Antifungal drugs Flashcards
why are fungal infections hard to treat
- They are slow growing
- occur in tissues that are poorly penetration by anti microbial agents
3require prolonged treatment
List the types of anti fungal infections
1.Superficial infections
eg they affect your nails ,skin
- Systemic infections eg deep tissues
List the types of superficial infections
- Dermatomycoses
* infections of skin ,hair and nails eg ring warm
- Tinea pedis ;foot
- tinea cruris -groin
- tinea corporis -body
- tinea capitis -scalp
- tinea unguium -nails
2.Candidiasis
yeast like infections that affect mucous membranes of eg mouth , skin , vagina
Discuss the types of systemic infections
- Systemic candidiasis
* can disseminate vital organs - Cryptococcosis
* Enter through lungs and travel to the brain and can cause meningitis (crytpotomeningitis) - Systemic aspergillosis
* seen in immunocompromised patients eg aids, patients - Blastomycosis
* Affect the lungs - histoplasmosis : affects the lungs
- Emergomycosis: affect the lungs in immune incompetent patients
What are the uses of amphotericin B
*Used intravenously for systemic fungal infections
*Oral preparations are used to treat thrush
*
What can amphotericin treat (systemic infections )
- candida albicans and Cryptococcus neoformans ,mycoses eg histoplasma and blastomycoses
- molds like aspergillus
What are the MOA of amphotericin
- binds with ergosterol(component of fungal cell membrane )
- Forming a pore that leads to monovalent ion eg K+,Ca+,H+ and Cl- leakage
*leading to fungal death
Amphotericin B are insoluable in water and are poorly absorbed from the GIT
What are the side effects of amphotericin
*infusion reactions toxicity eg high fever ,shaking ,chills ,hypotension
INFUSE OVER 4 HOURS OR REDUCE DAILY DOSE IN ORDER TO REDUCE INFUSION REACTION
NB; NEPHROTOXIC
cUMULATIVE TOXICITY
*renal damage
- intrathecal( admin into spinal cord) admin may cause seizures
- anamia
- hypokalaemia
- ABNORMALITIES IN LIVER FUNCTION
PATIENT MUST BE
Must knows
Liposomal amphotericin b is newer and has less side effects but is more costly
Nystatin has similar structure to amphotericin but too toxic thus not given through IV but through orally
What are the pharmacokinetics of amphotericin
*admin IV
*not absorbed orally thus it is not useful for systemic infections but it can be used for local infections in the lumen of GIT
*Used as induction therapy then replaced by newer Azole drug of choice once the fungal burden is reduced
*t1/2 of 24 hrs
*widely distributed but poor BBB crossing
*Eliminated via urine
*
Drug interaction of amphotericin B with others drugs
Drugs like aminoglycosides ,tenofovir ,ciclosporin ,diuretics and digoxin also inhibit renal function thus they must not be combined
T/F ; Some Triazoles can be used for systemic and topical functions
true
Discuss the characteristics of azoles
- They are a class of drugs
* They have a broad spectrum against dermatophytes and invasive yeast infections eg candida ,Cryptococcus
Discuss the MOA of Azoles
*Inhibit fungal Cytp450(enzymes-demethylase) ,leading to a reduction in ergosterol synthesis
What are the adverse effects of azole
*nausea
*vomiting
*diarrhea
*skin rash
hepatotoxity(incraese hepatic enzymes)
what are the contraindications of azole
*Pregnancy ,it is excreted in breast milk and it is thus not recommended
What are the adverse effects of voriconazole
- visual disturbance which resolves in 30 min
- photosensitivity dermatitis
- toxicity : rash and raised hepatic enzymes
NB should not be given to pregnant woman
what are the pharmacokinetics of voriconazole
- well absorbed orally ,with more than 90% bioavailability
- Absorption is reduced by food
- it is hepatically metabolized
- It is excreted as an inactivated metabolite
- It is an cytp450 inhibitor
- can be administered as oral or IV
What can voriconazole be used to treat
- TREATMENT CHOICE FOR INVASIVE ASPERGILLOSIS ( mold type of infection ,usually inhaled and cause respiratory infections )
- candida spp and infections resistant to fluconazole
- oropharyngeal and esophageal candidiasis
- less toxic than amp
*Treats invasive fungal infections
*These are generally seen in immune incompetent’s
patients
It is not useful for urinary tract infections
What is fluconazole used to treat
Used for treatment and prevention of superficial and systemic infections and mostly commonly used in treatment of mucocutaneous candida eg
