Pharmacology of Antifungals Flashcards
Fungus: Review
Mainly seen as opportunistic or “superinfections”
* Cutaneous infections:
* Systemic infections:
common, chronic, seldom dangerous
difficult to diagnose, treat, and often lethal
Visible fungal infection of the mouth can tell you:
(2)
- Immune status
- Drugs they are taking
● Daily oral steroids?
● Immunosuppressive drugs: transplant?
● Antibiotics, Augmentin?
● Leukemia, lymphoma?
● Chemotherapy drugs – neutropenia?
● HIV/AIDS?
Opportunistic mycoses
Treating Fungal Infections- Selective Toxicity
(2)
- Rigid cell walls
contain chitin
and the cell
membrane
contains
ergosterol - Selective toxicity
achieved by
targeting
ergosterol
Medically Important Fungal Groups
(3)
Molds (Dermatophytes) |
Yeasts (Candida, Cryptococcus, Aspergillus)
Dermatophytes:
Dermatophytes:
(4)
Subgroup of molds that live on skin.
Normal inhabitants of skin, contagious, spread by contact.
Produce keratinases that dissolve keratin
Hyphal filaments penetrate into keratin
Invades hair shafts & nail beds
►Dermatophyte (Tinea) infections affect
keratinized tissues
– skin, nails, hair, etc.
Mold: Dermatophytes
Three common pathogenic dermatophytes:
(3)
Trichophyton Common
Epidermophyton
Microsporum
“Tinea” diseases: (“cutaneous mycoses”)
Tinea capitis –
Tinea corporis –
Tinea pedis –
Tinea cruris –
Tinea unguium –
Tinea capitis – scalp, common in children
Tinea corporis – body
Tinea pedis – athlete’s foot
Tinea cruris – groin
Tinea unguium – toenails (onychomycosis)
ALLYLAMINES
(2)
»Terbinafine (Lamisil oral or topical)
»Naftifine (Naftin)
ALLYLAMINES
* Binds/inhibits squalene epoxidase
(2)
- Squalene precursors build up and are also
toxic aiding toxicity - Requires actively growing fungi
ALLYLAMINES
* Fungicidal against Dermatophytes Only.
(3)
- Weak fungistatic activity against Candida
- Little drug interaction potential
- Few side-effects
Yeast: Candida albicans
Candida:
(2)
Most common fungal infection in mouth
» C. albicans normal habitat is the human oral cavity
» propensity to invade and cause disease when an imbalance is created
Oropharyngeal candidiasis (thrush)
Symptoms: (4)
Many patients are —
Immunosuppressed patients with thrush often have concomitant —
cottony feeling in the mouth, loss of taste, and/or painful eating and
swallowing.
asymptomatic
Candida esophagitis
Yeast: Candida albicans
Treatment
Oropharyngeal (Tx: 10-days duration)
(3)
- Clotrimazole troches (one 10-mg troche dissolved slowly five times daily)
- difficult to adhere, poor choice in xerostomia, contains sucrose, DDIs in HIV, taste alterations
- Miconazole mucoadhesive buccal tabs (50mg 1xdaily apply to mucosal surface
over canine fossa) - Daily dosing, tasteless & sugar free, more expensive, best patient compliance.
