Antifungals Flashcards
Treatment of Fungal Infections
Fungi are eukarotic cells, thus there is the potential of serious side effects resulting from drug treatments that target essential cellular processes
There are two classes of therapies:
- Treatment of superficial infections e.g., ring worm, athlete’s foot, oral thrush, vaginal infection. Dermatophytes- primarily infect the skin and nails.
- Treatment of system icinfections e.g., systemic candidiasis, coccidioidomycosis “Valley Fever”, cryptococcal meningitis, histoplasmosis, blastomycosis
Whats the blood brain barrier?
- Blood brain barrier: vasculature of the CNS is diffferent than in the periphery. The endothelial cells in the CNS that line the blood vessels are very tightly appressed to eachother so that drugs and other metabolites can only pass through either if there is a transporter present in the endothelial cell membranes or if the compound is sufficiently nonpolar to bypass both layers of plasma membrane (lipid soluble).
Predisposing Conditions Associated with Systemic Fungal Infections
- Long term treatment with broad- spectrum antibiotics
- AIDS
- Patients on immunosuppressive drugs
Solubility of Polyene Antibiotics
These compounds are usually not that soluble, so they’re usually administered in a colloid with sodium desoxycholate. Sodium desoxycholate forma a complex with the compound similar to the way that the apoproteins involved in cholesterol transport in the blood help to keep the cholesterol present in the bloodstream.
Polyene Antibiotics
- Example: Amphotericin B and Nystatin.
- Obtained from Streptomycesbacteria
- MOA:Induces pores in plasma membrane. Specificity is due to high binding affinity for ergosterol.
- Administered IV as a colloid with sodium desoxycholate
- Used to treat systemic infections (effective in treating CNS infections)
If Polyene Antibiotics target compounds the plasma membrane, how do they not effect us?
Since we also have plasma membranes, this may not seem like the best target for a selective antifungal drug, but it turns out that there is a good degree of specificity because these drugs target a sterol called ergosterol that is not found in plasmam membranes of animal cells. So its a strictly fungal sterol. These are the most effective treatments for CNS infections. Many antifungal drugs cannot cross the blood brain barrier. They have a high enough lipid solubility to go from the blood to the CNS tissues.
When do fungal infections tend to occur?
-Usually an agent that is an opportunist or an outright pathogen. In the case of an immunosuppressed individual, or someone who has been treated with broad
spectrum antibiotics where the normal bacteria flora has been wiped out, fungal infections can spring up.
What does the structure of Amphotericin B look like?
Amphotericin B is amphipathic- it has polar and nonpolar regions.
Amphotericin B doesnt look like a sterol at first glance, but when it cyclizes it can form a structure similar to the ring nucleus to cholesterol with a side chain.
How did we find out that amphotericin B targets ergosterol?
- Experiment involved isolation of a particulate fraction of Neurospora crassa. If you take and lyse Neurospora (sonication, detergent lysis, or other methods) and then centrifuge, youll get a pellet that will include plasma membranes (since fungi have a cell wall attached to the membrane it drags the plasma membrane into the pellet. So they took this fraction and took some nystatin, radioactively labeled it so they could trace where it was going, and mixed it with the fraction and were able to measure they amount of drug that was bound to the fraction. They were then able to extract the drug and bound substances from the fraction, and then either add nothing back (see no binding), add extract back (see good amount of binding), and then only add ergosterol back (see a little less binding but still a good amount), indicating that the drug was mostly biding to ergosterol.
How do we know the MOA of amphotericin B?
- Made lipid vesicles to obtain ergosterol, then add the vesicles to solution containing ions, then do ion-sepcific probe measurements to measure voltage changes across the membrane. Idea was that if ergosterol was allowing for ions to cross the
membrane, then there should be an increased conductance. Results hinted towards ions
being able to leak out of the cell, which results in fungal death.
Amphotericin (general info):
- Used to treat serious systemic fungal diseases. Can have serious side effects.
- Administered IV.
- Effectiveness reduced if administered with azole antifungals.
- Liposome-encapsulated drug ($$= more expensive) is better tolerated. Gets around
the solubility issues.
Adverse Effects of Amphotericin B
- Many patients develop a serious acute reaction involving histamine release: fever, chills, hypotension, nausea, vomiting, headache, weakness. Reactions are typically dose-dependent and probably not due to drug allergy. Non-allergic response is dose dependent. Allergic response is not
- Electrolyte imbalances (hypokalemia, hypomagnesemia)
- Multiple organ damage (severe and can be irreversible)
- Nephrotoxicity, liver and liver failure. Kidney and liver failure.
- Anemia
- Cardiac arrhythmias, cardiac failure. Seen more frequently if the patient is also taking corticosteroids.
- Liposome-encapsulated drug ($$) is better tolerated
- Dont want to give amphotericin B in combination with Azole antifungals.
What is the relationship between mast cells and histamine?
- Mast cells can release histamine in response to some drugs. Some drugs promote lysis of the mast cells which can also lead to release.
Azole Antifungal Agents
- Used to treat both systemic and superficial infections (dermatophytes). Also effective in treating seborrheic dermatitis.
- MOA:InhibitorsofthefungalP450enzyme lanoside 14-alpha-demethylase; blocks conversion of lanosterol to ergosterol leading to defective plasma membrane formation
- Orally available (fluconazole can also be given IV). Administered in a cream for fungal infections of the skin. so can be given orally or topically. Can even be given IV if dealing with systemic infection.
Types of Azole Antifungal Agents
- Imidazoles (e.g. ketoconazole) require acid pH for absorption (absorption may be inhibited by drugs that reduce stomach acidity). The chlorides can come off, giving the molecule a negative charge. In the acidc conditions of the stomach you end up getting the sites protonated.
- Triazoles (e.g. fluconazole) are more specific for fungal over mammalian P450. Better water solubility than imidazoles. Triazoles are a better choice if there are issues with side effects stemming from not enough specificity towards fungal P450 enzymes. When giving an antifungal in topical form, very little of it is able to get into the bloodstream so you generally dont have to worry about systemic side effects.