27) Anti-Fungals Flashcards
Drugs acting on fungi actions
- Alter cell membrane permeability
- Block beta-glucan synthesis
- Block nucleic acid synthesis
- Disrupt microtubule functions
Anti-fungals altering cell membrane permeability
- Azoles
- Polyenes
- Terbinafine
Anti-fungals that block beta-glucan synthesis
- Echinocandins
Anti-fungals that block nucleic acid synthesis
- Flucytosine
Anti-fungals that disrupt microtubule functions
- Griseofulvin
Ergosterol
- Sterol found in cell membranes of fungi
- Role like cholesterol in humans to keep the membrane integrity and fluidity
Polyene antibiotics (amphipathic)
- Amphotericin B
- Nystatin
Polyene
- Molecule with multiple conjugated double bonds
Amphotericin B and nystatin MOA
- Change the permeability and transport properties of the fungal membrane
Polyenes’ lipophilic (or hydrophobic) region
- Binds to ergosterol via hydrophobic interactions
- Causes formation of artificial pores, leading to leakage and cell death
Reduction of amphotericin B hydrophobic chain
- May result in polyene binding to cholesterol
- Makes it toxic to animals/humans
Amphotericin B pharmacokinetics
- Distributes to all tissues except CNS
- Unknown metabolism
- Hepatic elimination
- T1/2 = 2 weeks
Amphotericin B immediate toxicity
- Fever, chills
- Muscle pain
- Headache
- Vomiting
- Hpotension
- Infusion reaction
Amphotericin B late toxicity
- Reversible renal damage
- Renal tubular acidosis, hypokalemia, hypomagnesemia
- Abnormal liver function test (LFT)
- Anemia and loss of erythropoietin formation
Cerebral damage associated with amphotericin B toxicity
- When given intrathecally there is a risk of neurologic effects as seizures
Amphotericin B deoxycholate
- Conventional form
- Deoxycholate to improve solubility
Amphotericin B lipid complex (ABLC)
- Abelcet (brand)
- Linked to 2 phospholipids
Liposomal Amphotericin B (L-amphB)
- Ambisome (brand)
- Liposome
Amphotericin B colloidal dispersion
ABCD
- In cholesterol; lipid disk
- Amphotec (brand)
Amphotericin B lipid formulations
- Amphotericin B lipid complex (ABLC)
- Liposomal Amphotericin B (L-amphB)
- Amphotericin B colloidal dispersion
(ABCD)
Amphotericin B lipid formulations characteristics
- Better tolerated
- Less renal toxicity
- Less infusion-related SE
- Release the drug at the site of action
Amphotericin B side effects
- Hypotension
- Headache, chills
- Hypokalemia
- Hypomagnesemia
- Anorexia, diarrhea, nausea, vomiting
- Anemia
- Local: pain at injection site
- Respiratory: tachypnea
- Fever
Nystatin characteristics
- Bio-statin (brand)
- Poorly absorbed
Nystatin contraindication
- Hypersensitivity
Nystatin side effects
- Mostly GI
- Diarrhea
- Nausea
- Stomach pain
Azoles
- Inhibition of ergosterol synthesis
- Inhibit the step 14 α-demethylation of lanosterol (which is catalyzed by a fungal cytochrome P450 isozyme)
Imidazole (non-selective azoles) names
- Ketoconazole (tablets, topical)
- Clotrimazole (lozenges, topical)
- Miconazole (tablets, topical)
Ketoconazole CI/warnings
- Hypersensitivity
Ketoconazole side effects
- Adrenal suppression
- Bone fragility
- Prthostatic hypotension
- Fatigue
- Pruritis
- Decrease in platelets count
- Menstrual irregularities
- Decreased libido, impotency, - Gynecomastia
Ketoconazole pharmacokinetics
- Well distributed in body except in BBB
- Metabolized hepatically
All non-selective imidazole (azoles) pharmacokinetics
- Substrate and inhibitor of CYP3A4
All non-selective imidazole (azoles) US box warning
- Hepatotoxicity
- QT prolongation
Imidazole (non-selective) MOA
- Inhibits adrenal and gonadal sterioids
Clotrimazole CI/warnings
- Hypersensitivity
- Hepatic impairment
Clotrimazole side effects
- Increase LFT
- Pruritis
- Nausea, vomiting
Miconazole CI/warnings
- Hypersensitivity
- Hepatic impairment
Miconazole brand name
- Oravig
Miconazole side effecs
- Headache
- Pruritis
- Nausea
- Diarrhea
Triazoles (selective azols) names
- Fluconazole (PO and IV)
- Itraconazole (capsule, solution)
- Voriconazole (tablets, IV)
- Posaconazole (tablet, IV)
- Terconazole (vaginal cream, suppositories)
- Isavuconazonium
sulfate (capsule, solution)
Fluconazole brand name
- Diflucan
Itraconazole brand name
- Onmel
- Sporanox
- Pulsepak
Voriconazole brand name
- Vifend
Posacnonazole brand name
- Noxafil
Terconazole brand names
- Terazol
- Zazole
Isavuconazon brand name
- Cresemba
Fluconazole (Difulcan) side effects
- Arrythmias
- Dizziness
- Seizures
- Hepatotoxicity
- Prolongs QT interval
Fluconazole (Difulcan) pharmacokinetics
- Inhibitor of CYP2C19
- Crosses BBB
- Excreted in the urine
Itraconazole (Onmel, Sporanox, Pulsepak) CI/warnings