- Nystatin swish and swallow (400,000 to 600,000 units four times daily)
- not always palatable, contains sucrose, concerning for dental caries over prolonged time periods
- Good in xerostomia, good in HIV, co-dispense lozenge if has appliances
Yeast: Candida albicans
Treatment
Esophagitis
(1)
- Fluconazole - 400 mg as a loading dose and then 200 to 400 mg daily for 14 to 21
days given orally
Clotrimazole (Mycelex)
Pro: (1)
Con: (6)
Pro:
* Highly effective
Con:
* Ease of use (5x /day)
* Expense
* Drug interactions
possible
* Irritating to mucosa
* Alters taste
* Contains sugar
Miconazole (Oravig)
Pro: (4)
Con: (2)
Pro:
* Ease of use (daily
troche)
* Highly effective
* Tasteless
* No sugar
Con:
* Expense
* Drug Interactions
possible
Nystatin
Pro: (3)
Con: (4)
Pro:
* No drug interactions
* Inexpensive
* Not irritating to mucosa
Con:
* Ease of use (QID)
* Ease of use (swish contact
time)
* Less effective
* High sugar content
Yeast: Candida albicans
Angular cheilitis (perlèche)
(2)
Acute or chronic inflammation of lateral
commissures
Caused by excessive moisture and maceration
from saliva
Yeast: Candida albicans
Angular cheilitis (perlèche)
Treatment:
(2)
- Topical barriers keep moisture out, prevent
reoccurrences - Barrier creams (eg, zinc oxide paste) or
petrolatum
May have Candida superinfection
?
Pharmacology of “Azole’s”
MOA:
Inhibit cytochrome P450 14-alpha-demethylase
Fungal cell membrane synthesis
Ergosterol
Azole Antifungal CYP P450 14-alpha-demethylase
Lanosterol
First Generation Azoles: Imidazoles
Miconazole, Clotrimazole: Not taken systemically
Clotrimazole & miconazole oral formulations less cariogenic; better tolerated vs Nystatin.
Miconazole (Oravig): 50 mg (1 tablet) applied to upper gum once daily for
7-14 days
- Apply in morning after brushing. Alternate sides of mouth with each
application; do not crush, chew, or swallow. Avoid chewing gum while
in place. - If the tablet does not adhere to gum or falls off within 6 hours of
application, same tablet should be repositioned immediately. - Exposure time important: goal entirety of waking hours.
First Generation Azoles: Imidazoles
Clotrimazole (Mycelex): 10mg (1 troche) dissolved slowly 5 times daily for 7-14 days
- Metabolized in liver – 3A4. Contraindicated in liver disease.
- Avoid in combination with benzodiazapines; HIV
- Oral Troche for management of oral candidiasis
- Patient Education: 5 times daily. Swallow the saliva. No eating or drinking for 30min
following medication - Dissolves over 30 minutes and remains in saliva for up to 3 hours
Second Generation Azole: Triazoles
Fluconazole (Diflucan), itraconazole, voriconazole, posaconazole, isavuconazole
- First line drugs for systemic fungal infections
- Fewer drug-drug interactions and expanded spectrum
- Still metabolized via the cytochrome P450 enzyme system
- All azole agents are both metabolized by and slow down hepatic cytochrome P450 activity
- Safer side-effect profiles than ketoconazole for systemic use
Second Generation Azole: Triazoles
Fluconazole (Diflucan), itraconazole, voriconazole, posaconazole, isavuconazole
Dentistry:
Esophogeal candidiasis or
refractory, resistant oral candidiasis.
Resistance a big problem: 2 Mechanisms-
Efflux pumps & altered binding site on
demethylase
Second Generation Azole: Triazoles
Fluconazole (Diflucan)
(5)
- High absorption after oral administration with high distribution into all tissues
- Long half-life (approx. 24hrs) allows for once-daily dosing
- Significant excretion via kidney – dose adjustment when administered to renal impairment
- Strong inhibitor of CYP2C19 and a moderate inhibitor of CYP2C9 and CYP3A4
- Caution: benzodiazepines; warfarin
- Pregnancy Category C – drug also excreted in breast milk
- Avoid in breastfeeding and pregnancy.
Fluconazole (Diflucan)
Dentistry:
Esophogeal candidiasis or refractory, resistant oral candidiasis.
