INTRODUCTION:

The US Food and Drug Administration authorised ketoconazole as a broad-spectrum azole antifungal in 1981 for systemic fungal contamination. Azole antifungals impede the formation of ergosterol, an essential structural constituent of fungal cell membranes, and cause necrobiosis by inhibiting the P450-dependent enzyme lanosterol 14-demethylase. In the 1980s, ketoconazole was the sole oral antifungal drug available for treating systemic mycoses. Reports of major side effects such as adrenal deficiency, hepatotoxicity, and drug drug interactions led to the removal of oral ketoconazole from Australia and Europe in 2013, as well as label modifications in North America to take out the prescription for the treatment of nail and skin fungal infections. Oral ketoconazole is now only recommended for the treatment of endemic mycoses when no other antifungal medications are available or tolerated.

The Food and Drug Administration has authorised and approved topical ketoconazole formulations containing 2% shampoo and seborrheic dermatitis, 1% shampoo, 2% cream, 2% gel, and 2% aerosol foam. All 2 percent shampoos require a prescription, whereas 1 percent shampoos are available over the counter. Except for the 1% shampoo and 2% gel, generic alternatives are available. Topical fungal infections are not easy to treatment, and while longer management times can yield better results, patient compliance is low. In comparison to shampoo or cream, formulations like 2 percent aerosol foam and 2 percent gel were created in the hope of boosting patient conformity with less messy or repeated administration. In vitro and in vivo experiments using lipophilic and keratophilic ketoconazole lacquers or nanoemulgels show improved transungual transport and suggest that they might be useful for onychomycosis. When compared to systemic antifungal administration without help, prophylactic administration of topical antifungals like clotrimazole or ketoconazole may result in improved cure and decreased relapse rate of recalcitrant, superficial dermatophyte infections, Candida, or Pityriasis. However, more research is needed to determine the efficacy of antifungal prophylaxis. Current research focuses on employing nanostructured lipid carriers, co-polymeric micelles, micro emulsions, liposomes, and niosomes to improve topical KTZ delivery. KTZ is protected from light degradation by nanostructure lipid carriers, while co-polymeric micelles micro emulsions give improved thermodynamic strength and percutaneous permeability. Both liposomes and noisome improve medication withholding in the skin, resulting in a prolonged duration of action.¹

ANTIFUNGAL ACTIVITY:

Ketoconazole is active against a wide range of fungi in vitro, having a variety of actions that mirror those of miconazole, an older imidazole antifungal medication. Dimorphic fungi (Coccidioides immitis, Histoplasma capsulatum), dermatophytes (Epidermophyton, Trichophyton), yeasts (Cryptococcus neoformans), and a variety of additional fungi are all included in the spectrum of action.² Researchers have been disputing the role of lipophilic yeast for some years. Pityrosporumovale (orbiculare) (Malasseziaovalis) is involved in the formation of dandruff pityriasis capitis, seborrheic dermatitis, Pityrosporum folliculitis, and pityriasis versicolor, among other superficial dermatoses. The use of an antimycotic drug, either topically or orally, is recommended as first-line therapy for both pityriasis versicolor and Pityrosporum folliculitis. The utilisation of ketoconazole, an effective anti-Pityrosporum agent, in the management of seborrheic dermatitis and dandruff established that Pityrosporum organisms do play a vital role in the pathogenesis of that condition.³

CHEMICAL STRUCTURE:

Figure 1:- Ketoconazole

Molecular Weight: 531.4

Molecular Formula: C₂₆H₂₈Cl₂N₄O₄

IUPACName:1-acetyl-4-(4-{[2-(2, 4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1, 3-(dioxolan-4-yl] methoxy} phenyl piperazine ethenone⁴.

