Demeclocycline

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Demeclocycline
Demeclocycline.svg
Demeclocycline 3D.png
Clinical data
Trade names Declomycin
Other namesRP-10192, demethylchlortetracycline
AHFS/Drugs.com Monograph
MedlinePlus a682103
Routes of
administration 		Oral
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 60–80%
Protein binding 41–50%
Metabolism Hepatic
Elimination half-life 10–17 hours
Excretion Renal
Identifiers
  • (2E,4S,4aS,5aS,6S,12aS)-2-[amino(hydroxy)methylidene]-7-chloro-4-(dimethylamino)-6,10,11,12a-tetrahydroxy-1,2,3,4,4a,5,5a,6,12,12a-decahydrotetracene-1,3,12-trione
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.004.396 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C21H21ClN2O8
Molar mass 464.86 g·mol−1
3D model (JSmol)
  • NC(=O)C1C(=O)[C@@]2(O)C(O)=C3C(=O)c4c(O)ccc(Cl)c4[C@@H](O)[C@H]3C[C@H]2C(C=1O)N(C)C
  • InChI=1S/C21H21ClN2O8/c1-24(2)14-7-5-6-10(16(27)12-9(25)4-3-8(22)11(12)15(6)26)18(29)21(7,32)19(30)13(17(14)28)20(23)31/h3-4,6-7,14-15,25-26,28-29,32H,5H2,1-2H3,(H2,23,31)/t6-,7-,14-,15-,21-/m0/s1 Yes check.svgY
  • Key:FMTDIUIBLCQGJB-SEYHBJAFSA-N Yes check.svgY
   (verify)

Demeclocycline (INN, BAN, USAN, brand name Declomycin) is a tetracycline antibiotic which was derived from a mutant strain of Streptomyces aureofaciens . [1] [2]

Contents

Uses

Demeclocycline is officially indicated for the treatment of various types of bacterial infections. [3] It is used as an antibiotic in the treatment of Lyme disease, [4] acne, [5] and bronchitis. [6] Resistance, though, is gradually becoming more common, [7] and demeclocycline is now rarely used for treatment of infections. [8] [9]

It is widely used (though off-label in many countries including the United States) in the treatment of hyponatremia (low blood sodium concentration) due to the syndrome of inappropriate antidiuretic hormone (SIADH) when fluid restriction alone has been ineffective. [10] Physiologically, this works by reducing the responsiveness of the collecting tubule cells to ADH. [11]

The use in SIADH actually relies on a side effect; demeclocycline induces nephrogenic diabetes insipidus (dehydration due to the inability to concentrate urine). [10] [12] [13]

The use of demeclocycline in SIADH was first reported in 1975, [14] and, in 1978, a larger study found it to be more effective and better tolerated than lithium carbonate, the only available treatment at the time. [15] Demeclocycline used to be the drug of choice for treating SIADH. [13] Meanwhile, it might be superseded, now that vasopressin receptor antagonists, such as tolvaptan, became available. [15]

Contraindications

Like other tetracyclines, demeclocycline is contraindicated in children and pregnant or nursing women. All members of this class interfere with bone development and may discolour teeth. [9]

Side effects and interactions

The side effects are similar to those of other tetracyclines. Skin reactions with sunlight have been reported. [15] Like only few other known tetracycline derivatives, demeclocycline causes nephrogenic diabetes insipidus. [16] Furthermore, demeclocycline might have psychotropic side effects similar to lithium. [17]

Tetracyclines bind to cations, such as calcium, iron (when given orally), and magnesium, rendering them insoluble and inadsorbable for the gastrointestinal tract. Demeclocycline should not be taken with food (particularly milk and other dairy products) or antacids. [9]

Mechanism of action

As with related tetracycline antibiotics, demeclocycline acts by binding to the 30S ribosomal subunit to inhibit binding of aminoacyl tRNA which impairs protein synthesis by bacteria. It is bacteriostatic (it impairs bacterial growth, but does not kill bacteria directly). [1] [7]

Demeclocycline inhibits the renal action of antidiuretic hormone by interfering with the intracellular second messenger cascade (specifically, inhibiting adenylyl cyclase activation) after the hormone binds to vasopressin V2 receptors in the kidney. [18] [19] [20] Exactly how demeclocycline does this has yet to be elucidated, however. [20]

Brand names

Brand names include Declomycin, Declostatin, Ledermycin, Bioterciclin, Deganol, Deteclo, Detravis, Meciclin, Mexocine, and Clortetrin.[ citation needed ]

Related Research Articles

<span class="mw-page-title-main">Diabetes insipidus</span> Condition characterized by large amounts of dilute urine and increased thirst

Diabetes insipidus (DI), alternately called arginine vasopressin deficiency (AVP-D) or arginine vasopressin resistance (AVP-R), is a condition characterized by large amounts of dilute urine and increased thirst. The amount of urine produced can be nearly 20 liters per day. Reduction of fluid has little effect on the concentration of the urine. Complications may include dehydration or seizures.

