Valsartan/hydrochlorothiazide: Difference between revisions

{{Short description|Chemical compound}}

{{Use dmy dates|date=October 2022}}

{{cs1 config |name-list-style=vanc |display-authors=6}}

| verifiedrevid = 412259800

| type = combo

| image = Valsartan.svg

| alt =

| image2 = hydrochlorothiazide.svg

| alt2 =

| caption =

<!-- Combo data -->

| component1 = Valsartan

| class1 = [[Angiotensin II receptor antagonist]]

| component2 = Hydrochlorothiazide

| class2 = [[Thiazide]] [[diuretic]]

<!-- Clinical data -->

| tradename = Co-vasotec, Diovan HCT, Co-Diovan, others

| Drugs.com = {{drugs.com|ppa|valsartan-and-hydrochlorothiazide}}

| MedlinePlus = a611032

| DailyMedID = Valsartan hydrochlorothiazide

| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->

| pregnancy_AU_comment =

| pregnancy_category =

| routes_of_administration = [[Oral administration|By mouth]]

| ATC_prefix = C09

| ATC_suffix = DA03

| ATC_supplemental =

<!-- Legal status -->

| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled -->

| legal_AU_comment =

| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->

| legal_BR_comment =

| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->

| legal_CA_comment =

| legal_DE = <!-- Anlage I, II, III or Unscheduled -->

| legal_DE_comment =

| legal_NZ = <!-- Class A, B, C -->

| legal_NZ_comment =

| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->

| legal_UK_comment =

| legal_US = Rx-only

| legal_US_comment = <ref name="Diovan HCT FDA label" />

| legal_EU = Rx-only

| legal_EU_comment = <ref>{{cite web | title = Active substance: valsartan, hydrochlorothiazide / valsartan | work = List of nationally authorised medicinal products | publisher = European Medicines Agency | date = 14 January 2021 | url = https://www.ema.europa.eu/documents/psusa/valsartan-hydrochlorothiazide/valsartan-list-nationally-authorised-medicinal-products-psusa/00010396/202004_en.pdf}}</ref><ref>{{cite web | title=Dafiro HCT EPAR | website=[[European Medicines Agency]] (EMA) | date=12 November 2009 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/dafiro-hct | access-date=21 April 2021}}</ref><ref>{{cite web | title=Exforge HCT EPAR | website=[[European Medicines Agency]] (EMA) | date=12 November 2009 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/exforge-hct | access-date=21 April 2021}}</ref>

| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->

| legal_UN_comment =

| legal_status = <!-- For countries not listed above -->

<!-- Identifiers -->

| CAS_number = 186615-83-8

| CAS_supplemental =

| PubChem = 9810581

| IUPHAR_ligand =

| DrugBank_Ref =

| DrugBank =

| ChemSpiderID_Ref =

| ChemSpiderID =

| UNII_Ref =

| UNII =

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D09197

| ChEBI_Ref =

| ChEBI =

| ChEMBL_Ref =

| ChEMBL =

| NIAID_ChemDB =

| PDB_ligand =

| synonyms =

<!-- Chemical and physical data -->

<!-- Definition and medical uses -->

'''Valsartan/hydrochlorothiazide''', sold under the brand name '''Diovan HCT''' among others, is a medication used to treat [[high blood pressure]] when [[valsartan]] is not sufficient.<ref name=BNF76>{{cite book|title=British national formulary : BNF 76|date=2018|publisher=Pharmaceutical Press|isbn=9780857113382|pages=179|edition=76}}</ref> It is a combination of valsartan, an [[angiotensin II receptor antagonist|angiotensin receptor blocker]] with [[hydrochlorothiazide]], a [[diuretic]].<ref name=MTM2019/> It is taken by mouth.<ref name=MTM2019/>

<!-- Side effects and mechanisms -->

Common side effects include dizziness and headaches.<ref name=MTM2019/> Serious side effects may include [[allergic reactions]], [[electrolyte abnormalities]], and [[glaucoma]].<ref name="Diovan HCT FDA label"/> Use in [[pregnancy]] is not recommended.<ref name="Diovan HCT FDA label">{{cite web | title=Diovan HCT- valsartan and hydrochlorothiazide tablet, film coated | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d76a0419-05ee-437e-884c-65807aea9569 | access-date=20 January 2021}}</ref>

<!-- Society and culture -->

The combination was approved for medical use in the United States in 1998.<ref name=MTM2019>{{cite web |title=Hydrochlorothiazide and valsartan Uses, Side Effects & Warnings |url=https://www.drugs.com/mtm/hydrochlorothiazide-and-valsartan.html |website=Drugs.com |access-date=10 March 2019 |language=en}}</ref> It is available as a [[generic medication]].<ref name=BNF76/> In 2021, it was the 224th most commonly prescribed medication in the United States, with more than 1{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2021 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=14 January 2024 | archive-date=15 January 2024 | archive-url=https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Hydrochlorothiazide; Valsartan - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/HydrochlorothiazideValsartan | access-date = 14 January 2024}}</ref>

== Structure–activity relationship ==

Valsartan has the structure that most ARBs have with the extended biphenyl group and tetrazole which mimics the carboxylate group as a bioisostere but is not held to the same metabolic inactivation. One special note about the molecule in terms of how it differs with other angiotensin receptor blockers, is that the molecule at the 2-prime position has a tetrazole, which has an acidic hydrogen attached to it.

