Antifungals

what's up ninja nerds in this video today we're going to be talking about antifungals as i've said before with the antibiotics antivirus lots to cover not as much as when we talk about antibiotics and antivirals but it's still important it's a pretty cool topic that being anti-fungals go to our website down below the description link in the description box below go check that out we'll have some really awesome illustrations some great notes for you guys to follow along with me during this lecture so let's start off first when we talk about antifungals how do they

work so we have a fungal cell here a lot of these drugs they have a very very interesting mechanism of action and it's actually straightforward so we talk about these we're gonna talk about these top three then we'll sit down we'll come talk about the bottom three down here but generally there's a couple drugs one of the first ones that i want you guys to remember is you know inside of our actual fungi they have a nucleus in order for the nucleus to be able to undergo the division process for the fungal cell to divide

make more fungal cells it utilizes these things here called microtubules so you see these things right here these guys right here are called your microtubules now microtubules are obviously super crucial to the cell division process what if i had a particular drug that can bind onto the tubulin proteins that make up the microtubules and inhibit it from being able to allow for the cell division of fungi to occur that'd be pretty interesting right and that would be a good antifungal we have a drug that's called gristiofulvin so griseofolvin will actually bind to the tubulins in

the microtubules and inhibit the microtubule function and what will this lead to this will lead to decreased cell division so the fungal cell will not be able to divide so that's one particular drug so i want you to remember gracious inhibits the microtubules by preventing cell division it binds to the tubulin proteins and inhibits the microtubular function boom chrysiofolvin done all right flucitasine this one's a little interesting a little funky a little weird but it's a cool anti-metabolite drug so how this drug works is inside the nucleus of the fungal cell we have dna right

dna is obviously responsible for being able to what is this called if you take dna and you make more of the dna that's called dna replication right so we take dna make dna but if we take dna we make rna so a single stranded that we're going to utilize to make proteins this is called transcription so flu cytosine is an interesting drug so what happens is flucitan gets taken up into the fungal cell when it gets taken up into the fungal cell it gets acted on by an enzyme here i don't want you to work

too much to remember this one i'm going to abbreviate it it's called cytosine deaminase what cytosine dminase does is is it actually converts flucytosine into a drug called 5-fluorouracil fu don't get your minds clear so what happens is 5-fluorouracil is a very interesting drug or metabolite here where it can actually bind to specific components of the nucleic acids and inhibit them from being able to function properly so subsequently it will inhibit dna replication and it will inhibit dna transcription to make rna if you can't replicate dna will the actual fungal cell be able to divide

and pass on its nuclear machinery will it be able to make fungal proteins that are essential to its function no so flucitosine would be able to again inhibit dna replication and dna transcription by being converted into a metabolite called 5-fluorouracil 5-fu and then inhibiting that type of function so that's one of the other drugs flucidasine all right boom roasted next one is echinocannons now econo cannons are a really cool drug category so when we talk about these there's actually um a couple different ones if you really can't remember the names of them that's okay i

want you to remember that echino cannons always end in fungi pretty original right so fungi so two big ones that you'll probably see microfunction this is the one that i have at my shop at the hospital and then there's another one called caspofungen there's also another one as well but these are probably gonna be the most commonly two utilized fungions that you'll see are the echino candidates now these drugs are really interesting you know you see this cute little enzyme here this little bird enzyme this guy here is called a beta one three glucan synthase

you're like what the this cool little dude right here what he does is he takes specific types of like carbohydrate molecules and converts them into a molecule called beta one three glucan i bet you couldn't figure that out by the name of this enzyme name but what it does it actually takes and makes these particular molecules called beta one three glucans and there's other components here in the cell wall beta one six glucan but this structure here is integral to the actual cell wall and what do we know about cell walls cell walls are supposed

to provide you know in general in this fungi resistance to osmotic forces so generally if it's providing good resistance to the osmotic forces imagine i give a drug called echinocanus what do you think it's going to do it's going to inhibit this beta 1-3 glucan synthase will it be able to take carbohydrate molecules and incorporate into 3 beta-1-3-glucan to incorporate into the cell wall no so we have a decrease in the beta 1 3 glucan and the cell wall activity will now be hindered because there's now going to be decreased resistance to osmotic forces and

this this this this fungal cells all kinds of jacked up then it's going to end up undergoing cell death by cell lysis processes so that's this type of drug category so so far we have gracious inhibits the microtubules right we have flucytosin forms a metabolite called 5fu which inhibits dna and dna replication and dna transcription and then we have the kind of cannons the fungi microfungus and gastrofunction which inhibit the beta 1 3 glucan synthase inhibiting the glucan molecules that are important to the cell wall resisting osmotic forces now you get rid of that you