Rx: Fluconazole 200mg tablet, #15
400mg once, then 200mg PO daily x 14days
Polyenes Mechanism of Action
(4)
- Binds
ergosterol in
fungal cell
membrane - Forms pores
in cell
membrane - Cell contents
leak out - Fungal cell
death
Polyenes
»Binds to ergosterol in fungal membranes. Fungicidal
Amphotericin B (Liposomal): Broad spectrum fungicidal for intravenous use
(3)
- 1st line IV drug for most systemic yeasts: Histoplasmosis, Aspergillosis, Crypto.
- Standard Tx: Cryptococcal meningitis.
- Severe, potentially lethal side-effects (dose-dependent nephrotoxicity
Polyenes
Nystatin (Mycostatin): Broad spectrum fungicidal
(4)
- No GI absorption - entirely excreted in feces – Pregnancy Category B (safe)
- Topical only for mucocutaneous candidiasis
- Length of contact important = 2 MINUTES
- Suspension, high sucrose concentration
- Alternative to clotrimazole/miconazole
Nystatin
Patient Counseling:
(3)
- Swish in mouth then,
- Hold in mouth for as long as possible then,
- No eating or drinking for 30mins
Magic Mouthwash
* Common Indications:
(3)
- Apthous stomatitis
- Recurrent aphthous ulcers (RAU)
- Chemo-induced oral mucositis
Magic Mouthwash
Formula (2)
- NO STANDARD formula
- 80% of healthcare facilities compound their own unique formula
Magic Mouthwash Ingredients
* Most Common:
(6)
- Diphenhydramine (Benadryl) >90%
- Viscous lidocaine 90%
- Magnesium hydroxide/ Aluminum hydroxide (Maalox) 80%
- Nystatin 30%
- Corticosteroids 10%
- Tetracyclines 10%
Diphenhydramine (Benadryl)
(2)
- Antihistamine / reduce inflammatory process
- Limit pain sensation
- Reduce swelling, erythema
- May be useful for trauma, food allergens, or infections
Viscous Lidocaine
(3)
- Topical anesthetic
- Relieves pain associated with irritated oral/pharyngeal mucous
membranes - IMPORTANT: ingesting too much can lead to arrhythmias
- Use minimal amounts
- Swish and SPIT
Magnesium Hydroxide / Aluminum Hydroxide
(2)
- Antacid – Maalox and Mylanta
- Primarily used as vehicle to enhance coating of other ingredients
within the mouth
Nystatin
(4)
- Fungicidal polyene for mucocutaneous candidiasis
- Nonabsorbable by oral route
- Not appropriate for RAU or mucositis without fungal etiology
- Use if active oral candidiasis infection in concert with RAU or mucositis
Corticosteroids
(3)
- Hydrocortisone, dexamethasone, betamethasone, beclomethasone
- Reduce inflammatory process
- Limit pain sensation
- Reduce swelling, erythema
- Limited evidence for use / controversial
Pain/Oral Irritation
(3)
- Diphenhydramine - analgesic
- Viscous Lidocaine - analgesic
- Magnesium hydroxide/ aluminum hydroxide - vehicle
- 1-to-1-to-1 ratio
- Hx of arrhythmias, atrial fibrillation, etc – may avoid viscous lidocaine
- Or 2-1-2 ratio
Oral Mucocutaneous Candidiasis
* Diphenhydramine - analgesic
* Nystatin - antifungal
* Magnesium hydroxide/ aluminum hydroxide - vehicle
* Corticosteroid – in an opportunistic infection???
NO!
Administration
(2)
- 2 tablespoons (30mL) every four to six hours
- Swish and spit to avoid systemic side effects
- Pharyngeal involvement?
Side Effects
(4)
- taste disturbances (49%)
- burning and/or tingling in the oral cavity (29%)
- drowsiness or any central nervous system adverse effects (11%)
- gastrointestinal symptoms - constipation, diarrhea and nausea (11%)
Evidence
The evidence is limited and controversial
Controversial because of Formulation Heterogeneity
(5)
- Diphenhydramine for all indications
- Maalox® for all indications
- Lidocaine for pain
- Nystatin for candidiasis
- Avoid steroids
