH Antagonists  Clinical Cases and Discussions  Practice Questions & Answers/Explanations Marc Imhotep Cray, M.D.

Key Abbreviations          

PCT, Proximal convoluted tubule DCT, Distal convoluted tubule TAL, thick ascending limb of the loop of Henle CCD, cortical collecting duct (including late DCT forming initial collecting duct) MCD, medullary collecting duct GFR, glomerular filtration rate ENaC, epithelial sodium channel NCC, Na-Cl cotransporter (formerly NCCT or thiazide-sensitive Na–Cl co-transporter) NKCC2, Na–K–2Cl co-transporter ROMK, rectifying outer medullary potassium channel

Marc Imhotep Cray, M.D.

High-Yield Terms to Learn  Bicarbonate diuretic A diuretic that selectively increases sodium bicarbonate excretion. Example: a carbonic anhydrase inhibitor  Diluting segment A segment of nephron that removes solute without water; TAL and DCT are active salt-reabsorbing segments that are not permeable by water  Hyperchloremic metabolic acidosis A shift in body electrolyte and pH balance involving elevated serum chloride, diminished bicarbonate concentration, and a decrease in pH in the blood. Typical result of bicarbonate diuresis  Hypokalemic metabolic alkalosis A shift in body electrolyte balance and pH involving a decrease in serum potassium and an increase in blood pH. Typical result of loop and thiazide diuretic actions Marc Imhotep Cray, M.D.

High-Yield Terms to Learn cont.  Nephrogenic diabetes insipidus Loss of urine-concentrating ability in kidney caused by lack of responsiveness to ADH (ADH is normal or high)  Pituitary diabetes insipidus Loss of urine-concentrating ability in kidney caused by lack of ADH (ADH is low or absent)  Potassium-sparing diuretic A diuretic that reduces exchange of potassium for sodium in collecting tubule; a drug that increases sodium and reduces potassium excretion. Example: aldosterone antagonists  Uricosuric diuretic A diuretic that increases uric acid excretion, , usually by inhibiting uric acid reabsorption in the proximal tubule. Example: ethacrynic acid Marc Imhotep Cray, M.D.

Key Concepts in Clinical Renal Pharmacology  Diuretic drugs: their sites and modes of action, classification, adverse effects and uses in cardiac, hepatic, renal and other conditions.  Carbonic anhydrase inhibitors.  Cation-exchange resins and their uses.  Alteration of urine pH.  Drugs and the kidney.  Adverse effects.  Drug-induced renal disease: by direct and indirect biochemical effects and by immunological effects.  Prescribing for renal disease: adjusting the dose according to the characteristics of the drug and to the degree of renal impairment.  Nephrolithiasis and its management.  Pharmacological aspects of micturition.  Benign prostatic hyperplasia.  Erectile dysfunction. Marc Imhotep Cray, M.D.

Role of Renal System  The kidneys comprise only 0.5% of body-weight, yet they receive 25% of the cardiac output.  Drugs that affect renal function have important roles in cardiac failure and hypertension  Disease of kidney must be taken into account when prescribing drugs that are eliminated by it

Marc Imhotep Cray, M.D.

Role of Renal System (2): Volume Homeostasis Kidneys are part of an integrated homeostatic mechanism for maintaining volume of extracellular fluid (ECF) and thus mean arterial pressure (MAP) Other organs involved in this mechanism include:  Heart (eg, cardiac output and heart rate),  CNS (eg, sympathetic tone and ADH release),  Lungs (eg, conversion of angiotensin I to angiotensin II), and  Adrenal gland (eg, release of aldosterone)

Marc Imhotep Cray, M.D.

Volume Homeostasis (2) Several feedback control mechanisms operate among components of this control mechanism ensure responses to  volume expansion (increased extracellular fluid) and  volume contraction (decreased extracellular fluid) Design of drugs that selectively target components of this system has led to major advances in therapy for cardiovascular diseases such as hypertension and heart failure  Discussed in Unit 4 Drugs Used In Disorders of the Cardiovascular System

Marc Imhotep Cray, M.D.

Volume expansion feedback control

Marc Imhotep Cray, M.D.

Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Saunders, 2014

Volume contraction feedback control

Marc Imhotep Cray, M.D.

Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Saunders, 2014

Pharmacology Diuretic Drugs  Definition: A diuretic is any substance that increases urine and solute excretion  This wide definition includes substances not commonly thought of as diuretics, e.g. water  To be therapeutically useful a diuretic should  increase output of sodium as well as of water because diuretics are normally required to remove edema fluid, composed of water and solutes (of which sodium is most important)

Marc Imhotep Cray, M.D.

Diuretic Drugs (2) Each day body produces 180 L of glomerular filtrate which is modified in its passage down renal tubules to appear as 1.5 L of urine 

Thus, if reabsorption of tubular fluid falls by 1%, urine output doubles

 Most clinically useful diuretics are organic anions transported directly from blood into tubular fluid  Following is a brief account of tubular function with particular reference to sodium transport 

Intended to help to explain where and how diuretic drugs act o it should be understood with reference to Figure following text

Marc Imhotep Cray, M.D.

Diuretic Drugs (3) Sites and modes of action Proximal convoluted tubule (PCT)  Some 65% of filtered sodium is actively transported from lumen of PCT by sodium pump (Na+, K+-ATPase)  Chloride is absorbed passively, accompanying sodium  Bicarbonate is also absorbed through an action involving carbonic anhydrase  These solute shifts give rise to iso-osmotic reabsorption of water with result that more than 70% of glomerular filtrate is returned to blood from this section of nephron  Epithelium of PCT is described as “leaky” because of its free permeability to water and a number of solutes Marc Imhotep Cray, M.D.

Diuretic Drugs (4) Sites and modes of action Proximal convoluted tubule cont.  Osmotic diuretics such as mannitol are non-resorbable solutes which retain water in tubular fluid (Site 1 in Figure)  Their effect is to increase water rather than sodium loss reflected in their special use acutely to reduce intracranial or intraocular pressure and not states associated with sodium overload

Marc Imhotep Cray, M.D.

Diuretic Drugs (5) Sites and modes of action Loop of Henle  Tubular fluid now passes into loop of Henle where 25% of filtered sodium is reabsorbed  There are two populations of nephron:  those with short loops confined to cortex, and  juxtamedullary nephrons whose long loops penetrate deep into medulla  are concerned principally with water conservation o following discussion refers to these long loops

Marc Imhotep Cray, M.D.

Diuretic Drugs (6) Sites and modes of action Loop of Henle cont.  Physiologic changes best understood by first considering ascending limb  In TAL (Site 2, Figure) sodium and chloride ions are transported from tubular fluid into interstitial fluid by the three-ion co-transporter system (i.e. Na+/K+/2Cl- called NKCC2) driven by sodium pump o dependent on potassium returning to lumen through rectifying outer medullary potassium (ROMK) channel otherwise K+ would be rate limiting  As tubule epithelium is “tight” here, i.e. impermeable to water tubular fluid becomes dilute interstitium becomes hypertonic and  fluid in adjacent descending limb, which is permeable to water becomes more concentrated as it approaches tip of loop o b/c hypertonic interstitial fluid sucks water out of this limb of tubule

Marc Imhotep Cray, M.D.