don't have strength against osmotic forces boom the cell can actually undergo lysis and die all right we're not done now we've got to come on to these bottom three drugs here and talk about them all right so the next thing when we talk about this next drug called terbenaphine it's actually pretty cool but we have to go through a little pathway so when we talk about the pathway within the side of the fungi there's a very important component here see these like green structures here it's called ergosterol let's actually write that up so this molecule

here is called ergosterol so er gasterol now ergosterol is kind of like a cholesterol molecule if you will it's a so what happens is in order for us to be able to make this it first off it plays a role within the stability of the cell membrane so stability of the cell membrane is the primary function of our gastro which is a cholesterolic molecule we know that generally cholesterol plays a big role in cell membrane stabilization especially with like temperature and ph changes etc so we need to make ergosterol in order to incorporate that into

the cell membrane to provide stability how do we make it so you start off with a particular drug called squalene so squalene such a funny name gets acted on by a very specific enzyme called squalene epoxidase which converts squalene into what do you know squalene epoxide then squalene epoxide is then converted into another molecule called lanosterol and then linosterol is then going to be converted into ergosterol via this other enzyme and then we'll talk about that one right there all right so we have this kind of pathway here if you will so squalene to squalene

epoxide is acted on but it's actually particularly this reaction occurs based upon the presence of this cute little blue enzyme what's this cute little blue enzyme called this blue enzyme here is called squalene epoxidase it's called squalene epoxidase and this drug here called terbenophene will actually inhibit the squalene epoxidase if you inhibit squalene epoxides you reduce the conversion of squalene to squalene epoxide then if you reduce the production of squalene epoxide you don't make as much linosterol if you don't make as much lanosterol you don't have as much ergosterol if you don't have ergosterol you

have decreased stabilization of the cell membrane therefore it's at risk of the fungal self dying that's an important process here so terbenaphine inhibits the squalene epoxidase inhibiting ergosterol synthesis important for cell membrane synthesis so so far we've got graciofulvin microtubules flucyitosine inhibits dna and rna synthesis echinocannons inhibits beta one gluco three glucan synthase and then terbenaphine inhibits squalene oxidase okay we got another one obviously it's this cute little guy here this one here it's got a heck of a name so we had all this space here it's called and it's specifically going to stimulate this

particular process this is called the cyp 450 14 alpha d-methylase oh my gosh that's such a long name but this enzyme is responsible for converting linosterol into ergosterol so if i give a particular set of drugs called azoles the azoles will inhibit the cyp45014 alpha dimethylase which is basically going to reduce the conversion of linosterol into ergosterol if there's lesser gastro there's less stabilization of the cell membrane and more likely for the cell to be able to die that is the process of these two drugs so if you want to know for the actual synthesis

of our gastro there's two drugs one inhibit squealing epoxidase that's trabinophene one inhibits the other enzymes cyp 450 14 alpha dimethylase that's your azoles now azol's there's a couple of these drugs one is called your triazoles and one is the amidazoles okay with these your triazoles are very potent very powerful drugs so you can remember what's called avoriconazole as one of these you can remember what's called itra conazole for this one and you can remember isa vueconazole these are very very powerful drugs another one here is called posaconazole this one we don't see too much

it may be used in like prophylaxis in certain situations but this last one here is another big one that you guys have probably heard it's called fluconazole fluconazole so these are your triazole so your triazoles are going to be voriconazol itraconazole isovuconazole posaconazole and fluconazole for the imidazoles these are less of those potent agents and this is going to be something called myconazole clotrimozole and the last one here is called ketoconazole all right and we'll talk about all the functions like which ones what kind of infections does these cover versus what these cover and etc

with all of these but i just want you to have an idea about the actual azole's mechanism of action okay we got the mechanism of action done now we know that these are inhibiting the argosterol synthesis which is important for cell membrane stabilization there's one last drug category here and these are called polyenes now polyes are very very interesting so if we take a look let's say that we actually zoom in on the cell membrane at this level here so what we're going to do is we're going to take this kind of portion here and

we're going to zoom in on it really really well and we see here we have our cell membrane so all of this component here is going to be the inner cell membrane of the actual fungus and then here we're going to have our gastro molecules here here's our gastro molecules in green what happens is is you have this drug which are called your polyenes polyes are really cool because what they can do is they have two different types of like surfaces on them if you will one of the surfaces is going to have a surface

where it can actually bind to lipid molecules so one surface is actually going to be loving to bind to the lipids so it's the lipophilic surface the other surface of this molecule actually wouldn't mind interacting with water and other kinds like water soluble molecules so it's more of a hydrophilic molecule so because of that it binds kind of perfectly like this so this lipophilic end here kind of like draw like this is going to bind perfectly with this green or gastro molecule and it's going to do something like this look at this so here's the