DOSES FORM OF KETOCONAZOLE:

Ketoconazole is available in a variety of dosage forms, such as ketoconazole ointment, gel, and cream, as well as emulgel and polymeric film.⁵

MECHANISM OF ACTION:

Ketoconazole is an antifungal drug that acts by blocking the enzyme cyto P450 14-demethylase. The manufacturing of phospholipids and triglycerides by fungus is inhibited by this enzyme. Ketoconazole, in particular, suppresses the formation of lanosterol, a raw material for ergosterol biosynthesis. Fungi need ergosterol to protect their membrane integrity. The fluidity of the membrane increases lacking ergosterol, preventing fungal development. In large dosages, ketoconazole can compete with androgen receptors, for example, those of testosterone and dihydrotestosterone, lowering testosterone and dihydrotestosterone activity in prostate cancer. The enzymes 17, 20-lyase, and 17-alpha-hydroxylase, which are required for the manufacture of steroids in the adrenal cortex, can be inhibited by ketoconazole. The enzyme 21-hydroxylase is inhibited by ketoconazole. In the adrenal cortex, this enzyme is required for the production of glucocorticoids and mineralocorticoids like cortisol. Ketoconazole can be used to treat Cushing's syndrome by blocking enzymes involved in cortisol production^.6

Figure 2. MECHANISM OF ACTION OF KETOCONAZOLE

PHARMACOKINETIC PROPERTY:

ABSORPTION:

Ketoconazole is not absorbed systemically when used topically. No measurable serum concentrations were found when ketoconazole 2 percent cream was applied to the backs, arms, and chests of 12 healthy people. In dogs, repeated applications of this cream on abraded skin had comparable outcomes. After applying a 2% lotion to skin with severe tinea pedis, no ketoconazole was detected in plasma in six individuals.⁷

PLASMA BINDING:

Ketoconazole binds to plasma albumin 84% of the time and blood cells 15% of the time, for a total of 95% binding in plasma.⁸

DISTRIBUTION:

Ketoconazole is delivered to the skin through the bloodstream. Ketoconazole was detectable in suction blister fluid 3 hours after a 200mg dosage in healthy participants at a maximal concentration of 0.91mg/L, which had reduced to 0.22mg/L by 9 hours. Skin ketoconazole concentrations 2 hours after the previous treatment varied between 1.4 and 11.9% p.g/g in subjects. The skin mean concentrations had dropped to 2.6 and 1.3 p.g. g/g five and ten days following the last injection, respectively. Ketoconazole did not develop in the roots of hairs epilated 2 hours, 5 days, or 10 days after the previous dosage.⁷

ELIMINATION:

Extensive metabolism produces inactive metabolites, which are primarily eliminated in the feces. Hepatic first-pass metabolism is likely to be saturable. The half-life of ketoconazole is dose-reliant and rises over time, implying metabolic auto-inhibition. After oral administration, the kinetics suit a two-compartment model.⁷

METABOLISM:

Hepatotoxicity has been documented with ketoconazole (KT), which is most likely not due to an immunoallergic mechanism. Although hepatic microsomal enzymes extensively metabolise KT, the composition, mechanism of production, and toxicity of putative metabolites remain mostly unknown.⁹

INTERACTION:-

1) Absorption Interactions:

Because ketoconazole is water insoluble, its absorption is influenced by stomach acidity. Concurrent treatment with drugs that lower stomach acid output, such as cimetidine, has been observed to interfere with its absorption. Ex. A 28-year-old lady with cryptococcal arthritis and renal failure was given 200mg of ketoconazole per day. She was also given sodium bicarbonate, aluminium oxide, and cimetidine at the same time. Ketoconazole plasma concentrations were less than 1 WgimI even at dosages of 400 mgiday. Ex.Vander Meer and colleagues 63 then evaluated three healthy adult male volunteers. The subjects' antifungal plasma levels at 1, 2, 4, and 6 hours are presented. The AUC was higher when cimetidine was administered 2 hours before 200mg of ketoconazoledecreased by more than 60% The AUC was more than 50% higher when ketoconazole was put in an acidic solution and provided 2 hours after cimetidine than when the medication was given alone. By giving ketoconazole in an acidic solution, this interaction can be avoided. If antacids or histamine-2 blockers be required, they must be given at least 2hr after the ketoconazole to allow for full absorption before the stomach pH is adjusted^10.

