Loteprednol

Last updated
Loteprednol
Loteprednol etabonate.svg
Clinical data
Trade names Lotemax
Other names11β,17α,Dihydroxy-21-oxa-21-chloromethylpregna-1,4-diene-3,20-dione 17α-ethylcarbonate
AHFS/Drugs.com Micromedex Detailed Consumer Information
Routes of
administration
Eye drops
Drug class Corticosteroid; glucocorticoid
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability None
Protein binding 95%
Metabolism Ester hydrolysis
Metabolites Δ1-cortienic acid and its etabonate
Onset of action ≤2 hrs (allergic conjunctivitis)
Elimination half-life 2.8 hrs
Identifiers
  • Chloromethyl 17-ethoxycarbonyloxy-11-hydroxy-10,13-dimethyl-3-oxo-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthrene-17-carboxylate
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.167.120 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C24H31ClO7
Molar mass 466.96 g·mol−1
3D model (JSmol)
Melting point 220.5 to 223.5 °C (428.9 to 434.3 °F)
Solubility in water 0.0005 mg/mL (20 °C)
  • CCOC(=O)O[C@@]1(CC[C@@H]2[C@@]1(C[C@@H]([C@H]3[C@H]2CCC4=CC(=O)C=C[C@]34C)O)C)C(=O)OCCl
  • InChI=1S/C24H31ClO7/c1-4-30-21(29)32-24(20(28)31-13-25)10-8-17-16-6-5-14-11-15(26)7-9-22(14,2)19(16)18(27)12-23(17,24)3/h7,9,11,16-19,27H,4-6,8,10,12-13H2,1-3H3/t16-,17-,18-,19+,22-,23-,24-/m0/s1 X mark.svgN
  • Key:DMKSVUSAATWOCU-HROMYWEYSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Loteprednol (synthesized as the ester loteprednol etabonate) is a topical corticosteroid used to treat inflammations of the eye. It is marketed by Bausch and Lomb as Lotemax [2] and Loterex.

Contents

It was patented in 1980 and approved for medical use in 1998. [3] It is available as a generic medication. [4]

Medical uses

Applications for this drug include the reduction of inflammation after eye surgery, [2] seasonal allergic conjunctivitis, uveitis, [5] and chronic forms of keratitis - such as adenoviral, Thygeson's keratitis, vernal keratoconjunctivitis,pingueculitis, giant papillary conjunctivitis, and episcleritis. [6]

Contraindications

Contraindications: As corticosteroids are immunosuppressive, loteprednol is contraindicated in patients with viral, fungal or mycobacterial infections of the eye. [2] [5] [7]

Adverse effects

The most common adverse effects in patients being treated with the gel formulation are anterior chamber inflammation (in 5% of people), eye pain (2%), and foreign body sensation (2%). [8]

Interactions

Because long term use (more than 10 days) can cause increased intraocular pressure, loteprednol may interfere with the treatment of glaucoma. Following ocular administration, the drug is very slowly absorbed into the blood, therefore the blood level is limited to an extremely small concentration, and interactions with drugs taken by mouth or through any route other than topical ophthalmic are very unlikely. [2]

Pharmacology

Mechanism of action

Corticosteroids mediate their anti-inflammatory effects mainly through the modulation of the cytosolic glucocorticoid receptor (GR) at the genomic level. Preclinical studies demonstrated that loteprednol etabonate is highly lipophilic and has strong binding affinity to glucocorticoid receptors. After it binds to the GR in the cytoplasm, the activated corticosteroid-GR complex migrates to the nucleus, where it upregulates the expression of anti-inflammatory proteins and represses the expression of proinflammatory proteins. Corticosteroids inhibit inflammatory cytokines, chemokines, adhesion molecules, and other inflammatory mediators. They also reduce synthesis of histamine, stabilize cell membranes, and inhibit degranulation of mast cells. Recent work suggests that the activated corticosteroid-GR complex also elicits nongenomic effects, particularly the inhibition of vasodilation, vascular permeability, and migration of leukocytes. [9] [10] [11]

Pharmacokinetics

Neither loteprednol etabonate nor its inactive metabolites Δ1-cortienic acid and Δ1-cortienic acid etabonate are detectable in the bloodstream, even after oral administration. A study with patients receiving loteprednol eye drops over 42 days showed no adrenal suppression, which would be a sign of the drug reaching the bloodstream to a clinically relevant extent. [2]

