1 - SYSTEMIC ANTIFUNGAL AGENTS Flashcards
The 5 main antifungal systemic agents for superficial dermatologic indications I.e. Onychomycosis and tinea capitis include:
(1) terbinafine (allylamine)
(2) itraconazole (triazole)
(3) fluconazole (triazole)
(4) griseofulvin (spiro-benzo[b]furan)
(5) ketoconazole (imidazole)
True
Systemic Griseofulvin (spiro-benzo[b]furan) and ketoconazole (imidazole) have limited use in the management of onychomycosis and other dermatomycoses
True
Terbinafine is an allylamine
True
Itraconazole and fluconazole are first generation triazoles
True (voriconazole, posaconazole, and ravuconazole are second generation triazoles)
Voriconazole, posaconazole, and ravuconazole are second generation triazoles
True (Voriconazole and posaconazole have been respectively approved for the treatment and prophylaxis of invasive fungal infections, whereas ravuconazole is still under clinical investigation)
Griseofulvin is a spiro-benzo[b]furan isolated from the mold Penicillium griseofulvin Dierckx
True
Even though the use of griseofulvin (spiro-benzo[b]furan) has declined in the treatment of superficial fungal infections, it is still widely used for the treatment of tinea capitis in children
True
Ketoconazole is an imidazole
True
Antifungal agents fall into 3 structural families:
(1) triazoles - itraconazole, fluconazole, Voriconazole, posaconazole, ravuconazole
(2) imidazoles - ketoconazole
(3) allylamines - terbinafine, naftifine (topical formulation only)
True (triazoles and imidazoles are subsets of the broader category of azole antifungals)
Itraconazole (triazole) has a bioavailability of 55% and is extensively metabolised by the liver; in contrast to fluconazole (another triazole) which has a bioavailability of >90% and undergoes little hepatic metabolism where much of the dose is excreted as the unchanged parent drug
True (itraconazole should be used with caution in patients with liver disease)
Terbinafine (allylamine) has a bioavailability of 40% and is extensively metabolised by the liver
True (terbinafine should be used with caution in patients with liver disease)
In patients with liver cirrhosis, terbinafine (allylamine) clearance is reduced by approximately 50% compared to normal volunteers and careful monitoring is required
True (terbinafine is metabolised by the liver)
In patients with liver cirrhosis, the itraconazole (triazole) elimination half-life showed a 2-fold increase and careful monitoring is required
True (itraconazole is metabolised by the liver)
70% of Terbinafine (allylamine) is excreted in the kidneys
True (terbinafine clearance is decreased by about 50% in patients with renal insufficiency)
Itraconazole (triazole) bioavailability is slightly reduced for subjects with renal insufficiency
True (use itraconazole with caution in renal impairment)
With the exception of fluconazole (first generation triazole), other antifungal agents I.e. terbinafine (allylamine), itraconazole, Voriconazole, posaconazole (triazoles); and griseofulvin (spiro-benzo[b]furan) are mainly protein bound and metabolised by the liver
True (only 11-12% of fluconazole is membrane bound and undergoes little first pass hepatic metabolism as it is much less lipophilic but rather more hydrophilic than the other Azoles which accounts for its low protein binding)
With the exception of the second generation triazole posaconazole which is excreted in the faeces, the other antifungal agents I.e. terbinafine (allylamine), Itraconazole, fluconazole, Voriconazole (triazoles); and griseofulvin (spiro-benzo[b]furan) are excreted in the kidneys
True
Terbinafine (allylamine) is delivered to the stratum corneum by passive DEJ diffusion through sebum and through incorporation of drug from migrating basal keratinocytes
True
Terbinafine (allylamine) is not detected in eccrine sweat
True (this is in contrast to itraconazole which becomes detected in sweat within 24 hours and is extensively excreted in sebum unlike the other antifungal agents griseofulvin, ketoconazole and fluconazole)