lipophilic end and then here's going to be the hydrophilic on the other side same thing here's another one of these actual molecules here are polyenes one surface is going to love to bind to the actual gastro because it's lipophilic and the other one doesn't mind interacting with water molecules so that's going to be your hydrophilic end and it's going to look like this now if you kind of imagine what this does this makes kind of an interesting like type of pore molecule and it puts it into the cell membrane so now i have a pore

inside of the fungal cell membrane the problem with that is that now i can have different types of ions moving in and out of this actual fungal cell causing a lot of electrolyte imbalances and increasing cell lysis and subsequent cell death so what are the drugs that actually can form these pores inside of the actual fungal cell membrane causing electrolyte disturbances because one side of it combined with the ergosterol the other side can interact with water these are your palines and there's two particular drugs here one is called amphotericin b and the other one here

is called nestatin and again we're going to talk about all these actual drugs and what kind of like functions they have now that we talked about the mechanism of action let's move into what are the clinical usages all right so now we're going to talk about the clinical usages of these antifungals so there's a lot of different fungal infections that we'll go over and we'll kind of go over like which particular areas that you see these types of fungal infections in we're not going to go crazy crazy in detail because we'll cover these fungal infections

like each one specifically like candidiasis and aspergillus in like the actual infectious disease section but for right now let's say you have a patient who has candidiasis and it depends upon where the actual candida infection is to determine which antifungal we will pick if it's in the oral cavity or near the fence they have like the oral thrust or they have some candidiasis near the actual pharynx or tonsils what are you giving them generally nestatin tends to be the actual preferred agent now nestatin is super super powerful if you give it intravenously so we cannot

give it intravenously so generally it's more of a topical agent or you can actually put it in the mouth swish it up and then swallow generally that's going to be the preferred function here in oropharyngeal candidiasis so we can do nestatin but it's important to remember that this is not going to be an oral in the stat it's not going to be an intravenous it's generally going to be this is no joke we actually say swish and swallow for the actual nastatin the second agent that we can also use is clotrimozole but particularly it's like

a lawson so it's not really an oral like agent it's actually more of a lawsuit that we can have the patient kind of have and like dissolve over time so the other agent that you could utilize and chloramizol which one was that was that the actual amidazole or the triazoles it was the imidazole along with meconazole and ketoconazole so clotrimazole would be the other agent here that you could utilize and this is going to be like in a lozenge kind of form so these would be the two agents that we utilize for oropharyngeal candidizes now

let's say that actually gets into the esophagus if it gets into the esophagus and start causing like esophageal lesions there what do we do for this one this one's generally oral fluconazole or itraconazole that's one of your triazoles so in this one we can do fluconazole or we can do something called itraconazole but it's important to remember for these ones we need a little bit more systemic involvement so these are both going to be po oral okay next one is volvo vaginal candidiasis so if someone develops a nasty vocal vaginal candidiasis what do we utilize

for this one so you start off with topical azoles and this is not the triazoles this is the topical imidazoles so topical would be the preferred type here for meconazole or clutromazol so you try this as the first line agent if they do not respond to that then you do something called fluconazole so this is going to be po and if they don't respond to that you could add on that drug called flucitosine do you remember what flu cytosine did so cytosine was that 5fu molecule inhibits the dna rna type of activity whereas the azoles

are inhibiting d c y p 450 14 alpha dimethylase and then the statin is the polyene forms the pores just trying to see if we can go back and remember these things all right so we got oropharyngeal esophageal volvo vaginas what about intertrigonous type of candida infections this is where you have very very moist areas where sometimes that moisture can allow for candida to kind of just thrive in generally this is the axillary and the anal genital area so in the axillary or the anal general area where there's lots of moisture this can be an

area where candida can thrive and generally nestatin as a topical agent would be the preferred type of agent that we would utilize in this infection for intertriginous candida so so far we've covered oropharyngeal we've covered esophageal we've covered volvo vaginal and the last one here or the almost last one is the intertrigonous one we now need to talk about the worst case scenario what if the candida gets into the bloodstream becomes more systemic or causes a lot of a deep infections that are not mucocutaneous in that situation we're getting into candidemia candiduria what do we

do for that let's come down and talk about that if you have a patient who has systemic candidiasis there's likely generally in most fungal infections like systemic fungal infections there's likely immunosuppressed in some way so transplant hiv have severe diabetes something that's really making their immune system severely depressed that allows for these kinds of fungi to cause nasty infections if a patient ends up with like nasty systemic infections so they have like for example candida causes like endocarditis and that's a possibility sometimes you can see endocarditis or you see like really nasty like bloodstream infections

