PharmGKB: The Pharmacogenomics Knowledge Base

Drug/Small Molecule:
hydrochlorothiazide

2D structure

Overview

Generic Names: Dihydrochlorothiazid; Dihydrochlorothiazide; Dihydrochlorothiazidum; Dihydrochlorurit; Dihydrochlorurite; Dihydroxychlorothiazidum; HCTZ; HCZ; Hydrochlorothiazid; Hydrochlorthiazide
Trade Names: Acuretic; Aldoril; Apresazide; Aquarills; Aquarius; Bremil; Caplaril; Capozide; Chlorosulthiadil; Chlorzide; Cidrex; Dichlorosal; Dichlorotride; Dichlotiazid; Dichlotride; Diclotride; Dicyclotride; Direma; Disalunil; Diu-Melusin; Drenol; Esidrex; Esimil; Fluvin; Hidril; Hidrochlortiazid; Hidroronol; Hidrotiazida; Hydril; Hydro-Aquil; Hydro-Diuril; Hydrodiuretic; Hydropres; Hydrosaluric; Hydrothide; Hydrozide; Hypothiazid; Hypothiazide; Idrotiazide; Ivaugan; Jen-Diril; Lotensin Hct; Maschitt; Megadiuril; Moduretic; Nefrix; Neo-Codema; Neoflumen; Newtolide; Panurin; Ro-Hydrazide; Servithiazid; Thiaretic; Thiuretic; Thlaretic; Timolide; Urodiazin; Vetidrex; Ziac
PharmGKB Accession Id: PA449899

Description

A thiazide diuretic often considered the prototypical member of this class. It reduces the reabsorption of electrolytes from the renal tubules. This results in increased excretion of water and electrolytes, including sodium, potassium, chloride, and magnesium. It has been used in the treatment of several disorders including edema, hypertension, diabetes insipidus, and hypoparathyroidism. PubChem (source: Drug Bank)

Indication

For the treatment of high blood pressure and management of edema. (source: Drug Bank)

ATC Therapeutic Category

  • C03AA:Thiazides, plain

Pharmacology, Interactions, and Contraindications

Mechanism Of Action

As a diuretic, hydrochlorothiazide inhibits active chloride reabsorption at the early distal tubule via the Na-Cl cotransporter, resulting in an increase in the excretion of sodium, chloride, and water. Thiazides like hydrochlorothiazide also inhibit sodium ion transport across the renal tubular epithelium through binding to the thiazide sensitive sodium-chloride transporter. This results in an increase in potassium excretion via the sodium-potassium exchange mechanism. The antihypertensive mechanism of hydrochlorothiazide is less well understood although it may be mediated through its action on carbonic anhydrases in the smooth muscle or through its action on the large-conductance calcium-activated potassium (KCa) channel, also found in the smooth muscle. (source: Drug Bank)

Pharmacology

Thiazides such as hydrochlorothiazide promote water loss from the body (diuretics). They inhibit Na<sup>+</sup>/Cl<sup>-</sup> reabsorption from the distal convoluted tubules in the kidneys. Thiazides also cause loss of potassium and an increase in serum uric acid. Thiazides are often used to treat hypertension, but their hypotensive effects are not necessarily due to their diuretic activity. Thiazides have been shown to prevent hypertension-related morbidity and mortality although the mechanism is not fully understood. Thiazides cause vasodilation by activating calcium-activated potassium channels (large conductance) in vascular smooth muscles and inhibiting various carbonic anhydrases in vascular tissue. (source: Drug Bank)

Food Interactions

Avoid alcohol.
Avoid excess salt/sodium unless otherwise instructed by your physician.
Avoid natural licorice.
Do not take calcium, aluminum, magnesium or Iron supplements within 2 hours of taking this medication.
Increase potassium intake; add a banana or orange juice; unless instructed otherwise.
Take with food. (source: Drug Bank)

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

Hydrochlorothiazide is not metabolized. (source: Drug Bank)

Protein Binding

67.9% (source: Drug Bank)

Absorption

50-60% (source: Drug Bank)

