Antivirals | HIV, Hepatitis, Influenza, Herpes Treatment

0:06what's up ninja nerds in this video

0:08today we are going to be talking about

0:09antivirals there is so much to go over

0:12just like antibiotics we're going to

0:14cover every antiviral we're going to

0:15talk about those against hiv against

0:17influenza against hepatitis against the

0:19herpes viruses and so there's so much to

0:21cover so what i urge you guys to do to

0:24really understand this stuff assist in

0:25your understanding of this please go

0:27down in the description box below

0:29that'll take you to our website on our

0:30website we'll have illustrations we'll

0:32have notes for you guys to follow along

0:34with and really really help and aid in

0:36this very difficult topic okay

0:38so let's talk about antivirals

0:41when we talk about antivirus we're going

0:42to go over the first category against

0:44hiv so these are going to be your

0:46antiretroviral therapies now hiv is a

0:49nasty virus it's a type of retrovirus

0:52when we think about that retroviruses

0:54are basically viruses that take rna and

0:57they can be converted into dna now what

0:59kind of host cells do these usually

1:01attack they attack our immune system

1:03particularly you know what kind of cells

1:04they love to attack they love to attack

1:07our cells called the t

1:08helper cells so our t helper cells are

1:11the big cells that are constantly being

1:13attacked are cd4 positive cells really

1:16so when we think about this

1:18imagine we have this hiv virus when the

1:20hiv virus works to bind onto our t

1:22helper cells our immune system cells

1:25it utilizes very specific types of

1:27proteins to gain its fusion and entry

1:30into the actual host cell

1:32now what are those different proteins so

1:34there's a couple of them you see this

1:36little ball point here like this little

1:38blue point here this protein right here

1:40is called

1:41gp

1:4341

1:44and then this kind of like longer stick

1:46protein which is bound to is called

1:49gp120 now these proteins are integral to

1:53the hiv virus to allow for it to bind

1:55onto the host cell's receptors what are

1:57those host cell receptors that it needs

1:59to bind with

2:00generally this pink protein which the

2:03gp41 will bind with is called a cd4

2:06protein and then on most of the ta

2:10helper cells there's two types of blue

2:13proteins here that bind with the gp 120.