*Viginal and oropharyngeal candidiasis not responding to topical tx
- Oesophageal and systemic candidiasis
- cryptococcal meningitis and to prevent relapse of of cryptococcal diseases in aids patients
has not activity against aspergillus
MOA of fluconazole
inhibits the fungal cytochrome p45 enzyme .This inhibition interferes with ergosterol synthesis
fluconazole pharmacokinetics
- good oral absorption
- distribution is wide in the body including CSF
- T1/2 is 20-50 hours
- excreted in the urine *Penetrates the CSF best
- has widest therapeutic index thus allows aggressive dosing
Side effects of fluconazole
rash ,headache , vomiting ,nausea, abdominal pain and elevated hepatic enzymes ( has least increase in hepatic enzymes’ among azole drugs)
rare: anorexia ,fatigue ;constipation
What can itraconazole treat
- Dermatophytosis
- onychomycosis( infection of the nail and it only respnds to systemic treatments )
- candidiasis if not responding to topcal treatment
- DRUG OF CHOICE for
- dimorphic fungi infections
- alternative therapy for aspergillosis
oral solutions are preferred in oropharyngeal and oesophageal candidiasis
mechanism of itraconazole
similar to fluconazole
pharmacokinetics of itraconazole
- food and gastric acid increases absorption
- widely distributed except for CSF
- t1/2 is 21 hrs
- metabolized in the liver
- excreted in urine and feces
- admin orally or IV
- Has broader spectrum than fluconazole but not as broad as voriconazole
- low bioavailability when taken orally and liquid solution must be taken on an empty stomach
Side effects of itraconazole
rash ,headache, nausea ,diarrhea
abdominal pain ,elevated hepatic enzymes
what are posaconazole treat
- Most species of candida , alternate in oropharyngeal or oesophageal candidiasis
- Has activity against aspergillosis ,used when voriconazole doesnt work
murcomyscosis
The pharmacokinetics of posaconazole
- available as oral suspension in SA
- metabolized by liver
- fatty meal increase absorption
Echinocandins -capsofungin MOA
Specifically inhibit D-glucan synthesis essential to cell wall integrity of fungi thus compromising integrity of cell wall to become permeable causing cell lysis
What can echinocandins -capsofungin treat
Candidasis ( invasive oropharyngeal and oesopharyngeal )
- Aspergillus ( last resort)
- Emperic therapy for febrile neutropenia
- No activity against cryptococcus
Echinocandins -capsofungin pharmacokinetics
- Only through IV
- t1/2 is 9 - 11 hrs
- poor CSP
- well tolerated with minor GIT and flushing
What are the examples of echinocandins
capsofungin and micafungin and anidulfungin
How are anidulfungin and micafungin admin and what do they treat
Treat :
*ANI ; Invasive candidiasis
Availiable as IV
MIC ; Invasive candisiasis and availiable as IV
MOA and pharmacokinetics of griseofulvin
inhibit fungal mitosis
- Used to treat dermatophytosis via oral treatment
- 2-6 weeks for skin and hair infection
- months of treatment for nail infection and it allows regrowth of the new protected nail
- Largely been replaced by itraconazole and terbinafine
*fatty food increase absorption
*
griseofulvin side effects
headache , skin rash,dry mouth and altered taste sensation
What can terbinafine treat
- Dermatophytsosis of skin ,hair and nails
- Candida albicans
*oncmycosis
Pharmacokinetics of terbinafine
- distributed preferentially to skin ,skin ,nail bed
- Metabolized in liver
- Available in oral and topical formulation
- highly lipophilic
What is the adverse effects of terbinafine
GIt upset ,headache ,skin reactions , arthralhia ,hepatotoxicity and taste disturbance
What is the terbinafine MOA
inhibits squalene epoxidase which inhibits ergosterol synthesis( Squalene is not converted to lanosterol and ultimately ergosterol)
What is nystatin used to treat
*topical antifungals
- Used in candida yeast infections
- Not effective against dermatophyte skin infection
- oropharyngeal thrush
- vaginal candidiasis
- intertriginous candidal infections
How is nystatin ( topical)
- Too toxic for parental admin thsu it is used for suppression of local candidial infection
- treatment for 14 days is usually adequate but prolonged therapy needed in some cases
- Poorly absorbed through skin ,mucous membrane or GIT low toxicity
- unpleasent taste
- safe for use in infants
