Anti-Fungals Flashcards
Who is the amphibian terrorist Amphotericin B ?
A sterol, He comes in the blood stream and set off dynamite in the Ergosterol and the Kidney.
How would you administer Amphotericin B ?
Due to the fact that it is nearly insoluble in water it is prepared as a colloidal suspension of amphotericin B and sodium desoxycholate and given as an IV injection
Other than a colloidal suspension what is another way you could administer Amphotericin B ?
It can be prepared as a liposomal suspension
Can amphotericin B be absorbed in the GI tract ?
No, so it is only given orally when the fungal infection is in the lumen of the GI tract
How is amphotericin B metabolized ?
It is more than 90% bound to serum proteins and although it is mostly metabolized there is a small amount that will be excreted in the urine. The serum half life is 12 days
Will you have to make a dose adjustment for patients on dialysis, with hepatic impairment, or renal impairment ?
No, Hepatic impairment, Renal Impairment, and dialysis have very little impact on the drug levels so you do not need to make a dosage adjustment
Describe the distribution of Amphotericin B ?
It is widely distributed throughout the body but only penetrates the CSF by 2-3% so to treat fungal meningitis you will need intrathecal administration of the drug
What is a danger of Amphotericin B
Increased BUN and Creatinine (azotemia) that is dependent on dose and can necissitate dialysis. Often reversed when drug is stopped
Acute Febril reactions: Shakes
Anemia
Phlebitis at site of injection
How are the toxic effects of Amphotericin B circumvented ?
Lipid packing of the drug which makes the binding to mammalian cholesterol much less prevalent. Amphotericin has an affinity for the liposomal delivery vesicle which acts like a reservoir
How does Amphotericin B work ?
Amphotericin B is selective in its fungicidal effect because it exploits the difference in lipid composition of fungal and mammalian cell membranes. Amphotericin binds to ergosterol which alters the permeability of the fungal membrane inducing pore formation.
What is the primary Cell membrane sterol in fungus ?
Ergosterol. which is a cell membrane sterol found in fungal membranes
How does amphotercin form a pore in the fungal cell membrane ?
It is an amphoteric molecule. The portion of the molecule with the double bond will associate with the Ergosterol and the hydrophillic portion will associate with water. When numerous Amphotericin molecules form a complex they can induce pore formation in the fungal cell wall.
Can the fungus develop resistance to Amphotericin ?
Yes. Resistance to Amphoterecin can occur if the ergosterol binding properties are altered
Describe a typical dosing regemen for a patient who has a life threatening systemic fungal infection.
Amphotericin is used for the induction regimen to rapidly reduce the fungal burden. This is good because Amphotericin is a broad spectrum anti-fungal that is effective against most life threatening fungal infections. Then the patient will usually be moved to an Azole drugs which is much less toxic
For the treatment of systemic fungal disease how is amphotericin administered ?
In a slow IV infusion.
What are the two categories of adverse effects when using amphotericin ?
Immediate reactions from the infusion of the drug then longer toxic effects can be observed.
How is infusion toxicity characterized ?
When infusion is too rapid or if too much is infused into the patient. Fever chills muscle spasms headache and vomiting will ensue. This is counteracted by giving less drug over a longer period of time.
What is a proactive way to prevent infusion toxicity ?
Premedication with antipyretics, antihistamines, corticosteroids
What is the greatest concern for the clinician when considering amphotericin for treatment of a fungal infection ?
Renal Damage commonly manifested by by tubular acidosis and severe potassium and manganese wasting
What are some adverse effects when using this drug intrathecally ?
Arachodontitis seizures and neurologic sequelae
What is the mechanism of selective toxicity for Amphotericin ?
The different Sterols in the cell membranes of Fungus and Humans
How are Flucytosine and Amphotericin similiar and how are they different ? ( this is the tag team wrestling partner with amphrotracin B)
Flucytosine has a much narrower spectrum of action and differentiates between fungal and eukaryotic cells by their metabolic pathways instead of sterol composition of the cell membranes. They are similiar in that they are synergistic and can be given together but you have to be really careful about renal toxicity.
How is Flucytosine absorbed ?
It is well absorbed and can be given orally (Cytosine Permease) . It penetrates well into all the fluid compartments and is excreted by Glomerular Filtration.
If you perscribed Flucytosine what do you need to make sure your nurses are doing to your patient so you don’t get fucked over ?
Make sure they are taking serum concentration readings ( this sounds like a nightmare to get nurses to do ) This is very important for patients with renal insufficiency
How is Flucytosine taken up by fungal cells ?
Cytosine Permease and through a series of reactions it is converted into Fluorouridine Triphosphate which inhibits DNA and RNA synthesis.
How does flucytosine differentiate between human and fungal cells
People do not have the molecular machinery to convert the drug into its active form and are spared
Flycytosine acts synergistically with what drug ?
Amphoterecin B and Inraconazole
Is flucytosine used as a single agent or in a combined therapy ?
It is used in a combined therapy because if its narrow effectiveness limited to C neoformans and Candida sp. If given alone there is a high chance of the fungus developing resistance
How can flucytosine be toxic ?
It can be converted to the antineoplastic compound Fluorouracil which will cause thrombocytopenia, Leukopenia, anemia, and bone marrow toxicity
What are Azols ?
14- alpha demethylase Inhibitors
Synthetic compounds classified by the number of Nitrogen Atoms in the Five membered Azol Ring ( Imidazoles and Triazols )