Diuretic Drugs (7) Sites and modes of action, Loop of Henle cont.  High osmotic pressure in medullary interstitium is sustained by descending and ascending vasa recta (long blood vessels of capillary thickness that lie close to loops of Henle and act as countercurrent exchangers) for incoming bld receives sodium from outgoing bld  Furosemide, bumetanide, torasemide and ethacrynic acid act principally at Site 2 by inhibiting the three-ion transporter (NKCC2) thus preventing sodium ion reabsorption and lowering the osmotic gradient between cortex and medulla results in formation of large volumes of dilute urine  Hence, these drugs are called “loop” diuretics Marc Imhotep Cray, M.D.

Diuretic Drugs (8) Sites and modes of action Distal convoluted tubule (DCT)  Ascending limb of the loop then re-enters renal cortex where its morphology changes into thin-walled DCT (Site 3, Figure)  

Here uptake is still driven by sodium pump but sodium and chloride are taken up through a different transporter Na-Cl cotransporter, called NCC (formerly NCCT) Both ions are rapidly removed from interstitium b/c cortical blood flow is high and there are no vasa recta present

 Epithelium is also tight at Site 3 and consequently urine becomes more dilute 

Thiazides act principally at this region of cortical diluting segment by blocking NCC transporter

Marc Imhotep Cray, M.D.

Diuretic Drugs (9) Sites and modes of action Cortical collecting duct (CCD)  In collecting duct (Site 4), Na ions are exchanged for K and H ions  Na ions enter through epithelial Na channel (called ENaC), which is stimulated by aldosterone  The aldosterone (mineralocorticoid) receptor is inhibited by competitive receptor antagonist spironolactone whereas  sodium channel is inhibited by amiloride and triamterene  All three of these diuretics are potassium sparing b/c K+ is normally secreted through K+ channel, ROMK (see Figure), down potential Marc Imhotep Cray, M.D. created by sodium reabsorption gradient

Diuretic Drugs (10) Sites and modes of action Cortical collecting duct (CCD) cont.  All other diuretics, acting proximal to Site 4, cause potassium Loss b/c they dump sodium into collecting duct  Removal of this sodium through ENaC increases potential gradient for potassium secretion through ROMK  K+ sparing diuretics are weak diuretics b/c Site 4 is normally responsible for “only” 2–3% of sodium reabsorption  

cause less sodium loss than thiazides or loop diuretics NB: Although ENaC does not have capacity to compensate for lg. Na losses (e.g. loop diuretic usage) it is main site of physiologic control (via Marc Imhotep Cray, M.D. aldosterone) over sodium loss

Diuretic Drugs (11) Sites and modes of action Cortical collecting duct (CCD) cont.  Collecting ducts then travels back through medulla to reach papilla in doing so it passes through a gradient of increasing osmotic pressure which draws water out of tubular fluid  This final conc. of urine is under influence of ADH = increases water permeability by increasing expression of specific water channels (or aquaporins) o In ADH’s absence water remains in collecting duct  Ethanol causes diuresis by inhibiting release of ADH from posterior pituitary

NB: Diuresis may also be achieved by extrarenal mechanisms, by raising cardiac output and increasing renal blood flow, e.g. with dobutamine and dopamine.

Marc Imhotep Cray, M.D.

Marc Imhotep Cray, M.D. Bennett PN, Brown MJ and Sharma P. Clinical Pharmacology 11th Ed. Edinburgh: Churchill Livingstone, 2012.

Diuretic Drugs (12) Classification ď ą Maximum efficacy in removing salt and water that any diuretic achieves is dependent on its site of action, thusď&#x192; it is appropriate to rank diuretics according to their natriuretic capacity (as set out in slides that follow) ď&#x201A;§ Classes: 1. High efficacy 2. Moderate efficacy 3. Low efficacy NB: Percentages refer to highest fractional excretion of filtered sodium under carefully controlled conditions and should not be taken to represent average fractional sodium loss during clinical use. Marc Imhotep Cray, M.D.

Diuretic Drugs (13) Classification

1. High efficacy Furosemide and other “loop” diuretics can cause up to 25% of filtered sodium to be excreted  Their action impairs powerful urine-concentrating mechanism of loop of Henle and confers higher efficacy compared with drugs that act in relatively hypotonic cortex

Progressive increase in dose is matched by increasing diuresis,  i.e. they have a “high ceiling” of effect  they are so effective that over-treatment can readily dehydrate patient

Loop diuretics remain effective at a glomerular filtration rate (GFR) below 10 mL/min (nml 120 mL/min)

Marc Imhotep Cray, M.D.

Diuretic Drugs (14) Classification 2. Moderate efficacy  The thiazide family, including chlorthalidone, chlorothiazide, hydrochlorothiazide, metolazone and indapamide, cause 510% of filtered sodium load to be excreted

 Increasing dose produces relatively little added diuresis compared to loop diuretics  i.e. they have a “low ceiling” of effect  Cease to be effective once GFR has fallen below 20 mL/min (except metolazone) Marc Imhotep Cray, M.D.

Diuretic Drugs (15) Classification 3. Low efficacy Triamterene, amiloride and spironolactone cause 2–3% of filtered sodium to be excreted  They are potassium sparing and combine with more efficacious diuretics to prevent potassium loss, which other diuretics cause Osmotic diuretics, e.g. mannitol, also fall into this category

Marc Imhotep Cray, M.D.

Diuretic Drugs (16) Indications  Edema states associated  with sodium overload, e.g. cardiac, renal or hepatic disease, and also  without sodium overload, e.g. acute pulmonary edema following myocardial infarction NB: Edema may also be localized, e.g.  angioedema over face and neck or around ankles with some calcium channel blockers, or  due to low plasma albumin, or immobility in elderly  in none of these circumstances is a diuretic indicated  Hypertension, by reducing intravascular volume and other mechanisms too, e.g. reduction of sensitivity to noradrenergic vasoconstriction Marc Imhotep Cray, M.D.

Diuretic Drugs (17) Indications cont.  Hypercalcemia Furosemide reduces calcium reabsorption in ascending limb of loop of Henle action may be utilised in emergency reduction of raised plasma calcium levels, in addition to rehydration and other measures  Idiopathic hypercalciuria, a common cause of renal stone disease, may be reduced by thiazide diuretics  Syndrome of inappropriate secretion of antidiuretic hormone secretion (SIADH) may be treated with furosemide if there is a dangerous degree of volume overload  Nephrogenic diabetes insipidus, paradoxically, may respond to diuretics which, by contracting vascular volume, increase salt and water reabsorption PCT thus reduce urine volume Marcin Imhotep Cray, M.D.

Individual Agents/Classes High-efficacy (loop) diuretics Furosemide… Moderate-efficacy diuretics Thiazides… Low-efficacy (K+ sparing) diuretics Spironolactone… Osmotic diuretics Mannitol… Carbonic Anhydrase Inhibitors Acetazolamide… Marc Imhotep Cray, M.D.