2:15there's two types so one that i want you

2:17to remember is called

2:19ccr5 so ccr5 is the big one that i want

2:22you guys to remember ccr5 don't forget

2:24this one and the other one is called

2:27cxcr4

2:29now

2:30why is all of this important

2:33once the actual virus utilizes these

2:35proteins like the gp41 to bind with the

2:37cd4 the gp 120 to bind with the ccr5 or

2:40the cxcr4 it then fuses with the actual

2:43proteins here on the host cell and then

2:45it gets shuttled into the actual host

2:47cell and then releases you see that

2:49little blue structure that little

2:50squiggly line releases its rna so once

2:54this kind of fusion occurs

2:56it then allows for the entry of the

2:58actual virus

3:00into the host cell so now look

3:02now that rna is in the host cell okay

3:06that's the that's the issue here so we

3:08can actually try to have drugs

3:10that can really prevent this fusion and

3:13entry

3:14of the actual viral rna into the host

3:16cell what are those drugs i'm glad you

3:17asked

3:18one of them

3:20is called infervetid

3:22and infervertide is that type of like

3:24fusion or entry inhibitor inhibits the

3:25actual entry of the viral rna into the

3:27host cell and what enfevertide will do

3:29is

3:30is it'll inhibit this interaction

3:33it won't allow for the gp41

3:36on the hiv virus to bind with the cd4

3:38protein if that doesn't bind are you

3:39going to allow for this to fuse enter

3:41and release the viral rna to the whole

3:43cell no

3:44so that's one big thing to be able to

3:46remember

3:47the second thing is this ccr5 remember i

3:50kind of astrix that one that's a very

3:51important one not all particular types

3:54of t helper cells will express this type

3:56of ccr5 which the hiv virus will bind to

3:59not all of them only some people with

4:01the genotype for that you have to test

4:03for that in order to use this particular

4:05drug but maravaroc prevents the virus

4:08from docking to the cell that's the way

4:10that the first aid usmle utilizes this

4:13but miravaroc will basically prevent

4:17this interaction it'll inhibit the gp120

4:21from interacting with the ccr5 receptor

4:24therefore the virus can't dock and

4:26release the rna into the actual host

4:28cell so we see how these two drugs work

4:31maravaroc prevents the actual virus from

4:33docking releasing the rna and then fever

4:35tight inhibits the fusion of the gp-41

4:38to the cd4 inhibiting the release of the

4:40rna into the cell that's one step

4:43now that's not it though

4:45the rna once inside of the host cell

4:48it's very interesting it also releases

4:50you see how there's like these little

4:51maroon proteins inside of the virus so

4:53not only does it release its rna but it

4:56also releases off this other type of

4:58protein so there's other proteins that

4:59it also releases into the host cell when

5:01it fuses and releases it i'm going to

5:03draw all these kind of like maroon dots

5:05but what i'm going to do is i'm going to

5:06zoom in on one of those maroon dots you

5:08see this guy right there that's one of

5:10those maroon dots this enzyme is called

5:12a reverse transcriptase we're going to

5:14put here reverse

5:16transcriptase actually let's make them

5:17bigger so this is a reverse now what

5:19does reverse transcriptases do reverse

5:21transcriptases are really interesting

5:23they're cool little enzymes here

5:26and they take so transcription is

5:27generally you take dna and make rna

5:29right that's transcription if it's

5:31reverse i'm taking rna and making dna

5:34that's all it is so in this process i'll

5:36take and utilize this cute little enzyme

5:39and convert rna

5:41over a process here and make something

5:43called

5:44dna

5:45so that is going to be my reverse

5:47transcription process now why is that

5:49significant because now i have viral dna

5:52viral dna that i can actually put into

5:54the host cell and try to incorporate it

5:56into the host cell's dna this t helper

5:59cells dna

6:00that's bad news bears what if i had

6:03drugs

6:04that could inhibit that reverse

6:05transcriptase inhibitor if i inhibit it

6:08we'll be able to take rna incorporate

6:10into dna make dna i'm sorry and then

6:12incorporate into the host cell use the

6:14host cells nuclear machinery to make

6:16proteins and make more viral uh rna

6:19molecules

6:20if i stop this process i could

6:21potentially inhibit that so i'm going to

6:23use a bunch of drugs to do that

6:26one of the drug categories so this is a

6:28general category these are reverse

6:30transcriptase inhibitors here let's just

6:31do one

6:32big line from all these big mamas here

6:34so reverse transcriptase inhibitors are

6:36going to work to inhibit this cute

6:39little enzyme how does it do that

6:41let's talk about them

6:43these names are painful believe me

6:45that's why i wrote them down i can't

6:46remember all but i have a little way

6:48that i can try to help you guys to

6:49remember all of these painful names

6:51so the first category that i want you to

6:53remember is this is actually the most

6:55important one because it's the hallmark

6:56it's the basic foundation of highly

7:00active antiretroviral therapy which

7:01we'll talk about a little bit

7:03and this is your nrtis that stands for

7:05nucleoside

7:07reverse transcriptase inhibitors

7:10now what these drugs do is very very

7:13interesting well in order to be able to

7:15take this hiv rna let's make this pretty

7:18simple and to make dna so this was going

7:20to do it's going to be utilized by this

7:21enzyme to be able to make

7:23this

7:24hiv

7:26dna

7:27now in order to do that to take rna and

7:30to make this

7:31dna

7:32i need nucleotides i'm going to read the

7:35rna strand

7:36when i read the rna strand i'm going to

7:38use the particular nucleotides on the

7:40rna strand use nucleotides that i have

7:42around

7:43and add accordingly to the complementary

7:46base and make dna from that rna strand

7:49but i need nucleotides guess what

7:51reverse transcriptase isn't that smart

7:53it's not smart enough to be able to

7:54recognize the difference between a real

7:56nucleotide and a nucleoside reverse

7:59transcriptase inhibitor such as one of

8:00these drugs so when it grabs one let's

8:03say that it grabs a nucleoside reverse

8:05transcriptase inhibitor and adds it onto

8:08the growing dna strand that you're

8:09trying to build off of this rna

8:11when it does that guess what you can't

8:13add any more nucleotides to that

8:16afterwards because

8:18that nucleoside reverse transcriptase it

8:20actually stops

8:21any more dna formation from this rna

8:24template and we stop that process so

8:27that's how these drugs particularly work

8:29now

8:31i wish there was a way of being able to

8:33remember

8:34all of these as i have for some of these

8:36other ones the only thing that i can

8:39think of that would actually help us to

8:41be able to remember this particular drug

8:43category is zales

8:47td so if you get your girls the sales

8:49ring yeah you'll end up in the touchdown

8:50you're getting a touchdown i don't know

8:52but it's basically zydoviudin a bakavir

8:55lamivudine m tricidibine stabudine

8:58tenofovir and didenosine there's no

9:01particular in some of these there's a

9:03very specific core root type of word

9:06in the actual name that's easy to

9:08remember for these there's not really

9:10that particular root word i'm sorry but

9:13what i want you to remember is that

9:15these particular drugs are going to

9:16inhibit the reverse transcriptase from

9:19taking rna and making dna by stopping

9:22the growing dna template by acting like

9:24a nucleotide even though it's not it'll

9:26terminate the actual formation of dna

9:29off of this rna template strain

9:31that's that drug category

9:33now the in rtis are the

9:36non-nucleoside reverse transcriptase

9:38inhibitors these are very interesting so

9:40you see how this like little reverse

9:41transcriptase has a little like pocket

9:43around its shoulder

9:44well what happens is these little drugs

9:46these little buggers will actually bind

9:49onto this little allosteric site you see

9:51a little allosteric site that little

9:53pocket there these in an rtis will bind

9:56onto that little site there when it

9:58binds onto it you know allosteric sites

10:00when it binds onto it it changes the

10:02shape of the enzyme when it changes the

10:04shape of the enzyme it doesn't allow for

10:05the enzyme to be able to work as well as

