Medicinal Chemistry of Diuretics and Aquaretics Reading Materials PDF

Medicinal Chemistry of Diuretics and Aquaretics Reading Materials Ra’ed S. Khashan, PhD, MS, RPh Ben & Maytee Fisch College of Pharmacy at the University of Texas at Tyler Pre-Class Assi...

Medicinal Chemistry of Diuretics and Aquaretics Reading Materials Ra’ed S. Khashan, PhD, MS, RPh Ben & Maytee Fisch College of Pharmacy at the University of Texas at Tyler Pre-Class Assignments Study the material guided by the following reading objectives. Objectives 1. Describe the mechanism of action for each class of diuretics and aquaretics. 2. Discuss the limitations for each class of the diuretics and aquaretics. 3. Relate the relative efficacy and potency of one drug to its analogs using structural differences. 4. Explain the reason for combining potassium-sparing diuretics with other diuretics. 5. Assess the importance of the site of action of a diuretic on its efficacy. 6. Relate the structural differences to the resulting changes in side effects. 7. Differentiate between allergy to arylamine sulfonamide drugs, and non-arylamine sulfonamide drugs. In Class Assignments 1. iRAT/tRAT over the material in the handout and linked to the objectives. 2. TBL application exercises will be provided in class. References 1. An Introduction to Medicinal Chemistry, 5th ed. Graham Patrick. Oxford University Press. ISBN: 978-0-199697397. 2. Foye’s Principles of Medicinal Chemistry, 7th ed. Thomas Lemke et. al. Wolters Kluwer Health ISBN: 978-1-609133450. 3. Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry, 12th ed. John M. Beale Jr., and John Block. LWW North American Edition (©2010). ISBN: 978-0-781779296. 4. Burger's Medicinal Chemistry, Drug Discovery and Development, 7th ed. Donald J. Abraham, David P. Rotella. Wiley (©2010). ISBN: 978-0-470278154. 5. Basic and Clinical Pharmacology, 12th ed. Katzung BG, Masters, SB, Trevor AJ. McGraw-Hill Education. (©2012). ISBN: 978-0-071764018. 6. Therapeutic Advances in Chronic Disease. 2014 Jan; 5(1): 30–43. Page 1 of 7  Diuretics and Aquaretics DIURETICS  Diuretics: Chemicals that increase the rate of urine formation. They increase the excretion of electrolytes (especially sodium and chloride ions) and water from the body without affecting protein, vitamins, glucose, or amino acids. 1) Carbonic Anhydrase (CA) Inhibitors CA is an enzyme that catalyzes (facilitates) the reaction:  They inhibit CA within proximal convoluted tubules (PCT).  This will limit the number of hydrogen ions available to promote sodium reabsorption. Thus, diuresis is induced. **Reminder: H+ are exchanged for Na+, thus causing reabsorption of the Na+, HCO3-, and the associated water molecules from the tubules back into the body.  However, for diuretic response to be observed, 99% of the CA enzyme must be inhibited. CA inhibitors affect only 20% – 25% of Na+ reabsorption since they are reabsorbed by the ascending loop of Henle and more distal parts of the nephron.  Therefore, CA inhibitors are not highly efficacious diuretics.  On the other hand, prolonged use of CA inhibitors will result into the urine becoming more alkaline, and the blood becoming more acidic (aka, metabolic acidosis). When equilibrium is reached, CA inhibitors will lose their effectiveness. As a result, this class of drugs has limited diuretic use. o They are commonly used in treatment of glaucoma, by reducing the rate of aqueous humor formation. o Other limited uses are: alkalinizing the urine, reducing metabolic alkalosis, and prophylactically to reduce acute mountain sickness (low oxygen causing alkalosis).  Although they contain sulfonamide groups, allergic reactions to other sulfonamide-containing drugs are not common. Acetazolamide, Methazolamide, and Dichlorphenamide  Acetazolamide was the first CA inhibitor that is orally effective, but as mentioned earlier, its diuretic action is limited due to the systemic acidosis it produces.  Methazolamide was designed by adding a methyl group to acetazolamide, which decreases polarity of the compound, and thus, improve the penetration into the ocular fluid, where it acts as CA inhibitor to reduce intraocular pressure.  All three drugs have non-selective distribution into the ocular compartment, and they can inhibit multiple CA isozymes in other tissues leading to undesirable effects. Dorzolamide, and Brinzolamide  To improve the selectivity of CA inhibitors for treating glaucoma conditions, topical eye administration is considered. Thus, a more water soluble CA inhibitors are needed to allow for preparation of topical eye solutions.  