another one is uti so genital urinary candida or believe it or not ocular candidiasis you can actually get infections of the eye with candida so some type of ocular involvement but i think the big thing is that it's disseminated it's in it's used the term maybe systemic or invasive it's really starting to involve other organs and it's not just at the skin level now it's actually gotten to the bloodstream and spread to other areas or it's involving deeper organs in those situations the preferred first line agent is echinocandins do you remember the echino cannons the

echinocannons was your funjins this was your microfungan your casper fungi what did it do it inhibited the beta-13 glucan synthase i know you guys knew that but let's actually put that this is the first line other agents that you can consider as an add-on it just doesn't cover all the candida species it covers a good chunk of them though is fluconazole and again this has to be po and then the other one would be amphotericin b so amphotericin b is another potential option here sometimes they will say that you should add on another agent like

flucytosin to that one but generally amphotericism would kind of be the last line so generally you'll start off with of echinocannons first line if that doesn't work fluconazole and then generally amphotericin but again important to remember here for the systemic invasive infections if somebody says which one do you treat with first it's always echinocannon so i would actually try to remember that one significantly fluconazole would be kind of your second line agent amphoterible or amphotericin would be kind of like the last line for these all right we talked about candidiasis let's now move into the

other fungal infections all right so let's talk about aspergillus so this is an interesting type of like mold infection so when we talk about aspergillus it really tends to particularly involve the lungs all right so primarily the respiratory system it starts off kind of like causing like a little bit of like a pneumonitis or like a bronchopulmonary like involvement but then it can actually cause the trachea and really cause like a necrotizing tracheitis then extend down and if somebody prior had like a tb and they had a cavity here from the tb the actual fungus

can hop into that and cause like a really nasty like fungal infection there almost like a fungal ball not even kidding it's called an aspergilloma and sometimes from here it can actually disseminate so it can really really cause the lungs to wreak a lot of havoc on the lungs so in general when somebody has some type of aspergillus infection we treat them very very intensely for invasive aspergillosis so preferably the first-line agent in aspergillus is going to be voriconazole so voryconazole will always be the answer as the first line agent second one would be the

isovuconazole you could consider that one if they can't take the voriconazole for some particular reason another agent is echinocannons echinocannons are also very very good at covering your invasive aspergillosis the last one i would say would be really like if you really need to because the refractory to all the above things would be your amphotericin but that would be pretty much your last line so i would actually remember your voriconazole first line isobiconazole also has some pretty good coverage and then the kind of cannons last one for severe refractory cases you can consider amphotericin be

the next one here is cryptococcus it's kind of like a yeast like species if you will and it really loves to kind of harvest hair in the lungs and cause a lot of like pneumonia but it also can spread to the meninges and cause a really nasty cryptococcal meningitis so whenever we're covering cryptococcus is a two-part therapy there's the induction kind of like the first two weeks that someone's actually been diagnosed with so in the first two weeks of diagnosis we actually do a two-part combo we do amphotericin b and then we add on here

what's called flu cytosine so we do this for the first two weeks then after that as a maintenance therapy after those two weeks we then can keep them on something called fluconazole so then it'll just be fluconazole and we'll drop the amphotericin b and drop the flucidacy all right so that'd be cryptococcus so we so far we got aspergillus we got cryptococcus and we covered all the candidiasis let's come down talk about our endemic fungi and then we'll talk about the really nasty mucomicosis and then some dermatophyte infections all right so the next one blastomycosis

histoplasmosis coccidiomycosis generally these are endemics so they're dependent upon the geographical area that's a little bit beyond the scope so we're not going to go into that i would just want you to know if you have a patient in their vignette they're diagnosed with blastomycosis or histoplasmosis or carcinoicosis these can involve tons of organs so generally they most of them at least 70 of the time always are going to cause some type of pneumonia involvement they may even cause some type of meningeal involvement especially histo in the coccidio you can see a lot of skin

kind of involvement a lot of like skin and bone lesions particularly in blasto and histo as well so either way you can see a lot of different types of involvement primarily always involve the lungs some type of meningeal involvement and skin and bone lesions in these situations if the patient comes back positive for these particular type of fungi how do we treat them the preferred agent some of the evidence is saying that itraconazole may be superior but another drug that you could utilize is fluconazole so if you have an option between these two i would

