Antifungals Flashcards

1
Q

Treatment of Fungal Infections

A

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

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2
Q

Whats the blood brain barrier?

A
  • 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).
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3
Q

Predisposing Conditions Associated with Systemic Fungal Infections

A
  • Long term treatment with broad- spectrum antibiotics
  • AIDS
  • Patients on immunosuppressive drugs
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4
Q

Solubility of Polyene Antibiotics

A

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.

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5
Q

Polyene Antibiotics

A
  • 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)
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6
Q

If Polyene Antibiotics target compounds the plasma membrane, how do they not effect us?

A

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.

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7
Q

When do fungal infections tend to occur?

A

-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.

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8
Q

What does the structure of Amphotericin B look like?

A

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.

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9
Q

How did we find out that amphotericin B targets ergosterol?

A
  • 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.
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10
Q

How do we know the MOA of amphotericin B?

A
  • 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.
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11
Q

Amphotericin (general info):

A
  • 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.
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12
Q

Adverse Effects of Amphotericin B

A
  • 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.
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13
Q

What is the relationship between mast cells and histamine?

A
  • Mast cells can release histamine in response to some drugs. Some drugs promote lysis of the mast cells which can also lead to release.
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14
Q

Azole Antifungal Agents

A
  • 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.
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15
Q

Types of Azole Antifungal Agents

A
  • 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.
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16
Q

Some Adverse Reactions to Ketoconazole

A
  • Nausea & vomiting (may be reduced by taking with meals).
  • Reduced sperm production gynomastia have been seen with high doses (inhibits testosterone synthesis).
  • Liver damage (rare)
  • Many drug interactions due to effects on human P450 enzymes: inhibits metabolism of cyclosporine; when used with rifampin ketoconazole has shorter half-life due to P450 induction by rifampin.
  • Most common side effects are the drug-drug interactions even though the
    fungal P450 is the main target, the mammalian one can be affected at high enough dosages.
  • Rifampin induces the expression of the P450 that metabolizes ketoconazole, so therefor this increases the duration time of ketoconazole (dereases the half-life).
17
Q

Fluocytosine

A
  • Antimetabolite. Involved in DNA synthesis.
  • MOAs: A pro-drug deaminated selectively by fungal cell cytosine deaminase to 5- fluorouracil. A secondary mechanism involves inhibition of RNA synthesis
  • Should be administered with another antifungal agent to reduce the chance of drug resistance
  • Primary use is in the treatment of cryptococcal meningitis in combination with amphotericin. cryptococcal is a fungus that can get across the blood brain barrier and get into the CNS.
18
Q

What is 5-Fluorouracil?

A
  • 5-Fluorouracil is a DNA synthesis inhibitor and at high enough concentrations this will affect mammalian DNA synthesis. By giving it as a prodrug that is only converted to the active form by the fungal cytosine deaminase enzyme it will only be affecting fungal cells. So it may be taken up by mammalian cells but wont be in the active form. Also inhibits fungal RNA synthesis. Be able to recognize folic acid structure which mimics base structure of nucleotides. So know both.
19
Q

Terbinafine

A
  • Lamisil.
  • Used to treat superficial infections (especially
    “jock itch” and athlete’s foot
  • Faster acting than other antifungals.
  • MOA:Inhibits squalene epoxidase,blocking ergosterol synthesis, causing a toxic buildup of squalene and depletion of ergosterol (leads to membrane defects).
  • Given orally (for infections of the nail)or as a cream for skin infections.
  • doesn’t seem to work well for most systemic infections, and cant cross the blood brain barrier effectively.
20
Q

Whats difficult about treating nail fungal infections?

A
  • High keratin content of nails makes it hard for the compounds to penetrate, and also you need the compounds to get to the nail tissue which is hard to reach. So giving it orally can help this aspect, but oral treatment of the nail will take longer to work than if you had a skin infection and were treating it with the cream.
21
Q

How fast do fungal treatments usually work?

A
  • One of the problems with antifungal agents is that they tend to work quiet slowly requiring weeks to months of treatments. Terbinafine can exert its effects in a matter of days. Also has a tripple carbon bond which is unique. Has very few side effects because it is not used systemically. Has a dual effect so you can get greater killing of fungi at lower concentrations of drug.
22
Q

Terbinafine Side Effects (oral administration)

A
  • frequency of side effects are less for this drug.
  • Headache, dizziness, vertigo.
  • Liver inflammation, hepatitis, liver failure.
  • Depression, anxiety, insomnia.
  • Loss of taste, distorted taste.
  • Rashes, hives.
  • Fatigue (anemia).
  • Increased heart rate.
  • Vision disorders including “green vision”.
  • Most of these are effects on the CNS, so neurotransmission is believed to be affected.
23
Q

Ecinocandins

A
  • Produced by Aspergillis
  • Currently used drugs are
    semisynthetic
  • MOA:Inhibit1,3-beta-glucan synthesis (fungal cell wall formation)
  • IV administration
  • Used to treat systemic candidiasis and aspergillosis
  • Mild side effects
  • Even though Ecinocandins are produced by Aspergillis, at high enough concentrations they will inhibit the growth Aspergillis. So its fungistatic for Aspergillis and fungicidal for candidiases. May be used by the organism to get rid of other fungal competitors.
  • Looks like a scorpion.
24
Q

Griseofulvin

A
  • Source Penicillium
  • Orally administered
  • MOA:Binds to fungal microtubules; Promotes mitotic arrest
  • Concentrated in keratin
  • Used to treat infections of the nails and skin.
  • Very slow action on nail infections
  • Side effects minor compared with other systemically administered antifungals
25
Q

Specificity of griseofulvin

A
  • At high concentrations, griseofulvin can affect mammalian microtubules. Concentrated in keratin, so that explains why its selective. Nails arent dividing, so its ok that it gets concentrated there.