Cyclothiazide

Synonyms :
6-chloro-3-(2-Norbornen-5-yl)-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine 1,1-dioxide, 6-chloro-3,4-dihydro-3-(2-Norbornen-5-yl)-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, 6-chloro-3,4-dihydro-3-(2-Norbornen-5-yl)-7-sulfamoyl-1,2,4-benzothiadiazine 1,1-dioxide, 6-chloro-3,4-dihydro-3-(5-Norbornen-2-yl)-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, Ciclotiazida, Ciclotiazide, Cyclothiazide, Cyclothiazidum

Status : approved

Category

Antihypertensive Agents

Therapeutic Classification

LOW-CEILING DIURETICS, THIAZIDES

CARDIOVASCULAR SYSTEM
DIURETICS
LOW-CEILING DIURETICS, THIAZIDES
Diuretics

Description

As a diuretic, cyclothiazide 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 cyclothiazide 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 cyclothiazide 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. Cyclothiazide is indicated as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. It is also indicated in the management of hypertension either as the sole therapeutic agent or to enhance the effectiveness of other antihypertensive drugs in the more severe forms of hypertension.

Used

Cyclothiazide is indicated as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. It is also indicated in the management of hypertension either as the sole therapeutic agent or to enhance the effectiveness of other antihypertensive drugs in the more severe forms of hypertension.

Mechanism Of Action

Hydrochlorothiazide, a thiazide diuretic, inhibits water reabsorption in the nephron by inhibiting the sodium-chloride symporter (SLC12A3) in the distal convoluted tubule, which is responsible for 5% of total sodium reabsorption. Normally, the sodium-chloride symporter transports sodium and chloride from the lumen into the epithelial cell lining the distal convoluted tubule. The energy for this is provided by a sodium gradient established by sodium-potassium ATPases on the basolateral membrane. Once sodium has entered the cell, it is transported out into the basolateral interstitium via the sodium-potassium ATPase, causing an increase in the osmolarity of the interstitium, thereby establishing an osmotic gradient for water reabsorption. By blocking the sodium-chloride symporter, hydrochlorothiazide effectively reduces the osmotic gradient and water reabsorption throughout the nephron.Hydrochlorothiazide, a thiazide diuretic, inhibits water reabsorption in the nephron by inhibiting the sodium-chloride symporter (SLC12A3) in the distal convoluted tubule, which is responsible for 5% of total sodium reabsorption. Normally, the sodium-chloride symporter transports sodium and chloride from the lumen into the epithelial cell lining the distal convoluted tubule. The energy for this is provided by a sodium gradient established by sodium-potassium ATPases on the basolateral membrane. Once sodium has entered the cell, it is transported out into the basolateral interstitium via the sodium-potassium ATPase, causing an increase in the osmolarity of the interstitium, thereby establishing an osmotic gradient for water reabsorption. By blocking the sodium-chloride symporter, hydrochlorothiazide effectively reduces the osmotic gradient and water reabsorption throughout the nephron.

Pharmacodynamics

Like other thiazides, cyclothiazide promotes water loss from the body (diuretics). It inhibits Na+/Cl 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. Cyclothiazide affects the distal renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosages, all thiazides are approximately equal in their diuretic efficacy. Cyclothiazide increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate.

Toxic Effect

Oral LD50 in mouse is > 10000 mg/kg, and > 4000 mg/kg in rat. Signs of overdose include 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.

Chemical Classification

This compound belongs to the class of organic compounds known as benzothiadiazines. These are organic compounds containing a benzene fused to a thiadiazine ring (a six-member ring with two nitrogen atoms and a sulfur atom).