Steroid receptor affinity was 4.3 times that of dexamethasone in animal studies. [2]

Retrometabolic drug design

Loteprednol etabonate was developed using retrometabolic drug design. It is a so-called soft drug, meaning its structure was designed so that it is predictably metabolised to inactive substances. These metabolites, Δ1-cortienic acid and its etabonate, are derivatives of cortienic acid, itself an inactive metabolite of hydrocortisone. [2] [7] [12]

Chemistry

Loteprednol etabonate is an ester of loteprednol with etabonate (ethyl carbonate). The pure chemical compound has a melting point between 220.5 °C (428.9 °F) and 223.5 °C (434.3 °F). Its solubility in water is 1:2,000,000, [7] therefore it is formulated for ophthalmic use as either an ointment, a gel, or a suspension. [13]

Loteprednol is a corticosteroid. The ketone side chain of classical corticosteroids such as hydrocortisone is replaced by a cleavable ester, which accounts for the rapid inactivation. [14] (This is not the same as the etabonate ester.)

Hydrocortisone Cortisol2.svg
Hydrocortisone
Loteprednol etabonate Loteprednol etabonate.svg
Loteprednol etabonate

Chemical synthesis

Loteprednol.png [15]

Related Research Articles

<span class="mw-page-title-main">Corticosteroid</span> Class of steroid hormones

Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involved in a wide range of physiological processes, including stress response, immune response, and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior.

<span class="mw-page-title-main">Hydrocortisone</span> Glucocorticoid and Mineralocorticoid hormone Cortisol supplied as a medication

Hydrocortisone is the name for the hormone cortisol when supplied as a medication. Uses include conditions such as adrenocortical insufficiency, adrenogenital syndrome, high blood calcium, thyroiditis, rheumatoid arthritis, dermatitis, asthma, and COPD. It is the treatment of choice for adrenocortical insufficiency. It can be given by mouth, topically, or by injection. Stopping treatment after long-term use should be done slowly.

<span class="mw-page-title-main">Glucocorticoid</span> Class of corticosteroids

Glucocorticoids are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebrate animal cell. The name "glucocorticoid" is a portmanteau and is composed from its role in regulation of glucose metabolism, synthesis in the adrenal cortex, and its steroidal structure.

<span class="mw-page-title-main">Prednisolone</span> Chemical compound (steroid medication)

Prednisolone is a corticosteroid, a steroid hormone used to treat certain types of allergies, inflammatory conditions, autoimmune disorders, and cancers. Some of these conditions include adrenocortical insufficiency, high blood calcium, rheumatoid arthritis, dermatitis, eye inflammation, asthma, and multiple sclerosis. It can be taken by mouth, injected into a vein, used topically as a skin cream, or as eye drops. It differs from the similarly named prednisone in having a hydroxyl at the 11th carbon instead of a ketone.

<span class="mw-page-title-main">Uveitis</span> Inflammation of the uvea of the eye

Uveitis is inflammation of the uvea, the pigmented layer of the eye between the inner retina and the outer fibrous layer composed of the sclera and cornea. The uvea consists of the middle layer of pigmented vascular structures of the eye and includes the iris, ciliary body, and choroid. Uveitis is described anatomically, by the part of the eye affected, as anterior, intermediate or posterior, or panuveitic if all parts are involved. Anterior uveitis (iridocyclitis) is the most common, with the incidence of uveitis overall affecting approximately 1:4500, most commonly those between the ages of 20-60. Symptoms include eye pain, eye redness, floaters and blurred vision, and ophthalmic examination may show dilated ciliary blood vessels and the presence of cells in the anterior chamber. Uveitis may arise spontaneously, have a genetic component, or be associated with an autoimmune disease or infection. While the eye is a relatively protected environment, its immune mechanisms may be overcome resulting in inflammation and tissue destruction associated with T-cell activation.

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

Allergic conjunctivitis (AC) is inflammation of the conjunctiva due to allergy. Although allergens differ among patients, the most common cause is hay fever. Symptoms consist of redness, edema (swelling) of the conjunctiva, itching, and increased lacrimation. If this is combined with rhinitis, the condition is termed allergic rhinoconjunctivitis (ARC).

<span class="mw-page-title-main">Methylprednisolone</span> Corticosteroid medication

Methylprednisolone is a synthetic glucocorticoid, primarily prescribed for its anti-inflammatory and immunosuppressive effects. It is either used at low doses for chronic illnesses or used concomitantly at high doses during acute flares. Methylprednisolone and its derivatives can be administered orally or parenterally.

