`
`Complex Innovations EX 1019
`IPR of U.S. Pat. No. 7,829,595
`
`
`
`CHURCHILL LIVINGSTONE
`Medical Division of Longman Group UK
`Limited
`
`ACKNOWLEDGEMENTS
`
`Publishing manager.’ Timothy Horne
`Project coordinator.‘ Julia Merrick
`Design: Design Resource Unit
`Production.‘ I Macaulay Hunter, Lesley W Small
`Computer Services.‘ Janet Muncly and User Friendly Computer Services
`Copy editors.‘ Susan Boobis PhD, Jolyon Phillips PhD, Anne Russell
`Proof readers.‘ Pauline Cairns, Angus Macdonald, Paul Morgan,
`David Swinden, Jane Ward PhD
`Editorial Assistant.‘ Patricia Aubertel
`Sales promotion.‘ Hilary Brown
`
`The publishers also gratefully acknowledge the help given by
`many others, particularly the coordinators in the early stages
`of the project: Susan Faulding and Helen Orpe.
`
`Distributed in the United States of America by
`Churchill Livingstone Inc., 1560 Broadway,
`New York, N.Y. 10036, and by associated
`companies, branches and representatives
`throughout the world.
`
`© Longman Group UK Limited 1991
`
`All rights reserved. No part of this publication
`may be reproduced, stored in a retrieval system,
`or transmitted in any form or by any means,
`electronic, mechanical, photocopying, recording
`or otherwise, without either the prior written
`permission of the publishers (Churchill
`Livingstone, Robert Stevenson House,
`Baxter's Place, Leith Walk, Edinburgh
`EH1 3AF), or a licence permitting restricted
`copying in the United Kingdom issued by the
`Copyright Licensing Agency Ltd, 90 Tottenham
`Court Road, London, WCIE 7DP.
`
`l—3
`
`First published 1991
`
`ISBN D-'-4"-IEI-UEBLH:-X
`
`British Library Cataloguing in Publication Data
`CIP catalogue record for this book is available
`from the British Library.
`
`'
`Library of Congress-in-Publication Data
`Therapeutic drugs/edited by Sir Colin Dollery; editorial board,
`Alan R. Boobis
`[et al.].
`p. cm.
`Includes bibliographical references and indexes.
`1. Drugs—Handbooks, manuals, etc. 2. Pharrnacology—I-landbooks,
`manuals, etc. I. Dollery, Colin T.
`[DNLM; 1. Drug Tl1erapy—handbooks. 2. Drugs—handbooks. QV 39
`T398]
`J’
`RM30l.l2.T44 [991
`615.5'8—dC20
`DNLM/DLC
`for Library of Congress _
`
`u..‘....,.ri .,...i t..,......4 :.. mm... r.y..:¢..:..
`
`|...
`
`2
`
`
`
`Spironolactone
`
`Spironolactone is probably the most important steroidal lactone in
`clinical use;
`it acts as a diuretic and antihypertensive agent by
`antagonizing the sodium-retaining effects of aldosterone. and also in
`part by inhibiting the adrenocortical biosynthesis of aldosterone.
`
`Chemistry
`Spironolactone (Aldactone, Diatensee, Spiroctan, Spirolone)
`C24H:a2O4S
`7-0:-Acetyl-thlo-3—oxo-iYer-pregn—4—ene—2‘l—17,B—carbo|actone acid—',r—
`lactone
`
`“scocri,
`
`Molecular weight
`pKa
`Solubility
`in alcohol
`in water
`Octanol/water partition coefficient
`
`416.1
`not relevant
`
`in 80
`1
`insoluble
`—
`
`Spironolactone is a white to light tan powder with a slightly bitter
`taste and is usually odourless or has a slight odour ofthioacetic acid.
`It is prepared by chemical synthesis.
`Spironolactone is also available in oral combination with fruse-
`mide (Lasilactone=frusemide 20 mg and spironolactone 50 mg) and
`with hydroflumethiazide (Aldaetide 25=hydroflumethiazide 25 mg
`and spironolactone 25 mg).
`
`Pharmacology
`The antimineralocorticoid properties of the spirolactones were first
`recognized more than 30 years ago.1 Spironolactone is a competitive
`inhibitor of the binding of aldosterone to its receptor.
`Its most
`important site of action is the distal portion of renal tubules where it
`combines with soluble cytoplasmic aldosterone receptors to form
`complexes which are inactive and which do not bind to nuclear-
`aeceptor sites, thus preventing a chain of biochemical events leading
`to the synthesis of physiologically active proteins.” Thus it pro-
`motes a diuresis and acts as an antihypertensive agent. Administra-
`tion of spironolactone is associated with reversal of the electrolytic
`changes attributed to aldosterone and with a dose-dependent increase
`In plasma renin activity in rats.‘
`A separate but less important effect is direct inhibition of adrenal
`Synthesis of aldosterone.5
`
`Toxicology
`The acute toxicity of spironolactone is low in rats. mice and rabbits.