High-efficacy (loop) diuretics Furosemide (Prototype) Furosemide acts on thick portion of ascending limb of the loop of Henle (Site 2 in slide 25) to produce effects described above  b/c more sodium is delivered to DCT & CD (Site 4 in slide 25), exchange with potassium leads to urinary potassium loss and hypokalemia  Magnesium and calcium loss are increased by furosemide to same extent as sodium effect on calcium is utilized in emergency management of hypercalcemia

Pharmacokinetics  Absorption from GIT is subject to considerable intra- and interindividual variation and it is highly bound to plasma proteins  t½ is 2 hrs rises to over 10 h in renal failure Marc Imhotep Cray, M.D.

High-efficacy (loop) diuretics Furosemide cont. Uses  very successful for the relief of edema  Urine production rises progressively with increasing dose  Taken orally it acts within an hour and diuresis lasts up to 6 h

Caution  Enormous urine volumes can result and over-treatment may lead to hypovolemia and circulatory collapse  Given intravenously it acts within 30 min and can relieve acute pulmonary Edema partly by a venodilator action which precedes diuresis  Important feature  retains efficacy even at a low GFR (10 mL/min or less) Marc Imhotep Cray, M.D.

High-efficacy (loop) diuretics Furosemide cont. Adverse effects uncommon, apart from excess of therapeutic effect (electrolyte disturbance and hypotension due to low plasma volume) and  Nausea  Pancreatitis and,  rarely, deafness, which is usually transient and associated with rapid IV injection in renal failure Non-steroidal anti-inflammatory drugs (NSAIDs), notably indomethacin, reduce furosemide-induced diuresis by inhibiting formation of vasodilator prostaglandins in kidney Marc Imhotep Cray, M.D.

High-efficacy (loop) diuretics cont. Bumetanide, piretanide and ethacrynic acid are similar to furosemide Bumetanide may be preferred over furosemide in heart failure b/c of its more predictable oral absorption Ethacrynic acid is less widely used as it is more prone to cause adverse effects, especially nausea and deafness  Not a sulfonamide as are other loop diuretics, thus useful option in sulfa-allergic pts. Torasemide is an effective antihypertensive agent at lower (non-natriuretic) doses (2.5–5 mg/day) than those used for edema (5–40 mg/day) Marc Imhotep Cray, M.D.

Moderate-efficacy diuretics Thiazides Thiazides depress salt reabsorption in DCT (Site 3 in slide 25), i.e. upstream of region of sodium–potassium exchange at CD (Site 4 in slide 25)  Hence , have important effect of raising potassium excretion  Thiazides lower blood pressure, initially due to a reduction in intravascular volume but chronically by a reduction in peripheral vascular resistance  accompanied by diminished responsiveness of vascular smooth muscle to Epi/NE  also have a direct action on vascular smooth muscle membranes Marc Imhotep Cray, M.D.

Moderate-efficacy diuretics Thiazides cont. Uses  given for mild cardiac failure and mild hypertension, or for more severe degrees of HTN, in combination with other drugs

Pharmacokinetics  Thiazides are well absorbed orally and most begin to act within an hour  Differences among numerous derivatives lie in duration of action Relatively water-soluble agents, e.g. chlorothiazide, hydrochlorothiazide (HCTZ), are most rapidly eliminated, peak effect within 4–6 h and passing off by 10–12 h  excreted unchanged in urine and active secretion by PCT contributes to high renal clearance and t½ of less than 4 h Marc Imhotep Cray, M.D.

Moderate-efficacy diuretics Thiazides cont. Pharmacokinetics ď ąRelatively lipid-soluble members, e.g. polythiazide, hydroflumethiazide, distribute more widely into body tissues and act for >24 h ď&#x201A;§ can be problematic if used for diuresis, but there is no evidence this property makes them more effective at controlling hypertension

ď ąWith exception of metolazone, thiazides are not effective when renal function is moderately impaired (GFR <20 mL/min), b/c they are not filtered in sufficient concentration to inhibit NCC (NaCl cotransporter) Marc Imhotep Cray, M.D.

Moderate-efficacy diuretics Thiazides cont. Adverse effects  Adverse effects in general are discussed below  Rashes (sometimes photosensitive)  thrombocytopenia and  agranulocytosis occur

 Thiazide-type drugs increase total plasma cholesterol concentration  But in long-term use this is less than 5%, even at high doses  Questions about appropriateness of thiazides for mild hypertension, of which ischemic heart disease is a common complication, are laid to rest by their proven success in randomized outcome comparisons Marc Imhotep Cray, M.D.

Moderate-efficacy diuretics Diuretics related to thiazides Several compounds, not strictly thiazides, share structural similarities and act at same site on nephron (moderate therapeutic efficacy) Overall, these substances have a longer duration of action, are used for edema and hypertension, and their profile of adverse effects is similar to thiazides  Chlortalidone acts for 48–72 h after a single oral dose  Indapamide is structurally related to chlortalidone but lowers blood pressure at subdiuretic doses perhaps by altering calcium flux in vascular smooth muscle  Metolazone is effective when renal function is impaired o It potentiates diuresis produced by furosemide and combination can be effective in resistant edema although risk of hypokalemia is Marc Imhotep Cray,very M.D. high

Low-efficacy diuretics  Spironolactone (Aldactone) is structurally similar to aldosterone and competitively inhibits its action in distal tubule (exchange of potassium for sodium, Site 4 in slide 25)  Excessive secretion of aldosterone contributes to fluid retention in  hepatic cirrhosis  nephrotic syndrome  congestive heart failure and  primary hypersecretion (Conn’s syndrome)  Spironolactone is also useful in treatment of resistant hypertension  increased aldosterone sensitivity is increasingly recognized as a contributory factor Marc Imhotep Cray, M.D.

Low-efficacy diuretics cont.  Spironolactone has a short t½ (1.6 h), being extensively metabolized, and its prolonged diuretic effect is due to most significant active metabolite, canrenone (t½ 17 h)  relatively ineffective when used alone  more efficient when combined with a drug that reduces sodium It is given orally in one or more doses totaling 100–200 mg/day  Maximum diuresis may not occur for up to 4 days  Spironolactone (and amiloride and triamterene) usefully reduces K+ loss caused by loop diuretics Warnings:  combination with another K+ sparing diuretic must be avoided as hyperkalemia will result  Dangerous K+ retention is particularly likely if spironolactone is given to pts. with impaired renal function Marc Imhotep Cray, M.D.

Low-efficacy diuretics cont. Adverse effects  Estrogenic effects are major limitation to its long-term use  the Randomized Aldactone Evaluation Study (RALES) even 25 mg/day caused breast tenderness or enlargement in 10% of men  Women may also report breast discomfort or menstrual irregularities, including amenorrhea

 Minor gastrointestinal upset also occurs and there is increased risk of gastroduodenal ulcer and bleeding  reversible on stopping the drug  Spironolactone is reported to be carcinogenic in rodents, but many years of clinical experience suggest that it is safe in humans  Nevertheless, UK license for its use in essential hypertension was withdrawn (i.e. possible use long term in a patient group that includes the relatively young), but is retained for other indications Marc Imhotep Cray, M.D.