10:07it should what is the job of it the job

10:10of it is to take this rna

10:13read it grab nucleotides and make

10:16dna

10:18if we

10:20utilize these particular drugs to bind

10:21to this allosteric site we don't allow

10:24for it to have a particular structure

10:25that allows for it to properly read the

10:27rna grab nucleotides add on to it and

10:31make a new dna strand and then a

10:33subsequent new dna strand so that would

10:35inhibit this particular process

10:38and that is the actual drugs here the in

10:40rtis now

10:42there actually is a way to remember

10:43these so you have never

10:45efevirans urtravarian and delaviridine

10:49do you notice here that at least in all

10:52of these there's a veer somewhere in it

10:55and it's in the actual center of it so i

10:57want you to remember anytime you see a

11:00veer

11:01in the center of one of these types of

11:03drugs that would be a nnnrti a

11:06non-nucleoside reverse transcriptase

11:08inhibitors so nrti zales dt

11:11acts as a kind of like a nucleotide and

11:13then when you add it you terminate the

11:15formation of further dna because it

11:17won't allow for further dna to be formed

11:20in an rti allosteric inhibitor binds

11:22onto a particular site inhibiting the

11:24reverse transcriptase enzyme from being

11:26able to properly function and taking rna

11:29and making dna

11:31we got through a beast there okay

11:34that's these drug categories

11:36so we have the drugs that are basically

11:38inhibiting the fusion and entry of the

11:39actual hiv rna into the cell in

11:41fuverytide moravarock we have the drugs

11:43that are inhibiting the reverse

11:44transcriptase that takes rna and makes

11:47dna nrtis and nrtis one acts like a

11:50nucleotide but it's not it's a

11:51nucleoside we're not going to get into

11:53the structure of that but again they

11:55help to be able to prevent the growing

11:57dna strand from your rna template in

12:00rtis bind onto an allosteric site and

12:02inhibit the enzyme from being able to

12:04properly function now we move on to the

12:06next thing

12:07from here the dna of this hiv virus will

12:11then get taken up into the host cell's

12:12nucleus

12:14once it gets taken up into the host

12:15cells nucleus here is your host dna

12:18this is the host dna

12:19you see this black enzyme here this

12:21black enzyme you know what it does

12:23it takes and finds a particular site

12:26here on the host dna and makes a cut

12:29and then when it makes that cut

12:31it then takes the actual viral dna and

12:34incorporates it into the actual host dna

12:37so then from there we're going to get

12:39something a little bit like this if you

12:41will

12:42we're going to have kind of a mixture

12:45of these two

12:47so now i'm going to have my viral dna

12:49mixed

12:50in with the actual host cells dna isn't

12:53that crazy that's kind of scary if you

12:54think about it pretty sneaky by this

12:57actual virus but what is the name of

12:58that enzyme that integrates

13:02that integrates the actual viral dna

13:05into the host cell's dna because now

13:07this is a mix i have a little bit of

13:08viral dna mixed in there

13:13this enzyme is called integrase

13:15what if i had a drug category that could

13:18work to be able to inhibit wouldn't it

13:21be a beautiful thing if i had a drug

13:23category that could work to inhibit this

13:25integrase

13:26enzyme therefore not allowing for the

13:28actual viral dna to be incorporated into

13:30the host cell dna and why is that a

13:31problem because if you incorporate this

13:33guess what every time you try to

13:35replicate this dna guess what else

13:36you're replicating you're replicating

13:38the actual viral dna every time you

13:40transcribe this dna guess what you're

13:42transcribing you're transcribing the

13:44viral dna to make more viral rna that's

13:47bad news bears so we need to have

13:49particular drugs that can inhibit this

13:50process

13:52what are those drug categories

13:54so within the integrase inhibitors here

13:56again we have that same concept here

13:57here is your host cell dna this is a

14:00host dna i'm going to put hose dna this

14:02is the

14:03viral dna i'm going to combine these two

14:06take a little cut out of this add this

14:08viral dna into the host cell's dna so

14:11now i have the combo there that's what

14:13this actual drug will i'm sorry this

14:15enzyme will do

14:16if i give particular drugs that inhibits

14:18that that will inhibit this process

14:20these drugs are dolutegravir routagravir

14:23and elvatecravir do you guys notice a

14:25very specific like

14:27similarity between all of these

14:29you notice this part here tegra veer

14:32it's in every single one of them so we

14:35can remember the integrase inhibitors by

14:38ending in

14:39tegra veer we can remember the in rtis

14:43by having a veer somewhere in the center

14:45of the actual drug name

14:47so far we're making some steps okay so

14:50if you're not sure you get a question

14:51you're like i don't remember which one

14:53of these are it's okay if you don't

14:54remember the entire name just look for

14:56one of the actual common root words

14:57against all of these all right

15:00that's our integrase inhibitors

15:01the next one we're going to have to talk

15:02about is the protease inhibitors but

15:04let's kind of go over this continual

15:05process of how this virus is actually

15:07causing problems

15:08so we said that this actual viral dna

15:11will do something else

15:13let's say that we have this process

15:14where we take the actual

15:17transcription process so i have my

15:19transcription process where i'm actually

15:20going to read the actual dna and that

15:23includes the viral dna

15:25transcribe that and when i transcribe it

15:28guess what i'm going to do

15:30i'm going to transcribe some of the

15:31viral dna and make viral

15:34rna so now i'm going to have some viral

15:35rna that i'm going to make now what

15:37happens here when i actually do that

15:39when i make some of this rna so i'm

15:41going to start popping out tons of viral

15:43rna here

15:46when i pop out all of this viral rna

15:48guess what's going to happen here this

15:50rna is then going to go out into the

15:52cytoplasm and find some ribosomes

15:56when it goes and binds on to these

15:58ribosomes it'll then use the ribosomes

16:01to undergo translation so this process

16:04here where we take the actual dna the

16:05viral dna make more rna is called

16:08transcription the process where i take

16:10the actual viral rna and then try to

16:12make proteins as a result of that is

16:14called translation

16:16so this is the transcription process the

16:18translation process now

16:20i make these particular proteins

16:22utilizing the actual viral

16:24rna once i make these i make these

16:27things called poly proteins now these

16:30polyproteins are just a clump of

16:32proteins and what we need to do is is we

16:35need to utilize a very specific enzyme

16:37called proteases because what proteases

16:39do is they take and cleave the actual

16:42polyprotein so that we can make a lot of

16:44different types of structural and

16:46functional proteins so the proteins that

16:48are going to be important for the actual

16:50viral structure as well as other

16:51particular types of enzymes so we're

16:53going to use this to make a bunch of

16:55structural proteins

16:57and we're also going to use this to make

16:58a bunch of

17:00functional proteins but this will not

17:02happen unless i have what particular

17:04enzyme present the proteases so the

17:07proteases will enable this particular

17:10process they are integral and being able

17:12to cleave these polyproteins into

17:15structural and functional proteins if

17:16that doesn't happen i won't be able to

17:18make all of the integroviral proteins

17:20the ones that are like such as reverse

17:22transcriptase such as some of the actual

17:24proteins that make up the actual

17:25structure of the virus

17:27so very important that that enzyme is

17:29present

17:30what if i use a drug category that will

17:33actually work to inhibit these proteases

17:37and if i inhibit these proteases they

17:39won't be able to take the polyproteins

17:41that were translated and they won't be

17:43able to cleave them and so if i can't

17:45cleave them i will not be able to make

17:47any structural and functional proteins

17:50if i can't make any of these dang