Both contain ionizable amino groups, due to efforts to develop water-soluble CA inhibitors that retain sufficient lipophilicity to penetrate the cornea. They are only indicated for topical eye administration in glaucoma patients.  Ocular discomfort (burning and stinging) occurs in 12.2% versus 3% of patients receiving dorzolamide and brinzolamide, respectively.6 Plus, brinzolamide is more potent; brinzolamide is available in 1% topical eye solutions compared to 2% for dorzolamide. On the other hand, brinzolamide is ~15X more expensive than Dorzolamide. Page 2 of 7 2) Thiazide Diuretics  In an effort to find more efficacious CA inhibitors, further studies provided compounds with higher degree of diuretic activity but were weak CA inhibitors.  These compounds, known as benzothiadiazine or thiazide diuretics, represent a new series of diuretics.  Their major site of action at the distal convoluted tubule.  They compete for the chloride binding site of the Na+/Cl- symporter (or cotransport system) and inhibit the reabsorption of Na+ and Cl- ions. For this reason, they are referred to as saluretic (i.e., causing loss of NaCl salt).  They also inhibit reabsorption of potassium and bicarbonate ions, but to a lesser degree.  Thus, adverse effects related to electrolyte imbalances are: hyponatremia, hypokalemia, and hypochloremia (causing hypochloremic alkalosis). In addition to hypomagnesemia, hypercalcemia, and hyperuricemia. **NOTE: Long-term use of thiazides may cause decreased glucose tolerance (causing hyperglycemia), and increased blood lipid content (hyperlipidemia).  Potassium and magnesium supplements may be administered to treat hypokalemia and hypomagnesemia, but their use is not always necessary. Example on these supplements: potassium chloride (Klor-Con), potassium gluconate, potassium citrate, magnesium oxide (Mag-Ox), or magnesium lactate (Mag-Tab). (How Na+, & Cl-are supplemented?) **NOTE: Potassium-sparing diuretics (will be discussed soon) can also be used to prevent hypokalemia. Combination preparations of thiazides and potassium-sparing diuretics are available, e.g., Dyazide (HCTZ & triamterene), Moduretic (HCTZ, & amiloride), and Aldactazide (HCTZ, & spironolactone). Structure-Activity Relationship of Thiazides  The hydrogen atom at N2 is most acidic due to the electron withdrawing effect of neighboring sulfone group. The acidic H+ allows the formation of water-soluble sodium salts for IV administration.  An electron withdrawing group at C6 is necessary for diuretic activity. E.g., chlorine and trifluoromethyline, the latter is more lipophilic and have longer duration of action. Compare compounds number 3 and 7 in the table.  Replacement or removal of sulfonamide group at C7 causes loss of activity.  Saturation of the double bond between C3 & N4 (see structure II in table) results in 10-folds increase in diuretic activity.  Substituting C3 with a lipophilic groups increases potency, lipid solubility, and duration of action. E.g., haloalkyl, aralkyl, and thioether groups.  Alkyl substitution on N2 decreases polarity & increases duration of action.  Although these compounds do have carbonic anhydrase activity, there is no correlation of this activity to their diuretic (saluretic) activity. Page 3 of 7 3)Thiazide-like Diuretics They are structurally diverse group of sulfonamide derivatives that do not contain the benzothiadiazine (thiazide) ring. Notice the replacement of one of the two sulfone groups (-SO2-) with a ketone group (-CO2-). They have the same mechanism of action, similar therapeutic activities, and adverse effects as the thiazide diuretics. This group of diuretics has longer duration of action compared to thiazide diuretics, as a result of protein binding, and/or binding to carbonic anhydrase in the erythrocytes. The longest is indapamide exhibiting biphasic kinetics. Metolazone, and indapamide have increased potency, and in contrast to thiazides, they may be effective as a diuretic when GFR (Glomerular Filtration Rate) falls below 40 mL/min. 4) High-Ceiling or Loop Diuretics  In the search for a more efficacious diuretic than carbonic anhydrase, these drugs were found to produce a peak diuretic effect much greater than all other diuretics, and hence were called high-ceiling diuretics.  Their high efficacy offers a great advantage in chronic renal insufficiency, particularly in cases with low GFR.  Their main site of action is loop of Henle, hence they are also called loop diuretics, where they inhibit the Na+/K+/2Cl- symporter (or cotransport system). Additional effects on the proximal and distal tubules are also possible.  They are characterized by quick onset (~30 minutes), and short duration of action (~6 hours).  