Low-efficacy diuretics cont. ď ą Eplerenone is a spironolactone analog licensed for use in heart failure that appears to be free of estrogenic effects; b/c of its lower affinity for estrogen receptor ď ą It is useful in patients who need an aldosterone-receptor blocking agent, but are intolerant of endocrine effects of spironolactone

Marc Imhotep Cray, M.D.

Low-efficacy diuretics cont. Amiloride blocks ENaC sodium channels in distal tubule  Action complements thiazides with which it is frequently combined to increase sodium loss and limit potassium loss  Example, coamilozide (amiloride 2.5–5 mg plus hydrochlorothiazide 25–50 mg) is used for hypertension or edema  maximum effect of amiloride occurs about 6 h after an oral dose, with a duration of action greater than 24 h (t½ 21 h)  oral dose is 5–20 mg daily

Marc Imhotep Cray, M.D.

Low-efficacy diuretics cont.  Triamterene (Dytac) is a potassium-sparing diuretic with an action and use similar to amiloride (blocks ENaC sodium channels in DCT)  Diuretic effect extends over 10 h Adverse effects  Gastrointestinal upsets occur Drug-drug interaction  Reversible, non-oliguric renal failure may occur when triamterene is used with indomethacin (and other NSAIDs)  may also give urine a blue coloration Marc Imhotep Cray, M.D.

Osmotic diuretics  Osmotic diuretics are small molecular weight substances that are filtered by the glomerulus but not reabsorbed by renal tubule and thus increase osmolarity of tubular fluid

 Thus they prevent reabsorption of water (and also, by more complex mechanisms, of sodium) principally in PCT and also loop of Henle  Result is urine volume increases according to load of osmotic diuretic Marc Imhotep Cray, M.D.

Osmotic diuretics cont.  Mannitol, a polyhydric alcohol (mol. wt. 452), is used most commonly given intravenously  In addition to its effect on kidney, mannitol encourages movement of water from inside cells to extracellular fluid which is thus transiently expanded before diuresis occurs  These properties define its uses, which are for rapid reduction of intracranial or intraocular pressure, and to maintain urine flow to prevent renal tubular necrosis  b/c mannitol increases circulatory volume, it is contraindicated in congestive cardiac failure and pulmonary edema Marc Imhotep Cray, M.D.

Carbonic Anhydrase Inhibitors  The enzyme carbonic anhydrase facilitates reaction betw. CO2 and H2O to form carbonic acid (H2CO3), which then breaks down to hydrogen (H+) and bicarbonate (HCO3-) ions  This process is fundamental to production of either acid or alkaline secretions, and high concentrations of CA are present in gastric mucosa, pancreas, eye and kidney  MOA b/c number of H+ ions available to exchange with Na+ in PCT is reduced, sodium loss and diuresis occur  But HCO3- reabsorption from tubule is also reduced, and its loss in urine leads within days to metabolic acidosis which attenuates diuretic response to carbonic anhydrase inhibition o Consequently, inhibitors of CA are obsolete as diuretics • Still have specific uses  Acetazolamide is most widely used CAI Marc Imhotep Cray, M.D.

Carbonic Anhydrase Inhibitors cont. Reduction of intraocular pressure  action is not due to diuresis  rather, formation of aqueous humor is an active process requiring a supply of bicarbonate ions which depends on carbonic anhydrase  Inhibition of CA reduces formation of aqueous humor and lowers IOP o this is a local action and is not affected by development of acid–base changes elsewhere in body, i.e. tolerance does not develop  In pts. w acute glaucoma, acetazolamide taken either PO or IV  Acetazolamide is not recommended for long-term use b/c of risk of hypokalemia and acidosis but brinzolamide or dorzolamide are effective as eye drops, well tolerated, and thus suitable for chronic use in glaucoma Marc Imhotep Cray, M.D.

Carbonic Anhydrase Inhibitors cont. Acetazolamide for High-altitude (mountain) sickness  High-altitude (mountain) sickness may affect unacclimatized people at altitudes over 3000 meters, especially after rapid ascent  symptoms range from  nausea  lassitude and headache to  pulmonary and cerebral edema  Initiating cause is hypoxia:  at high altitude, normal hyperventilatory response to falling oxygen tension is inhibited b/c alkalosis is also induced  Acetazolamide induces metabolic acidosis increases respiratory drive, notably at night when apnetic attacks may occur, and thus helps to maintain arterial tension Marc Imhotep Cray, oxygen M.D.

CAIs cont., acetazolamide for high-altitude Dosage  Usual dose is 125–250 mg twice daily, given orally on day before ascent and continued for 2 days after reaching intended altitude  250 mg twice daily is used to treat established high-altitude sickness, combined with a return to a lower altitude (Note: this is an unlicensed indication in UK)

 As an alternative or in addition to acetazolamide dexamethasone may be used:  2 mg q6 hrs. for prevention, and  4 mg q6 hrs. for treatment Marc Imhotep Cray, M.D.

CAIs cont., acetazolamide ď ąAcetazolamide has two other uses 1. In periodic paralysis, where sudden falls in plasma K+ conc. occur due to its exchange with Na+ in cells ď&#x201A;§ rise in plasma H+ caused by acetazolamide provides an alternative cation to K+ for exchange with Na+ 2. Acetazolamide may be used occasionally as a second-line drug for tonicâ&#x20AC;&#x201C;clonic and partial epileptic seizures

Marc Imhotep Cray, M.D.

CAIs cont., acetazolamide Adverse effects  High doses of acetazolamide may cause  drowsiness and fever  rashes (it is a sulfonamide-type drug) and  paranesthesia may occur (from the acidosis)  blood disorders have been reported  Renal calculi may develop, b/c urine calcium is in less soluble form, owing to low citrate content of urine a consequence of metabolic acidosis  Dichlorphenamide is a similar, but a more potent, inhibitor of carbonic anhydrase Marc Imhotep Cray, M.D.

Adverse effects of diuretics and Drug-Drug Interactions

Marc Imhotep Cray, M.D.

Potassium depletion  Diuretics that act at Sites 1, 2 and 3 of slide 25 cause more sodium to reach sodium–potassium exchange site in the distal tubule (Site 4) and so increase potassium excretion  This subject warrants discussion b/c hypokalemia may cause cardiac arrhythmia in patients at risk (e.g. receiving digoxin)  The safe lower limit for plasma potassium concentration is 3.5 mEq/L  Whether or not diuretic therapy causes significant lowering of serum potassium levels depends both on drug and on circumstances in which it is used: The following slides explain more

Marc Imhotep Cray, M.D.

Potassium depletion ď ą The loop diuretics produce a smaller fall in serum K+ conc. than do thiazides, for equivalent diuretic effect, but have a greater capacity for diuresis, i.e. higher efficacy especially in large doseď&#x192; so are associated with greater decline in potassium levels ď ą If diuresis is brisk and continuous, clinically important potassium depletion is likely to occur

Marc Imhotep Cray, M.D.