17:51structural functional proteins what do

17:52you think is going to happen then i'm

17:54not going to be able to do what

17:56i'm not going to be able to use

17:58this particular proteins run it through

17:59the golgi apparatus and then from here

18:02use this to make my particular virus

18:04proteins so i won't be able to have like

18:06my core proteins or the capsimir

18:07proteins i won't be able to make some of

18:09the particular enzymes inside of this

18:11actual virus i won't be able to make

18:13some of these actual

18:15gp proteins here on the surface and so

18:17that's all going to be

18:18inhibited that's a bad that's not that's

18:20not going to be helpful i can't actually

18:21make a new virus that way

18:23so

18:24i'm going to use these drugs to be able

18:26to inhibit this process

18:28now if you look at these drugs there's

18:29like a million of them right you're like

18:30oh my gosh zach i can't remember all

18:32these things don't worry i don't

18:33remember him either but if you notice

18:34here addazanovir dorinovir and denver le

18:37penavir nuffinover sequinovir to

18:39pranavir

18:40do you notice something you notice

18:42naveer is at least present in every

18:45single one of these that's what i want

18:46you to remember if you see the ending

18:49with naveer you have a protease

18:51inhibitor so in an rti's there's a veer

18:54in the center integrase inhibitors

18:56there's a tegravere at the end and

18:58protease inhibitors there is a nevere at

19:00the end and again we know how these

19:02drugs particularly work they actually

19:03work to again they work on these

19:05polyproteins and specifically there's

19:07something called gagpal polyproteins and

19:09what they do is they help to be able to

19:11act as a protease to cut these actual

19:13polyproteins into all the different

19:15types of structural functional proteins

19:16that are integral into making the actual

19:18virus

19:19now

19:20remember i told you that you have that

19:22viral rna some of the viral rna guess

19:25where that viral rna is going to go

19:27the viral rna that we actually have out

19:29here

19:30we're going to have that get taken up

19:32into the golgi apparatus in combination

19:35with all of these different types of

19:36proteins that we made from it and then

19:38we're going to incorporate that actual

19:41rna into the virus then from there we're

19:44going to put it into a vesicle from the

19:46golgi apparatus

19:47and then have it move to the actual cell

19:50membrane where it'll fuse with the cell

19:51membrane and exotize exocytosis all of

19:54these viruses and release it out into

19:56the actual interstitial fluid or into

19:58the vascular system to go and infect

19:59other cells

20:00if we work so particularly utilize maybe

20:03a combination of some of these drugs to

20:06inhibit particular parts of this actual

20:09life cycle of the hiv we can potentially

20:11prevent this viral replication and again

20:15continual spread of the virus but what

20:17is the particular regimen that we should

20:19actually utilize

20:20the heart regimen or the highly active

20:22antiretroviral therapy regimen is really

20:25based upon the foundation of

20:27nrtis we need at least two of those

20:30nrtis to be able to perform this process

20:34so it's always going to be two in our

20:37ti's no matter what

20:39so you can pick any one of those above

20:43we'll talk about some of the adverse

20:44effects and contract indications of some

20:46of them that would obviously deter you

20:47from using that one but it's always

20:49going to be two nrtis now once you do

20:53that you can add on one of the other

20:55agents we can do utilize either a

20:58in

21:00in rti and again the utilization of one

21:02of those depends upon the side effects

21:04or the adverse effects and

21:05contraindications that you want to avoid

21:07or an integrase inhibitor we're going to

21:09put i

21:11n i

21:12or a protease inhibitor we're going to

21:14put pi

21:16and again the choice of which one of

21:18these you pick can kind of also depend

21:20upon the hiv genotype but it also

21:22depends upon the actual adverse effects

21:23that you're trying to avoid or

21:24contraindications now

21:26that's the baseline heart regimen what

21:28about these other two drugs that was the

21:29purpose of even mentioning these

21:31these are adjuncts that you can add on

21:33to this particular therapy so remember i

21:35told you what was the point of even

21:36talking about rava rocker and fever tide

21:39the the reason we would add on morave

21:41rock is again they have to have a ccr5

21:43receptor so you can use this

21:45in your hiv resistant strange

21:47but particularly it's an add-on if they

21:50have they have to have a ccr5 positive

21:53receptor but you can utilize moravirock

21:57as an add-on in the hiv-resistant

21:59strains especially to the nrtis but they

22:02have to have they have to be positive

22:03for this ccr5 receptor if they're not

22:06positive it's not going to provide any

22:07actual additional benefit

22:09the other one here

22:10is inferior type so infuriating we'll

22:13add this bad boy on

22:16and the hiv-resistant strains that again

22:19are resistant to the nrtis so this is an

22:22add-on as well particularly in hiv

22:26resistance

22:29very specifically to the

22:32nrtis

22:34that is the basis of the mechanism of

22:37action of these drugs the names of these

22:40drugs the categories of these drugs and

22:42then again the particular regimen that

22:44you would put a patient on who's been

22:46diagnosed with hiv

22:48again

22:49that is the basis there we have to now

22:50talk about adverse effects

22:52contraindications things that you should

22:53worry about when you put these actual

22:55medications on a patient all right so

22:57now we're going to talk about the

22:58adverse effects and contraindications of

22:59these

23:00anti-hiv medications now when we talk

23:02about these we'll go over them based

23:04upon the category so we talked obviously

23:05about inferior time or avarock nrtis n

23:08and rtis integrase inhibitors and

23:10protease numbers we went over the

23:11mechanism of action the names that don't

23:13remember all the names just remember

23:14again the big root word if you can for

23:15those

23:16but what i want you now to remember is

23:18particularly the adverse effects so this

23:19is obviously important whenever you're

23:20getting ready to put a patient on one of

23:22these medications it's important to

23:24think about what kind of like medical

23:25history they have and then again that

23:26might actually deter you from using this

23:28particular drug and trying another one

23:30so

23:31nrtis are the backbone

23:33to a lot of your um heart therapy right

23:35the highly active antiretroviral therapy

23:37regimen if you notice there was always

23:38two of those with one of the integras or

23:40one of the proteases or one of the and

23:42in rtis one of the big effects that you

23:44can see with all of these is

23:45mitochondrial toxicity so it has some

23:47type of way of being able to alter the

23:49mitochondrial activity and so you can

23:51see mitochondrial

23:54toxicity now there are so many things

23:57that the mitochondria does so it's

23:59important to remember one of those

24:01things is that it obviously is important

24:02for a lot of energy production so atp

24:05formation that's super crucial when it

24:07comes to muscles being able to function

24:09if you don't have that atp the muscles

24:11will actually start to have issues with

24:12that and you can develop something

24:14called myopathy

24:16the other thing here is we don't know

24:18exactly how but it actually may alter

24:19the neurons in some type of way

24:21particularly the peripheral neurons

24:23where they actually actually have some

24:24type of damage as well and this may lead

24:26to peripheral neuropathy the other thing

24:29that's important here

24:31is that it's also involved in fatty acid

24:33oxidation so we take particular fatty

24:35acids and we oxidize them into

24:37acetyl-coa in the mitochondria if you

24:38cause mitochondria toxicity are you

24:40going to be able to perform fatty acid

24:41oxidation no and so then what happens is

24:43fats build up inside of particular

24:45tissues one of the big tissues there is

24:46the liver and guess what happens if you

24:48have lots of fats building up in the

24:49liver this can cause steatosis so you