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

Latanoprost, sold under the brand name Xalatan among others, is a medication used to treat increased pressure inside the eye. This includes ocular hypertension and open angle glaucoma. It is applied as eye drops to the eyes. Onset of effects is usually within four hours, and they last for up to a day.

<span class="mw-page-title-main">Mometasone</span> Steroid medication

Mometasone, also known as mometasone y 3 s, is a steroid medication used to treat certain skin conditions, hay fever, and asthma. Specifically it is used to prevent rather than treat asthma attacks. It can be applied to the skin, inhaled, or used in the nose. Mometasone furoate, not mometasone, is used in medical products.

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

Amcinonide is a topical glucocorticoid used to treat itching, redness and swelling associated with several dermatologic conditions such as atopic dermatitis and allergic contact dermatitis. Amcinonide can also be classified as a multi-functional small molecule corticosteroid, which has been approved by the FDA and is currently marketed as an ointment, lotion, or cream. It acts as both a transcription factor for responses to glucocorticoids and modulator for other transcription factors while also regulating phospholipase A2 activity.

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

Hydrocortisone aceponate is a veterinary corticosteroid that is used in form of creams for the treatment of various dermatoses. It is an ester of hydrocortisone (cortisol) with acetic acid and propionic acid.

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

Corneal neovascularization (CNV) is the in-growth of new blood vessels from the pericorneal plexus into avascular corneal tissue as a result of oxygen deprivation. Maintaining avascularity of the corneal stroma is an important aspect of corneal pathophysiology as it is required for corneal transparency and optimal vision. A decrease in corneal transparency causes visual acuity deterioration. Corneal tissue is avascular in nature and the presence of vascularization, which can be deep or superficial, is always pathologically related.

<span class="mw-page-title-main">Selective glucocorticoid receptor modulator</span> Class of experimental drugs

Selective glucocorticoid receptor modulators (SEGRMs) and selective glucocorticoid receptor agonists (SEGRAs) formerly known as dissociated glucocorticoid receptor agonists (DIGRAs) are a class of experimental drugs designed to share many of the desirable anti-inflammatory, immunosuppressive, or anticancer properties of classical glucocorticoid drugs but with fewer side effects such as skin atrophy. Although preclinical evidence on SEGRAMs’ anti-inflammatory effects are culminating, currently, the efficacy of these SEGRAMs on cancer are largely unknown.

<span class="mw-page-title-main">Herpes simplex keratitis</span> Medical condition

Herpetic simplex keratitis is a form of keratitis caused by recurrent herpes simplex virus (HSV) infection in the cornea.

<span class="mw-page-title-main">Retrometabolic drug design</span>

In the field of drug discovery, retrometabolic drug design is a strategy for the design of safer drugs either using predictable metabolism to an inactive moiety or using targeted drug delivery approaches. The phrase retrometabolic drug design was coined by Nicholas Bodor. The method is analogous to retrosynthetic analysis where the synthesis of a target molecule is planned backwards. In retrometabolic drug design, metabolic reaction information of drugs is used to design parent drugs whose metabolism and distribution can be controlled to target and eliminate the drug to increase efficacy and minimize undesirable side effects. The new drugs thus designed achieve selective organ and/or therapeutic site drug targeting and produce safe therapeutic agents and safe environmental chemicals. These approaches represent systematic methodologies that thoroughly integrate structure-activity (SAR) and structure-metabolism (SMR) relationships and are aimed at designing safe, locally active compounds with improved therapeutic index.

<span class="mw-page-title-main">Topical glucocorticoids</span>

Topical glucocorticoids are the topical forms of glucocorticoids. Topical glucocorticoids are used in the treatment of many skin conditions. They provide anti-inflammatory, antimitotic, and immune-system suppressing actions through various mechanisms.

<span class="mw-page-title-main">Antiarthritics</span> Drug class

An antiarthritic is any drug used to relieve or prevent arthritic symptoms, such as joint pain or joint stiffness. Depending on the antiarthritic drug class, it is used for managing pain, reducing inflammation or acting as an immunosuppressant. These drugs are typically given orally, topically or through administration by injection. The choice of antiarthritic medication is often determined by the nature of arthritis, the severity of symptoms as well as other factors, such as the tolerability of side effects.