2) Metabolic Interactions-

Lmidazole derivatives have been shown to inhibit hepatic microsome enzymatic activity¹⁰.

ADVERSE EFFECTS:

· Nausea, vomiting, and stomach discomfort are some of the side effects of using ketoconazole. These side effects are dose dependent and can be avoided if ketoconazole is taken through meals.

· Transient increases in blood concentrations of liver enzymes might occur asymptomatically. It's also possible to develop gynecomastia, hepatitis, oligospermia, menstrual abnormalities, and adrenal cortical suppression.

· Further side effects include allergic responses such as angioedema and urticaria, as well as anaphylaxis in rare circumstances. Ketoconazole medication can cause itchiness, rash, alopecia, headache, dizziness,somnolence and impotence^.11

· In dogs, the most prevalent side effects include dose-related vomiting, diarrhea, hepatic damage, and uncommon thrombocytopenia. Elevated liver enzymes are frequent. In animals, ketoconazole inhibits hormone synthesis and lowers cortisol, testosterone, and other hormone levels. In certain animals, ketoconazole may cause a lighter hair coat color. It has been linked to the development of cataracts in dogs.¹²

CONTRAINDICATION:

Ketoconazole is not recommended for people who are hypersensitive to it. Because of its low penetration into the central nervous system, it should not be utilized to treat fungal meningitis. Concurrent administration of triazolam is not recommended.¹¹

Ketoconazole is not recommended for those who have acute or chronic liver illness since it can cause hepatotoxicity, which can be deadly. Because large dosages of ketoconazole decrease adrenocortical function, it is contraindicated in adrenal insufficiency. Ketoconazole should not be administered to individuals who have previously experienced a hypersensitive reaction to the drug. Because ketoconazole can raise the risk of myopathy when used with HMG-CoA reductase inhibitors, it should never be used together. Ketoconazole is not recommended for people taking benzodiazepines since it can cause drowsiness by increasing plasma concentrations. Because ketoconazole can cause QT elongation and torsade de pointes in patients using antiarrhythmic medicines including cisapride, pimozide, quinidine, and ranolazine, it should never be given to them. Ketoconazole should be taken with caution in individuals with more bone fragility, for example postmenopausal women and the aged, to avoid the risk of fracture. Ketoconazole is metabolised by the CYP3A4 liver enzyme, hence it should be used with caution in individuals who are taking medicines that reduceor metabolized by CYP3A4. Because ketoconazole can be found in mother milk, nursing is not suggested while taking it.¹³

TOXICITY:

The FDA advises that taking ketoconazole by mouth might cause adrenal deficiency and hepatotoxicity, and that ketoconazole associated hepatotoxicity is prevalent. Ketoconazole has a wide range of off-label applications. As a result, due to substantial hepatotoxic side effects, cautious selection of ketoconazole as a therapy is required.¹³

TERATOGENIC STUDY OF KETOCONAZOLE:

Ketoconazole, a wide-ranging imidazole antifungal, has been shown to effectively treat a variety of systemic andsuperficial mycoses. However, investigations in pregnant rats have indicated that this medication has teratogenic and embryo toxic potential when given by gavages at higher dosages. Following the treatment of 80 mg per kg (Ten times the mostsuggestedperson dose) of ketoconazole to pregnant rats, syndactyly and oligodactyly in foetuses have been recorded. Another research utilizing different dosages (Ten, twenty five or fifty mg per kg) of ketoconazole in pregnant rats on gestational days six through twenty one found a high rate of foetal resorption with a large percentage of stillbirths demonstrating fetotoxicity and embryo toxicity.Because there are nocontrolled andenoughstudy in humans, and animal studies have exposed that drugs have teratogenic potential, the FDA has classified ketoconazole as Pregnancy Category C, which means that these drugs must only be used throughout pregnancy if the potential advantage outweighs the potential threat to the foetus. In human medicine, antifungal medicines are widely employed. As a result, both maternal exposure and reproductive outcome must be determined to determine their reproductive toxicologic effects¹⁴.