== Medical uses ==

=== High blood pressure ===

Valsartan and hydrochlorothiazide are both medications [[Indication (medicine)|indicated]] as initial therapy for [[high blood pressure]]. When high blood pressure is not effectively controlled on a single medication they can be used in a combination.<ref>{{Cite web|title=VIII. Choice of therapy for adults with hypertension without compelling indications for specific agents | publisher=Hypertension Canada |url=https://guidelines.hypertension.ca/prevention-treatment/uncomplicated-hypertension-therapy/|access-date=21 April 2021}}</ref>

== Contraindications ==

The use of valsartan in pregnancy is avoided due to the potential risk of fetal toxicity.<ref>{{Cite book| vauthors = Briggs G, Freeman R, Towers C, Forinash A |url=https://web-a-ebscohost-com.uml.idm.oclc.org/ehost/ebookviewer/ebook/ZTAwMHhuYV9fMTg1NzU5OV9fQU41?sid=bd8b88ef-4aa8-4d53-ad7c-d8ecbfa6ff54@sdc-v-sessmgr02&vid=0&format=EK&lpid=NavPoint-7&rid=0|title=Drugs in Pregnancy and Lactation|publisher=Wolters Kluwer|year=2017|isbn=9781496349620|location=Philadelphia}}</ref> The U.S. [[Food and Drug Administration]] has a [[black box warning]] for valsartan/hydrochlorothiazide use during pregnancy.<ref name="Diovan HCT FDA label" /> The use of hydrochlorothiazide is avoided in those with [[anuria]] or severe kidney disease.<ref name=":0">{{Cite web |date=25 April 2012|title=Drug Product Database Online Query|url=https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=65570|access-date=22 April 2021|website=Health Canada }}</ref>

== Adverse effects ==

Side effects that are most often seen with this medication include dizziness, [[hypotension]], headache.<ref name="Diovan HCT FDA label" /> A clinical trial done on over 7000 participants showed higher rates of [[Common cold|nasopharyngitis]] in those taking valsartan/hydrochlorothiazide (2.4% versus 1.9% in placebo).<ref name="Diovan HCT FDA label" /><ref name=":0" /> A dose-related side effect seen is hypotension, occurring in 0.7% of participants on the highest dose of the medication.<ref name="Diovan HCT FDA label" /><ref name=":0" /> Risk of hypotension and [[hyperkalemia]] increases when valsartan/hydrochlorothiazide is used with [[ACE inhibitors]] or [[aliskiren]].<ref name="Diovan HCT FDA label" /><ref name=":2">{{cite journal | vauthors = Kondrack R, Mohiuddin S | title = Valsartan/hydrochlorothiazide: pharmacology and clinical efficacy | journal = Expert Opinion on Drug Metabolism & Toxicology | volume = 5 | issue = 9 | pages = 1125–34 | date = September 2009 | pmid = 19689218 | doi = 10.1517/17425250903136730 | s2cid = 207490609 }}</ref> Less common side effects that occur less than 1% of the time include [[Angina|angina pectoris]], [[rash]], [[Syncope (medicine)|syncope]], abdominal pain, and [[vertigo]].<ref name="Diovan HCT FDA label" /><ref name=":0" />

== Overdose ==

Cases of overdose are quite rare. In the event of an overdose people may experience severe [[hypotension]], [[electrolyte imbalance]]s or [[Arrhythmia|abnormal heart rhythms]]. People are advised to contact emergency services or a poison control centre and are treated based on symptoms.<ref name="Diovan HCT FDA label" /><ref>{{Cite web|title=Valsartan/Hydrochlorothiazide - Oral|url=https://www.healthlinkbc.ca/medications/fdb4372|access-date=23 April 2021|website=HealthLink BC|language=en}}</ref>

== Interactions ==

There are a few types of medications that interact with [[valsartan]]. Combined use with [[nonsteroidal anti-inflammatory drug]]s (NSAID) such as [[naproxen]] or [[ibuprofen]] can result in kidney injury in people who are elderly, dehydrated, or have reduced kidney function.<ref name="Diovan HCT FDA label" /> One study conducted Lapi F., et al. found that there was no increased risk of kidney injury when only using either a [[diuretic]] or [[Angiotensin II receptor blocker|angiotensin receptor blocker]] with an NSAID but did find an increased risk when all three medications were used together.<ref>{{cite journal | vauthors = Lapi F, Azoulay L, Yin H, Nessim SJ, Suissa S | title = Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case-control study | journal = BMJ | volume = 346 | pages = e8525 | date = January 2013 | pmid = 23299844 | pmc = 3541472 | doi = 10.1136/bmj.e8525 }}</ref> Valsartan usage with angiotensin receptor blocker, ACE inhibitors, or aliskiren results in additive side effects.<ref name=":0" />