Hyponatremia or hyponatraemia is a low concentration of sodium in the blood. It is generally defined as a sodium concentration of less than 135 mmol/L (135 mEq/L), with severe hyponatremia being below 120 mEq/L. Symptoms can be absent, mild or severe. Mild symptoms include a decreased ability to think, headaches, nausea, and poor balance. Severe symptoms include confusion, seizures, and coma; death can ensue.

<span class="mw-page-title-main">Vasopressin</span> Mammalian hormone released from the pituitary gland

Human vasopressin, also called antidiuretic hormone (ADH), arginine vasopressin (AVP) or argipressin, is a hormone synthesized from the AVP gene as a peptide prohormone in neurons in the hypothalamus, and is converted to AVP. It then travels down the axon terminating in the posterior pituitary, and is released from vesicles into the circulation in response to extracellular fluid hypertonicity (hyperosmolality). AVP has two primary functions. First, it increases the amount of solute-free water reabsorbed back into the circulation from the filtrate in the kidney tubules of the nephrons. Second, AVP constricts arterioles, which increases peripheral vascular resistance and raises arterial blood pressure.

<span class="mw-page-title-main">Posterior pituitary</span> Posterior lobe of the pituitary gland

The posterior pituitary is the posterior lobe of the pituitary gland which is part of the endocrine system. The posterior pituitary is not glandular as is the anterior pituitary. Instead, it is largely a collection of axonal projections from the hypothalamus that terminate behind the anterior pituitary, and serve as a site for the secretion of neurohypophysial hormones directly into the blood. The hypothalamic–neurohypophyseal system is composed of the hypothalamus, posterior pituitary, and these axonal projections.

<span class="mw-page-title-main">Desmopressin</span> Medication

Desmopressin, sold under the trade name DDAVP among others, is a medication used to treat diabetes insipidus, bedwetting, hemophilia A, von Willebrand disease, and high blood urea levels. In hemophilia A and von Willebrand disease, it should only be used for mild to moderate cases. It may be given in the nose, by injection into a vein, by mouth, or under the tongue.

The syndrome of inappropriate antidiuretic hormone secretion (SIADH), also known as the syndrome of inappropriate antidiuresis (SIAD), is characterized by a physiologically inappropriate release of antidiuretic hormone (ADH) either from the posterior pituitary gland, or an abnormal non-pituitary source. Unsuppressed ADH causes a physiologically inappropriate increase in solute-free water being reabsorbed by the tubules of the kidney to the venous circulation leading to hypotonic hyponatremia.

<span class="mw-page-title-main">Chlorpropamide</span> Chemical compound

Chlorpropamide is an antidiabetic drug, belonging to the sulfonylurea class of organic compounds. It is used to treat diabetes mellitus type 2. It is a long-acting first-generation sulfonylurea.

<span class="mw-page-title-main">Chlortalidone</span> Thiazide-like diuretic drug

Chlortalidone, also known as chlorthalidone, is a thiazide-like diuretic drug used to treat high blood pressure, swelling, diabetes insipidus, and renal tubular acidosis. Because chlortalidone is effective in most patients with high blood pressure, it is considered a preferred initial treatment. It is also used to prevent calcium-based kidney stones. It is taken by mouth. Effects generally begin within three hours and last for up to three days. Long-term treatment with chlortalidone is more effective than hydrochlorothiazide for prevention of heart attack or stroke.

<span class="mw-page-title-main">Conivaptan</span> Chemical compound

Conivaptan, sold under the brand name Vaprisol, is a non-peptide inhibitor of the receptor for anti-diuretic hormone, also called vasopressin. It was approved in 2004 for hyponatremia. The compound was discovered by Astellas and marked in 2006. The drug is now marketed by Cumberland Pharmaceuticals, Inc.