Toxicity

The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias. The oral LD50 of hydrochlorothiazide is greater than 10 g/kg in the mouse and rat. (source: Drug Bank)

Isomeric SMILES Code:

c1c2c(cc(c1Cl)S(=O)(=O)N)S(=O)(=O)NCN2 (source: Drug Bank)

Curated Annotations (Curated Annotation)

  1. rs4686799 at chr3:187933930 in KNG1
    This study investigated aldosterone response to two antihypertensive drugs with the result that the existence of one or more variants in the KNG1gene influences interindividual variation in aldosterone response. SNP rs4686799 was associated in African-American and European-American responders to the diuretic (p=0.04 and p=0.07 respectively).
    Related Drugs:
    Antihypertensives, hydrochlorothiazide
    Evidence:
    PMID:19584173
  2. rs5030062 at chr3:187936874 in KNG1
    This study investigated aldosterone response to two antihypertensive drugs with the result that the existence of one or more variants in the KNG1gene influences interindividual variation in aldosterone response. The SNPs rs5030062 and rs698078 were significantly associated in European-American responders to the diuretic (p=0.05 and p=0.01) and European-American responders to the angiotensin receptor blocker (p=0.04 and p=0.02).
    Related Drugs:
    Antihypertensives, candesartan, hydrochlorothiazide
    Evidence:
    PMID:19584173
  3. rs698078 at chr3:187941921 in KNG1
    This study investigated aldosterone response to two antihypertensive drugs with the result that the existence of one or more variants in the KNG1gene influences interindividual variation in aldosterone response. The SNPs rs5030062 and rs698078 were significantly associated in European-American responders to the diuretic (p=0.05 and p=0.01) and European-American responders to the angiotensin receptor blocker (p=0.04 and p=0.02).
    Related Drugs:
    Antihypertensives, candesartan, hydrochlorothiazide
    Evidence:
    PMID:19584173
  4. rs4961 at chr4:2876505 in ADD1
    In a study of Italian hypertensives, patients carrying at least one I allele of ACE:I/D and one 460Trp allele (T variant) of alpha-adducin ADD1:Gly460Trp (rs4961 G>T) had the largest mean blood pressure decrease with hydrochlorothiazide treatment.
    Variant Name:
    ADD1:Gly460Trp, rs4961 G>T, alpha-adducin Gly460Trp
    Related Drugs:
    hydrochlorothiazide
    Evidence:
    PMID:12623934

Non-Curated Annotations (Non-Curated Annotation)

  1. rs317689 at chr12:68013457
    GWAS results: Genomic association analysis suggests chromosome 12 locus influencing antihypertensive response to thiazide diuretic (Initial Sample Size: 194 blacks, 195 whites; Replication Sample Size: NR). This variant is associated with Response to diuretic therapy.
    Related Drugs:
    hydrochlorothiazide, thiazide derivatives
    Related Diseases:
    Hypertension
    Evidence:
    PMID:18591461
    http://www.genome.gov/gwastudies/
  2. rs315135 at chr12:68049254 in YEATS4
    GWAS results: Genomic association analysis suggests chromosome 12 locus influencing antihypertensive response to thiazide diuretic (Initial Sample Size: 194 blacks, 195 whites; Replication Sample Size: NR). This variant is associated with Response to diuretic therapy.
    Related Drugs:
    hydrochlorothiazide, thiazide derivatives
    Related Diseases:
    Hypertension
    Evidence:
    PMID:18591461
    http://www.genome.gov/gwastudies/
  3. rs7297610 at chr12:68110291
    GWAS results: Genomic association analysis suggests chromosome 12 locus influencing antihypertensive response to thiazide diuretic (Initial Sample Size: 194 blacks, 195 whites; Replication Sample Size: NR). This variant is associated with Response to diuretic therapy.
    Related Drugs:
    hydrochlorothiazide, thiazide derivatives
    Related Diseases:
    Hypertension
    Evidence:
    PMID:18591461
    http://www.genome.gov/gwastudies/
Variant names are different names that have been used in the literature and other resources to refer to the same variant. Non-curated variant information is accumulated solely by computational methods and has not been verified by the scientific staff at PharmGKB.