MEDICAL USES:

Topical antifungal:

Ringworm, candidiasis (thrush or yeast infection), tinea versicolor, athlete's foot and jock itch are all fungal diseases of the skin and mucous membranes that are treating with topically applied ketoconazole. Topical ketoconazole is also used to treat dandruff (seborrheic dermatitis of the scalp) and seborrheic dermatitis on other parts of the body, possibly by decreasing level of the fungus Malassezia furfur on the skin in these disorders.¹⁵

Systemic antifungal:

Ketoconazole is effective against Histoplasma,Candida, Coccidioides, and Blastomyces (but not Aspergillus), paracoccidioidomycosis, and chromomycosis, among other fungus that can cause human illness. Ketoconazole was the 1^st orallyactive azole antifungal drug, being developed in 1977. Because of ketoconazole's slower absorption, higher toxicity, and restricted spectrum of effectiveness, alternative azole antifungal medications, such as itraconazole, have essentially supplanted it as a first-line systemic antifungal treatment.¹⁶

Other:

In rare circumstances, limited clinical research show that using ketoconazole shampoo alone or in conjunction with other therapies can help reduce hair loss.^17-22

CONCLUSION:

Ketaconazole is synthetic antifungal agent which is used to treat various fungal infections like chronic mucocutaneous candidosis, genital candidosis, etc. It has good pharmacokinetic profile like it is well absorbed orally. It also has some adverse effect like Nausea, vomiting, and stomach discomfort. Other side effects contain allergic responses such urticaria and angioedema, as well as anaphylaxis in rare circumstances.Ketoconazole is contraindicated in patients with chronic oracute hepatic disease due to its organization with liver toxicity.Ketoconazole is contraindicated in those known to be oversensitive to it.Therefore from this review we concluded that ketoconzole has plenty of application in various antifungal infections and other disorders like hair loss, along with that it shows hepatotoxityso it is used cautiously.

REFERENCES:

1. Malviya VR, Pande SD, Bobade NN. Preparation and Evaluation of Sustained Release Beads of Zolmitriptan Hydrochloride. Research Journal of Pharmacy and Technology. 2019 Dec 30; 12(12):5972-6.

2. Malviya VR, Pande SD. Road CKN. Preparation ad Evaluation of Zolmitriptan Hydrochloride Lozenge. J Pharma Res. 2019; 8(8):624-9.

3. Malviya V, Ladhake V, Gajbiye K, Satao J, Tawar M. Design and Characterization of Phase Transition System of Zolmitriptan Hydrochloride for Nasal Drug Delivery System. International Journal of Pharmaceutical Sciences and Nanotechnology. 2020 May 31; 13(3):4942-51.

4. Malviya V, Thakur Y, Gudadhe SS, Tawar M. Formulation and evaluation of natural gum based fast dissolving tablet of Meclizine hydrochloride by using 3 factorial design 2. Asian Journal of Pharmacy and Pharmacology. 2020; 6(2):94-100.

5. Malviya VR, Tawar MG. Preparation and Evaluation of Oral Dispersible Strips of Teneligliptin Hydrobromide for Treatment of Diabetes Mellitus. International Journal of Pharmaceutical Sciences and Nanotechnology. 2020 Jan 31; 13(1):4745-52.

6. Malviya V, Manekar S. Design, Development and Evaluation of Aceclofenac and Curcumin Agglomerates by Crystallo Co-Agglomeration Technique. Research Journal of Pharmacy and Technology. 2021 Mar 1; 14(3):1535-41.

7. Malviya V. Preparation and Evaluation of Emulsomes as a Drug Delivery System for Bifonazole. Indian Journal of Pharmaceutical Education and Research. 2021 Jan 1; 55(1):86-94.