Itraconazole (triazole) is delivered to the skin as a result of passive diffusion from the plasma to the keratinocytes with strong drug adherence to keratin
True
Itraconazole (triazole) becomes detectable in sweat within 24 hours
True (this is in contrast to terbinafine which is not detectable in sweat)
There is extensive excretion of itraconazole (triazole) into sebum
True (whereas excretion of itraconazole into sweat is minimal; in contrast to griseofulvin, and the imidazole ketoconazole)
Itraconazole (triazole) is eliminated as the stratum corneum renews itself and when the hair and nails grow out
True (may persist in the stratum corneum for 3-4 weeks after discontinuation of therapy)
Fluconazole (triazole) accumulates in the stratum corneum through sweat and by direct diffusion through the dermis and epidermis
True (excretion in the sebum may be more limited) - fluconazole is effective in the treatment of cutaneous fungal infections given as a once weekly dose
Griseofulvin (spiro-benzo[b]furan) is metabolised by the liver and mainly excreted in the kidneys
True
Terbinafine (allylamine) and itraconazole (triazole) diffuses into the nail plate via both the nail matrix and nail bed
True
Fluconazole (triazole) diffuses from the nail bed to the nail plate
True
The faster clearance of systemic antifungal agents from the fingernails than toenails is due to the faster outgrowth of fingernails
True
There is potential for ongoing improvement in onychomycosis well after discontinuation of active systemic antifungal therapy as the drug is still detectable in the nail plate beyond active drug therapy
True
Terbinafine (allylamine) is delivered to the hair shaft via sebum and is therefore more effective against tinea capitis caused by endothrix organisms (Trichophyton tonsurans) than against ectothrix infections (Microsporum canis) as terbinafine accumulates preferentially in the hair shaft
True
Itraconazole (triazole) is delivered to the hair by 2 routes:
(1) via the sebum
(2) incorporation into the hair follicle
True
The systemic antifungals interfere with the enzymes involved in the manufacture of ergosterol, a crucial component of the fungal cell membrane
True (deficiency of ergosterol interferes with membrane function and lead to an arrest in cell growth which may be fungicidal or fungistatic)
Terbinafine and topical naftifine (allylamine) inhibit squalene epoxidase, leading to accumulation of squalene followed by a subsequent deficiency of ergosterol
True
Squalene and lanosterol are 2 of the most important precursors that lead to formation of ergosterol, an essential component of all fungal cell wall membranes
True (antifungal agents inhibit the enzymes involved in converting these 2 precursors to ergosterol)
Step 1 - squalene epoxidase = squalene > precursors of lanosterol
Step 2 - 14-alpha demethylase = precursors of lanosterol > 14-alpha demethyl lanosterol > ergosterol (essential component of all fungal cell wall membranes)
The 2 enzymes squalene epoxidase and 14-alpha demethylase play a role in converting squalene > ergosterol (the essential component of fungal cell membranes)
True
Step 1 - squalene epoxidase = squalene > precursors of lanosterol
Step 2 - 14-alpha demethylase = precursors of lanosterol > 14-alpha demethyl lanosterol > ergosterol (essential component of all fungal cell wall membranes)
Squalene epoxidase converts squalene to precursors of lanosterol
True
Step 1 - squalene epoxidase = squalene > precursors of lanosterol
Step 2 - 14-alpha demethylase = precursors of lanosterol > 14-alpha demethyl lanosterol > ergosterol (essential component of all fungal cell wall membranes)
14-alpha demethylase converts lanosterol to 14-alpha demethylase lanosterol
True
Step 1 - squalene epoxidase = squalene > precursors of lanosterol
Step 2 - 14-alpha demethylase = precursors of lanosterol > 14-alpha demethyl lanosterol > ergosterol (essential component of all fungal cell wall membranes)
Both allylamine (terbinafine and naftifine) and benzylamine (butenafine) antifungal agents inhibit the enzyme squalene epoxidase, leading to accumulation of squalene metabolites which are fungicidal in vitro