- US Box warning: congestive heart failure (CHF)
Itraconazole (Onmel, Sporanox, Pulsepak) side effects
- CNS depression
- Hearing loss
- Heart failure
- Hepatotoxicity
- Neuropathy
- Diarrhea
- Nausea
- Hypertension
- Increase LFTs
Itraconazole (Onmel, Sporanox, Pulsepak) pharmacokinetics
- Substrate of CYP3A4
- Food increase its absorption
Voriconazole (Vifend) CI/warnings
- Arrythmia, QT prolongation
- Blurred vision
- Renal toxicity
Voriconazole (Vifend) side effects
- Tachycardia
- Hypokalemia
- Increase LFTs
- Hepatotoxicity
- Increased serum creatinine
- Visual changes
- Intensified hallucinations
Voriconazole (Vifend) pharmacokinetics
- Substrate for CYP2C19 and CYP2C9
- Inhibits CYP2C19
- Crosses BBB
Posaconazole (Noxafil) CI/warnings
- Arrythmia
- Renal impairment
Posaconazole (Noxafil) side effects
- Thrombophlebitis
- Hyper/hypotension
- Tachycardia
- Hepatotoxicity
- Hypokalemia, hypocalcemia hypomagnesemia
- Hyperglycemia
Posaconazole (Noxafil) pharmacokinetics
- Substrate for UGT1A4
- Excretion in feces
Terconazole (Terazol, Zazole) CI/warnings
- Epidermal necrolysis: life-threatening dermatologic disorder characterized by spread erythema, necrosis
Terconazole (Terazol, Zazole) side effects
- Headaches
- Abdominal pain
- Dysmenorrhea
Terconazole (Terazol, Zazole) pharmacokinetics
- Not known
Isavuconazon (Cresemba) side effects
- Hepatotoxicity
- Peripheral edema
- Hypokalemia, hypotension
- Hypomagnesemia, hypoalbuminemia, hypoglycemia, hyponatremia
- Hematuria, agranulocytosis
- Leukopenia
- Back pain
Isavuconazon (Cresemba) pharmacokinetics
- Substrate for CYP3A4
ALL triazole (selective) azoles share CI/warning with
- Hypersensitivity
ALL triazole (selective) azoles are inhibitors of
- CYP3A4
ALL triazole (selective) azoles lack
- Endocrine side effects
Allylamine derivative
- Terbinafine
Allylamine derivative (terbinafine) MOA
- Inhibit the enzyme squalene epoxidase which decreases the concentration of ergosterol in the fungal cell membrane
- Inhibition of squalene epoxidase leads to the accumulation of squalene which is toxic to the fungi
Allylamine derivative (terbinafine) contraindication
- Hypersensitivity
Allylamine derivative (terbinafine) adverse effects
- CNS: headache
- NVD
- Vision color change (especially in children)
- Upper respiratory tract infection (especially in children)
- Depression
- Taste disturbance
- Reversible neutropenia
- Hepatic failure cases
- Thrombotic microangiopathy
Allylamine derivative (terbinafine) pharmacodynamics
- Renally excreted
- Inhibits CYP2D6
Echinocandins (cell wall inhibitors)
- Caspofungin
- Anidulafungin
- Micafungin
Echinocandins (caspofungin, anidulafungin, micafungin) MOA
- Inhibit the synthesis of β-(1-3) glucan (a critical component of fungal cell wall)
Echinocandins (caspofungin, anidulafungin, micafungin) contraindication
- Hypersensitivity
Caspofungin and micafungin (echinocandins) pharmacokinetics
- Hepatically metabolized
- Renally excreted
Anidulafungin (echinocandins) pharmacokinetics
- Renally excreted only
Caspofungin and anidulafungin (echinocandins) side effects
- Hypotension
- Headaches
- Skin rash
- Anemia
- Increase serum creatinine
- Hyperglycemia
- Hypomagnesemia, hypokalemia
- NVD
Micafungin (echinocandins) side effects
- Neutropenia
- Thrombocytopenia
- Anemia
- Hypernatremia
- Hypomagnesemia, hypokalemia
ALL echinocandins…
- Increase FLTs
- Have infusion side effects
Nucleic acid inhibitor
- Flucytosine (5-FC)
Flucytosine (5-FC)
- Nucleic acid inhibitor
- Antimetabolite specifically uracil/pyramidine analogue
Flucytosine (5-FC) MOA
- Enters fungal cell via permease enzyme and converted by cytosine deaminase to 5-FU
- This false nucleotide inhibits thymidylate synthase
- Deprives organism of thymidine (which is essential for DNA synthesis)
Humans lack
- Permease
- Cytosine deaminase
Flucytosine (5-FC) contraindication
- Hypersensitivity
Flucytosine (5-FC) side effects
- Bone marrow toxicity
- Cardiotoxicity
- Hypoglycemia, hypokalemia
- Ulcerative colitis
- Azotemia
- Anemia
- Agranulocytosis
- Leukopenia
- Eosinophilia
- Thrombocytopenia
- Hepatic injury
- Hearing loss
- Increased blood urea nitrogen
- Dyspnea
- Fever
Flucytosine (5-FC) pharmacokinetics
- Renally excreted unchanged
- Widely distributed, penetrates well the CSF
- Fungistatic
Anti-mitotic
- Griseofulvin
Griseofulvin (anti-mitotic) MOA
- Interferes with microtubule function in dermatophytes (ringworms)
- Inhibit the synthesis of nucleic acids
- Inhibit fungal cell mitosis at metaphase
Griseofulvin (anti-mitotic) pharacokinetics
- Fungistatic
- Hepatically metabolized
- Induction of hepatic CYT P450 by griseofulvin