Imidazoles and Triazoles

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Chapter: Essential pharmacology : Antifungal Drugs

Four imidazoles are entirely topical, while ketoconazole is used both orally and topically. Two triazoles fluconazole and itraconazole have largely replaced ketoconazole for systemic mycosis because of greater efficacy, longer t½, fewer side effects and drug interactions.


IMIDAZOLES AND TRIAZOLES

 

These are presently the most extensively used antifungal drugs.

 

Four imidazoles are entirely topical, while ketoconazole is used both orally and topically. Two triazoles fluconazole and itraconazole have largely replaced ketoconazole for systemic mycosis because of greater efficacy, longer t½, fewer side effects and drug interactions.

 

The imidazoles and triazoles have broad-spectrum antifungal activity covering dermatophytes, Candida, other fungi involved in deep mycosis (except mucor), Nocardia, some gram-positive and anaerobic bacteria, e.g. Staph. aureus, Strep. faecalis, Bac. fragilis and Leishmania.

 

The mechanism of action of imidazoles and triazoles is the same. They inhibit the fungal cytochrome P450 enzyme ‘lanosterol 14demethylase’ and thus impair ergosterol synthesis leading to a cascade of membrane abnormalities in the fungus. The lower host toxicity of triazoles compared to imidazoles has correlated with their lower affinity for mammalian CYP450 enzymes and lesser propensity to inhibit mammalian sterol synthesis. However, because they are active against certain bacteria as well (which do not have ergosterol), other mechanisms of action also appear to be involved.

 

Development of fungal resistance to azoles has been noted among Candida infecting advanced AIDS patients, but has not so far posed significant clinical problem.

 

Clotrimazole

 

It is effective in the topical treatment of tinea infections like ringworm: 60–100% cure rates are reported with 2–4 weeks application on a twice daily schedule. Athletes’ foot, otomycosis and oral/cutaneous/vaginal candidiasis have responded in >80% cases. It is particularly favoured for vaginitis because of a long lasting residual effect after once daily application. A 7 day course is generally used. For oropharyngeal candidiasis 10 mg troche of clotrimazole is allowed to dissolve in the mouth 3–4 times a day, or the lotion/gel is applied/ swirled in the mouth for as long as possible. It is also effective in skin infections caused by Corynebacteria.

 

Clotrimazole is well tolerated by most patients. Local irritation with stinging and burning sensation occurs in some. No systemic toxicity is seen after topical use.

 

SURFAZ, CLOTRIN, CLODERM 1% lotion, cream, powder; 100 mg vaginal tab. CANDID 1% cream, gel, lotion, powder.

 

Econazole

 

It is similar to clotrimazole; penetrates superficial layers of the skin and is highly effective in dermatophytosis, otomycosis, oral thrush, but is somewhat inferior to clotrimazole in vaginitis. No adverse effects, except local irritation in few is reported.

 

ECONAZOLE 1% oint, 150 mg vaginal tab; ECODERM 1% cream.

 

Miconazole

 

It is a highly efficacious (>90% cure rate) drug for tinea, pityriasis versicolor, otomycosis, cutaneous and vulvovaginal candidiasis. Because of its good penetrating power, it has been found effective, though partially, even in onychomycosis; single application on skin acts for a few days.

 

Irritation after cutaneous application is infrequent. No systemic adverse effects are seen. However, a higher incidence of vaginal irritation is reported in comparison to clotrimazole; even pelvic cramps have been experienced.

 

DAKTARIN 2% gel, 2% powder and solution; GYNODAKTARIN 2% vaginal gel; ZOLE 2% oint, lotion, dusting powder and spray, 1% ear drops, 100 mg vaginal ovules.

 

Oxiconazole

 

Another recently marketed topical imidazole antifungal effective in tinea and other dermatophytic infection, as well as vaginal candidiasis. Local irritation can occur in some patients.