True
Step 1 - squalene epoxidase = squalene > precursors of lanosterol
Step 2 - 14-alpha demethylase = precursors of lanosterol > 14-alpha demethyl lanosterol > ergosterol (essential component of all fungal cell wall membranes)
Both triazole (itraconazole, fluconazole) and imidazole (ketoconazole) antifungal agents inhibit 14-alpha demethylase, leading to increase in lanosterol and reduced ergosterol synthesis, which is fungistatic in vitro
True
Step 1 - squalene epoxidase = squalene > precursors of lanosterol
Step 2 - 14-alpha demethylase = precursors of lanosterol > 14-alpha demethyl lanosterol > ergosterol (essential component of all fungal cell wall membranes)
Accumulation of squalene metabolites is fungicidal in vitro (effect of allylamine and benzylamine antifungal agents inhibiting squalene epoxidase)
True
Step 1 - squalene epoxidase = squalene > precursors of lanosterol
Step 2 - 14-alpha demethylase = precursors of lanosterol > 14-alpha demethyl lanosterol > ergosterol (essential component of all fungal cell wall membranes)
Accumulation of lanosterol is fungistatic in vitro (effect of azole antifungal agents inhibiting 14-alpha demethylase)
True
Step 1 - squalene epoxidase = squalene > precursors of lanosterol
Step 2 - 14-alpha demethylase = precursors of lanosterol > 14-alpha demethyl lanosterol > ergosterol (essential component of all fungal cell wall membranes)
The enzyme 14-alpha demethylase is cytochrome P450 dependant, therefore explaining the role of the triazoles (itraconazole, fluconazole) and imidazoles (ketoconazole) as enzyme inhibitors I.e. these Azoles inhibit 14-alpha demethylase in the phase I metabolism systems
True
Step 1 - squalene epoxidase = squalene > precursors of lanosterol
Step 2 - 14-alpha demethylase = precursors of lanosterol > 14-alpha demethyl lanosterol > ergosterol (essential component of all fungal cell wall membranes)
The fungistatic effects of azole antifungals (due to inhibition of 14-alpha demethylase) may explain the incidence of azole-resistant organisms following prophylaxis or long-term therapy
True
Terbinafine (allylamine) and itraconazole (triazole) are similarly effective against the main Trichophyton species T. rubrum, T. mentagrophytes and T. tonsurans; as well as Microsporum species and Epidermophyton floccosum
True (in contrast to Fluconazole triazole agent)
The triazoles (itraconazole and fluconazole) are more effective than terbinafine (allylamine) against Candida alibi and and C. parapsilosis
True
Terbinafine (allylamine) is FDA approved for the treatment of dermatophyte onychomycosis of the toenails and/or fingernails in adults
True
Granule formulation of Terbinafine (allylamine) is also approved for tinea capitis in patients 4 years and older
True
Itraconazole (triazole) is FDA approved for the treatment of dermatophyte onychomycosis of the toenails and/or fingernails in immunocompetent adults
True
Itraconazole (triazole) is also FDA approved in the treatment of systemic mycoses such as blastomycosis, histoplasmosis and aspergillosis in immunocompromised and immunocompetent patients intolerant or refractory to amphotericin B
True
Fluconazole (triazole) is indicated for the treatment of vaginal, oropharyngeal and oesophageal candidiasis, and cryptococcal meningitis
True
Griseofulvin (spiro-benzo[b]furan) is indicated for the treatment of dermatophyte infections of the skin, scalp and nails and the use of griseofulvin is not justified for the treatment of tinea infections that would be expected to respond satisfactorily to topical antifungals
True
Griseofulvin (spiro-benzo[b]furan) is not effective in the treatment of pityriasis versicolor, bacterial infections, candidiasis, or deep mycotic infections
True
Voriconazole (second generation triazole) is indicated for the treatment of invasive aspergillosis, oesophageal candidiasis, candidaemia in non-neutropenic patients and other disseminated candida infections in patients intolerant of or refectory to other therapy
True (posaconazole is indicated for similar conditions)