== Pharmacology ==

Valsartan is an angiotensin II receptor blocker this class of drug competes with [[Angiotensin|angiotensin II]] for the [[Angiotensin type I receptor|angiotensin type I (AT₁)]] receptors located throughout the body.<ref name="Diovan HCT FDA label" /> Angiotensin II is a key component of the [[Renin–angiotensin system|renin-angiotensin-aldosterone system]] which is responsible for [[vasoconstriction]] of blood vessels and promotes release of [[vasopressin]] from the [[Posterior pituitary|posterior pituitary gland]] of the [[hypothalamus]] which helps promote water retention.<ref name=":1">{{Cite book| vauthors = Silverthorn DU |title=Human Physiology An Integrated Approach 7th Edition|publisher=Pearson Education|year=2015|isbn=978-0321981226|location=San Francisco, CA|pages=595, 630–633}}</ref> [[Aldosterone]] is also released by the [[adrenal gland]] in response to angiotensin II which helps to reabsorb sodium which leads to water reabsorption that results in a rise in blood pressure.<ref name=":1" /> Blocking angiotensin II from binding to AT₁ receptors will in turn prevent it from raising blood pressure which is why angiotensin II receptor blockers are useful medications in the treatment of blood pressure.<ref name="Diovan HCT FDA label" /><ref name=":1" /> [[Hydrochlorothiazide]] inhibits the [[Sodium-chloride symporter|NaCl co-transporters]] in the [[distal convoluted tubule]] of the [[nephron]]s located in the kidneys which are responsible for the excretion of sodium and chloride in exchange for reabsorption of calcium.<ref name="Diovan HCT FDA label" /><ref name=":1" /> Inhibition of the NaCl co-transporters result in water excretion which is believed to be the mechanism of action in diuresis and lowering blood pressure.<ref>{{cite book | vauthors = Herman L, Bashir K | chapter = Hydrochlorothiazide|date=2021| chapter-url=http://www.ncbi.nlm.nih.gov/books/NBK430766/| title = StatPearls|place=Treasure Island (FL)|publisher=StatPearls Publishing|pmid=28613517|access-date=23 April 2021}}</ref>

== Pharmacokinetics ==

Valsartan has an oral [[bioavailability]] of approximately 25% and reaches peak blood concentrations around 2–4 hours after ingestion.<ref name="Diovan HCT FDA label" /><ref name=":2" /> The estimated [[elimination half-life]] is determined to be approximately 6 hours, volume distribution of 17 litres, and a protein binding of 95% is seen.<ref name=":0" /><ref name=":2" /><ref name=":3">{{Cite web| work = PubChem | publisher = U.S. National Library of Medicine |title= Valsartan|url=https://pubchem.ncbi.nlm.nih.gov/compound/60846 |access-date=23 April 2021 }}</ref> The elderly may see increases in half life of the drug by up to 35% but dosing adjustment will not typically be warranted, however the drug should be used with caution in severe liver or kidney impairment.<ref name=":2" /> Majority of the drug is eliminated through the feces (83%) while only a small portion is eliminated in the urine (13%).<ref name=":3" /> Most of the drug excreted is unchanged, only small portion of the drug is metabolized to its inactive form 4-hydroxyvaleryl valsartan, the enzyme suspected to be responsible for this is the liver enzyme [[CYP2C9]].<ref name=":3" /> Hydrochlorothiazide has an oral bioavailability of 70% and reaches peak concentration around 1.5–2 hours following ingestion. The half-life is quite variable for this drug and can range from 5–15 hours. This drug is not metabolized and is mostly excreted unchanged in the urine (60-70%).<ref name=":2" /><ref>{{Cite web |work = PubChem | publisher = U.S. National Library of Medicine |title=Hydrochlorothiazide |url= https://pubchem.ncbi.nlm.nih.gov/compound/3639|access-date=23 April 2021 }}</ref> Protein binding ranges between 40 and 70% and volume of distribution varies from 4-8L/kg.<ref name=":0" /><ref name=":2" />

== References ==

{{reflist}}

{{Angiotensin II receptor antagonists}}

{{Angiotensin receptor modulators}}

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{{Authority control}}

{{DEFAULTSORT:Valsartan Hydrochlorothiazide}}

[[Category:Angiotensin II receptor antagonists]]

[[Category:Combination antihypertensive drugs]]

[[Category:Drugs developed by Novartis]]

[[Category:Wikipedia medicine articles ready to translate]]