Benzothiadiazines

Organic compounds

Organoheterocyclic compounds

Thiadiazines

Benzothiadiazines

Chemical Name

6-chloro-3-(2-Norbornen-5-yl)-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine 1,1-dioxide

Drug Drug Interactions

  •  Alfentanil  : Analgesics (Opioid) may enhance the adverse/toxic effect of Diuretics.
  •  Buprenorphine  : Analgesics (Opioid) may enhance the adverse/toxic effect of Diuretics.
  •  Butorphanol  : Analgesics (Opioid) may enhance the adverse/toxic effect of Diuretics.
  •  Codeine  : Analgesics (Opioid) may enhance the adverse/toxic effect of Diuretics.
  •  Dihydrocodeine  : Analgesics (Opioid) may enhance the adverse/toxic effect of Diuretics.
  •  Fentanyl  : Analgesics (Opioid) may enhance the adverse/toxic effect of Diuretics.
  •  Hydrocodone  : Analgesics (Opioid) may enhance the adverse/toxic effect of Diuretics.
  •  Hydromorphone  : Analgesics (Opioid) may enhance the adverse/toxic effect of Diuretics.
  •  Levorphanol  : Analgesics (Opioid) may enhance the adverse/toxic effect of Diuretics.
  •  Methadone  : Analgesics (Opioid) may enhance the adverse/toxic effect of Diuretics.
  •  Morphine  : Analgesics (Opioid) may enhance the adverse/toxic effect of Diuretics.
  •  Nalbuphine  : Analgesics (Opioid) may enhance the adverse/toxic effect of Diuretics.
  •  Oxycodone  : Analgesics (Opioid) may enhance the adverse/toxic effect of Diuretics.
  •  Oxymorphone  : Analgesics (Opioid) may enhance the adverse/toxic effect of Diuretics.
  •  Pentazocine  : Analgesics (Opioid) may enhance the adverse/toxic effect of Diuretics.
  •  Pethidine  : Analgesics (Opioid) may enhance the adverse/toxic effect of Diuretics.
  •  Remifentanil  : Analgesics (Opioid) may enhance the adverse/toxic effect of Diuretics.
  •  Sufentanil  : Analgesics (Opioid) may enhance the adverse/toxic effect of Diuretics.
  •  Tapentadol  : Analgesics (Opioid) may enhance the adverse/toxic effect of Diuretics.
  •  Tramadol  : Analgesics (Opioid) may enhance the adverse/toxic effect of Diuretics.

Calculated Property

kind Value Source
logP 1.32 ALOGPS
logS -3.1 ALOGPS
Water Solubility 2.79e-01 g/l ALOGPS
logP 0.94 ChemAxon
IUPAC Name 3-{bicyclo[2.2.1]hept-5-en-2-yl}-6-chloro-1,1-dioxo-3,4-dihydro-2H-1λ⁶,2,4-benzothiadiazine-7-sulfonamide ChemAxon
Traditional IUPAC Name cyclothiazide ChemAxon
Molecular Weight 389.878 ChemAxon
Monoisotopic Weight 389.027075102 ChemAxon
SMILES NS(=O)(=O)C1=C(Cl)C=C2NC(NS(=O)(=O)C2=C1)C1CC2CC1C=C2 ChemAxon
Molecular Formula C14H16ClN3O4S2 ChemAxon
InChI InChI=1S/C14H16ClN3O4S2/c15-10-5-11-13(6-12(10)23(16,19)20)24(21,22)18-14(17-11)9-4-7-1-2-8(9)3-7/h1-2,5-9,14,17-18H,3-4H2,(H2,16,19,20) ChemAxon
InChIKey InChIKey=BOCUKUHCLICSIY-UHFFFAOYSA-N ChemAxon
Polar Surface Area (PSA) 118.36 ChemAxon
Refractivity 92.65 ChemAxon
Polarizability 37.1 ChemAxon
Rotatable Bond Count 2 ChemAxon
H Bond Acceptor Count 5 ChemAxon
H Bond Donor Count 3 ChemAxon
pKa (strongest acidic) 9.06 ChemAxon
pKa (strongest basic) -2.5 ChemAxon
Physiological Charge 0 ChemAxon
Number of Rings 4 ChemAxon
Bioavailability 1 ChemAxon
Rule of Five 1 ChemAxon
Ghose Filter 1 ChemAxon
MDDR-Like Rule 0 ChemAxon

Affected organism

Humans and other mammals

Target within organism

  • Sodium/potassium-transporting ATPase subunit gamma : in Human
  • Carbonic anhydrase 1 : in Human
  • Carbonic anhydrase 2 : in Human
  • Carbonic anhydrase 4 : in Human