Resolution of dermatophyte onychomycosis (Trichophyton species, Microsporum species, Epidermophyton species) typically requires oral therapy
True
Although griseofulvin is approved for tinea infections of the nails, it’s affinity for keratin is low and long term therapy of at least 9-12 months is required
True (treatment efficacy is also low, and the newer azole and allylamine antifungals have largely replaced griseofulvin for Onychomycosis)
Treatment efficacy of griseofulvin for onychomycosis is low due to the low affinity for keratitis, therefore the newer azole and allylamine antifungals have largely replaced griseofulvin for Onychomycosis
True
Terbinafine 250mg daily for 6-12 weeks is recommended for fingernail and toenail onychomycosis
True
The FDA approved regimen for toenail onychomycosis in immunocompetent patients with or without fingernail involvement is continuous itraconazole 200mg daily for 12 weeks
True (when only fingernails are infected, pulse itraconazole 200mg BD for 1 week per month for a total of 2 pulses; although pulse therapy for 3-4 pulses has become a standard for toenail onychomycosis as well)
Fluconazole (triazole) is used in certain countries for onychomycosis consisting of 150-300mg weekly dose until the abnormal appearing nail has grown out
True
Non-dermatophyte moulds and Candida species are rarely diagnosed as causative organisms in onychomycosis infections and are usually associated with immunocompromised status (chronic mucocutaneous candidiasis, HIV infection, use of immunosuppressive drugs)
True
Compared to its efficacy against dermatophytes, terbinafine (allylamine) is less effective when the causative agent of the onychomycosis is Candida species, particularly C. albicans
True
Itraconazole (triazole) continuous regimens and pulse regimens have been effective against Candida onychomycosis
True
Experience with fluconazole (triazole) for the treatment of onychomycosis caused by non-dermatophyte moulds is limited
True
Fluconazole (triazole) has been effective against Candida onychomycosis with a longer treatment course needed for toenails
True
Oral antifungals have been a great benefit in the effective treatment of tinea capitis, they are able to penetrate the infected hair shaft where topical therapies cannot
True (although topical therapies such as ketoconazole shampoo, selenium sulfide and povidone-iodine can also have an important role as adjunct therapy)
Griseofulvin and terbinafine are the only antifungals approved for use in tinea capitis
True
Terbinafine = endothrix organisms I.e. Trichophyton
Griseofulvin = ectothrix organisms I.e. Microsporum
Terbinafine seems to be superior than griseofulvin for the treatment of Trichophyton tonsurans (endothrix) tinea capitis infections whereas Griseofulvin remains the treatment of choice for Microsporum canis (ectothrix) tinea capitis infections
True (this observation may reflect the different infection patterns of the organisms in that Trichophyton infections are endothrix I.e. Inside the hair shaft, where drug accumulation may help eradicate infection; whereas Microsporum are ectothrix I.e. Outside the hair shaft, requiring the drug to be secreted to the hair surface via sweat or sebum)
As children have little sebum secretion prior to puberty, terbinafine may not reach ectothrix infections caused by Microsporum species adequately, whereas its incorporation into the hair shaft is effective in endothrix infections caused by Trichophyton species
True
Trichophyton species causes endothrix tinea capitis infections
True (endothrix = Inside the hair shaft)
Microsporum species causes ectothrix tinea capitis infections
True (ectothrix = outside the hair shaft)
Griseofulvin and the Azoles tend to be secreted in sweat and may reach ectothrix tinea capitis infections more effectively than terbinafine which is secreted in sebum
True (ectothrix = outside the hair shaft)
Successful treatment of tinea corporis, tinea cruris and tinea pedis is provided by topical antifungal medications and oral antifungals are not generally approved for these indications