 

OXIZON, ZODERM: oxiconazole 1% with benzoic acid 0.25% cream/lotion; apply topically once or twice daily.

 

 

Ketoconazole (KTZ)

 

It is the first orally effective broad-spectrum antifungal drug, useful in both dermatophytosis and deep mycosis. The oral absorption of KTZ is facilitated by gastric acidity because it is more soluble at lower pH. Hepatic metabolism is extensive; metabolites are excreted in urine and faeces. Elimination of KTZ is dose dependent: t½ varies from 1½ to 6 hours. Penetration in CSF is poor: not effective in fungal meningitis. However, therapeutic concentrations are attained in the skin and vaginal fluid.

 

In spite of relatively short t½, a single daily dose is satisfactory in less severe cases. The usual dose is 200 mg OD or BD; higher doses are sometimes required.

 

FUNGICIDE, NIZRAL, FUNAZOLE, KETOVATE 200 mg tab.

 

FUNGINOC 2% oint, 2% shampoo (for dandruff), KETOVATE 2% cream. NIZRAL 2% cream, 2% lotion; DANRUF 2% shampoo, HYPHORAL 2% lotion.

 

Adverse Effects

 

Ketoconazole is much less toxic than AMB, but more side effects occur than with itraconazole or fluconazole, that have largely replaced it for systemic use.

 

The most common side effects are nausea and vomiting; can be reduced by giving the drug with meals. Others are—loss of appetite, headache, paresthesia, rashes and hair loss.

 

Ketoconazole decreases androgen production from testes, and it displaces testosterone from protein binding sites. Gynaecomastia, loss of hair and libido, and oligozoospermia may be the manifestations. Menstrual irregularities occur in some women due to suppression of estradiol synthesis.

 

A dose-dependent decrease in serum hydrocortisone due to synthesis inhibition has also been noted, but without any clinical manifestations in normal individuals.

 

Mild and asymptomatic elevation of serum transaminases occurs in ~5% patients, but serious hepatotoxicity is infrequent.

 

It is contraindicated in pregnant and nursing women.

 

Interactions

 

H2 blockers, proton pump inhibitors and antacids decrease the oral absorption of KTZ by reducing gastric acidity.

 

Rifampin, phenobarbitone, carbamazepine and phenytoin induce KTZ metabolism and reduce its efficacy.

 

Ketoconazole inhibits cytochrome P450, especially CYP3A4, and raises the blood levels of several drugs including:

 

Phenytoin      

Digoxin

Diazepam      

Cyclosporine

Haloperidol   

Nifedipine and other DHPs

Warfarin       

HIV protease inhibitors

Sulfonylureas 

Statin hypolipidaemics

 

The dangerous interaction with terfenadine, astemizole and cisapride resulting in polymorphic ventricular tachycardia due to excessive rise in plasma levels of these drugs has resulted in withdrawal of these drugs from the market in many countries.

 

Use

 

Orally administered KTZ is effective in dermatophytosis because it is concentrated in the stratum corneum; is an alternative to griseofulvin, but use is restricted due to potential adverse effects.

 

Though effective in monilial vaginitis, oral therapy (for 5–7 days) with KTZ is reserved for recurrent cases or those not responding to topical agents.

 

Systemic Mycosis: Administered orally, KTZ is effective in several types of systemic mycosis, but itraconazole and fluconazole, being more active with fewer side effects, have largely replaced it for these indications except for considerations of cost.

 

KTZ is occasionally used in dermal leishmaniasis and kala azar.

 

Highdose KTZ has been used in Cushing’s syndrome to decrease corticosteroid production.

 

Fluconazole

 

It is a water-soluble triazole having a wider range of activity than KTZ; indications include cryptococcal meningitis, systemic and mucosal candidiasis in both normal and immunocompromised patients, coccidioidal meningitis and histoplasmosis.