Potassium depletion cont.  Low dietary intake of potassium predisposes to hypokalemia risk is particularly notable in elderly, many of whom ingest less than 50 mEq per day (dietary normal is 80 mEq).  Hypokalemia may be aggravated by other drugs, e.g. β2agonists, theophylline, corticosteroids, amphotericin  Hypokalemia during diuretic therapy is also more likely in hyperaldosteronism  whether primary or more commonly secondary to severe liver disease, congestive heart failure or nephrotic syndrome Marc Imhotep Cray, M.D.

Potassium depletion cont.  Potassium loss occurs with diarrhea, vomiting or small bowel fistula and may be aggravated by diuretic therapy  When a thiazide diuretic is used for hypertension no case for routine prescription of a potassium supplement if no predisposing factors are present

Marc Imhotep Cray, M.D.

Potassium depletion cont. Potassium depletion can be minimized or corrected by:  Maintaining a good dietary potassium intake (fruits, fruit juices, vegetables)  Combining a potassium-depleting with a potassium sparing agent  Intermittent use of potassium-losing drugs, i.e. drug holidays  Potassium supplements: KCl preferred b/c chloride is principal anion excreted along with sodium when high-efficacy diuretics are used  Potassium-sparing diuretics defend plasma potassium more effectively than potassium supplements NB: All forms of potassium are irritant to GIT, and in esophagus may cause ulceration. Elderly, in particular, should be warned never to take such tablets dry but always with a large cupful of liquid and sitting upright or standing. Marc Imhotep Cray, M.D.

Hyperkalemia  Hyperkalemia may occur, esp. if a K+ sparing diuretic is given to a patient with impaired renal function  ACE inhibitors and ARBs can also cause a increase in plasma K+ levels  They may cause dangerous hyperkalemia if combined with KCl supplements or other potassium sparing drugs, in presence of impaired renal function  However, with suitable monitoring combination can be used safely, as was well illustrated by the RALES trial  Cyclosporine, tacrolimus, indomethacin and possibly other NSAIDs may cause hyperkalemia with potassium-sparing diuretics

Marc Imhotep Cray, M.D.

Hypovolemia  Hypovolemia can result from over-treatment  Acute loss of excessive fluid leads to postural hypotension and dizziness  A more insidious state of chronic hypovolemia can develop, especially in elderly  After initial benefit, pt. becomes sleepy and lethargic  Blood urea concentration (BUN) rises and Na+ conc. may be low o Renal failure may result Marc Imhotep Cray, M.D.

Urinary retention Urinary retention ď ą Sudden vigorous diuresis can cause acute retention of urine in presence of bladder neck obstruction ď&#x201A;§ e.g. due to prostatic enlargement

Marc Imhotep Cray, M.D.

Hyponatremia  Hyponatremia may result if Na+ loss occurs in pts who drink a large quantity of water when taking a diuretic  Other mechanisms are involved, including enhancement of ADH release  Such pts. have reduced total body Na+ and ECF vol. and are edema free  Discontinuing diuretic and restricting water intake are effective  The condition should be distinguished from hyponatremia with edema, which develops in patients with CHF, cirrhosis or nephrotic syndrome  Here salt and water intake should be restricted b/c ECF volume is expanded  Combination of a potassium-sparing diuretic and ACE inhibitor can also cause severe hyponatremia  more commonly than life-threatening hyperkalemia Marc Imhotep Cray, M.D.

Urate retention Urate retention with hyperuricemia and, sometimes, clinical gout occurs with thiazides and loop diuretics  Effect is unimportant or negligible with low-efficacy diuretics, e.g. amiloride and spironolactone  Two mechanisms responsible  First, diuretics cause volume depletion, reduction in glomerular filtration and increased absorption of almost all solutes in proximal tubule, including urate  Second, diuretics and uric acid are organic acids and compete for transport mechanism that pumps such substances from blood into tubular fluid  Diuretic-induced hyperuricemia can be prevented by allopurinol or probenecid (which also antagonizes diuretic efficacy by reducing their transport into urine) Marc Imhotep Cray, M.D.

Magnesium deficiency Magnesium deficiency: Loop and thiazide diuretics cause significant urinary loss of magnesium  potassium-sparing diuretics cause magnesium retention  Magnesium deficiency brought about by diuretics is rarely severe enough to induce classic picture of neuromuscular irritability and tetany  but cardiac arrhythmias, mainly of ventricular origin, do occur  respond to repletion of magnesium (2 g of Mg2+ is given as 4 mL 50% magnesium sulfate infused i.v. over 10–15 min followed by up to 70 mmol infused over the next 24 h)

Marc Imhotep Cray, M.D.

Carbohydrate intolerance  Carbohydrate intolerance is caused by those diuretics that produce prolonged hypokalemia, i.e. loop and thiazide type Mechanism  May affect depolarization and entry of calcium into islet cells which is necessary to stimulate formation and release of insulin so glucose intolerance is probably due to secondary insulin deficiency  Insulin requirements thus increase in established diabetics and disease may become manifest in latent diabetics  effect is generally reversible over several months

Marc Imhotep Cray, M.D.

Calcium homeostasis  Renal calcium loss is increased by loop diuretics  In short term this is not a serious disadvantage and furosemide may be used in management of hypercalcemia after rehydration achieved  In long term hypocalcaemia may be harmful, especially in elderly patients, who tend in any case to be in negative calcium balance  Thiazides, by contrast, decrease renal excretion of calcium  this property may influence choice of diuretic in a potentially calciumdeficient or osteoporotic individual as thiazide use is associated with a reduced risk of hip fracture in elderly  Hypocalciuric effect of thiazides has also been used effectively in patients with idiopathic hypercalciuria commonest metabolic cause of renal stones Marc Imhotep Cray, M.D.

Drug-Drug Interactions  Loop diuretics (especially as intravenous boluses) potentiate ototoxicity of aminoglycosides and nephrotoxicity of some cephalosporins  NSAIDs tend to cause sodium retention, which counteracts the effect of diuretics mechanism may involve inhibition of renal prostaglandin formation  Diuretic treatment of a patient taking lithium can precipitate toxicity from this drug (increased sodium loss is accompanied by reduced lithium excretion)  Other drugs that may induce hyperkaliemia, hypokalemia, hyponatremia or glucose intolerance with diuretics are described above Marc Imhotep Cray, M.D.

Alteration Of Urine pH Alteration of urine pH by drugs is sometimes desirable  most common reason is in treatment of poisoning (a fuller account is given in poisoning and overdose)

A summary of main indications follows:  Alkalinization of urine:  increases elimination of salicylate, phenobarbital and chlorophenoxy herbicides  treats crystal nephropathy by increasing drug solubility, e.g. of methotrexate, sulfonamides and triamterene  reduces irritation of an inflamed urinary tract  discourages growth of certain organisms, e.g. Escherichia coli Marc Imhotep Cray, M.D.