actually go with itraconazole it's actually believed to be more superior than fluconazole but fluconazole is also a decent option all right if these two particular drugs aren't available or first more specifically if you have a severe refractory case of blasto histo or coccidio you can consider amphotericin b but this would be let's actually put this down ampho terrace and b would be more for severe kind of refractory cases really but the preferred agent remember it console so again aspergillus vorticon is all crypto two part ampho flucidazine then fluconazole blastohistococcidio itraconazole first line and then you

can consider fluconazole ampho if it's severe the last one here is mucormycosis so this is a type of mold and it's a really really nasty one i actually would think that you guys should remember that you can see this particularly in patients who have diabetes especially if they have like a diabetic ketoacidosis so whenever a patient has diabetes mellitus they definitely have like a little bit of immunosuppression and this actual kind of mold can cause a lot of infections of the sinuses that can actually sometimes extend up into the actual brain tissue it's going to

cause kind of like a really nasty rhino cerebral sinusitis okay so you can get a really nasty type of sinusitis here they can actually cause black escars to form within the tissue sometimes you have to debride so really nasty sinusitis and then sometimes it can even spread into the actual lung tissue and cause a pretty bad pneumonia so if somebody has much or mycosis look for a patient who has diabetes in the clinical vignette look for really nasty black escarg like sinusitis also look for pneumonia involvement what do you use to treat these patients generally

iso vuconazole is going to be the first line agent if that one isn't available you can consider or they don't they have some type of contraindication to getting an azole like a severe hepatotoxicity of some particular region you can consider amphotericin b if there is some particular contraindication to the above here but oftentimes because of these nasty like infectious lesions you also sometimes have to debride the lesions as well so i'd also don't forget it's not it's a little bit beyond this lecture but just remember that that's not the only treatment is the antifungals sometimes

you may need debridement of the actual lesions as well all right that covers these particular nasty systemic fungal infections let's kind of finish it off with the easy commonly remembered ones which is your dermatophyte infections and tina versa color all right so the next one tina versa color so these are like these hypopigmented like lesions here that you can sometimes see like on the actual body like on the trunk and generally with teeny a versa color it's always going to be a topical agent preferably you can try something like a topical azole but these would

be your imidazole so ketoconazole and mechanozol tend to actually be the preferred in these situations so you would do something like atopical and with these topicals you would do something like meconazole but actually preferred seems to be ketoconazole so i would actually remember ketoconazole as the preferred agent in this condition so i kind of put like an asterisk there for that one all right teeny versus color done the last one is your dermatophyte infection so these are also your teenia infections but we don't consider teenia versacolor to be a part of this one so with

the dermatophyte infections it actually depends upon where so these are like your superficial fungal infections and it depends upon where the actual infection is that determines what kind it is so really quickly if it's kind of like generally like near the head we call that teenia capitus and then if it's occurring kind of like near the uh generally like near the beard region we call it tina barbara if it's near the actual body we call that tinia corporis if it's occurring near the actual growing region we call that tinia crores if it's occurring near the

actual feet region so like an athlete's foot we call that tinia pedis and the last one is if it actually involves the toenail and causes some actual a fungal infection of the toenail we have two names for it it's called tinea ungium but oftentimes you'll see onconcomicosis as the actual common name that you'll sometimes see too artenia ungium so generally these are the types of infections that we can see now with all of these regardless of which type it is tinea capitis teenio kapoor's tiny occurrence teenapedis we can treat all of these pretty much with

the same particular agents so what are those agents that we would utilize for these infections so generally the preferred agents here is you start off with the topical azole so topical agents would kind of be the first thing that you would try and so this would be again your meconazole this would be the clotrimozole this would even be attempting the ketoconazole if these don't work as the first then the second thing that you can attempt to is something like a oral itraconazole so oral hydroconazole would be another particular agent here that you can try the

other thing here that we can sometimes see utilized is griseofolvin so griseofulvin may also be utilized that's kind of like your last line agent though so i'd say you're topical azolez then an oral itrachonazole if that doesn't work griseofolvin the last thing is over oncomycosis for oncomycosis the only particular treatment that we see best suited for oncomycosis is something called terbenophene so this would be the only times i would actually see this drug really being utilized as terbenavine sometimes they say griseofolvin but terbenaphine is obviously way more superior than oncomycosis and compared to graciofulvin okay

so so far we've covered all of the different types of fungal infections that we would use antifungals for now that we've gone through that the next thing that we have to be aware of okay we put these patients on these antifungals and they are at risk for what types of adverse effects what kind of things should i be monitoring looking for which would make me want to not pick this drug and pick another drug depending upon their clinical history and medications that they take let's talk about that all right so let's talk about the adverse