True (oral antifungals I.e. Griseofulvin may be practical where the tinea involvement is extensive and application of a topical is not feasible)
Griseofulvin is indicated for the treatment of tinea corporis, tinea cruris, tinea pedis that would not be expected to respond satisfactorily to topical antifungals
True (Griseofulvin is first line oral antifungal for tinea corporis/cruris/pedis after topicals; followed by second line oral antifungal Ketoconazole)
Oral ketoconazole may be used for the treatment of severe recalcitrant cutaneous dermatophyte infections in patients who have not responded to topical therapy or oral griseofulvin, or who are unable to take griseofulvin
True (strongly recommended that liver transaminases be monitored should ketoconazole be used in these uncommon circumstances)
Pityriasis versicolor and seborrheic dermatitis are most often successfully treated with topical therapy, although oral therapy is occasionally used when large areas of the body are affected
True
The Azoles Itraconazole, fluconazole (triazole) and ketoconazole (imidazole) may be used for pityriasis versicolor although ketoconazole is reserved for severe recalcitrant disfiguring or disabling disease in patients who have not responded to topical therapy
True
A single dose of 400mg oral itraconazole monthly for 6 months may be useful as prophylaxis for pityriasis versicolor patients who suffer recurrent outbreaks
True
Ketoconazole (imidazole), itraconazole (triazole) and terbinafine (allylamine) may be useful for seborrheic dermatitis
True (facial lesions did not benefit from terbinafine)
With the exception of tinea capitis, most superficial dermatophyte infections are infrequently diagnosed in children
True
Oral antifungal use are typically not formally approved for use in children due to low incidence of fungal infections in children (with the exception of tinea capitis), although paediatric use has been documented widely in the literature and demonstrate a safety profile similar to use in adults
True
When using oral antifungals in children, dosing regimens are typically adjusted by weight
True
Where possible, topical antifungals are preferred over oral antifungals for dermatophyte onychomycosis in children
True (if oral antifungals are required for onychomycosis in children, terbinafine and itraconazole are safe and effective)
Terbinafine (allylamine) is not recommended for patients with chronic or active liver disease
True (metabolised by the liver)
Terbinafine (allylamine) may not be a suitable choice for patients with renal impairment
True (renal excretion, and terbinafine clearance is reduced by 50% in renal impairment)
Terbinafine (allylamine) is a CYP2D6 inhibitor and should be used with caution with CYP2D6 substrates
True CYP2D6 substrates: TCA = Doxepin and amitriptyline SSRI Beta-blockers Antiarrhythmics class 1C (flecainide) Monoamine oxidase inhibitors
Itraconazole (triazole) should not be administered in patients with evidence of ventricular dysfunction such as congestive cardiac failure, as temporarily decreased cardiac contractility has been noted in a healthy volunteer study
True (similarly caution is advised when using any of the Azoles in patients with potentially proarrhythmic conditions)
For both itraconazole and fluconazole (triazoles), serious cardiovascular events such as QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest and sudden death has been noted; therefore concurrent cisapride, pimozide, and quinidine which are known to prolong the QT interval is contraindicated with all the Azoles
True (including Voriconazole and posaconazole)
Itraconazole (triazole) is strongly discouraged in patients with active liver disease, elevated/abnormal liver enzymes, or previous experience of liver toxicity with other drugs
True (metabolised by the liver) - caution is advised when any Azoles are used in these patient populations (including fluconazole even though it has little liver metabolism); monitoring before and during therapy is suggested for Azoles