`50 that there is a high potential therapeutic ratio.
`During chronic testing histological changes were noted in rat liver,
`thyroid gland and male genitalia. There were also changes in monkey
`testes and male mammary glands.
`In a 78-week study in rats. a
`Hllmber of malignant tumours occurred, mainly affecting skin and
`
`with a control group it was not clear that the incidence of tiimours
`was greater than would be expected in any ageing rat p0pula1ion_
`Thus. whether Spironolactone predisposes to tumour
`formation
`remains an unresolved question.“
`
`Clinical pharmacology
`Spironolactone is a competitive inhibitor of aldosterone through
`binding at receptor sites,
`the most important of which lie in the late
`distal renal
`tubules and the renal collecting system. Thus urinary
`sodium and water loss and retention ofpotassium and hydrogen result
`and the clinical effects are a diuresis and lowering of blood pressure.7
`Spironolactone also inhibits adrenocortical aldosterone biosynthe-
`sis in patients with primary hyperaldosteronism, of which ‘spirono-
`lactone bodies‘
`identified in the adrenal
`tumour cells of treated
`patients are thought to be a morphological expressions Theoreti-
`Cally, such a mechanism could enhance diuretic activity but
`its
`therapeutic importance is uncertain.
`Spironolactone is primarily useful as a diuretic in patients with
`hyperaldosteronism. Thus it is efiiective in patients with ascites clue to
`liver failure, and in patients with resistant heart failure (i.c. where
`other diuretics have failed). It is less useful as a first—line diuretic. lts
`antihypertensive effects are relatively modest in essential hyperten-
`sion but it is of value in the treatment ofhypertension due to primary
`hyperaldosteronism where other definitive treatments (e.g. surgery)
`are not feasible.
`Single-dose studies in normal volunteers in the range 50—800 mg
`produced a dose-dependent reversal of aldosterone—induced sodium
`retention and/or decrease in the plasma Na,i’K ratio.9 In essential
`hypertension no dilference in antihypertensive effect was found
`between daily doses of 100, 200 or 400 mg” and a maximum dose of
`75-100 mg per day has been recommended.” However. there was a
`dose relationship with plasma sodium. potassium and weight.” By
`comparison. spironolactone in doses of up to 400 mg per day may be
`necessary in the treatment of primary hyperaldosteronisrn.7“ Be-
`cause of the prolonged duration of activity of its metabolites,
`spironolactone may be administered in a singie daily dose.
`Spironolactone causes a number of electrolyte changes. notably a
`reduction in plasma Sodium and bicarbonate,
`together with dose-
`dependent elevations in plasma renin, potassium and creatinine.
`Fasting blood sugar, cholesterol and triglycerides are not significantly
`alTected."'13
`Spironolactone was thought to increase calcium excretion through
`a direct efiect on tubular transport, but this was later refuted.”
`
`Pharmacokinetics
`In the past spironolactone has been assayed using a speetroph0tofiu-
`orimetric method” but now a HPLC assay is in more common use
`which has a sensitivity1“‘” of 5 ug.l"’. However, because the drug is
`extensively metabolized to canrenone and other metabolites which
`are also competitive antagonists of aldosterone. pharniacokinetic
`studies focus on the metabolic pathways.
`Oral absorption of spironolactone is variable because of its low
`aqueous solubility. In rhesus monkeys almost complete absorption of
`the drug was obtained f1'om an aqueous ethanolic solution, and in
`man, absorption is enhanced by micronization of the drug in the
`tablet.1B‘19 There is improved absorption if the drug is taken after
`food, probably because by delaying gastric emptying. food promotes
`disintegration of the tablet and improves dissolution of the drug.
`Furthermore, bile acids secreted in response to the meal may
`dissolve spironolactone. which is very lipophilicm The peak plasma
`concentration was observed at
`1 hour in normal volunteers after a
`standardized meal. Systemic bioavailability has been estimated at
`60—70% and the plasma halflife is l.3 10.3 (SD) hours. The drug can
`still be detected up to 8 hours after ingestion but it
`is extensively
`metabolized so that the free drug is not detected in urine.‘“”13
`Spironolactone is 98% protein bound but its volume of distribu-
`tion is unknown.“ The extent oftissue accumulation of the drug and
`its ability to cross the blood—brain barrier are not known.
`In
`lactating women taking spironolactone. levels of canrenone in milk
`were low and it was estimated that
`the maximum quantity of
`canrcnone ingested daily by the human infant via milk was 0.2% of
`the maternal daily dose of spironolactone.”
`
`3