Alteration Of Urine pH cont.  Urine can be made alkaline by sodium bicarbonate i.v., or by potassium citrate by mouth Caution: Sodium overload may exacerbate cardiac failure, and sodium or potassium excess are dangerous when renal function is impaired

Acidification of urine:  used as a test for renal tubular acidosis  increases elimination of amphetamine, MDMA or “Ecstasy”, quinine and phencyclidine (very rarely needed)  Oral NH4Cl, taken w food to avoid vomiting, acidifies urine o It should not be given to pts with impaired renal or hepatic function  Other means include arginine hydrochloride, ascorbic acid and Marc Imhotep Cray, M.D. calcium chloride by mouth

ADH Antagonists      

Demeclocycline Lithium Lixivaptan Satavaptan Conivaptan Tolvaptan

Marc Imhotep Cray, M.D.

Antidiuretic Hormone Antagonists  A variety of medical conditions, including  Congestive heart failure (CHF) and  Syndrome of inappropriate ADH secretion (SIADH) cause water retention as a result of excessive ADH secretion o Inability to form dilute urine in fully hydrated condition is characteristic of SIADH • Antagonists of ADH are needed to treat this condition  Patients with CHF who are on diuretics frequently develop hyponatremia secondary to excessive ADH secretion Dangerous hyponatremia can result Marc Imhotep Cray, M.D.

Antidiuretic Hormone Antagonists (2) Until recently, two nonselective agents  lithium and  demeclocycline (a tetracycline antimicrobial drug), were used for their well-known interference with ADH activity  Mechanism for this interference has not been completely determined for either of these agents  Demeclocycline is used more often than lithium because of many adverse effects of lithium administration  Demeclocycline is now being rapidly replaced by several specific ADH receptor antagonists (vaptans), which have yielded good clinical results Marc Imhotep Cray, M.D.

Antidiuretic Hormone Antagonists (3) Vaptans

 There are 3 known vasopressin receptors, V1a , V1b , and V2  V1 receptors are expressed in vasculature and CNS  V2 receptors are expressed specifically in kidney  Conivaptan (currently available only for intravenous use) exhibits activity against both V1a and V2 receptors  Oral agents tolvaptan, lixivaptan, and satavaptan are selectively active against V2 receptor  Tolvaptan, is very effective in treatment of hyponatremia, SIADH and as an adjunct to standard diuretic therapy in patients with CHF Marc Imhotep Cray, M.D.

Antidiuretic Hormone Antagonists (4) Pharmacokinetics  Half-life of conivaptan and demeclocycline is 5–10 hours, while that of tolvaptan is 12–24 hours Pharmacodynamics  Antidiuretic hormone antagonists inhibit effects of ADH in collecting tubule  Conivaptan and tolvaptan are direct ADH receptor antagonists  both lithium and demeclocycline reduce ADH-induced cAMP by mechanisms that are not completely yet clarified Marc Imhotep Cray, M.D.

Antidiuretic Hormone Antagonists (5) Clinical Indications & Dosage A. Syndrome of Inappropriate ADH Secretion  For SIADH, water restriction is often treatment of choice  ADH antagonists are used to manage SIADH when water restriction has failed to correct abnormality  Generally occurs in outpatient setting, where water restriction cannot be enforced, but Can occur in hospital when large quantities of intravenous fluid are needed for other purposes o Demeclocycline (600–1200 mg/d) or tolvaptan (15–60 mg/d) can be used for SIADH • Appropriate plasma levels of demeclocycline (2 mcg/mL) should be maintained by monitoring • Tolvaptan levels are not routinely monitored Marc Imhotep Cray, M.D.

Antidiuretic Hormone Antagonists (6) Clinical Indications cont. B. Other Causes of Elevated Antidiuretic Hormone  Antidiuretic hormone is also elevated in response to diminished effective circulating blood volume, as often occurs in heart failure  When Tx by volume replacement is not desirable, hyponatremia may result  As for SIADH, water restriction is often treatment of choice o In patients with heart failure, this approach is often unsuccessful in view of increased thirst and large number of oral medications being used  For patients with heart failure, intravenous conivaptan may be particularly useful b/c it has been found that blockade of V1a receptors leads to decreased peripheral vascular resistance and increased cardiac output Marc Imhotep Cray, M.D.

Antidiuretic Hormone Antagonists (7) Toxicity A. Nephrogenic Diabetes Insipidus If serum Na + is not monitored closely, any ADH antagonist can cause severe hypernatremia and nephrogenic diabetes insipidus  If lithium is being used for a psychiatric disorder, nephrogenic diabetes insipidus can be treated with a thiazide diuretic or amiloride B. Renal Failure Both lithium and demeclocycline have been reported to cause acute renal failure  Long-term lithium therapy may cause chronic interstitial nephritis Marc Imhotep Cray, M.D.

Antidiuretic Hormone Antagonists (8) C. Other Adverse Effects Dry mouth and thirst are common with many of these drugs Tolvaptan may cause hypotension Multiple adverse effects associated with lithium therapy have been found and are discussed in CNS Drugs Demeclocycline should be avoided in patients with liver disease and in children younger than 12 years Marc Imhotep Cray, M.D.

Renal Drugs Summary Table

Marc Imhotep Cray, M.D.

Rosenfeld GC and Loose DS. Board Review Series Pharmacology 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2014.

Case-based Discussions

Marc Imhotep Cray, M.D.

Case 7-Diuretics A 64-year-old female with a past medical history of coronary artery disease, hypertension, and congestive heart failure (CHF) presents with dyspnea at rest and with exertion, orthopnea, and lower extremity pitting edema. Her symptoms have worsened over the last 2 weeks and also include orthopnea, worsening exercise tolerance, and tachypnea. On examination, she is notably dyspneic and tachypneic, and also has jugular venous distension, 2+pitting edema, and rales on lung examination. Patient is also found to have an audible S3. Her chest x-ray, pro-Brain Natriuretic Peptide (BNP) level, and echocardiogram confirm the clinical suspicion of CHF exacerbation with pulmonary edema. She is already on maximal medical therapy with an ACE inhibitor, beta blocker, statin, and aspirin. She is appropriately placed on oxygen and given intravenous furosemide. _ What is the mechanism of action of furosemide? _ What electrolyte abnormalities can be caused by furosemide? Marc Imhotep Cray, M.D.

Summary: A 64-year-old woman with pulmonary edema is prescribed furosemide. â&#x20AC;˘ Mechanism of action of furosemide: Inhibit active NaCl reabsorption in the ascending limb of the loop of Henle, increasing water and electrolyte excretion. â&#x20AC;˘ Potential electrolyte abnormalities: Hypokalemia, hypomagnesemia, and metabolic alkalosis because of enhanced H + excretion.

Marc Imhotep Cray, M.D.

Clinical Correlation  Loop diuretics given intravenously promote diuresis within minutes, making them ideal for the treatment of acute pulmonary edema.  Furosemide is the prototype and most widely used drug in this class.  Loop diuretics inhibit NaCl reabsorption in the ascending limb of the loop of Henle. This causes a marked increase in the excretion of both water and electrolytes.  The excretion of potassium, magnesium, and calcium ions are all increased, which may cause clinically significant adverse effects.  A metabolic alkalosis may also occur as a result of the excretion of hydrogen ions. o However, the ability to cause excretion of these electrolytes may also provide a clinical benefit in certain situations. o Forced diuresis by giving IV saline and furosemide is a primary method of treatment of hypercalcemia. Marc Imhotep Cray, M.D.