Caution should be use when administering an azole agent to patients who have exhibited past sensitivity to another azole agent, as there may be some potential for cross-reaction between azole drugs
True
Itraconazole (first generation triazole) and posaconazole (second generation triazole) are CYP3A4 inhibitors
True
Itraconazole, posaconazole, ketoconazole = CYP3A4 inhibitor
Fluconazole = CYP3A4 and CYP2C9 inhibitors
Voriconazole = CYP3A4, CYP2C9, CYP2C19 inhibitors
Fluconazole (triazole) is to be used with caution in patients with renal impairment
True (excreted in the kidneys)
Fluconazole (first generation triazole) capsules contain lactose
True (caution with lactose intolerant patients)
Voriconazole (second generation triazole) tablets contain lactose
True (caution with lactose intolerant patients)
Fluconazole (first generation triazole) and Voriconazole (second generation triazole) are both CYP3A4 and CYP2C9 enzymes, with Voriconazole also a CYP2C19 inhibitor
True
Itraconazole, posaconazole, ketoconazole = CYP3A4 inhibitor
Fluconazole = CYP3A4 and CYP2C9 inhibitors
Voriconazole = CYP3A4, CYP2C9, CYP2C19 inhibitors
K, Mg and Ca levels ought to be corrected before starting the second generation triazoles Voriconazole and Posaconazole
True
In contrast to ketoconazole (imidazole), Fluconazole (triazole) at 25-50mg/day showed no significant effect on testosterone levels in healthy males
True
Headache is a common adverse effect with Terbinafine (allylamine) and Itraconazole (triazole) use
True (generally mild and transient)
GI symptoms of diarrhoea, dyspepsia, abdominal pain, nausea and flatulence are common adverse effects with Terbinafine (allylamine) and Itraconazole (triazole) use
True (generally mild and transient)
Rash, pruritus and urticaria are common adverse effects with Terbinafine use
True (generally mild and transient)
Liver enzyme abnormalities greater than or equal to 2X the upper limit of normal is a common adverse effect with Terbinafine (allylamine) and Itraconazole (triazole) use
True (generally mild and transient)
Taste disturbance is a common adverse effect with Terbinafine use
True (generally mild and transient)
Visual disturbance is a common adverse effect with Terbinafine use
True (generally mild and transient)
Severe skin reactions such as erythema multiforme, TEN and SJS are rare adverse effects with Terbinafine use
True (may present initially as a serum sickness-like reaction)
Idiosyncratic hepatobiliary dysfunction is a rare adverse effect with Terbinafine use, and typically develops within 4-6 weeks of treatment initiation and has both features of hepatocellular necrosis (transaminases) and cholestatic injury (GGT and ALP)
True (in most cases liver function returns to normal months after stopping terbinafine)
Symptoms of Depression is a rare adverse effect with Terbinafine use
True
Terbinafine infrequently precipitates or exacerbates cutaneous and systemic lupus erythematosus and should be discontinued in patients showing signs of LE
True
Haematologic abnormalities such as neutropenia, thrombocytopenia are rare adverse effects from both Terbinafine (allylamine), itraconazole and fluconazole (triazoles)
True (consider monitoring FBC in patients with known or suspected immunodeficiency on prolonged therapy I.e. Longer than 6 weeks)
Terbinafine (allylamine) is rated as pregnancy category B and is not recommended for use in pregnant or nursing women
True
In contrast to ketoconazole (imidazole), no effects on testosterone levels are detected with terbinafine (allylamine) use in a healthy male population
True
Rash and pruritus are common adverse effects with Itraconazole use
True
When Itraconazole is given as a pulse regimen, it may be associated with an improved adverse effect profile compared to the continuous regimen
True (abnormal LFTs lower with pulse therapy)
Severe skin reactions (angioedema, erythema multiforme and SJS) are very rarely reported with Itraconazole
True
Itraconazole is rated as pregnancy category C and is not to be used in women who are pregnant, planning a pregnancy or nursing
True