Cerebral salt-wasting syndrome (CSWS), also written cerebral salt wasting syndrome, is a rare endocrine condition featuring a low blood sodium concentration and dehydration in response to injury (trauma) or the presence of tumors in or surrounding the brain. In this condition, the kidney is functioning normally but excreting excessive sodium. The condition was initially described in 1950. Its cause and management remain controversial. In the current literature across several fields, including neurology, neurosurgery, nephrology, and critical care medicine, there is controversy over whether CSWS is a distinct condition, or a special form of syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Nephrogenic diabetes insipidus,, is a form of diabetes insipidus primarily due to pathology of the kidney. This is in contrast to central or neurogenic diabetes insipidus, which is caused by insufficient levels of vasopressin. Nephrogenic diabetes insipidus is caused by an improper response of the kidney to vasopressin, leading to a decrease in the ability of the kidney to concentrate the urine by removing free water.

<span class="mw-page-title-main">Primary polydipsia</span> Medical condition

Primary polydipsia and psychogenic polydipsia are forms of polydipsia characterised by excessive fluid intake in the absence of physiological stimuli to drink. Psychogenic polydipsia which is caused by psychiatric disorders, often schizophrenia, is often accompanied by the sensation of dry mouth. Some forms of polydipsia are explicitly non-psychogenic. Primary polydipsia is a diagnosis of exclusion.

<span class="mw-page-title-main">Vasopressin receptor 2</span> Protein-coding gene in the species Homo sapiens

Vasopressin receptor 2 (V2R), or arginine vasopressin receptor 2, is a protein that acts as receptor for vasopressin. AVPR2 belongs to the subfamily of G-protein-coupled receptors. Its activity is mediated by the Gs type of G proteins, which stimulate adenylate cyclase.

The actions of vasopressin are mediated by stimulation of tissue-specific G protein-coupled receptors (GPCRs) called vasopressin receptors that are classified into the V1 (V1A), V2, and V3 (V1B) receptor subtypes. These three subtypes differ in localization, function and signal transduction mechanisms.

<span class="mw-page-title-main">Aquaporin-2</span> Protein-coding gene in the species Homo sapiens

Aquaporin-2 (AQP-2) is found in the apical cell membranes of the kidney's collecting duct principal cells and in intracellular vesicles located throughout the cell. It is encoded by the AQP2 gene.

Frederic Crosby Bartter was an American endocrinologist best known for his work on hormones affecting the kidney and his discovery of syndrome of inappropriate antidiuretic hormone and Bartter syndrome. He had a separate interest in mushroom poisoning.

<span class="mw-page-title-main">Satavaptan</span> Chemical compound

Satavaptan is a vasopressin-2 receptor antagonist which was investigation by Sanofi-Aventis and was under development for the treatment of hyponatremia. It was also being studied for the treatment of ascites. Development was discontinued in 2009.

A vasopressin receptor antagonist (VRA) is an agent that interferes with action at the vasopressin receptors. Most commonly VRAs are used in the treatment of hyponatremia, especially in patients with congestive heart failure, liver cirrhosis or SIADH.

<span class="mw-page-title-main">Adipsia</span> Medical condition

Adipsia, also known as hypodipsia, is a symptom of inappropriately decreased or absent feelings of thirst. It involves an increased osmolality or concentration of solute in the urine, which stimulates secretion of antidiuretic hormone (ADH) from the hypothalamus to the kidneys. This causes the person to retain water and ultimately become unable to feel thirst. Due to its rarity, the disorder has not been the subject of many research studies.

Copeptin is a 39-amino acid-long peptide derived from the C-terminus of pre-pro-hormone of arginine vasopressin, neurophysin II and copeptin. Arginine vasopressin (AVP), also known as the antidiuretic hormone (ADH), is encoded by the AVP gene and is involved in multiple cardiovascular and renal pathways and abnormal level of AVP are associated with various diseases. Hence measurement of AVP would be useful, but is not commonly carried out in clinical practice because of its very short half-life making it difficult to quantify. In contrast, copeptin can be immunologically tested with ease and therefore can be used as a vasopressin surrogate marker.