The following genes are in curated knowledge about this drug.

  Gene Relationship Evidence
Phenotype data available Genotype Data Available Literature annotations available Has annotations
ACE
  • CO
  • PD
  •   
  •   
  • GN
Publications
No phenotype data Genotype Data Available Literature annotations available Not annotated
ACE2
  • CO
  • PD
  •   
  •   
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
ADD1
  • CO
  • PD
  •   
  • FA
  • GN
Publications, Variants
Phenotype data available Genotype Data Available Literature annotations available Not annotated
AGT
  •   
  •   
  •   
  •   
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
CYP11B2
  •   
  •   
  •   
  •   
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
GNB3
  •   
  • PD
  •   
  •   
  • GN
Publications
No phenotype data Genotype Data Available Literature annotations available Not annotated
KNG1
  •   
  • PD
  •   
  •   
  • GN
Publications, Variants
Phenotype data available Genotype Data Available Literature annotations available Not annotated
NOS3
  •   
  •   
  •   
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
SCNN1G
  •   
  •   
  •   
  •   
  • GN
Publications
Phenotype data available No genotype data Literature annotations available Not annotated
STK39
  • CO
  • PD
  •   
  •   
  • GN
Publications
Phenotype data available No genotype data Literature annotations available Not annotated
WNK1
  •   
  •   
  •   
  •   
  • GN
Publications

A list of non-curated publications that mention this drug along with other genes is available.

Drug Targets

Gene Description
CA1 Uncurated Annotation (source: Drug Bank)
CA2 Uncurated Annotation (source: Drug Bank)
CA4 Uncurated Annotation (source: Drug Bank)
KCNMA1 Uncurated Annotation (source: Drug Bank)
SLC12A3 Uncurated Annotation (source: Drug Bank)

The following drugs are in curated knowledge about this drug.

  Drug Relationship Evidence
No phenotype data No genotype data Literature annotations available Not annotated
atenolol
  • CO
  • PD
  •   
  •   
  •   
Publications

A list of non-curated publications that mention this drug along with other drugs is available.

Drug Interactions

Drug Description
amantadine Uncurated Annotation The diuretic increases the adverse effect of amantadine (source: Drug Bank)
diazoxide Uncurated Annotation Significant hyperglycemic effect (source: Drug Bank)
digitoxin Uncurated Annotation Possible electrolyte variations and arrhythmias (source: Drug Bank)
digoxin Uncurated Annotation Possible electrolyte variations and arrhythmias (source: Drug Bank)
dofetilide Uncurated Annotation Increased risk of cardiotoxicity and arrhythmias (source: Drug Bank)
lithium Uncurated Annotation The thiazide diuretic increases serum levels of lithium (source: Drug Bank)

Curated Information

The following diseases are in curated knowledge about this drug.

  Disease Relationship Evidence
Phenotype data available Genotype Data Available Literature annotations available Not annotated
Essential hypertension
  •   
  • PD
  •   
  •   
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
Hypertension
  • CO
  • PD
  •   
  •   
  • GN
Publications

Non-Curated Information

A list of non-curated publications that mention this drug along with other diseases is available.

Curated Phenotype Datasets

These datasets are sorted alphabetically by title.

  1. Genetic Epidemiology of Responses to Antihypertensives (GERA)
    • Genotype data available
    • Phenotype data available
    • No literature annotations
    • Not annotated
    • PD
    Submitted by Stephen T. Turner, MD involving ACE, ADD1, ADRB1, ADRB2, AGT, AGTR1, CYP11B2, GNB3, LPL, NOS3, REN, hydrochlorothiazide, and Essential hypertension

Additional Datasets

These datasets are minimally curated and are sorted alphabetically by title.

  1. The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease

Downloads

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LinkOuts

Web Resource:
Wikipedia
DrugBank:
DB00999
KEGG Drug ID:
D00340
PubChem Compound ID:
3639
PubChem Substance ID:
7847406

Common Searches

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Non-Curated Publications

A list of non-curated publications that mention this drug is available.

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