24:52may also see hepatic

24:54steatosis

24:56and the other thing here which is pretty

24:58straightforward as well is think about

25:01whenever you have a patient who are a

25:02general whenever you have something like

25:04a

25:05you have what's called pyruvate pyruvate

25:06is supposed to get taken up into the

25:07mitochondria and convert it into acetyl

25:09coa if the mitochondria isn't allowing

25:11for the pyruvate to get converted into

25:13acetic wave because of the toxic effect

25:14what does it actually get converted into

25:17pyruvate gets converted into lactic acid

25:20and so that can also be another issue

25:22where you make lots of lactic acid you

25:24can see something called lactic acidosis

25:26and so these are the possible effects of

25:28these drugs due to the mitochondrial

25:29toxicity you can see this in all of

25:31these again myopathy neuropathy and then

25:33hepatocytosis lactic acidosis

25:36the other thing that you can see here is

25:38something called pancreatitis so

25:40pancreatitis there's a lot of different

25:42reasons for this one do you guys

25:43remember when we did the video we talked

25:45about i get smashed it was the mnemonic

25:47to remember all of the particular causes

25:50and the d and i get smashed is drugs

25:52well there's a lot of drugs that can do

25:54this but one of these is your nrtis and

25:56there's two particular ones that i want

25:58you to remember one of them is called

26:00stavudine

26:02this is a big one and then i don't want

26:04you to forget this next one called

26:05didanese

26:07these are two of the particular drugs

26:08that may actually be able to induce some

26:10type of pancreatitis

26:12all right

26:14the next thing here is nephrotoxicity so

26:16these do have the ability to cause some

26:18type of nephrotoxic effect and lead to

26:21an acute kidney injury okay so

26:23nephrotoxicity is another big one that

26:25can lead to an acute kidney injury and

26:27the big one out of all of these is

26:29tenofovir tenofovir and what's

26:32interesting is tenofovir is actually

26:33technically not necessarily a nucleoside

26:35or virtual scriptase inhibitor it's

26:37actually a nucleotide reverse

26:39transcriptase it's actually one of the

26:40only ones an alpha bear and something

26:42called a defiber but either way that's

26:44the one that i want to remember and it

26:45has a nephrotoxic effect

26:48the other thing here

26:49is there may be some bone marrow

26:51suppression so bone marrow suppression

26:53you may see this particularly with

26:54zidovudine so zydovidine may actually

26:57cause a little bit of bone marrow

26:59suppression but it actually drops your

27:01number of red blood cells and drops your

27:03number of neutrophils and so that's

27:05another particular thing to remember is

27:07you can see anemia and neutropenia

27:09particularly with zydovidine

27:11now here's the other one that's really

27:12interesting this one it's a weird one

27:14but a back of here so a back of your can

27:17actually cause something called

27:19a

27:19hypersensitivity reaction so you can see

27:22a very significant hypersensitivity

27:24reaction so what happens is this drug

27:25may actually interact with particular

27:27types of mast cells and lead to a

27:30massive histamine response and this

27:32massive histamine response may lead to a

27:33lot of like nasty effects one is it may

27:36lead to nausea it may lead to vomiting

27:38it may lead to diarrhea it also may lead

27:40to a nasty rash it may lead to fever and

27:43it may lead into respiratory failure now

27:46it's important to remember that anytime

27:47you put somebody on a back of your to

27:48avoid any type of hypersensitivity

27:50reaction there are certain patient

27:52populations that are susceptible to this

27:54and so you want to check like an hla

27:56b

27:595701

28:00and generally the patients who have this

28:02type of hla susceptibility gene are at

28:04high risk of a hypersensitivity reaction

28:06such as developing nausea vomiting

28:08diarrhea abdominal pain rash fever and

28:10respiratory failure if you put them on

28:11this particular drug all right so big

28:13things to remember again for the adverse

28:15effects for the nrtis all of them cause

28:17mitochondrial toxicity pancreatitis is

28:19particular to saving the adenosine

28:21nephrotoxicity with tinofovir bone

28:23marrow suppression particularly anemia

28:24neutropenia with zydovieudine and a

28:26baccavier can cause a hypersensitivity

28:28reaction hlab

28:305701 haplotypes so make sure you check

28:33this because if not you give it to them

28:35they can develop fever rash they can

28:37also develop nausea vomiting diarrhea

28:38and respiratory distress

28:40all right the next category that i want

28:42us to be able to talk about is the

28:43nnrtis the non-nucleoside reverse

28:45transcriptase inhibitors so you guys

28:47remember these ones sales dt right says

28:49idoviadine a baccavir lamivudine m

28:52tricidabean stavudine uh tenofovir and

28:55then didannacy for in nrtis do you

28:57remember what they end in they always

28:59are they have the the root word it's the

29:01vire it's in the center right so f of

29:03irons never pin delaveradine

29:06now with these there's a couple

29:08different adverse effects that i want

29:09you guys to remember hepatotoxics is a

29:12relatively common one and we see this

29:14more specifically with f of irons

29:18so f of irons

29:20and nevirapine

29:23now you're going to notice a common

29:25trend that f of irons will really jack

29:27people up because that's one particular

29:28thing that you can see here is

29:30hepatotoxicity so you may see a bump in

29:32their lfts

29:33the other thing is that it can actually

29:35cause cns toxicity and we really say

29:37that this causes some insane and i mean

29:40vivid like dreams to where it's really

29:42really weird and so they can develop

29:44these crazy like you know odd vivid

29:48dreams and so we see this primarily with

29:50epivirus so f of irons will give you the

29:53hepatotoxicity it would also give you

29:54cns toxicity that'll cause like these

29:56insane vivid like dreams so f of irons

30:01and then the last one is going to be the

30:04teratogenic effect so we don't want to

30:06give this to a particular patient if

30:09they are pregnant so teratogenic one is

30:12epivirus

30:15and then the other one that i want you

30:17guys to remember is deliveridine

30:23all right that covers the in in rti

30:26adverse effects now let's come down talk

30:27about the integrase inhibitors and the

30:28protease inhibitors all right so the

30:30next thing with integrase inhibitors

30:31again if you guys remember the integral

30:32inhibitors this was the ones that

30:34actually had one particular thing the

30:35tegra veer at the end dawg you tegra via

30:38rod tiger veer el vitegravir so with

30:40integrase inhibitors what they've been

30:41actually showing this is an actual nice

30:42one to remember here is that they can

30:44actually cause rhabdomyolysis and so if

30:46you have some of those rhabdomyolysis

30:48you may expect an increase in there ck

30:51plus if you also have a lot of

30:53rhabdomyolysis your kidneys will take up

30:55a lot of that myoglobin and put a ton of

30:58that myoglobin inside of the urine so

31:00you may expect a lot of myoglobin in the

31:01urine and a increase in their actual ck

31:04so look for that in patients who have uh

31:07are taking into grace inhibitors now

31:08protease inhibitors is a big one as well

31:11now one of the things that this can

31:12actually do for produce numbers and

31:14again how do you remember these ones do

31:15you guys remember it was ending in navir

31:18so if it ends in the nevir then you know

31:20they have a protease number adizenovir

31:22ritanovir uh saquinovir many many of

31:24those drugs lapinovir keep going on but

31:27what happens here is that these drugs

31:29particularly can produce one of them can

31:31produce what's called a crystal induced

31:34nephropathy

31:36and when it produces this crystal

31:38induced nephropathy it can actually lead

31:40to some nasty acute tubular necrosis and

31:42lead to a nasty acute kidney injury and

31:44there's one particular drug that i do

31:46want you guys to remember for this one

31:48and this particular drug here is going

31:49to be indenavir

31:52and denver has been shown to be able to

31:54increase the formation of crystals that

31:55can actually cause an acute necrosis and