References

  1. 1 2 Chopra I, Hawkey PM, Hinton M (March 1992). "Tetracyclines, molecular and clinical aspects". The Journal of Antimicrobial Chemotherapy. 29 (3): 245–277. doi:10.1093/jac/29.3.245. PMID   1592696.
  2. ↑ Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 356–. ISBN   978-1-4757-2085-3.
  3. ↑ "Demeclocycline Hydrochloride - demeclocycline tablet". DailyMed. U.S. National Library of Medicine. Retrieved 2008-12-20.
  4. ↑ Rosner B (2007). "The Antibiotic Rotational Protocol". The Top 10 Lyme Disease Treatments: Defeat Lyme Disease with the Best of Conventional and Alternative Medicine. BioMed Publishing. pp. 84, 86. ISBN   9780976379713.
  5. ↑ "Ad Hoc Committee report: systemic antibiotics for treatment of acne vulgaris: efficacy and safety". Archives of Dermatology. 111 (12): 1630–1636. December 1975. doi:10.1001/archderm.1975.01630240086015. PMID   128326.
  6. ↑ Beatson JM, Marsh BT, Talbot DJ (1985). "A clinical comparison of pivmecillinam plus pivampicillin (Miraxid) and a triple tetracycline combination (Deteclo) in respiratory infections treated in general practice". The Journal of International Medical Research. 13 (4): 197–202. doi:10.1177/030006058501300401. PMID   3930309. S2CID   23485353.
  7. 1 2 Schnappinger D, Hillen W (June 1996). "Tetracyclines: antibiotic action, uptake, and resistance mechanisms". Archives of Microbiology. 165 (6): 359–369. Bibcode:1996ArMic.165..359S. doi:10.1007/s002030050339. PMID   8661929. S2CID   6199423.
  8. ↑ Klein NC, Cunha BA (July 1995). "Tetracyclines". The Medical Clinics of North America. 79 (4): 789–801. doi: 10.1016/S0025-7125(16)30039-6 . PMID   7791423.
  9. 1 2 3 Lexi-Comp (August 2008). "Demeclocycline". The Merck Manual Professional . Retrieved on October 27, 2008.
  10. 1 2 Goh KP (May 2004). "Management of hyponatremia". American Family Physician. 69 (10): 2387–2394. PMID   15168958. Archived from the original on 2008-10-16. Retrieved 2008-10-28.
  11. ↑ Kortenoeven ML, Sinke AP, Hadrup N, Trimpert C, Wetzels JF, Fenton RA, Deen PM (December 2013). "Demeclocycline attenuates hyponatremia by reducing aquaporin-2 expression in the renal inner medulla". American Journal of Physiology. Renal Physiology. 305 (12): F1705–F1718. doi:10.1152/ajprenal.00723.2012. PMID   24154696. S2CID   17815411.
  12. ↑ Hayek A, Ramirez J (August 1974). "Demeclocycline-induced diabetes insipidus". JAMA. 229 (6): 676–677. doi:10.1001/jama.1974.03230440034026. PMID   4277429.
  13. 1 2 Miell J, Dhanjal P, Jamookeeah C (December 2015). "Evidence for the use of demeclocycline in the treatment of hyponatraemia secondary to SIADH: a systematic review". International Journal of Clinical Practice. 69 (12): 1396–1417. doi:10.1111/ijcp.12713. PMC   5042094 . PMID   26289137.
  14. ↑ Cherrill DA, Stote RM, Birge JR, Singer I (November 1975). "Demeclocycline treatment in the syndrome of inappropriate antidiuretic hormone secretion". Annals of Internal Medicine. 83 (5): 654–656. doi:10.7326/0003-4819-83-5-654. PMID   173218.
  15. 1 2 3 Tolstoi LG (2002). "A brief review of drug-induced syndrome of inappropriate secretion of antidiuretic hormone". Medscape Pharmacotherapy . 4 (1). Archived from the original on June 6, 2013.
  16. ↑ Cox M (1982). "Tetracycline Nephrotoxicity". In Porter GA (ed.). Nephrotoxic Mechanisms of Drugs and Environmental Toxins. Boston, MA: Springer. pp. 165–177. doi:10.1007/978-1-4684-4214-4_15. ISBN   978-1-4684-4216-8.
  17. ↑ Mørk A, Geisler A (January 1995). "A comparative study on the effects of tetracyclines and lithium on the cyclic AMP second messenger system in rat brain". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 19 (1): 157–169. doi:10.1016/0278-5846(94)00112-U. PMID   7708928. S2CID   36219362.
  18. ↑ Verbalis JG (2014). "Disorders of water metabolism". In Fliers E, Korbonits M, Romijn JA (eds.). Clinical Neuroendocrinology. Handbook of Clinical Neurology. Vol. 124. Elsevier Science. pp. 37–52 (43). doi:10.1016/B978-0-444-59602-4.00003-4. ISBN   978-0-444-62612-7. PMID   25248578.
  19. ↑ Kovács L, Lichardus B (6 December 2012). Vasopressin: Disturbed Secretion and Its Effects. Springer Science & Business Media. pp. 180–. ISBN   978-94-009-0449-1.
  20. 1 2 Singh AK, Williams GH (12 January 2009). Textbook of Nephro-Endocrinology. Academic Press. pp. 251–. ISBN   978-0-08-092046-7.
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