Julia Agustin | N5 Dermatologicals

ANTIFUNGALS
I. Introduction
Mycoses are common among the population generally affecting the skin and mucous
membranes. From an unthreatening health problem, fungal infections can also be possibly fatal
once they gain access to the systemic circulation. Factors like spread of AIDS and use of
immunosuppressant are few of the factors for increasing prevalence of opportunistic infections,
making the older people, pregnant women, wound victims and diabetic patients most
vulnerable to it.
Fungi are specific in their choice of preferred location. They are mainly grouped in four,
a) yeasts, b) yeast-like fungi that produce structure resembling a mycelium, c) filamentous fungi
that produce a structure resembling a mycelium d) dimorphic fungi which may grow as either
yeast or filamentous fungi depending on nutritional constraints. The efficacy of antifungal drugs
vary for each group.
Again, fungal infections can be superficial or systemic and so the drug preparation
would depend on this factor. Therapeutic agents come in two different classification: first would
be composed of naturally occurring antifungal antibiotics and the second would be the synthetic
drugs.

II. Antifungal Antibiotics

A. Amphotericin
Pharmacokinetics
given orally for infection of the upper GIT
also available in topical preparations
slow IV injection complexed with liposomes or other lipid-containing preparations -
improves pharmacokinetics and reduce side effects
penetrates tissues and membranes poorly
found in concentrations of inflammatory exudates
when meninges get inflamed, it can readily cross through the blood-brain barrier
metabolized via kidneys and excreted in urine
Pharmacodynamics
site of action: fungal cell membranes
interferes with permeability and transport actions
creates a transmembrane ion channel, causing gross disturbances in ion balance
including the loss of intracellular K+
selective action: fungi = some protozoa > mammalian cells
great avidity with ergosterol, sterol found in fungi and protozoa which performs the
same function of cholesterol to animal cells
Pharmacotherapeutics
gold standard for treating disseminated infections
synergistic combination: enhances effect of flucytosine
Toxicology
 renal toxicity - may recover after treatment has stopped but damage to glomerular
filtration may remain
hypokalaemia, hypomagnesaemia, anaemia, impaired hepatic function,
thrombocytopenia, anaphylactic reactions
intrathecal injections may cause neurotoxicity
topical application cause skin rash

B. Griseofulvin
Pharmacokinetics
given orally
poorly soluble in water
taken up selectively by newly formed skin and concentrated in urine
plasma half-life: 24 hours
potently induces cyctochrome P450 enzymes
Pharmacodynamics
interferes with mitosis by binding to fungal microtubules
Pharmacotherapeutics
can be used to treat dermatophyte infection of skin or nails when local treatment
becomes ineffective
Toxicology
infrequent
gastrointestinal upsets, headache, photosensitivity, allergic reactions
contraindicated to pregnant women

C. Echinocandins
Pharmacokinetics
Caspofungin and Anidulafungin are gicen intravenously, once daily
Pharmacodynamics
inhibit synthesis of of 1,3--glucan, necessary for maintaining the structure of
fungal cell walls
Pharmacotherapeutics
Caspofungin has been proven effective for treatment of candidiasis and invasive
aspergillosis which are refractory to amphotericin
Anidulafungin used mainly for invasice candidiasis
Toxicology
nausea, vomiting, diarrhoea, skin rash

III. Synthetic Drugs

A. Azoles
Pharmacokinetics
Ketoconazole
first azole given orally for systemic fungal infections
well absorbed in GIT
 does not reach therapeutic concentrations in the CNS unless high doses are given
inactivated in the liver
excreted in bile and urine
plasma half-life: 8 hours
Fluconazole
orally or intravenously
reaches high concentrations in cerebrospinal fluid, ocular fluids, vaginal tissue,
saliva, skin, nails
plasma half-life: app. 25 hours
excreted unchanged in the urine
Itraconazole
may be given orally but undergoes extensive hepatic metabolism
intravenously administered when formulated within pockets of -cyclodextrin to
prevent problems in GIT absorption
does not penetrate cerebrospinal fluid
half-life: 36 hours
excreted in urine
Miconazole
given topically for oral and GIT infections
should be given every 8 hrs due to short plasma life
reaches therapeutic concentration in bone, joints, and lung tissue
does not reach CNS
inactivated in the liver

Pharmacodynamics
inhibit fungal cytochrome P450 3A enzyme, lanosine 14a-demethylase, responsible
for converting lanosterol to ergosterol
depletion of ergosterol level causes inhibition of replication as net effect
inhibit transformation of candida yeast cells into hyphae, the invasive and
pathogenic form of parasite
fluconazole used to treat types of fungal meningitis

Pharmacotherapeutics
Ciclosporin and astemizole increase plasma concentrations of ketoconazole, the
interacting drug or both
Rifampicin decrease absorption of ketoconazole
Itraconazole used for range of dermatophytes

Toxicology
Ketoconazole
relapse, liver toxicity, gastro disturbances, pruritus, inhibition of adrenocortical
steroid and testosterone synthesis with high doses
Fluconazole
 generally mild
nausea, headache, abdominal pain
effect to AIDS patients: exfoliative skin lesions
Itraconazole
hepatoxicity, Stevens-Johnson syndrome
Miconazole
gastrointestinal disturbances, pruritus, blood dyscrasias, hyponatraemia
contraindicated to patients with impaired hepatic function