effects of these antifungals so the first one is amphotericin b so we obviously use the funny little term anfo terrible just a lot of adverse effects that we've got to be careful of so one of the big things that is extremely nephrotoxic so you have to be careful monitoring the patient's creatininal function is very very critical when you're giving this medication okay so ampliturism b remember it has nephrotoxicity so you want to be monitoring the patient's renal function when they're taking this drug all right the next thing is if you give this drug it has

the ability to cause a lot of inflammation and irritation to the actual blood vessels whenever you infuse it sometimes it can even cause fever and chills during the infusion of it but it can cause phlebitis so kind of inflammation and irritation of the actual blood vessel the next thing is it can actually suppress the bone marrow particularly preventing the formation of red blood cells so you may see a patient drop their red cell count when you do a repeat cbc so you may see anemia here's the other thing it also can increase the risk of

arrhythmias tachyarrhythmias so particularly what it does is it actually leads to a low potassium and it also can lead to low magnesium levels and this can actually increase the qt interval and put a patient at high risk of something called torsades de points so it's important to remember here that there's nephrotoxic effects phlebitis and sometimes even fevers and chills during the infusion anemia from bone marrow suppression and lowers your kmag which can increase your qt interval and cause torsades to points all right what about terbenaphine since we're already here it can jack that liver up

there's a pretty common thing that you're going to notice from a lot of these drugs other than amphoteres and b so that'd be kind of maybe one of the reasons someone has like a very acute liver failure they have terrible bumps in their lfts and you're trying to figure out okay which one should i put them on well they already have like almost acute liver failure probably shouldn't put them on some of these other drugs ample tears and be maybe a little bit of a better option but terbenaphine if you're treating somebody with oncomycosis what

would turbanife potentially need to monitor you need to monitor their lft so it is have the ability to cause a paddle toxicity so you can see a bump in their lft so monitoring that while they're on the drug the other thing is it can actually cause change in taste so a decrease or loss of taste and we call this dysqueezia such a seductive like name but dysqueezia for turbinifey all right the next one here is echinocandins echinocannons are going to be your caspar fungi microfungus albemino albimonofungen and these two drugs uh those two categories of

drugs particularly microphones and casper bunch are most commonly utilized are going to cause a patatoxic effect so you notice the common theme terbenaphine the kind of cannons probably all the other ones here are going to cause hepatotoxic so you're going to want to monitor their lfts during this here's the other thing echinocan is a casper fungi and microfunction when you're giving the particular drug it may activate certain mast cells in the skin and cause a release of histamines so particularly during the infusion of this drug it may cause a histamine response that causes kind of

a vasodilation of the actual blood vessels near the skin which can lead to a flushing type of reaction so you may see a lot of flushing during the actual administration of these particular drugs watch the lfts and watch for any kind of flushing all right now let's come down to talk about the azole's gristiofulvin and flucide have seen adverse effects all right so next thing azoles azol so again is your amidazoles your triazoles when we talk about these drugs i just kind of focus a little bit more particularly on the triasol so especially if you're

giving them systemically so fluconazole hydrocon is all isobutanosal posaconazole and voriconazole not so much the actual ketoconazoles although you can give ketoconazole orally especially in certain situations if you do give it orally you can see some more systemic side effects but usually with the topical formulation you don't see with mechanosol and chlorotramazole you don't see a lot of the adverse effects so i remember a lot of this you're particularly going to see it more with the oral agents but don't forget ketoconazole can be given po and you'll see two particular adverse effects from p.o ketoconazole

so azol's in general especially the triazoles remember that it is hepatotoxic so you're going to want to watch and monitor their lfts when you put them on this drug because you can't see a bump in that here's the other thing a lot of these azoles are cyp 450 inhibitors so they're sip fee for cyp450 inhibitors and so what that means is if you take a particular drug it actually metabolizes it by adding on particular molecules like glucuronate and different types of molecules to make it a little bit more polar but it's involved in drug metabolism

if we give one of these azoles it actually will increase the actual concentration of the drug so you'll have an increased concentration of the actual drug so for example let's say that you're having a patient who's taking warfarin and you put them on an azole as well the azole can inhibit the cyp-450 enzyme inhibiting the metabolism of particularly the warfarin to make it a little bit more polar but it actually increases the concentration of the total drug within the bloodstream so now they're high risk of bleeding the next thing is particularly with ketoconazole it actually

can cause gynecomastia so particularly ketoconazole you may see the effect of gyneco gynecomastia this is a little bit more specific to ketoconazole the other thing is it can't actually increase the risk of arrhythmia so it is slightly probogenic because it can cause low k levels and that low k levels may actually prolong the actual qt interval slightly and if you increase the qt interval slightly there is a slight increased risk of torsod points the other thing is that ketoconazole is very interesting because it is involved in in some of the steroid synthesis pathways um because

