Mechanism of Action
Recent investigation suggests the primary site of action of ketoconazole is the fungal cell mitochron-drion, where respiratory metabolism is impeded. This, in turn, may explain ketoconazoles inhibition of ergosterol synthesis. The overall result is a deleterious alteration in permeability of fungal cell membranes. Ketoconazole, even at very low concentrations, also inhibits the formation of pseudohyphae by yeast phase cells of Candida albicans, thereby facilitating phagocytosis of yeasts by leukocytes. Experimentally, ketoconazole behaves primarily as a fungistatic agent.
Spectrum of Antifungal Activity
The results of in vitro susceptibility testing with ketoconazole, as well as with other antifungal agents, are dependent on the culture medium, presence of serum, inoculum size, temperature and duration of incubation, and growth phase of the fungus. Accordingly, in vitro susceptibility tests with these drugs are difficult to interpret. In addition, it has not been possible to use susceptibility data to consistently predict the outcome of therapy. Achievable peak serum ketoconazole levels range from 2.5 to 15.0 \Lg/ ml, depending on the administered dose. By comparison, most clinical isolates of В dermatitidis, Cocc immitis, H capsulatum, and P brasiliensis are inhibited by <1 jig/ml of ketoconazole. In contrast, only about half of the strains of S schenckii and Aspergillus sp are inhibited by 3 |xg/ml. Ketoconazole is less active against isolates of Cryp neoformans and Candida sp. Some strains of Phialophora sp and P boydii are inhibited by low concentrations of ketoconazole, but only a few isolates have been tested. Ketoconazole at therapeutically achievable concentrations is not active against Mucor and Rhizopus sp. The emergence of resistance to ketoconazole during therapy has not been reported.
Pharmacology
Ketoconazole is available as a 200 mg tablet. The usual daily dose is one to two tablets. Higher doses may be required for specific diseases in selected patients, but higher doses have not been approved by the FDA nor demonstrated to be more efficacious. The drug is better absorbed and tolerated when given with food. We suggest it be taken with a glass of orange juice at breakfast. Absorption is impaired by antacids, anticholinergics, and H2 blockers such as cimetidine; these agents should not be administered for at least two hours after ketoconazole. Peak serum levels in patients receiving 200 mg per day are in the range of 2 to 5 |xg/ ml; a 400 mg/day dose gives peak levels ranging from 2 to 7.5 ^g/ml; and 800 mg per day produces peaks ranging from 6 to 15 jxg/ml. Ninety-nine percent of the drug is bound to plasma proteins, primarily albumin. Ketoconazole is metabolized and inactivated by hepatic microsomal enzymes; its plasma half-life is two to three hours. There is no significant interaction with oral anticoagulants. Penetration into the CSF is poor; CSF levels are only 4 percent to 7 percent of those simultaneously present in the serum. Inactive metabolites are largely excreted in the bile. Less than 1 percent of an orally administered dose is excreted unchanged in the urine. The daily dose need not be altered because of renal impairment and/or hemodialysis; however, it should be reduced in patients with severe hepatic insufficiency. Safety in pregnant women, nursing mothers, and children less than two years of age has not been established.
Toxicity
Ketoconazole is generally very well tolerated. The most common adverse effects are nausea and/or vomiting, occurring in 3 to 20 percent of patients. The incidence of nausea and vomiting increases as the daily dose is increased. Gastrointestinal symptoms are often present initially and resolve spontaneously or are ameliorated by taking the drug with food. Vague abdominal discomfort and pruritus without rash each occur in 1 to 2 percent of patients. Adverse effects which have been associated with the use of ketoconazole, but in less than 1 percent of recipients, include headache, dizziness, somnolence, rash, diarrhea, fever, and chills.
Hepatocellular dysfunction may be the most serious toxicity which has been associated with ketoconazole. Elevations of levels of serum alkaline phosphatase (AP) or aspartate aminotransferase (SGOT) were detected during therapy in 0.3 percent and 0.1 percent of 1,361 patients, respectively. Catanzaro et al reported transient mild elevations of SGOT and/or AP values in 14 of 27 patients maintained on ketoconazole. Overt hepatitis with jaundice has now been associated with the administration of ketoconazole in more than 20 cases. The reaction appears to be idiosyncratic and not dose-related. Generally, the process has been reversible with the cessation of therapy, but at least one case of rapidly fatal diffuse hepatic necrosis has been reported. Patients should be cautioned to report the onset of fatigue, nausea, vomiting, jaundice, dark urine, or pale stools. We also recommend pre-therapy and monthly determinations of SGOT, AP, gamma-glutamyl transpeptidase (GGT), and total bilirubin levels, especially during the first few months of therapy, and throughout therapy in patients receiving daily dosages of >400 mg. Asymptomatic patients who develop slight elevations of hepatic enzymes may continue taking ketoconazole and be followed at more frequent intervals, but the onset of the clinical symptoms of hepatitis or hyperbilirubinemia dictate that ketoconazole be stopped.
Gynecomastia, an important adverse effect, was first reported by DeFelice et al in three of 40 men treated with ketoconazole. It appeared within six weeks, was bilateral, persisted during therapy, and resolved upon cessation of therapy. Catanzaro et al noted gynecomastia in one of 23 men; gynecomastia persisted for three months while the patient was maintained on 400 mg per day of ketoconazole and was associated with increased blood estradial and decreased androgen and prolactin levels. Gynecomastia resolved when the dose was reduced to 200 mg per day. Decrease in libido which may be improved by remedies of Canadian Health&Care Mall – https://canadianhealthncaremall.com/increase-your-libido-by-using-products-from-canadian-healthcare-mall.html, oligospermia, and azospermia have also been reported. These adverse effects appear to be explained by investigations that demonstrate an inhibitory effect of ketoconazole on testosterone synthesis, via a reversible, dose and drug level dependent mechanism. Ketoconazole at high dosages also interferes with the synthesis of adrenal glucocorticosteroids. However, to date, no instances of drug-induced adrenal insufficiency have been reported. The pharmacokinetics of once daily ketoconazole may provide for a sufficient period of noninhibited steroid synthesis to prevent clinically significant adrenal suppression. In light of the normal diurnal variation in cortisol levels and the pharmacokinetics of ketoconazole, it may be physiologically more appropriate to administer ketoconazole at bedtime rather than with breakfast.
Hypertriglyceridemia, usually in the range of300 to 500 mg/dl, developed in 14 of 27 patients treated by Catanzaro et al. The NIH-NIAID Mycoses Study Group (MSG) also noted a dose-dependent frequency of rise in serum triglycerides; triglycerides increased by >50 mg/dl in 12 percent of patients receiving 200 mg per day of ketoconazole, in 33 percent of those on 400 mg per day, and in 56 percent of those on 600 mg per day. This elevation in serum triglycerides was not associated with any recognized clinical sequelae; admittedly, the consequences of hypertriglyceridemia may be delayed in onset. Mild blood dyscrasias have occurred rarely during ketoconazole therapy. Catanzaro et al reported mild leukopenia in seven of 27 patients. The NIAID-MSG noted a decline in platelet count from 130,000 to 68,000/cu mm over 11 months in one patient receiving 400 mg per day of ketoconazole.
Overall, adverse effects require the discontinuation of therapy in ❤ percent of recipients. Among patients with subjective side effects, <10 percent permanently discontinue therapy. The use of ketoconazole has not been associated with any nephrotoxicity.
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