Flashcards in Anti-Fungals Deck (75):
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
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 )
How do Azols inhibit Fungal Growth ?
The reduction of Ergosterol formation by the inhibition of Fungal Cyp 450 but can also affect human Cyp 450 so you have to be very careful
What is the spectrum of Efficiency for Azols ?
It is broad
What do you need to ALWAYS consider when patients are on Azols and other medications ?
That the Azol could be affecting the patients Cyp-450 Activity and you need to be aware of that.
What should you be thinking if you see that someone has placed orders for Ketoconazole ?
WTF!!!!! KETOCONAZOLE has been taken off the market because it affects Cyp-450 in humans more than fungus. It will disrupt all steroid hormone synthesis in the adrenals. As well as disrupt other drugs that use CYP 450
What is intraconazole ?
Oral and IV formulated Azol. IT affects the hepatic Cyp enzymes but not near the extent of Ketokonizol. It has poor Thecal penetration and is very effective against Dimorphic Fungi
What is a potential barrier that should be overcome when treating a patient with intraconazole ?
The question of bioavailability. Intraconizol getting INside the blood.
**It will legenthen the QT period and will also decrease contractility. This Azol is not good for patients with cardiomyopathy.
Takng intraconizol with what drug will lower the bioavailability ?
Which azol has the highest bioavailability ?
Fluoraconizol because it has high oral bioavailability and good CNS penetration. It also has the least effect on Hepatic Cyp Enzymes
What would you treat fungal meningitis with ?
Fluconazole- This antifungal is very water solubility and good CSF penetration.
Which Azol has the least impact on CYP-450 activity ?
Fluconazole- This is most widely used Azol in clinical medicine
**Pregnancy Class D so if you give it to a pregnant girl she will have birth defects in her child
What is a major factor to consider when administering Voracious- Voriconazole ?
Clinically relevant inhibitor of CYP3A4 and a dose reduction of a number of medications will be critical
If voricanizol is dangerous to CYP activity why would you use it ?
It has effects similiar to Amphotericin B but does not have the risk of renal toxicity
What Azol will inhibit CYP3A4
What is the advantage of Posaconazole ?
It distributes very rapidly to the tissues but maintains a low level in the blood
What is a disadvantage of Posaconazole ?
It has an inhibitory affect on CYP3A4
What is the broadest spectrum azol ?
Posaconazole- It is used most often as a prophylaxis for chemo patients undergoing bone marrow transplant patients with graft versus host disease. Also used as a pryphylaxis for patients undergoing induction for chemotherapy
How do Echinocandin's work ?
They block the synthesis of (1-3) glucan in the cell wall synthesis
What is something to be aware of when administering Echinocandins ?
They are hepatically metabolized so you need to keep that in your mind when treating patients with Hepatic insufficiency
What will caspofungin and cyclosporine do when administered together ?
Cause an abnormal increase in Liver enzymes. This should be avoided
What are the two oral systemic antifungal drugs for mucocutaneous infections
Griseofulvin and Terbinafine
What is Grisofulvin (Greasy Fulcrum) used for ?
It us used to pry Dermatophytosis off the foot - it is deposited in newly formed skin protecting it from infection. It is administered so that newly formed hair and skin has keratin that is not infected by fungus
What drugs will (Greasy Fulcrum) Grisofulvin interact with
Warfarin and Phenobarbitol
Does Grisofulvin actually kill the fungus ?
No it just prevents infection of newly grown skin hair and nails
What does terbinofine do ?
It is a keratinophilic medication used to treat dermatophytosis.
How does terbinofine actually work ?
It inhibits Ergosterol formation but does not affect CYP P450 activity.. Inhibits Squaline Epoxidase which leads to the accumulation of sterol squaline which is toxic to the fungus.
What is the main difference between Grisofulvin and Terbinofine ?
Terbinophine is fungicidal
What are the three topic antifungals mentioned in the reading ?
What are the two Topical Allylamines
Terbinafine and Naftifine
What are the topical Azoles?
Clotrimazole and miconazole both are OTC and used for vulvovaginal candidiasis. Both are also used for Dermatophytic infections
Nasty- Nystatin, what does this do ?
Macrolide very similar to Amphotericin B To toxic to give orally and likes to punch holes in the fungal cell walls
Why is Nasty- Nystatin not given orally ?
It is to toxic for parenteral administration and is only used topically. Also it is not absorbed from the skin, GI tract or mucous membranes. This is why it is great for cutaneous infections.
What drugs mentioned will cause QT prolongation ?
All the intraconizols
What is the pregnancy category scale ?
A B C D X with increasing severity of birth defects. A B and C have no evidance but increasing risk . Avoid D at all cost and X, your baby will have squid tentacles or some shit
What is a risk associated with Voriconazole ?
What are all the Azols ?
14-alpha Demethylase Inhibitors
What is a drug in the Polene class ? and what does this class do ( mechanism wise )
Amphotericin B, these drugs bind ergosterol
Why id Ketoconizol so toxic ?
It inhibits all the CYP enzymes that are responsable for converting cholesterol into Corticosterone, Cortisol, and Androsterone.
What antifungal will affect the bone marrow and erythrocytes, what will the result be ?
The result will be anemia, Flucytosine and Amphoteracin?
What should you be concerned of when treating Asians with fungal infections ?
Cyp 2c19 mutations will impair drug metabolism and could cause interactions
What is a common threat of all the Azols?
CYP34A mediated drug accumulation
Which Azols have a high risk of birth defects ?
Fluconizol and Voriconizol
What can photo-toxicity cause ?
What are the three classes of antifungal drugs that alter cell permeability ?
Azols, Polyenes, and Terbinofine
Which antifungal block DNA and RNA Synthesis ?