8. Khatua S, Paul S, Acharya K. Mushroom as the potential source of new generation of antioxidant: a review. Research Journal of Pharmacy and Technology. 2013; 6(5):496-505.

9. Malviya V, Pande S. Development and Evaluation of Fast dissolving Film of Fluoxetine hydrochloride. Research Journal of Pharmacy and Technology. 2021 Oct 31; 14(10):5345-0.

10. Malviya V. Design and Characterization of Thermosensitive Mucoadhesive Nasal Gel for Meclizine Hydrochloride. International Journal of Pharmaceutical Sciences and Nanotechnology. 2022 Feb 28; 15(1):5782-93.

11. Burange PJ, Tawar MG, Bairagi RA, Malviya VR, Sahu VK, Shewatkar SN, Sawarkar RA, Mamurkar RR. Synthesis of silver nanoparticles by using Aloe vera and Thuja orientalis leaves extract and their biological activity: a comprehensive review. Bulletin of the National Research Centre. 2021 Dec; 45(1):1-3.

12. Malviya V, Burange P, Thakur Y, Tawar M. Enhancement of Solubility and Dissolution Rate of Atazanavir Sulfate by Nanocrystallization. Indian Journal of Pharmaceutical Education and Research. 2021 Jul 1; 55(3):S672-80.

13. Malviya, Vedanshu, Mukund Tawar, Prashant Burange, and Rahul Jodh. "A Brief Review on Resveratrol." (2022): 157-162.

14. Paliwal R, Sharma V, Sharma S. Elucidation of free radical scavenging and antioxidant activity of aqueous and hydro-ethanolic extracts of Moringa oleifera pods. Research Journal of Pharmacy and Technology. 2011; 4(4):566-71.

15. Uttara J, Mohini U. Evaluation of antioxidant activity of aqueous extract bark of Ficus glomerata. Research Journal of Pharmacy and Technology. 2008; 1(4):537-8.

16. Malviya V, Arya A, Burange P, Gajbhiye K, Rathod G, Tawar M. To Evaluate the Cardioprotective effect of Hydroalcoholic Extract of Matricaria chamomilla Linn in Isoproterenol Induced Myocardial Infarction in Wistar Rats. Research Journal of Pharmacy and Technology. 2022 Sep 28; 15(9):3887-92.

17. Basavaraj H, Purnima A. In–vitro antioxidant activity of aqueous and ethanolic extract of Coscinium fenestratum root and Embelia ribes flower. Research Journal of Pharmacy and Technology. 2012; 5(4):513-7.

18. Kalita S, Kumar G, Karthik L, Rao KV. A Review on Medicinal Properties of Lantana camara Linn. Research Journal of Pharmacy and Technology. 2012; 5(6):711-5.

19. Abdulazeem L, Jassani J, Al-Sheakh MA. Free radical scavenging and antioxidant activity of silver nanoparticles synthesized from Cuminum cyminum (Cumin) seed extract. Research Journal of Pharmacy and Technology. 2021; 14(8):4349-54.

20. Elias J, MG R, NP A, Sunny S. Free Radical Scavenging Activity and Phytochemical Profiling of Acalypha indica Linn. Research Journal of Pharmacy and Technology. 2010; 3(4):1231-4.

21. Jawed R, Ahmad W. Effect of Ultraviolet Radiation on Various Bacterial Species. Asian Journal of Pharmaceutical Research. 2022; 12(1):1-4.

22. Rao US, Mohd KS, Halim SZ, Khamis MB. Screening of Phytochemicals and Comparative Antioxidant activity of Leaf and Fruit of MalaysianMengkudu Using Aqueous and Organic Solvent Extracts. Research Journal of Pharmacy and Technology. 2013; 6(9):1064-72.

Received on 16.07.2022 Modified on 05.09.2022

Asian J. Res. Pharm. Sci. 2023; 13(2):101-105.

DOI: 10.52711/2231-5659.2023.00019