In contrast to ketoconazole (imidazole), use of Itraconazole (triazole) showed no effect on androgen levels and that alteration of male reproduction is unlikely
True
Taste disturbance is a rare adverse effect with Itraconazole use
True
Visual disturbance is a rare adverse effect with Itraconazole use
True
Neurological symptoms such as peripheral neuropathy, paraesthesia and hyposthesia are rare adverse effects with Itraconazole use
True
Fluconazole (triazole) has shown a favourable adverse event profile and is similar in both adult and paediatric patients
True
Headache is a common adverse effect with Fluconazole, Voriconazole and Posaconazole (triazoles) use
True (just like terbinafine and itraconazole)
GI upset including nausea, vomiting, abdominal pain and diarrhoea are common adverse effects with Fluconazole, Voriconazole and Posaconazole (triazoles) use
True (just like terbinafine and itraconazole)
Taste perversion is a common adverse effect with Fluconazole (triazole) use
True (both terbinafine and itraconazole may also cause taste disturbance)
Skin rash and pruritus are common adverse effects with Fluconazole, Voriconazole and Posaconazole (triazoles) use
True (similar to terbinafine and itraconazole)
Exfoliative skin disorders such as TEN, SJS, angioedema and erythema multiforme are rare adverse effects with Fluconazole and Voriconazole (triazoles) use
True (similar to terbinafine)
Self limiting hepatic and biliary abnormalities were noted in 0.5% of patients using fluconazole (triazole)
True
Elevated enzyme levels (particularly AST) occurred in 10% of subjects on chronic fluconazole therapy
True
Fluconazole, Voriconazole and posaconazole (triazoles) should not be used in women who are pregnant, planning a pregnancy or nursing
True (Fluconazole is rated as pregnancy category D with birth defects noted by a few case reports in subjects using a high dose of 400-800mg/day) - Azoles are not to be used in general in this population
Skin photosensitivity leading to cases of melanoma and SCC is a rare adverse effect with Voriconazole (second generation triazole) use
True
Visual disturbances is a rare adverse effect with Voriconazole (second generation triazole) use
True (similar to first generation triazole itraconazole)
Terbinafine (allylamine) has relatively few drug interactions compared with the Azoles
True (CYP2D6 inhibitor) CYP2D6 substrates: TCA = Doxepin and amitriptyline SSRI Beta-blockers Antiarrhythmics class 1C (flecainide) Monoamine oxidase inhibitors
The Azole drugs (itraconazole, fluconazole, Voriconazole, posaconazole, ketoconazole) interfere to varying degrees with CYP3A4
True (fluconazole and Voriconazole also inhibit other CYP Isoforms)
Itraconazole, posaconazole, ketoconazole = CYP3A4 inhibitor
Fluconazole = CYP3A4 and CYP2C9 inhibitors
Voriconazole = CYP3A4, CYP2C9, CYP2C19 inhibitors
Drugs metabolised by the various CYP Isoforms/pathways (I.e. substrates of these CYP enzyme systems) may have drug concentrations altered when given concomitantly with an azole antifungal agent; hence monitoring or dose reduction may be indicated
True
Itraconazole, posaconazole, ketoconazole = CYP3A4 inhibitor
Fluconazole = CYP3A4 and CYP2C9 inhibitors
Voriconazole = CYP3A4, CYP2C9, CYP2C19 inhibitors
The most notable CYP2C9 interaction with the Azoles (particularly fluconazole and voriconazole) are through co-administration with warfarin which can lead to significant increases in INR values and excessive anticoagulation
True
Itraconazole, posaconazole, ketoconazole = CYP3A4 inhibitor
Fluconazole = CYP3A4 and CYP2C9 inhibitors
Voriconazole = CYP3A4, CYP2C9, CYP2C19 inhibitors
When itraconazole, and to a degree low dose fluconazole (both CYP3A4 inhibitors) and CsA (CYP3A4 substrate) are given concomitantly, careful monitoring of CsA concentration and serum creatinine is recommended
True
Itraconazole, posaconazole, ketoconazole = CYP3A4 inhibitor
Fluconazole = CYP3A4 and CYP2C9 inhibitors
Voriconazole = CYP3A4, CYP2C9, CYP2C19 inhibitors
Blood glucose levels may require careful monitoring when oral hypoglycaemic agents are used concomitantly with Azoles