31:57destruction of the actual kidney tubules

31:59leading to an acute kidney injury the

32:01next thing that i want you to remember

32:02is that all of these drugs have the

32:03ability to produce something called

32:04lipodystrophy

32:06and what happens is you see a lot of

32:07this fat accumulation and lipodystrophy

32:09and it can produce kind of like a

32:10cushing-like effect where you get like

32:12the buffalo hump the swollen moon face

32:14and that type of effect similar to

32:15cushing's syndrome

32:17the other one that's really really

32:18interesting here is that this can

32:19actually cause very very high levels of

32:21glucose so you can see something called

32:24hyperglycemia now why does this happen

32:26well what happens is most of these drugs

32:28they'll inhibit this particular

32:30transport here called a glute

32:31transporter and glute transporters are

32:34supposed to be able to take and shuttle

32:36glucose into our actual cells so they

32:39want to bring glucose into our cells but

32:41if you give particular drugs such as

32:43these protease inhibitors they will

32:44inhibit these glut transporters if you

32:47inhibit these can you take glucose into

32:49the cell no so if you can't take glucose

32:51into the cell where does it stay it

32:53builds up inside of the bloodstream this

32:55can cause hyperglycemia

32:57the last thing here is that you also

32:58have a lot of these particular enzymes

33:00called

33:01cyp450 enzymes that are involved in

33:03biotransformation taking a drug adding

33:05on different types of molecules like

33:07glucaronates and etc and making them a

33:09little bit more polar so it's involved

33:10in like drug metabolism we can have

33:13particular protease inhibitors one of

33:14the most specific ones here called

33:16ritanavir

33:18and rytanovir works to be able to

33:20inhibit the cyp450 enzymes and so what

33:23happens is if you inhibit them you

33:25develop higher levels of that drug

33:26concentration and that could be

33:28concerning depending upon what type of

33:29drug you're taking if you're taking like

33:30warfarin maybe you have a higher risk of

33:32now having bleeding so it's the common

33:34effect they're thinking about other

33:35drugs that they're taking if you put

33:36them on something like rhitonovir

33:38because you may be increasing the

33:39concentration of that drug because it

33:40inhibits the cyp 450 enzymes

33:42okay that is the adverse effects

33:45contraindications mechanism of action

33:47indication all the names of the drugs

33:49for hiv but we're not done now we got to

33:51do is we got to talk about influenza all

33:53right so now let's talk about the

33:54influenza medication so

33:56influenza is obviously the flu alright

33:58so if somebody actually becomes infected

34:00with influenza what happens is it

34:02primarily is spread through respiratory

34:03droplets and gets some part of your

34:05respiratory tract at least like an upper

34:06respiratory tract infection lower

34:08respiratory tract infection in some way

34:09shape or form so we know that the

34:11influenza virus usually gains access

34:13into our body into affecting our actual

34:15immune system via the respiratory tract

34:18so what happens is this will bind onto

34:20particular cells within the respiratory

34:21tract and what it does it'll actually

34:22bind into there get its actual viral

34:25structure into the uh particularly in

34:27this case it's viral rna into the actual

34:29host cell structure use it to be able to

34:31make more viruses so how do we come up

34:33with the particular drugs to be able to

34:35target the actual life cycle of the

34:38influenza virus well let's go quickly

34:39through the actual life cycle so once

34:42the actual influenza virus gets into the

34:43respiratory tract binds onto respiratory

34:45tract cell how does it actually do that

34:46well here's our influenza virus

34:48on the influenza virus we know that it's

34:50going to have an rna

34:52inside of it

34:53and we know that it's going to have all

34:54these different types of proteins around

34:56it one of the big things to remember

34:57here is you see these like blue proteins

34:58these baby blue proteins these proteins

35:00i want you to remember is going to just

35:01be we're going to put h4 this is the

35:02hemagglutinin all right so this is a

35:04hemagglutinin and protein then in red

35:06here you're going to have something

35:07called neuraminidases okay so these are

35:10your neuraminidases and then here in

35:12orange you're going to have something

35:14called a proton ion channel so we call

35:16this an m2

35:18channel so we're just going to put ion

35:20here we're going to put m2 ion channel

35:22now

35:23what happens

35:25is once this virus is actually spread

35:27via respiratory drop it gets into the

35:28respiratory tract and tries to bind onto

35:30some type of cell within the respiratory

35:31tract it utilizes these pink proteins

35:33you know what these pink proteins here

35:34are called these are called cyalic acid

35:37residues so this is called cyalic

35:40acid

35:41now with this cyalic acid we need these

35:44hemoglutinin proteins on the actual

35:47influenza virus to be able to bind with

35:50the actual cyalic acid residues once it

35:53binds once the hemagglutinin binds with

35:55the cyalic acid via a process called

35:57receptor mediated endocytosis it brings

36:00the virus into the actual host cell this

36:02respiratory tract epithelial cell

36:04once inside of the cell we need to be

36:07able to uncoat this virus so we can get

36:10that rna that nucleic acid out we want

36:12this nucleic acid this viral rna to be

36:15released

36:16we need that rna to be released that we

36:18can get it into the host cell nucleus so

36:21in order to do that i need to uncoat

36:23this virus that's where those m2

36:25proton channels come in

36:27so what i'm going to do now is i'm going

36:29to utilize particular m2 proton ion

36:32channels to pump protons

36:34into this structure to kind of allow for

36:37it to acidify

36:38and get this

36:40uncoding to occur so again these m2 ion

36:44proton channels will allow for uncoding

36:47of the virus so let's actually write

36:48that down so this process here is called

36:51uncoding

36:53so that we can release the actual viral

36:55rna

36:56once the viral rna has actually been

36:58released from this actual structure here

37:00it then gets taken up into the actual

37:02host cells nucleus and in the host cell

37:05nucleus you know that you have host dna

37:07right so this is going to be the host

37:08cell's dna inside of this actual

37:10respiratory epithelial cell

37:11what happens is

37:13this host dna is always making rna right

37:16so through a process called

37:17transcription it'll be making mrna

37:21now you know in order for mrna to

37:23actually interact with ribosomes you

37:25guys should know this right that we go

37:27through a particular like post

37:28transcriptional modification so in order

37:30for this ribosome to truly interact

37:34with the actual mrna

37:37it needs a very specific type of

37:39structure and we're going to put this

37:40structure here in purple here this is

37:42called our five prime cap so we need

37:44that five prime cap in order for this

37:46actual translational process to occur

37:48well guess what there is really no five

37:51prime cap on that viral rna so this

37:53viral rna is kind of stuck it won't be

37:55able to use the ribosomes to be able to

37:57create proteins so what i need is

38:00i need

38:01the five prime cap that's present on

38:04this host cell mrna to be switched over

38:07onto that viral rna

38:09and there is a very cute little nuclease

38:11enzyme here so you see this enzyme right

38:14here this is called a endonuclease

38:17and what the endonuclease will do is is

38:19it'll take and cut this actual five

38:22prime cap off and transfer that onto the

38:26viral rna

38:28and then the result here is that i'm

38:30going to have a viral rna

38:33with a nice little five prime cap

38:36on it and now i can actually utilize the

38:39host cells ribosomes to be able to make

38:41proteins so then from here

38:44this is going to be this five prime cap

38:46that's actually getting

38:47passed over

38:48and now i'm going to allow for this

38:50viral rna to come out of the actual

38:52nucleus and then interact with the

38:54actual host cell's ribosomes

38:56and now here it's going to be able to