Furosemide has free carboxyl group, and so it is a stronger acid than thiazide diuretics, and has a saluretic effect 8- to 10-folds that of the thiazide diuretics.  Furosemide causes marked excretion of Na+, Cl-, K+, Ca+2, Mg+2, and HCO3- ions. Thus causing hypokalemia (which can be counteracted by potassium supplements or coadministration of potassium-sparing diuretics), hypocalcemia (thus should be avoided in postmenopausal osteopenic women), hyperuricemia, glucose intolerance (hyperglycemia), and increased serum lipids (hyperlipidemia). In addition, ototoxicity (reversible), and GI effect may also be observed.  Furosemide is effective orally, but may be used parenterally when more prompt diuretic effect is needed.  Bumetanide resulted from changes at positions 4, 5, & 6, and thus it is 50-folds more potent than furosemide.  Torsemide has a sulfonylurea group instead of the sulfonamide moiety (yet it is still considered a sulfonamide drug).  In contrast to furosemide and bumetanide, torsemide does not act on the proximal tubule, and therefore does not increase phosphate or bicarbonate excretion.  Ethacrynic acid is the only loop diuretic that is not a sulfonamide derivative, and may be useful in patients who are allergic to (non-arylamine, aka, non-antibiotic) sulfonamides. More about sulfonamide allergy will be discussed soon.  Orally administered ethacrynic acid needs 1 hour to act and lasts for 6 to 8 hours.  Ethacrynic acid is the least potent among all. It is not widely used because it induces a greater incidence of ototoxicity and more serious GI effects than all other loop diuretics. (Relate potency to side effects). Page 4 of 7 5) Potassium-Sparing Diuretics  Hypokalemia has been encountered most frequently with the previously mentioned diuretics.  Thus, research efforts were directed toward the development of potassium-sparing diuretics.  Amiloride (1965), triamterene (1965), and spironolactone (1959), were discovered as a result of this effort.  They are weak diuretics, but, they’re generally used in with other diuretics to offset the effect of potassium loss. 5.a) Amiloride, and Triamterene  They exert the diuretic effect by blocking the sodium channel in late distal convoluted tubule (DCT) and collecting duct (CD). Thus, sodium is not reabsorbed, and potassium is not secreted.  Amiloride is more basic, and is might be the reason for its great potency (100 folds that of triamterene) as they compete with Na+ for the negatively charged regions of the sodium channel.  The most serious side effect is hyperkalemia, however, they are normally used in combination of other diuretics that produces hypokalemia. Thus, the hyperkalemic effect counteracts the hypokalemic effect. 5.b) Mineralocorticoid Receptor (MR) Antagonists: Spironolactone, and Eplerenone  The cortex of adrenal glands secretes aldosterone, a mineralocorticoid (a steroid hormone).  Aldosterone promotes retention of salt (Na+ & Cl-) and water, and excretion of potassium (K+) and hydrogen ion (H+), thus inducing retention of fluids into the body.  Aldosterone exerts this action by binding to the mineralocorticoid receptor (MR), which is a nuclear transcription factor, remember type of receptors? **NOTE: There are other mineralocorticoids that affect the electrolytic balance, but aldosterone is the most potent. Its ability to cause reabsorption of Na+/Cl-, and excretion of K+/H+ is 3000 fold that of hydrocortisone, for example.  Thus, substances that antagonizes the effects of aldosterone should be good diuretics. Example of such substances are spironolactone, and eplerenone, which are classified as potassium sparing diuretics.  The primary site of action, and hence the location of MR receptors, is the late distal tubule and collecting duct.  The antagonistic activity for MR is dependent on: o The presence of γ-lactone ring on C-17. o A substitution on C-7 to act as a sterically hinder its interaction with a methionine residue in MR binding site.  Spironolactone is useful in treating edema resulting primarily from hyperaldosteronism. Another use is in combination with potassium depleting diuretics to prevent diuretic-induced hypokalemia.  A primary concern with the use of MR antagonists is hyperkalemia, which can be fatal.  Spironolactone has sexual side effect, i.e., gynecomastia, decreased libido, and impotence due to the non-selective binding to androgen receptor (AR), glucocorticoid receptor (GR), and progesterone receptor (PR).  Eplerenone is a new drug discovered in 2002. Although it has a lower affinity to MR compared to spironolactone (20- to 40-folds), it is more selective to MR, and has limited or no inhibitory effects on AR, GR, and PR. Thus, had fewer sexual side effects. The change in affinity and selectivity is believed to be due to the 9α, 11α-epoxy group.  