March 20, 2007

Anti-Microbials  Fungal Infections o 2 major types of mycoses  Superficial and systemic  Antifungals o Not a lot of drug choices very limited o Use is limited by their toxicity o By treating fungi  Need to compare with virus and bacteria  Need to know sites of attack  Antifungals: Polyenes o Act by binding to sterols

ergosterol

phospholipid

o Amphotericin B (not in notes)  Used parenterally/topically  High doses for more resistant fungi, lower dosees for UTI/esophageal infections  Not penetrate BBB well (Still used)  Extensive LV metabolism (?) • Biomechanism pathway not sure of, so don’t know how it is broken down  Slow renal excretion, biphasic t1/2 • If were to graph it’s conc in the body it goes down and comes back up a little bit.

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The first 24 hrs would lose a substantial amount, but the small conc. Bodies would still last a long time (up to 15 days). This is where toxicity issues come into play o Amphotericin B: ‘Amphoterrible’ (not in notes)  Most toxic antibiotic used today  80% nephrotoxicity (causing azotemia, hypokalemia, hypomagnesemia)  Acute LV failure, cardiac arrhythmias, hematopoetic disorders  Less severe sx: n+v, chills, fever, HA Nystatin o Limited to more topical use o Very minimal side effects compared to amphotericin o Poor absorption in via mucous membrane Azoles o Can be fungistatic or fugicidal o Will inhibit synthesis of ergosterol (stop production of the sterol before it’s incorporated into the membrane) o Acetyl CoA  squaliene (conversion by p450 enzyme)  Langosterol Ergosterol o Decreased ergosterol leads to decreased fluidity o Problems with replication, transformation of candidal cells to hyphae o Effecting the ergosterol in different places in different ways Fluconazole o Inhibits P450 so also has some interactions with other drugs o Hypoglycemic agents are most commonly seen o Good agent to treat KI infections  Urinary tract Candida o Tends to conc in certain areas including the CSF o Where it has excellent penetration o Don’t need to know what it’s active against Antifungals: Azoles (not all in notes) o Fluconazole absorption is decreased 15-20% by cimetidine and may alter warfarin-adjusted PT time (benzo’s, HMG-coA reductase (-)) o Usually well tolerated o Systemic tx: skin rash, elevated LV enzymes/LV injury, hematopoietic toxicity, GI distress (N+V, diarrhea) Antifungals: Allylamines o Terbinafine  Metabolism via P450 mechanisms  Primary treatment for superficial dermatophitic infection Anti-Malarials o Look at diagram on last slide of package Malaria

o 4 malarial species o P. falciparum  Fever every few days  Makes RBC sticky  If treated no relapses o P. malariae  Not as aggressive o P. ovale  Rare o P. vivax  Less severe, rarely fatal  Problem: can persist for years and years o Best way to treat is to avoid it o Prevents digestion of Hemoglobin  Parasite then does not have AA to work with to build more of itself  Increase in Heme in the cell which is toxic to that organism o Choroquin  Well ablsorbed orally but can still be given iv/im  Concentrates in the parasitized RBC regardless of method delivered  Lasts in body for long time  Anti-virals o Herpes simplex o Resistance  Usually d/t the development of mutations  Anti-viral Tx o Most anti-viral drugs are anti-metabolites o Don’t kill of virus directly but freeze it (Stop replication – up to our body to get rid of it) o Resistance can happened o Successful anti-viral treatment depends on the host o