Echinocandins – Antifungals

00:01 Let’s continue our discussion on the antifungals.

00:04 Now we’re gonna move on to a certain class of drugs called the echinocandins.

00:09 Echinocandins are beta-glucan synthesis blockers or inhibitors.

00:15 Beta-glucan are the links of the chain that lash together the outer part of the membrane or cell wall of the fungus organism and the inner wall.

00:25 You can see there that the top layer are made up of proteins, the middle layer is made up of the beta-glucans, the third layer is made up of something called chitin and chitin is bound to the protein wall through these beta-glucans.

00:39 Blocking the beta-glucan synthase enzyme reduces the ability of the fungal organism to build a cell wall.

00:48 The mechanism of action therefore is it inhibits the beta-glucan synthase, this acts kind of like the penicillin of all anti-fungals and you have increased susceptibility to any kind of an osmotic force.

01:02 The cell simply isn’t as strong as it was without the beta-glucan there.

01:08 Side effects of this particular medications include although it’s generally well-tolerated you can get infusion or local site reactions.

01:17 Often you’ll see redness on the skin or where the IV site is.

01:22 You can often get a histamine rash especially when the infusion is given rapidly.

01:27 And finally, you can have elevation of liver enzymes particularly alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase.

01:38 Now take a look at the structure of this drug.

01:41 It’s an interesting structure but we’ve actually seen something very similar before.

01:45 It is a large polycyclic ring composed of many peptides and these peptides, there are six of them, are arranged in a super cyclic structure called a hexapeptoid cyclic structure.

01:59 There’s a chain that comes off the end. It’s a long N-linked acyl fatty chain that acts as an anchor for that particular drug to kind of penetrate into the cell membrane and act as a an anchor so it will hold it there in place for it to do its job.

02:18 These are large, large molecules - so the CSF penetration, the eye penetration and the excretion by urine is really not there so you have to make sure that you’re giving it in the compartment where the infection is.

02:34 If you’re treating an eye infection using this medication will be kind of difficult because it’s not gonan go into the eye structure itself.

02:43 There are several different drugs available in this class, I’m gonna talk about three which I think are particularly important.

02:50 Let’s start off with caspofungin.

02:53 Now caspofungin is interesting from a pharmacology point of view because it has a three phase pharmacokinetic profile and that pharmacokinetic profile is not linear, so sometimes it’s very hard to calculate volumes of distribution and how this drug is going to interact with other medications.

03:13 Younger patients will metabolize this drug faster than older patients so there is an age related component as well.

03:22 Now the other problem with this particular drug is that it interfere with cyclosporine metabolism now I don’t want you to get too excited or too worried about this particular drug and its pharmacokinetics, I’m only telling you this for your own interest, you’re not going to need to be able to calculate pharmacokinetics of this drug on your USMLE but perhaps if you do a pharmacology specialty, okay, then we’ll nail you with that.

03:48 The next drug in this list is micafungin.

03:50 Micafungin has nice, straight forward, linear pharmacokinetics so it’s relatively easy to calculate the dosage on and you can see how complicated a molecule it is.

04:02 Again, younger patients will metabolize this drug a lot faster and again it interferes with metabolism but this time it interferes with sirolimus metabolism.

04:14 The third of these drugs is anidulafungin, its quite a mouthful but then again it’s a very complicated molecule so I think it’s reasonable to have along a name.

04:24 There’s no dosage adjustment with this medication so you can give it with cyclosporine or tacrolimus or sirolimus and you don’t have to make adjustments in terms of the dosages that you’re going to be using.

04:36 Again, if you ignore the fact that there were three almost hexane rings on the anchor, it still works in the similar way where the long chains axes and anchor and then the supercyclic structure acts as sort of the mechanistic force that makes changes to the cell wall.

04:56 Now, in terms of the echinocandins the advantages of this class of drugs, all three of them, is that they have a fairly broad range of activity against different organisms in the fungal class.

05:06 They have a very long half-life, they have a relatively low toxicity all things considered and the nice thing is, is that these are not affected by the cytochrome system or by the p-glycoprotein system.

05:19 It is not specifically affected by renal failure which is another nice advantage of this medication and there’s no - for the most part, there’s no dosage adjustments based on age, gender or race except for the fact that younger patients will metabolize the drug a little bit faster than older patients.

05:38 The disadvantages of this medication is that it can be embryo toxic so we don’t wanna give it to pregnant women.

05:44 We do need to adjust it in patients who have liver failure and there’s very poor ocular penetration and you’d be surprised how often fungal infections in the eye come up using this particular drug class in ocular infections is just not going to work.

06:01 Well, that’s it for this class. I hope you enjoyed it and good luck on your exams.