Eplerenone is extensively metabolized by CYP3A4 to inactive metabolites, and thus, combination with potent inhibitors of CYP3A4 (e.g., ketoconazole, or erythromycin) should be avoided. Page 5 of 7 6)Osmotic Diuretics  Low molecular weight compounds that are freely filtered into the renal tubules.  Once in the renal tubule, they are not reabsorbed due to their high water solubility.  They increase the intraluminal osmotic pressure causing water and almost all of the electrolytes to pass from the body into the tubule causing the diuretic effect, as well as electrolytes disturbances (hypernatremia, and hyperkalemia).  The most commonly used drug is Mannitol. Others are: sorbitol, isosorbide, sugars (glucose and sucrose), and urea.  Mannitol is administered intravenously because it has poor oral absorption due to its high water solubility. (How?) AQUARETICS  Aquaretics: Similar to diuretics, aquaretics are chemicals that increase the rate of urine formation. However, aquaretics increase the excretion of water without electrolyte loss. Example is antidiuretic hormone (aka, ADH or vasopressin) receptor antagonists. The only example of aquaretics we have is antidiuretic hormone (ADH) antagonists. **NOTE: Aquaretics are preferred over diuretics in treatment of hyponatremia. (Why?) Antidiuretic Hormone (ADH, or Vasopressin) Antagonists (aka, Vaptans)  An important hormone for regulating the urine formation is antidiuretic hormone (ADH), aka vasopressin.  It is released from the posterior pituitary gland (located at the base of the brain) in response to reduced blood pressure and elevated plasma osmolality.  There are three vasopressin receptors: V1a, V1b, and V2. V1 receptors are expressed in the vasculature and CNS, while V2 receptors are expressed specifically in the kidney.  In the kidney, ADH acts on the collecting tubule to increase water permeability and reabsorption.  Until recently, two nonselective agents, lithium and demeclocycline (a tetracycline antimicrobial drug), were used for their well-known interference with ADH activity through unknown mechanism.  Demeclocycline is used more often than lithium because of the many adverse effects of lithium administration.  Demeclocycline is now being rapidly replaced by several specific ADH receptor antagonists (vaptans).  Conivaptan (Vaprisol®) is currently available only for intravenous use and exhibits activity against both V1a and V2.  Tolvaptan, lixivaptan, and satavaptan are available orally, and are selectively active against the V2 receptor.  Lixivaptan and satavaptan are still under clinical investigation, but tolvaptan, is FDA-approved.  Tolvaptan (Samsca®) is very effective in treatment of hyponatremia and as an adjunct to standard diuretic therapy in patients with congestive heart failure (CHF). **NOTE: A variety of medical conditions, including congestive heart failure (CHF) and the syndrome of inappropriate ADH secretion (SIADH), cause water retention as a result of excessive ADH secretion. Patients with CHF who are on diuretics frequently develop hyponatremia secondary to excessive ADH secretion. Dangerous hyponatremia can result. For these medical condition, vaptans can be useful.5 Page 6 of 7 SULFA ALLERGY  Allergy to arylamine sulfonamide drugs, such as sulfonamide antibiotics, and some sulfonamide anti-retrovirals (amprenavir, and fosamprenavir) are un-likely to cross react with non-arylamine sulfonamide drugs, such as: o Sulfur powder, sulfite preservatives, or sulfate salts (e.g., morphine sulfate). o Non-antibiotic sulfonamide drugs: CA inhibitors, thiazide or thiazide-like diuretics, loop diuretics, sulfonylureas (glipizide, glimepiride, gliclazide, and glibenclamide), anti-inflammatory (celecoxib), and others (sulfone, sumatriptan, topiramate, sotalol, and probenecid). Torsemide?? Thiazide-like & Fun Facts! Diuretics have also been used illicitly by some athletes for “sport doping”. This is a consequence of the drugs’ ability to quickly produce weight loss (via increased excretion of water) and masking of urine contents (via dilution of other drugs or metabolites that might be present in the urine). Furosemide, triamterene, and hydrochlorothiazide are the most commonly used diuretics for sport doping since they are eliminated rapidly and are therefore more difficult to detect in urine samples taken at later time points after use. Use of diuretics by athletes without a documented therapeutic need has been banned since 1988, and routine monitoring for these drugs and their degradation products is commonplace. Page 7 of 7