of that because it has actually worked remember we said squalene to squalene epoxide and then front to the nostril and our gastro that's all making a steroid molecule or gastro well ketoconazole can actually affect some of the actual steroid synthesis within the body the same way that it works in fungi it can work in the human body and can inhibit the production of particular hormones such as like cortisol and aldosterone and so you can actually develop an adrenal insufficiency if you have p.o ketoconazole so remember that sometimes we actually use that in treatment whenever patients

are making too much of those hormones so ketoconazole may cause adrenal uh insufficiency we're going to put down arrows there but i want you to remember this is particularly to ketoconazole the last one is going to be visual dysfunction so it can actually cause visual dysfunction uh visual disturbances and this is more specific because i want you to remember visual dysfunction you see the visual the voriconazole is the more particular agent v visual dysfunction voriconazole is going to be the most particular agent that has been shown to cause it actually can lead to reversible uh

visual dysfunction but so if your patient has this kind of like visual dysfunction when they take for a console you can just either decrease the dose or remove the medication if they can't tolerate it and then they'll have you know complete gain of function back of their eyes again but these are the medication adverse effects that i want you guys to watch out for with the azoles the gricio fulvin is the other one and this is why we kind of switch to terbenaphine generally um in comparison to graciofulvin for like oncomycosis and a lot of

the dermatophyte infections you use other agents like your azoles or your your topical asos or your oral asylums graciofulvin is pretty hepatotoxic that's one thing so you definitely because of that you want to monitor the patient's lfts and to be honest with you it's probably not a bad idea if a patient asks you know if you're asking the question what kind of labs would you want to monitor in a patient taking antifungals i'm sure the lfts you probably won't go wrong to be honest with you the other thing is azol's our cyp450 inhibitors this bad

boy is a cyp-450 inducer so meaning it actually is going to decrease the concentration of the actual drug circulating so if a patient is taking warfarin and you give them um a gracial folate then gristiofolive will act as an inducer reduce the concentration of the warfarin making them less able to well actually in this situation if you decrease the concentration of warfare now they're getting actually clot so that's the problem with that one so think about that with other drugs that they may be taking and maybe reducing the efficacy of those particular drugs the next

thing is teratogenic and carcinogenic so do not give this to people who are actually pregnant so that's one particular thing to remember and also if you really want to add this one in you have the brain space is it also has been shown to cause a disulfiram reaction so it can cause that kind of nausea vomiting flushing maybe even hypotension when you take this with alcohol the last particular drug here is flucytosin so just like gristio fulvin is toroidogenic flucytosine is also teratogenic so don't give this to patients who are pregnant and the last thing

is it can actually suppress the bone marrow and prevent the production of all cell lines so it can drop the production of your white blood cells and it can drop the production of your red blood cells and it can drop the production of your platelets so what do we call that whenever actually you drop all the actual cell lines both the white blood cells the white uh the platelets and on top of that the red blood cells this is called pancytopenia so watch out for pancetta penis or monitor their cbc whenever you have a patient

who is on flu cytosine all right my friends i know you think that that's it but we're not done we got to review this stuff because there was a lot that we covered so let's actually do some cases see if you guys can remember all this stuff and let's get at it what's up ninja nerds all right so let's go ahead and do some cases here we got to talk about some antifungals all right so your infectious disease attending is performing his rounds and he decides to say okay i'm going to ask you some questions

about antifungal therapy and let's go through their mechanism of action so he's going to pimp you out a little bit quizzy he says okay which drugs inhibit the squalene oxidase reducing the formation of linosterol in our gastro thereby reducing the stability of the cell membrane do you guys remember this you have squalene esquilion epoxide to linosterol to our gastro which is important incorporating into this cell membrane stability so if i give a drug to inhibit this create squalene oxidase this would be terbenifene the next one would be which is the drug that inhibits this cute

little enzymes let's go to that one which is the one that inhibits the cytochrome p450 14 alpha dimethylase enzyme this is going to be which one do you guys know the azoles so this is your triazoles voriconazole itraconazole isobuconnazole posaconazole fluconazole and then your imidazoles which is mechanozole chloramizal and ketoconazole good again both of these are inhibiting the formation of ergosterol which is important in cell membrane stability so terbenifene and azol's inhibit ergosterol formation all right which ones actually bind with ergosterol kind of form a pore because it has a hydrophilic and a hydrophobic portion

and when it binds to this our gastro creates a little pore that allows for ions to move in and out which can create the opportunity for cell lysis this is which ones do you guys remember which is the ones that actually form the pores these are the ones like nestatin and amphotericin b all right beautiful all right so the next thing is we're going to move on to the drugs that inhibit the beta 1 3 glucan synthase this is the guy that makes the beta 1 3 glucans which are important in cell wall stability resistance