 

Fluconazole is 94% absorbed; oral bioavailability is not affected by food or gastric pH. It is primarily excreted unchanged in urine with a t½ of 25–30 hr. Fungicidal concentrations are achieved in nails, vagina and saliva; penetration into brain and CSF is good. Dose reduction is needed in renal impairment.

 

Adverse Effects

 

Fluconazole produces few side effects: mostly nausea, vomiting, abdominal pain, rash and headache.

 

Selectivity for fungal cytochrome P450 is higher; unlike KTZ, it does not inhibit steroid synthesis in man: antiandrogenic and other endocrine side effects have not occurred.

Elevation of hepatic transaminase has been noted in AIDS patients.

 

It is not recommended in pregnant and lactating mothers.

 

Interactions

 

Though it affects hepatic drug metabolism to a lesser extent than KTZ, increased plasma levels of phenytoin, astemizole, cisapride, cyclosporine, warfarin, zidovudine and sulfonylureas have been observed. A few cases of ventricular tachycardia have been reported when fluconazole was given with cisapride. The same caution as with KTZ or itraconazole needs to be applied in co-administering other drugs. H2 blockers and proton pump inhibitors do not effect its absorption.

 

Use

 

Fluconazole can be administered orally as well as i.v. (in severe infections).

A single 150 mg oral dose can cure vaginal candidiasis with few relapses.

 

Oral fluconazole (150 mg/day for 2 weeks) is highly effective in oropharyngeal candidiasis, but is reserved for cases not responding to topical antifungals.

 

Most tinea infections and cutaneous candidiasis can be treated with 150 mg weekly fluconazole for 4 weeks, while tinea unguium requires weekly treatment for up to 12 months.

 

For disseminated candidiasis, cryptococcal/ coccidioidal meningitis and other systemic fungal infections the dose is 200–400 mg/day for 4–12 weeks or longer. It is the preferred drug for fungal meningitis, because of good CSF penetration. Long-term fluconazole maintenance therapy is needed in AIDS patients with fungal meningitis.

 

An eye drop is useful in fungal keratitis. Fluconazole is ineffective in aspergillosis and

 

mucormycosis, and inferior to itraconazole for histoplasmosis, blastomycosis and sporotrichosis.

 

SYSCAN, ZOCON, FORCAN, FLUZON 50, 100, 150, 200 mg caps, 200 mg/100 ml i.v. infusion. SYSCAN 0.3% eye drops.

 

Itraconazole

 

This newer orally active triazole antifungal has a broader spectrum of activity than KTZ or fluconazole; includes some moulds like Aspergillus. It is fungistatic, but effective in immunocompromised patients. Steroid hormone synthesis inhibition is absent in itraconazole, and serious hepatotoxicity is rare.

 

Oral absorption of itraconazole is variable. It is enhanced by food and gastric acid. Itraconazole is highly protein bound, has a large volume of distribution (10L/Kg), accumulates in vaginal mucosa, skin and nails, but penetration into CSF is poor. It is largely metabolized in liver by CYP3A4; an active metabolite is produced which is excreted in faeces; t½ varies from 30–64 hours. Itraconazole is well tolerated in doses below 200 mg/day. Gastric intolerance is significant at 400 mg/day. Dizziness, pruritus, headache and hypokalaemia are the other common side effects. Unsteadiness and impotence are infrequent. Plasma transaminase may rise transiently. However, antiandrogenic and other hormonal adverse effects are not seen. Impaired left ventricular function has been worsened in some patients.

 

Drug Interactions

 

Oral absorption of itraconazole is reduced by antacids, H2 blockers and proton pump inhibitors.

 

Rifampin, phenobarbitone, phenytoin and carbamazepine induce itraconazole metabolism and reduce its efficacy.

 

On the other hand, clarithromycin and HIV protease inhibitors reduce the metabolism of itraconazole and raise its blood levels.

 

Itraconazole inhibits CYP3A4; drug interaction profile is similar to KTZ; ventricular arrhythmias have occurred with terfenadine, astemizole, cisapride and class III antiarrhythmics. Phenytoin, digoxin, sulfonylureas, statins, dihydropyridines, protease inhibitors, warfarin and cyclosporine levels are also increased.