Case 8-Nondiuretic Inhibitors of Tubular Transport Following his third episode of gouty arthritis, a 50-year-old man sees you in the clinic. Each case was successfully treated acutely; however, your patient is interested in trying to prevent future episodes. He is not on regular medications and has a normal physical examination today. Blood work reveals an elevated serum uric acid level and otherwise normal renal function and electrolytes. A 24-hour urine collection for uric acid reveals that he is under-excreting uric acid. Suspecting that this is the cause of his recurrent gout, you place him on probenecid. _ What is the mechanism of action of probenecid? _ Which drugs could have their excretion inhibited by probenecid?

Marc Imhotep Cray, M.D.

Summary: A 50-year-old man with recurrent gout is prescribed probenecid. â&#x20AC;˘ Mechanism of action of probenecid: Inhibits secretion of organic acids and decreases reabsorption of uric acid, causing a net increase in secretion. â&#x20AC;˘ Other drugs whose secretion could be inhibited: Penicillin, indomethacin, and methotrexate.

Marc Imhotep Cray, M.D.

Clinical Correlation  Gout is a disease in which uric acid crystals deposit in joints, causing an extremely painful acute inflammatory arthritis.  Persons with recurrent gout often have chronically elevated levels of uric acid in their blood. This hyperuricemia is frequently caused by either overproduction of uric acid or under-excretion of uric acid by the kidneys.  Probenecid (and other uricosuric drugs) promotes the excretion of uric acid. o It works by inhibiting the secretion of organic acids from the plasma into the tubular lumen and blocking the reuptake of uric acid. o The net result of this is an increase in the excretion of uric acid.

 The benefit of this is the prevention of recurrent gout attacks in chronic under-excreters of uric acid.  In those individuals who overproduce uric acid, allopurinol or febuxostat is used. o These drugs inhibit xanthine oxidase, a key enzyme in the production of uric acid. o For patients with severe gout refractory to the above drugs, IV infusion of pegloticase can quickly reduce serum urate and reduce deposits in joints. Marc Imhotep Cray, M.D.

Practice Questions & Answers/Explanations

Marc Imhotep Cray, M.D.

Question 1 A patient taking an oral diuretic for about 6 months presents with elevated fasting and postprandial blood glucose levels. You check the patientâ&#x20AC;&#x2122;s HbA1c and find it is elevated compared with normal baseline values obtained 6 months ago. You suspect the glycemic problems are diuretic-induced. What was the most likely cause? a. Acetazolamide b. Amiloride c. Chlorothiazide d. Spironolactone e. Triamterene Marc Imhotep Cray, M.D.

Answer 1 The answer is c. Thiazides and thiazide-like diuretics (eg, chlorthalidone, metolazone) tend to elevate blood glucose levels, impair glucose tolerance, and cause frank hyperglycemia. Several mechanisms have been proposed to explain the effect: insulin resistance is the most likely mechanism. Elevations of blood glucose levels, or other manifestations of glycemic control, are rarely associated with treatment with acetazolamide (a), amiloride (b), spironolactone (d), or triamterene (e). Refs. G&G, pp 686-690; Katzung, pp 260-261.

Marc Imhotep Cray, M.D.

NB: You may recall that diazoxide (mainly used as a parenteral drug for prompt lowering of blood pressure) can be used in its oral dosage form to raise blood glucose levels in some hypoglycemic states. It is, chemically, a thiazide, but is not used as a diuretic.)

Question 2 A patient with essential hypertension is being treated with hydrochlorothiazide and a calcium channel blocker, and is doing well. He also takes atorvastatin for hypercholesterolemia, and aspirin to reduce his risk of an acute coronary syndrome. He is now diagnosed with a seizure disorder. We begin therapy with one of the suitable anticonvulsants that, fortunately, does not alter the metabolism of any of the medications prescribed for his cardiovascular problems. Weâ&#x20AC;&#x2122;ve also learn that systemic administration of acetazolamide may prove to be a useful adjunct to the anticonvulsant therapy: the metabolic acidosis it causes may help suppress seizure development or spread. So, we start acetazolamide therapy too. What is the most likely outcome of adding the acetazolamide? a. Excessive rises of plasma sodium concentration b. Hypertensive crisis (antagonism of both antihypertensive drugs) c. Hypokalemia via synergistic actions with the thiazide d. Spontaneous bleeding (potentiation of aspirinâ&#x20AC;&#x2122;s actions) e. Sudden circulating volume expansion, onset of heart failure 93

Answer 2 The answer is c. We seldom administer acetazolamide as a diuretic, because its effects are â&#x20AC;&#x153;mildâ&#x20AC;?; associated with significant changes of both urine pH (up) and blood pH (down; metabolic acidosis); and self-limiting (once sufficient bicarbonate has been lost from the blood, into the urine, refractoriness to further diuresis occurs). More often we administer acetazolamide and other carbonic anhydrase inhibitors for nonrenal/noncardiovascular problems, such as to lower intraocular pressure in some cases of glaucoma (carbonic anhydrase inhibitors inhibit aqueous humor formation) or as an adjunct to anticonvulsant therapy as described here. As a result, we may forget that these systemically administered drugs are diuretics, one common property of all the diuretics being increased renal sodium loss (a natriuretic effect; thus, answer a is not correct). We may even forget that carbonic anhydrase inhibitors, given systemically, are potassium-wasting diuretics: they act proximally and deliver extra sodium distally where, at the principal cells of the nephron, some extra Na+ is taken up in exchange for additional K+ that gets eliminated in the urine. Marc Imhotep Cray, M.D.

Answer 2 cont. In this scenario the patient is taking a thiazide, which is obviously potassium-wasting and has potential in its own right to cause hypokalemia. Add a carbonic anhydrase to the regimen and the risks of hypokalemia increase. Acetazolamide does not antagonize the antihypertensive effects of thiazides or calcium channel blockers, nor provoke hypertension or a hypertensive crisis (b). If there were any interactions between the acetazolamide and the aspirin, it would be antagonism, not potentiation (d) of aspirinâ&#x20AC;&#x2122;s antiplatelet effects. Aspirin undergoes renal tubular reabsorption, and that is a pH-dependent effect. Aspirinâ&#x20AC;&#x2122;s reabsorption is reduced (that is, its excretion increases) in an alkaline urine, which is precisely what occurs with acetazolamide. (You should recall that alkalinizing the urine is an important adjunctive measure in treating severe salicylate poisoning, in part because it reduces tubular reabsorption of salicylate.) There is no reason to suspect sudden rises of blood volume, with or without concomitant heart failure from that (e). Indeed, the added diuresis from the acetazolamide may, at least transiently, potentiate the effects of the thiazide on urine volume, blood pressure, or both. Refs. G&G, pp 677-681; Katzung, pp 256-257, 261-262, 265.