Peripheral Ulcerative Keratitis (PUK) is a group of destructive inflammatory diseases involving the peripheral cornea in human eyes. The symptoms of PUK include pain, redness of the eyeball, photophobia, and decreased vision accompanied by distinctive signs of crescent-shaped damage of the cornea. The causes of this disease are broad, ranging from injuries, contamination of contact lenses, to association with other systemic conditions. PUK is associated with different ocular and systemic diseases. Mooren's ulcer is a common form of PUK. The majority of PUK is mediated by local or systemic immunological processes, which can lead to inflammation and eventually tissue damage. Standard PUK diagnostic test involves reviewing the medical history and a completing physical examinations. Two major treatments are the use of medications such as corticosteroids or other immunosuppressive agents and surgical resection of the conjunctiva. The prognosis of PUK is unclear with one study providing potential complications. PUK is a rare condition with an estimated incidence of 3 per million annually.

<span class="mw-page-title-main">Uveitic glaucoma</span> Glaucoma caused by uveitis or its treatments

Uveitic glaucoma is most commonly a progression stage of noninfectious anterior uveitis or iritis.

<span class="mw-page-title-main">Topical hydrocortisone</span> Pharmaceutical drug

Topical hydrocortisone is a drug under the class of corticosteroids, which is used for the treatment of skin inflammation, itchiness and allergies. Some examples include insect bites, dermatitis and rash.

References

  1. "Prescription medicines: registration of new chemical entities in Australia, 2014". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 10 April 2023.
  2. 1 2 3 4 5 6 7 Haberfeld H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
  3. Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 488. ISBN   9783527607495.
  4. "First Generic Drug Approvals 2023". U.S. Food and Drug Administration (FDA). 30 May 2023. Archived from the original on 30 June 2023. Retrieved 30 June 2023.
  5. 1 2 Loteprednol Professional Drug Facts .
  6. Pavesio CE, Decory HH (April 2008). "Treatment of ocular inflammatory conditions with loteprednol etabonate". The British Journal of Ophthalmology. 92 (4): 455–459. doi:10.1136/bjo.2007.132621. PMID   18245274. S2CID   25873047.
  7. 1 2 3 Dinnendahl V, Fricke U (2008). Arzneistoff-Profile (in German). Vol. 6 (22 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN   978-3-7741-9846-3.
  8. "Highlights of Prescribing Information: Lotemax" (PDF). 2012.
  9. Comstock TL, Decory HH (2012). "Advances in corticosteroid therapy for ocular inflammation: loteprednol etabonate". International Journal of Inflammation. 2012: 789623. doi: 10.1155/2012/789623 . PMC   3321285 . PMID   22536546.
  10. Amon M, Busin M (October 2012). "Loteprednol etabonate ophthalmic suspension 0.5 %: efficacy and safety for postoperative anti-inflammatory use". International Ophthalmology. 32 (5): 507–517. doi:10.1007/s10792-012-9589-2. PMC   3459083 . PMID   22707339.
  11. Sheppard JD, Comstock TL, Cavet ME (April 2016). "Impact of the Topical Ophthalmic Corticosteroid Loteprednol Etabonate on Intraocular Pressure". Advances in Therapy. 33 (4): 532–552. doi:10.1007/s12325-016-0315-8. PMC   4846687 . PMID   26984315.
  12. Bodor N, Buchwald P (2002). "Design and development of a soft corticosteroid, loteprednol etabonate". In Schleimer RP, O'Byrne PM, Szefler SJ, Brattsand R (eds.). Inhaled Steroids in Asthma. Optimizing Effects in the Airways. Lung Biology in Health and Disease. Vol. 163. Marcel Dekker, New York. pp. 541–564.
  13. "Loteprednol (Professional Patient Advice)" . Retrieved October 4, 2018.
  14. Pavesio CE, Decory HH (April 2008). "Treatment of ocular inflammatory conditions with loteprednol etabonate". The British Journal of Ophthalmology. 92 (4): 455–459. doi:10.1136/bjo.2007.132621. PMID   18245274. S2CID   25873047.
  15. Druzgala P, Hochhaus G, Bodor N (February 1991). "Soft drugs--10. Blanching activity and receptor binding affinity of a new type of glucocorticoid: loteprednol etabonate". The Journal of Steroid Biochemistry and Molecular Biology. 38 (2): 149–154. doi:10.1016/0960-0760(91)90120-T. PMID   2004037. S2CID   27107845.

Further reading