True (oral hypoglycaemic agents are metabolised by the CYP system and loss of efficacy may result in reduced blood glucose control)
Itraconazole, posaconazole, ketoconazole = CYP3A4 inhibitor
Fluconazole = CYP3A4 and CYP2C9 inhibitors
Voriconazole = CYP3A4, CYP2C9, CYP2C19 inhibitors
Agents with narrow therapeutic window (phenytoin, theophylline) may need careful monitoring of drug levels as interactions secondary to Azoles may more easily predispose the patient to significant adverse events
True
Itraconazole, posaconazole, ketoconazole = CYP3A4 inhibitor
Fluconazole = CYP3A4 and CYP2C9 inhibitors
Voriconazole = CYP3A4, CYP2C9, CYP2C19 inhibitors
Co-administration of itraconazole (triazole and a potent CYP3A4 inhibitor) with cisapride (protease inhibitor), pimozide (antipsychotic agent), quinidine, dofetilide (both antiarrhythmic agents) or levomethadyl (narcotic) is contraindicated as levels of these drugs may become elevated and cause serious cardiovascular events such as QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest and/or sudden death
True (although cisapride is no longer available in many countries, these contraindications may still be relevant to others)
Co-administration of ketoconazole, fluconazole, voriconazole or posaconazole (Azoles and CYP3A4 inhibitors) with cisapride (protease inhibitor), pimozide (antipsychotic agent), quinidine, (antiarrhythmic agent), terfenadine or astemizole (antihistamines) is contraindicated as levels of these drugs may become elevated and cause serious cardiovascular events such as QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest and/or sudden death
True (cisapride, terfenadine, astemizole are no longer available in many countries, these contraindications may still be relevant to others)
Co-administration of the Azoles (mainly CYP3A4 inhibitors) with benzodiazepines may increase the drug levels/enhance the effects of benzodiazepines requiring monitoring
True (benzodiazepines are substrates/metabolised by the CYP enzyme system in the liver)
Itraconazole, posaconazole, ketoconazole = CYP3A4 inhibitor
Fluconazole = CYP3A4 and CYP2C9 inhibitors
Voriconazole = CYP3A4, CYP2C9, CYP2C19 inhibitors
Pre-exisiting liver disease should be assessed before prescribing terbinafine (serum transaminases AST and ALT)
True (terbinafine undergoes significant first pass metabolism by the liver and liver disease may cause toxicity due to inability to metabolise the drug)
Patients on terbinafine should be instructed to report any symptoms of liver dysfunction such as persistent nausea, anorexia, fatigue, vomiting, right upper abdominal pain or jaundice with dark urine and pale stools
True (terbinafine has been associated with idiosyncratic biliary dysfunction within 4-6 weeks on initiating therapy) - patients reporting such symptoms should discontinue terbinafine and have complete liver profile performed
Physicians should consider monitoring FBC in patients with known or suspected immunodeficiency who are administered oral terbinafine (allylamine) for longer than 6 weeks
True (may rarely cause haematologic abnormalities such as neutropenia, thrombocytopenia)
Patients on terbinafine should be instructed to report taste disturbance
True (rare adverse effect)
Patients on terbinafine should be instructed to report depressive symptoms
True (rare adverse effect)
Patients on terbinafine should be instructed to report a progressive rash
True (may progress to serious exfoliative drug rash)
When giving Azoles, LFTs monitoring should be considered for any subject, and should be performed for any subject with pre-existing hepatic dysfunction or previous experience of liver toxicity with other medications
True
During prolonged griseofulvin therapy, periodic assessment of renal, hepatic and haematologic function should be performed
True
Clinicians dealing with common cutaneous conditions should ideally avoid use of ketoconazole for more than 7-10 days (monitoring not needed for this duration of therapy)
True (marked hepatic adverse effects than other antifungal agents)