38:58use the host cells ribosomes to be able

39:01to synthesize a bunch of proteins and

39:04these are proteins that are structural

39:05proteins functional proteins i need

39:08these proteins to be able to allow for

39:09me to assemble a new virus so all these

39:12proteins will actually get taken to the

39:14actual golgi apparatus and then we'll

39:17also take something called the rna here

39:19and utilize that to make again a new

39:22virus that virus will then go again

39:24after it forms a vesicle from the golgi

39:26to the actual cell membrane fuse with

39:28the cell membrane and try to exocytose

39:29it and we'll get to this part in a

39:31second but we at least got to the rna

39:33here

39:34that required

39:36this five prime cap from that

39:38endonuclease

39:40to do this okay

39:42now the other thing here is that this

39:44rna right we're going to want to try to

39:46be able to make more of this rna and so

39:48there's processes where the actual rna

39:50will actually try to you know make more

39:52rna make more rna make more rna via

39:54particular rna polymerases and so what

39:57we're going to do is we're going to

39:58continue to keep trying to make

40:00more rna utilizing rna polymerases so

40:04now i'm going to make a bunch of this

40:05viral rna

40:07this rna that i actually am going to

40:08make is going to get taken to the actual

40:10golgi apparatus and then go through this

40:12process where i can incorporate that

40:14with the actual viral proteins to make a

40:16new virus okay

40:18now

40:19here's where it's actually really

40:20important that you understand we can

40:22actually have particular well actually

40:24one more thing one more thing so we have

40:25the rna we combined it with the actual

40:27structural functional proteins made the

40:29actual virus in the actual golgi

40:30apparatus formed a vesicle had to go

40:32fuse with the cell membrane when it

40:34fused with the cell membrane to try to

40:35release it it gets stuck so it's trying

40:37to get off of the actual epithelial cell

40:39so it can go and infect other epithelial

40:41cells but it can't do it you want to

40:43know why

40:44because that hemagglutinin protein

40:46remember this one

40:47this hemagglutinin protein is still

40:49stuck

40:51to the sialic

40:53acid

40:54and it can't release away from the

40:57cyalic acid

40:58unless we have another particular

41:00protein that comes in and cleaves that

41:02connection between the hemoglobin and

41:04the cyalic acid so that we can release

41:06the virus away from the actual cell so

41:08we can go and infect other cells there

41:09was one other that was missing and that

41:11was that red protein the neuraminidase

41:13so what happens is the neuraminidase

41:16protein will actually

41:18cut

41:19this particular structure here it'll cut

41:21the link between the cyalic acid residue

41:23and the hemagglutinin and that'll

41:25basically allow for the virus to butt

41:28away and be released away from the

41:30actual host cell so this will allow for

41:32the budding

41:34or the release

41:37if you will of the

41:39virus away from this host cell

41:41so we have a couple different parts here

41:43which are really really important one is

41:45the uncoding which is due to these m2

41:47ion proton channels pumping protons into

41:49this endosome here allowing for the rna

41:51to be released into the actual cell

41:53cytoplasm and then move into the nucleus

41:56second one

41:57is we have this five prime cap process

42:00so this is the first step second step is

42:02this endonuclease that allows for the

42:04transfer of the five prime cap from the

42:05host cell mrna to the viral rna and then

42:08the third step here is going to be the

42:10budding and the release of the virus

42:12from the actual host cell we have drugs

42:14that can target each one of these

42:15particular steps

42:16the first one here is the uncoding we

42:18have particular drugs that can actually

42:20inhibit this m2 ion proton channels

42:23inhibiting the ions from being able to

42:25get into the actual endosome and then

42:27release this rna what are the particular

42:30drugs that we can utilize to inhibit

42:34this particular process if we inhibit

42:35this process you will not allow for the

42:38release

42:39of the actual or the uncoding or the

42:41liberation of the viral rna out into the

42:43actual host cell cytoplasm and get

42:45utilized by the nuclear machinery to

42:46make more rna more proteins

42:49these are these particular drugs and

42:50this drug that we can actually utilize

42:51is called

42:52amantadine now amantadine is pretty much

42:55only utilized in influenza

42:58a

42:59you can you can see this in a couple

43:00other diseases you may see this in

43:02something like parkinson's disease

43:04but again big thing for amantadine is is

43:06primarily only used in influenza a

43:09now

43:10the second step here is this part here

43:13where you have this endonuclease

43:14transfer the five prime cap from the

43:16host the host cells mrna to the viral

43:18rna

43:19this

43:20endonuclease

43:22enzyme if we inhibit it what if we

43:24inhibited this cute little enzyme here

43:27so we inhibit this process

43:29if we inhibit this process it won't be

43:31able to transfer the five prime cap onto

43:33the viral rna if we don't have the five

43:35prime cap we won't be able to allow for

43:37this to bind with the ribosomes and the

43:39synthesis of the proteins will be shut

43:41down

43:42what is the name of the drug that would

43:44actually do this well it's an

43:45endonuclease inhibitor and this is

43:46called block severe

43:49so baloxaviras can be used in influenza

43:52type a and b but generally it has to be

43:56less than 48 hours

43:57of symptom onset so if someone develops

44:01particular symptoms of influenza and

44:03it's at least less than 40 hours since

44:05their symptoms actually developed we can

44:07utilize this drug to potentially reduce

44:10the severity of the symptoms but it's

44:12not going to prevent the infection it'll

44:14just reduce the severity of the symptoms

44:16that they'll have so again that's the

44:17whole process that i want you guys to

44:19remember and again just to recap it

44:20again

44:21you have here five prime cap on the

44:23actual host rna you're trying to

44:26transfer that five prime cap

44:28onto the viral rna so that it can be

44:31utilized by the actual ribosome to be

44:34able to make particular types of viral

44:37proteins when you give this drug

44:40biloxavir it inhibits this process the

44:43transfer of the viprime cap so you won't

44:44be able to cut this actual five prime

44:46cap off and then transfer it over onto

44:50the actual mrna

44:51all right that's the concept there for

44:53the second step the third step here is

44:55called your neuraminidase inhibitors now

44:58remember i told you that an aramid ace

45:00is designed to be able to cut the actual

45:01hemagglutinin which is basically the

45:03part of the virus that's stuck to the

45:04cyalic acid we can't get the virus to

45:07bud off and go and infect other cells

45:09unless it has that enzyme that cuts that

45:11connection there

45:13what if we used a drug that inhibited

45:15that neuraminidase from cutting the

45:17connection between the cyalic acid and

45:19the hemoglobin will be able to release

45:21the virus allow for it to butt off and

45:23go and infect other cells no

45:26so what if i utilize particular drugs

45:30to inhibit

45:31this particular process these are my

45:33neuraminidase inhibitors and these

45:35particular drugs are called osceltamivir

45:41and another one is called zenamovir

45:44and again these two particular drugs are

45:46only used again in influenza

45:48a and b

45:49you can also use this as a prophylaxis

45:52particularly in two situations in adults

45:57and in children so kids less than so

46:00greater than or equal to five years of

46:02age

46:02depending upon particular risk factors

46:04but again important to remember here for

46:06the influenza a and b is this has to be

46:09again less than 48 hours

46:11of symptom onset so if the patient

46:14developed symptoms of influenza arb

46:16they tested positive and it's at least

46:18been less than 48 hours you can put them

46:20on these drugs to reduce the severity of

46:21the symptoms of the actual influenza but

46:24again it is not actually going to

46:26prevent the infection there is some

46:28thought that maybe it can be used

