Polyenes – Antifungals

00:00 Let's take a look at some other classes of drugs that are used to treat fungal infections.

00:06 The polyenes, nystatin being the prototypical drug is used for superficial infections.

00:11 You can see where it acts on the cell wall down here.

00:14 It's used topically to suppress candida infections.

00:18 And it's used as "swish and swallow" for oral candidiasis.

00:22 The mechanism of action, remember that these polyene antifungal agents bind to ergosterol and caused artificial pores in the cell membrane.

00:34 This causes leakage of hydrogen ion, potassium ion, chloride ion and even sodium ion through that pore.

00:41 It also increases free radical formations within the cell itself which causes toxic intermediates inside the cell.

00:50 And causes fungal cell death.

00:54 The next polyene I want to talk about is amphotericin B.

00:57 And you'll notice that the slide is almost is exactly the same as nystatin.

01:02 Now these polyenes binds to ergosterol and caused artificial pores.

01:07 And once again as with the nystatin, it leaks hydrogen, potassium, chloride and sodium ions through this pore.

01:14 And you also have free radical formation within the cell that causes toxicity inside the fungal cell and cell death.

01:22 Now amphotericin B is a polyene and it is related to nystatin.

01:27 But it's usually intravenously administered.

01:30 Nystatin is usually what we call topical.

01:33 And so it's gargling kind of an agent that we use in oral candidiasis.

01:39 Amphotericin B is an intravenous drug and it's used for much more serious infections.

01:44 It's eliminated through the slow hepatic metabolism of it.

01:48 And it's half life is therefore quite long, 2 weeks.

01:52 It has minimal renal excretion.

01:54 But we do make small adjustments to this medication in class 4 or stage 4 renal failure.

01:59 Clinically we use it for systemic mycoses.

02:03 And usually ones that are fairly serious.

02:05 It's the widest antifungal spectra of any antifungal agent on the market.

02:11 It works against aspergillosis.

02:12 It works against blastomycosis.

02:15 It works against candida, cryptococcosis, histoplasmosis and mucor.

02:22 It also used intravenous or rarely intrathecally.

02:27 I have seen it used intrathecally once in my career.

02:30 Now mycotic corneal ulcers and keratitis are one of the potential treatments of that we can use amphotericin B for.

02:39 Now in terms of the toxicity of this medication, the most interesting thing that I've seen with this agent is, infusion related chills.

02:49 So patients suddenly start feeling very cold and -- I don't really have an explanation as to why that's occurring.

02:56 Patients will also have nausea, muscle spasms and vomiting.

02:59 And sometimes patients will have this shock like fall in blood pressure.

03:05 So a lot of time we will premedicate these patients with antihistamines or even glucocorticoids.

03:11 You have to be very aware that ampho B can cause renal tubular acidosis.

03:16 And can cause magnesium wasting and potassium wasting.

03:19 Now the magnesium and potassium wasting are kind of coming hand in hand.

03:23 Most of the time when you have magnesium wasting, you're also going to have potassium wasting.

03:28 The other toxic effects include anemia.

03:32 That's usually due to decreased erythropoietin production from the kidney.

03:37 You can have those nephrotoxic effects.

03:40 These are usually dose limited however.

03:42 Now we have a liposomal version of amphotericin B.

03:47 These amphotericin B liposomes package the amphotericin B on the inner surface or on the inside of these liposomes or I should say endozomes.

03:59 And the reduce renal toxicity, we call that lysosomal amphotericin B or liposomal amphotericin B.

04:08 The correct term is actually liposomal.

04:10 We do give intrathecally this medication but it is associated with seizures in neurologic damage.

04:18 So that is a treatment that we try to avoid unless we're really in trouble.