Question 3 An elderly patient with a history of heart disease is brought to the emergency room with difficulty breathing. Examination reveals that she has pulmonary edema. Which treatment is indicated? A. Acetazolamide. B. Chlorthalidone. C. Furosemide. D. Hydrochlorothiazide. E. Spironolactone.

Marc Imhotep Cray, M.D.

Answer 3 Correct answer is C. This is a potentially fatal situation. It is important to administer a diuretic that will reduce fluid accumulation in the lungs and, thus, improve oxygenation and heart function. The loop diuretics are most effective in removing large fluid volumes from the body and are the treatment of choice in this situation. In this situation, furosemide should be administered intravenously. The other choices are inappropriate.

Marc Imhotep Cray, M.D.

Question 4 A group of college students is planning a mountain climbing trip to the Andes. Which would be appropriate for them to take to prevent mountain sickness? A. A thiazide diuretic such as hydrochlorothiazide. B. An anticholinergic such as atropine. C. A carbonic anhydrase inhibitor such as acetazolamide. D. A loop diuretic such as furosemide. E. A Î˛-blocker such as metoprolol.

Marc Imhotep Cray, M.D.

Answer 4 Correct answer is C. Acetazolamide is used prophylactically for several days before an ascent above 10,000 feet. This treatment prevents the cerebral and pulmonary problems associated with the syndrome as well as other difficulties, such as nausea.

Marc Imhotep Cray, M.D.

Question 5 An alcoholic male has developed hepatic cirrhosis. To control the ascites and edema, which should be prescribed? A. Acetazolamide. B. Chlorthalidone. C. Furosemide. D. Hydrochlorothiazide. E. Spironolactone.

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Answer 5 Correct answer is E. Spironolactone is very effective in the treatment of hepatic edema. These patients are frequently resistant to the diuretic action of loop diuretics, although a combination with spironolactone may be beneficial. The other agents are not indicated.

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Question 6 A 55-year-old male with kidney stones has been placed on a diuretic to decrease calcium excretion. However, after a few weeks, he develops an attack of gout. Which diuretic was he taking? A. Furosemide. B. Hydrochlorothiazide. C. Spironolactone. D. Triamterene. E. Urea.

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Answer 6 Correct answer is B. Hydrochlorothiazide is effective in increasing calcium reabsorption, thus decreasing the amount of calcium excreted, and decreasing the formation of kidney stones that contain calcium phosphate or calcium oxalate. However, hydrochlorothiazide can also inhibit the excretion of uric acid and cause its accumulation, leading to an attack of gout in some individuals. Furosemide increases the excretion of calcium, whereas the K+-sparing osmotic diuretics, spironolactone and triamterene, and urea do not have an effect.

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Question 7 A 75-year-old woman with hypertension is being treated with a thiazide. Her blood pressure responds well and reads at 120/76 mm Hg. After several months on the medication, she complains of being tired and weak. An analysis of the blood indicates low values for which of the following? A. Calcium. B. Glucose. C. Potassium. D. Sodium. E. Uric acid. Marc Imhotep Cray, M.D.

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Answer 7 Correct answer is C. Hypokalemia is a common adverse effect of the thiazides and causes fatigue and lethargy in the patient. Supplementation with potassium chloride or foods high in K+ corrects the problem. Alternatively, a potassium sparing diuretic, such as spironolactone, may be added. Calcium, uric acid, and glucose are usually elevated by thiazide diuretics. Sodium loss would not weaken the patient.

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Question 8 Which is contraindicated in a patient with hyperkalemia? A. Acetazolamide. B. Chlorthalidone. C. Chlorothiazide. D. Ethacrynic acid. E. Spironolactone.

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Answer 8 Correct answer is E. Spironolactone acts in the collecting tubule to inhibit Na+ reabsorption and K+ excretion. It is extremely important that patients who are treated with any potassium-sparing diuretic be closely monitored for potassium levels. Exogenous potassium supplementation is usually discontinued when potassium-sparing diuretic therapy is instituted and spironolactone is contraindicated in patients with hyperkalemia. The other drugs promote the excretion of potassium.

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Question 9 Which of the following should be avoided in a patient with a history of severe anaphylactic reaction to sulfa medications? A. Amiloride. B. Hydrochlorothiazide. C. Mannitol. D. Spironolactone. E. Triamterene.

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Answer 9 Correct answer is B. Hydrochlorothiazide, like many thiazide and thiazide-like diuretics, contains a sulfa moiety within its chemical structure. It is important to avoid use in those individuals with severe hypersensitivity to sulfa medications. It may be used with caution, however, in those with only minor reaction to sulfa medications.

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Question 10 A male patient is placed on a new medication and notes that his breasts have become enlarged and tender to the touch. Which medication is he most likely taking? A. Chlorthalidone. B. Furosemide. C. Hydrochlorothiazide. D. Spironolactone. E. Triamterene.

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Answer 10 Correct answer = D. An adverse drug reaction to spironolactone is gynecomastia due to its effects on androgens and progesterone in the body. Eplerenone may be a suitable alternative if the patient is in need of an aldosterone antagonist but has a history of gynecomastia.

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Question 11 A patient presents to the emergency department with an extreme headache. After a thorough workup, the attending physician concludes that the pain is due to increased intracranial pressure. Which diuretic would work best to reduce this pressure? A. Acetazolamide. B. Indapamide. C. Furosemide. D. Hydrochlorothiazide. E. Mannitol.

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Answer 11 Correct answer = E. Osmotic diuretics, such as mannitol, are a mainstay of treatment for patients with increased intracranial pressure or acute renal failure due to shock, drug toxicities, and trauma.

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Question 12 Which diuretic has been shown to improve blood pressure in resistant hypertension or those already treated with three blood pressure medications including a thiazide or thiazide-like diuretic? A. Chlorthalidone. B. Indapamide. C. Furosemide. D. Mannitol. E. Spironolactone.

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Answer 12 Correct answer = E. Resistant hypertension, defined by the use of three or more medications without reaching the blood pressure goal, often responds well to aldosterone antagonists. This effect can be seen in those with or without elevated aldosterone levels.

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See next slide for sources and links to additional study tools and resources. Marc Imhotep Cray, M.D.

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Sources and further study: eLearning Renal cloud folder tools and resources MedPharm Guidebook: Unit 9 Drugs Used to Affect Renal Function Renal Pharmacology eNotes Clinical Pharmacology Cases 7, 8, & 55 (Learning Triggers) Textbooks Brunton LL, Chabner BA , Knollmann BC (Eds.). Goodman and Gilmanâ&#x20AC;&#x2122;s The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill, 2011 Katzung, Masters, Trevor. Basic and Clinical Pharmacology, 12th ed. New York: McGraw-Hill, 2012 Mulroney SE. and Myers AK. Netter's Essential Physiology. Philadelphia: Saunders, 2009 Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Philadelphia: Sanders, 2014 Toy E C. et.al. Case Files-Pharmacology Lange 3rd ed. New York: McGraw-Hill 2014. Marc Imhotep Cray, M.D.

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