 

Uses

 

Itraconazole is the preferred azole antifungal for most systemic mycosis (see Table 57.1) that are not associated with meningitis. It is superior to fluconazole for histoplasmosis, blastomycosis, sporotrichosis and is the drug of choice for para-coccidioidomycosis and chromomycosis. It also affords some relief in aspergillosis. A dose of 200 mg OD/BD with meals is used for 3 months or more.

 

Vaginal Candidiasis: 200 mg OD for 3 days: as effective as intravaginal clotrimazole. Dermatophytosis: 100–200 mg OD for 7–15 days: more effective than griseofulvin, but less effective than fluconazole.

 

Onychomycosis: 200 mg/day for 3 months. An intermittent pulse regimen of 200 mg BD for 1 week each month for 3 months is equally effective. Relapses have occurred after itraconazole therapy, though it remains in the nail for few months after completion of the course.

 

SPORANOX, CANDITRAL, CANDISTAT, ITASPOR, FLUCOVER 100 mg cap.

 

Important features of drugs used for systemic mycosis are compared in Table 57.2.



 

Voriconazole

 

It is a second generation broad-spectrum triazole introduced lately for difficult to treat fungal infections like invasive aspergillosis, disseminated infections caused by fluconazole resistant Candida, Fusarium infections, and febrile neutropenia not responding to antibacterial therapy. Serious cases are first treated i.v. followed by oral voriconazole. It is metabolized by several CYP isoenzymes (CYP2C19, CYP3A4, etc) and inhibits them as well. The drug interaction profile is similar to itraconazole. Rashes, visual disturbances, QTc prolongation and an acute reaction on i.v. injection are the significant adverse effects.

 

Terbinafine

 

This orally and topically active drug against dermatophytes and Candida belongs to a new allylamine class of antifungals. In contrast to azoles which are primarily fungistatic, terbinafine is fungicidal: shorter courses of therapy are required and relapse rates are low. It acts as a noncompetitive inhibitor of ‘squalene epoxidase’, an early step enzyme in ergosterol biosynthesis by fungi. Accumulation of squalene within fungal cells appears to be responsible for the fungicidal action. The mammalian enzyme is inhibited only by 1000fold higher concentration of terbinafine.

 

Approximately 75% of oral terbinafine is absorbed, but only 5% or less from unbroken skin. First pass metabolism further reduces oral bioavailability. It is lipophilic, widely distributed in the body, strongly plasma protein bound and concentrated in sebum, stratum corneum and nail plates. It is inactivated by metabolism and excreted in urine (80%) and faeces (20%); elimination t½ of 11–16 hr is prolonged to 10 days after repeated dosing.

 

Side effects of oral terbinafine are gastric upset, rashes, taste disturbance. Some cases of hepatic dysfunction, haematological disorder and severe cutaneous reaction are reported. Enzyme inducers lower, and enzyme inhibitors raise its steady-state plasma levels. Terbinafine does not inhibit CYP450.

 

Topical terbinafine can cause erythema, itching, dryness, irritation, urticaria and rashes.

 

Use

 

Terbinafine applied topically as 1% cream or orally 250 mg OD is indicated in tinea pedis/ corporis/cruris/capitis and pityriasis versicolor; 2–6 weeks treatment is required according to the site. Onychomycosis is treated by 3–12 months oral therapy. Efficacy in toe nail infection is 60–80%, which is higher than griseofulvin and itraconazole.

 

It is less effective against cutaneous and mucosal candidiasis: 2–4 weeks oral therapy may be used as an alternative to fluconazole.

 

LAMISIL, SEBIFIN, DASKIL 250 mg tab, 1% topical cream. EXIFINE 125, 250 mg tabs, 1% cream; TERBIDERM 1% cream.

 

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