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Diazoxide

Clinical data
Trade names	Proglycem
AHFS/Drugs.com	Monograph
License data	US DailyMed: Diazoxide
Pregnancy category	AU: C
Routes of administration	By mouth, intravenous
ATC code	C02DA01 (WHO) V03AH01 (WHO)
Legal status
Legal status	CA: ℞-only UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Protein binding	90%
Metabolism	Liver oxidation and sulfate conjugation
Elimination half-life	21-45 hours
Excretion	Kidney
Identifiers
IUPAC name 7-Chloro-3-methyl-4H-1,2,4-benzothiadiazine 1,1-dioxide
CAS Number	364-98-7
PubChem CID	3019
IUPHAR/BPS	2409
DrugBank	DB01119
ChemSpider	2911
UNII	O5CB12L4FN
KEGG	D00294
ChEBI	CHEBI:4495
ChEMBL	ChEMBL181
CompTox Dashboard (EPA)	DTXSID7022914
ECHA InfoCard	100.006.063
Chemical and physical data
Formula	C8H7ClN2O2S
Molar mass	230.67 g·mol
3D model (JSmol)	Interactive image
Melting point	330 to 331 °C (626 to 628 °F)
SMILES Clc1ccc2c(c1)S(=O)(=O)/N=C(\N2)C
InChI InChI=1S/C8H7ClN2O2S/c1-5-10-7-3-2-6(9)4-8(7)14(12,13)11-5/h2-4H,1H3,(H,10,11) Key:GDLBFKVLRPITMI-UHFFFAOYSA-N
(verify)

Diazoxide, sold under the brand name Proglycem and others, is a medication used to treat low blood sugar due to a number of specific causes. This includes islet cell tumors that cannot be removed and leucine sensitivity. It can also be used in refractory cases of sulfonylurea toxicity. It is generally taken by mouth.

Common side effects include high blood sugar, fluid retention, low blood platelets, a fast heart rate, increased hair growth, and nausea. Other severe side effects include pulmonary hypertension and heart failure. It is chemically similar to thiazide diuretics. It works by decreasing insulin release from the pancreas and increasing glucose release by the liver.

Diazoxide was approved for medical use in the United States in 1973. It is on the World Health Organization's List of Essential Medicines. It is available as a generic medication.

Medical uses

Diazoxide is used as a vasodilator in the treatment of acute hypertension or malignant hypertension.

Diazoxide also inhibits the secretion of insulin by opening ATP-sensitive potassium channel of beta cells of the pancreas; thus, it is used to counter hypoglycemia in disease states such as insulinoma (a tumor producing insulin) or congenital hyperinsulinism.

Diazoxide acts as a positive allosteric modulator of the AMPA and kainate receptors, suggesting potential application as a cognitive enhancer.

Side effects

Diazoxide interferes with insulin release through its action on potassium channels. Diazoxide is one of the most potent openers of the K+ ATP channels present on the insulin producing beta cells of the pancreas. Opening these channels leads to hyperpolarization of cell membrane, a decrease in calcium influx, and a subsequently reduced release of insulin. This mechanism of action is the mirror opposite of that of sulfonylureas, a class of medications used to increase insulin release in type 2 diabetics. Therefore, this medicine is not given to non-insulin dependent diabetic patients.

The Food and Drug Administration published a safety announcement in July 2015 highlighting the potential for development of pulmonary hypertension in newborns and infants treated with this drug.

Research

Diazoxide, formulated as its choline salt diazoxide choline, is an experimental antiobesity drug being tested in people with Prader-Willi syndrome and monogenic obesity caused by mutations in the SH2B1, PCSK1, or SIM1 genes.

References

1. "Product monograph brand safety updates". Health Canada. 7 July 2016. Retrieved 3 April 2024.
2. ^ "Diazoxide Monograph for Professionals". Drugs.com. Retrieved 11 October 2019.
3. ^ Doyle ME, Egan JM (March 2003). "Pharmacological agents that directly modulate insulin secretion". Pharmacological Reviews. 55 (1): 105–131. doi:10.1124/pr.55.1.7. PMID 12615955. S2CID 11121340.
4. World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
5. World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
6. British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 708. ISBN 9780857113382.
7. van Hamersvelt HW, Kloke HJ, de Jong DJ, Koene RA, Huysmans FT (August 1996). "Oedema formation with the vasodilators nifedipine and diazoxide: direct local effect or sodium retention?". Journal of Hypertension. 14 (8): 1041–1045. doi:10.1097/00004872-199608000-00016. PMID 8884561. S2CID 3283469.
8. Huang Q, Bu S, Yu Y, Guo Z, Ghatnekar G, Bu M, et al. (January 2007). "Diazoxide prevents diabetes through inhibiting pancreatic beta-cells from apoptosis via Bcl-2/Bax rate and p38-beta mitogen-activated protein kinase". Endocrinology. 148 (1): 81–91. doi:10.1210/en.2006-0738. PMID 17053028.
9. Randle JC, Biton C, Lepagnol JM (November 1993). "Allosteric potentiation by diazoxide of AMPA receptor currents and synaptic potentials". European Journal of Pharmacology. 247 (3): 257–265. doi:10.1016/0922-4106(93)90193-D. PMID 8307099.
10. Panten U, Burgfeld J, Goerke F, Rennicke M, Schwanstecher M, Wallasch A, et al. (April 1989). "Control of insulin secretion by sulfonylureas, meglitinide and diazoxide in relation to their binding to the sulfonylurea receptor in pancreatic islets". Biochemical Pharmacology. 38 (8): 1217–1229. doi:10.1016/0006-2952(89)90327-4. PMID 2650685.
11. "FDA Drug Safety Communication: FDA warns about a serious lung condition in infants and newborns treated with Proglycem (diazoxide)" (Press release). Food and Drug Administration. July 16, 2015. Retrieved 2015-07-19.
12. Miller JL, Gevers E, Bridges N, Yanovski JA, Salehi P, Obrynba KS, et al. (February 2024). "Diazoxide choline extended-release tablet in people with Prader-Willi syndrome: results from long-term open-label study". Obesity. 32 (2): 252–261. doi:10.1002/oby.23928. hdl:10044/1/107689. PMID 37919617. S2CID 264973612.
13. Kimonis V, Surampalli A, Wencel M, Gold JA, Cowen NM (23 September 2019). "A randomized pilot efficacy and safety trial of diazoxide choline controlled-release in patients with Prader-Willi syndrome". PLOS ONE. 14 (9): e0221615. Bibcode:2019PLoSO..1421615K. doi:10.1371/journal.pone.0221615. PMC 6756513. PMID 31545799.
14. Miller JL, Gevers E, Bridges N, Yanovski JA, Salehi P, Obrynba KS, et al. (June 2023). "Diazoxide Choline Extended-Release Tablet in People With Prader-Willi Syndrome: A Double-Blind, Placebo-Controlled Trial". The Journal of Clinical Endocrinology and Metabolism. 108 (7): 1676–1685. doi:10.1210/clinem/dgad014. PMC 10271219. PMID 36639249.
15. Clinical trial number NCT05532020 for "An Open-Label Study of Diazoxide Choline in Patients With Genetic Obesities" at ClinicalTrials.gov

• Medicine

• Carbonic anhydrase inhibitors
• Vasodilators
• Potassium channel openers
• AMPA receptor positive allosteric modulators
• Kainate receptor agonists
• Benzothiadiazines
• Sultams
• Chloroarenes
• World Health Organization essential medicines
• Experimental anti-obesity drugs