to osmotic forces if we inhibit this particular enzyme that will actually reduce the formation of these cell wall structures and reduce the ability to resist osmotic forces causing cell death this will be the kind of cannons microfungan caspar fungi right beautiful all right which is the ones that actually binds to the microtubules particularly the tubulin proteins inhibits the microtubule so now that you can't actually separate the chromosomal dna and help with the actual division of fungi passing on genetic material this is griseo fulvin beautiful i know you guys are killing it all right which is

the one that actually comes into the cell gets converted into five floor uracil vi cytosine deaminase binds with the actual dna inhibits it from being able to undergo dna replication and also dna transcription this is flue cytosine beautiful all right we move on now into the first case he says okay you have a patient has oropharyngeal candidiasis they got some thrush there what's the treatment what are the actual opportunities of what kind of drugs would you use you can say oh you can use the nostatin you can swish and swallow or the clutch tramazole lozenges

beautiful done all right he says okay you actually have a patient who has esophageal candidiasis and you see this here look at all that oh man that's rough what are you going to do for this patient this is oral fluconazole or itraconazole beautiful all right you have a patient has volvo vaginal candidiasis what are the treatment options for this one well first one we can consider is the topical azole's the imidazole so type of topical meconazole topical clatrimozole and if that doesn't work po fluconazole and if that doesn't work flu cytosine you guys remember this

right all right beautiful all right patient has intertriginous candidiasis meaning that they have some candida in the actual different folds like underneath the breast in the axilla and the anal anogenital area what would a potential treatment for this be we could do the statin topical beautiful all right we have a patient who has systemic or invasive candidiasis that's invaded their blood so there's in their systemic circulation it's caused endocarditis it's caused a urogenital tract infection it's caused an ocular infection some type of nasty invasive candidiasis what are the particular treatment options for these patients you

can do which one the echino candidates are going to be really good at this but you can also consider like pio fluconazole as well right and last but not least amphotericin all right you have a patient who has invasive aspergillus so aspergillus is a nasty thing that can cause like allergic bronchopulmonary aspergillus then it can actually cause like a pneumonia like a nodular kind of pneumonia it can cause aspergillomas like these fungal balls that can actually appear and it can really cause cavitations and can even spread throughout the body what will be the particular treatment

options for this what's the always the first line voriconazole yep then isoviconazole echinocandins and amphotericin b is another option all right patient has a cryptococcal meningitis and pneumonia what are the particular treatment options so you treat this within the first two weeks induce them with flu cytosine and what else amphotericin b and then after that we can put them on fluconazole for after that two weeks is maintenance therapy you guys remember that all right cool we have a patient who has what's called either blastomycosis or histoplasmosis or coccidiomycosis and as we talked about this is

kind of an endemic endemic type of fungal infection that's dependent upon the geographical location that you're at so as you can see histoplasmosis would be in this part of the actual u.s and you can see blastomycosis in this part of the u.s and then again you can see coccidiomycosis over here in this particular part of the u.s so it's obviously dependent upon the geographic location but either way it can cause you know pneumonia meningitis skin bone infections so because of that what are the particular treatment options for blasto histo or coccidio what is it itricondazole's

first line fluconazole is another option and then if you can actually consider adding on amphotericin b to fluconazole especially in those severe refractory cases all right patient has rhinos cerebral and lung mucour mycosis really nasty type of infection if they have this people who are at high risk for this is patients who are diabetic or hiv positive in this situation what's the preferred treatment for mucor it would be isobuconazole at its first line other ones would be amphotericism b if they're contraindicated of taking isoviconazole and then you need to consider debridement of the actual infected

area our patient has teenia versacolor if they have teenia versicolor right this type of dermatophyte infection what do you treat these patients with topical ketoconazole would be the preferred one or mica micondazole all right you have a patient who has a terrible day they have tinea capitis teneocriporus tina cruz and tediopetis right so they have an infection of this actual nasty uh fungus on the head they have it on the body they have it at the growing okay and even out of the feet if this happens what is the particular treatment for these patients in

a theoretical world we would treat them with topical agents first myconazole chloramizal ketoconazole we could even escalate to po itraconazole and then if that doesn't work we can even consider something like griseofulvin now if a patient has teenia ungium or what's called anecomycosis this is a really nasty infection that will not respond to topicals and really the only thing is piotr benefiting and some even say griseofolvin but turbinifen would be the preferred option all right engineers we covered all of the cases that i want you guys to remember for your anti-fungals i hope this made

sense i hope that you guys enjoyed it as always love you thank you and until next time [Music] you