46:29prophylactically in certain patients

46:30that are at high risk in adults and

46:32children who are greater than they are

46:33equal to five years of age but again not

46:35a lot of evidence there as well all

46:36right now let's talk about adverse

46:37effects and contraindications all right

46:39so the adverse effects thank goodness

46:40that a lot of these drugs block severe

46:41oscillatomavirs and amavir they really

46:44don't have many side effects they're

46:45well tolerated whenever they're given

46:47it's the amantadine that's actually the

46:49one that can actually cause some kind of

46:51toxic effects so amantadine is really

46:52the one that's worth remembering for the

46:54effects and what it can actually do is

46:56it can cause ataxia

46:58it can also cause libido reticularis

47:01which is a type of skin manifestation

47:04and

47:05it can also potentially work on the

47:07heart to be able to prolong

47:09the qt interval increasing the risk of

47:11torsos to points so when again when it

47:13comes down to amantadine amantadine can

47:14actually cause ataxia it can lead to

47:17laveto reticularis and it can also

47:19prolong the qt interval increasing the

47:20risk of torsos to points all right now

47:23that we've talked about that let's move

47:24on to the next virus which is the

47:26hepatitis medications all right so now

47:28we're going to talk about the

47:28anti-hepatitis medication so you have a

47:30patient who has hepatitis the big ones

47:31that we actually should know that we can

47:33treat with antivirals is hepatitis b

47:35virus and hepatitis c virus let's talk

47:37first about hepatitis b the antivirals

47:39that work against that and then after

47:40that we'll talk about hepatitis c its

47:42life cycle and again the antivirals that

47:44act against that

47:45so first thing is you'll obviously know

47:46that the hepatitis viruses hepatitis b

47:49virus in this case loves to attack which

47:51type of tissues the hepatic tissue so it

47:53loves the hepatocytes when it acts on

47:56the hepatocytes it obviously produces a

47:57lot of damage inflammation and then

47:59again increases the risk of

48:00hepatocellular carcinoma etc

48:03how does this actual virus work though

48:05what's the life cycle some crucial

48:07points along the way because there is

48:09very specific drugs that we're going to

48:11utilize to target very particular parts

48:13of its life cycle okay so we have here

48:16the hiv virus

48:17when the hiv i'm sorry the hepatitis b

48:20virus geez hepatitis b virus when the

48:23hepatitis b virus works on the

48:24hepatocytes it uses very specific types

48:27of protein channels like there's like an

48:29n

48:30ctp protein if you really want to know

48:32that but basically what happens is once

48:34the hepatitis b virus is bind with this

48:36it then uses these proteins to get taken

48:38up into the cell

48:40once it's taken into the actual

48:42hepatocyte what happens is it releases

48:46its partially double-stranded dna so

48:48this is a dna virus once it releases

48:51it's what's called partially

48:54double stranded dna

48:56it then will get taken up into the

48:58actual host cells nucleus

49:00once it gets taken up into the host

49:02cell's nucleus it'll utilize particular

49:05enzymes to be able to take this

49:07partially double-stranded dna and

49:09convert it into a completely

49:12circular double-stranded dna so then

49:14it'll actually convert this into a

49:15complete

49:17circular double-stranded

49:20dna and we call that

49:21ccc dna if you really want to know that

49:24now

49:26what happens here is from this process

49:29here's what's really interesting

49:31from this process we're going to take

49:32this complete dna this complete

49:35double-stranded circular dna

49:37and it's going to be able to replicate

49:38itself so it's going to be able to

49:40undergo kind of a consistent replicative

49:42cycle so we'll be able to undergo a lot

49:44of replication so this process here will

49:45be its replication okay

49:48the other thing that's really

49:49interesting about this is that this can

49:52also undergo a transcription process so

49:55when it undergoes a transcription

49:57process it'll make lots of rna and it'll

49:59make two different types of rna one of

50:01the rnas it'll actually make is mrna so

50:04it'll make a

50:05viral mrna but it'll also make another

50:08type of rna and this rna that it'll also

50:10make here besides the mrna is called

50:14pre-genomic

50:16rna we'll talk about what that means in

50:17just a second but what happens is

50:20you get this virus again to bind to the

50:23actual

50:24hepatocytes once it binds in it gets

50:26taken up the virus then gets uncoated

50:28and released releases its partially

50:30double stranded dna gets taken up into

50:32the nucleus gets converted into complete

50:35double-stranded circular dna

50:37that complete circular double-stranded

50:38dna can utilize particular enzymes dna

50:40polymerases to replicate itself and make

50:42more of it

50:44then on top of that it can utilize

50:46particular rna polymerases to make rna

50:48one of them is mrna and the other one is

50:50called pre-genomic rna

50:52the mrna will then go and utilize the

50:55host cells ribosomes to be able to make

50:58particular types of proteins and these

51:00proteins obviously that it's going to

51:02synthesize can be structural

51:04that are integral to the actual

51:06structure of making a new virus but it

51:08can also be functional so this can be

51:09particular types of enzymes dna

51:11polymerases rna polymerases proteases

51:13etc

51:15and so what happens is these proteins

51:16are very very crucial because we're

51:18going to take some of these proteins and

51:19move them towards the golgi apparatus

51:21with the end goal being that we're going

51:23to incorporate this into the virus make

51:25a new vesicle from the golgi and that's

51:27going to contain very structural

51:29proteins and functional proteins that

51:31are important to the viral structure and

51:33function

51:34now

51:35we have the protein component of the

51:36virus we need the nucleic acid component

51:38of the virus right now we have rna this

51:41virus is dna i need to be able to

51:43convert this pre-genomic rna back into

51:47dna what is the name of the particular

51:50enzyme that converts rna into dna that's

51:52got to be a reverse transcriptase enzyme

51:55and guess what this cute little blue

51:57enzyme is this is a reverse

52:00transcriptase and what it'll do is it'll

52:02take this pre-genomic rna

52:05and convert it into dna it actually

52:07turns into something called negative

52:09sense dna and then then positive sense

52:12dna but eventually we're going to

52:14convert this into

52:16partially double-stranded dna

52:19so that is the goal is to convert this

52:20back into the dna component that it was

52:22prior whenever it infected the cell

52:24because we want to replicate this virus

52:26and make more of it so that we can go

52:28ahead and pass this virus onto other

52:29cells damage more hepatic cells

52:32so this dna will then be taken to the

52:34golgi combined with all the different

52:36structural and functional proteins make

52:38a new virus and then from there it'll be

52:40put into a vesicle from the golgi and

52:42then fuse with the cell membrane and

52:44exocytose the hepatitis b virus more of

52:46them so they can go and infect other

52:48hepatocytes

52:49so we have particular things that we can

52:52do to shut this hbv virus from

52:56replicating and then passing on to other

52:58hepatocytes and damaging more

53:00what are those drugs i'm glad you asked

53:02well the big target here is this bad boy

53:05that's the biggest one this is probably

53:07the rate limiting step that we have to

53:08target as the reverse transcriptases if

53:10we inhibit this we won't be able to take

53:12the pre-genomic rna make dna it won't

53:14have the coding that it needs for it to

53:16be able to infect other cells make more

53:18proteins etc so if we shut it down right

53:21here we'll essentially prevent viral

53:24replication formation infection of other

53:26types of hepatocytes this is a big step

53:29so we need reverse transcriptase

53:31inhibitors

53:32to be able to inhibit this particular

53:35enzyme if we inhibit this we will not

53:38allow for this step to occur we won't

53:40allow for us to be able to incorporate

53:42the actual dna into the actual hepatitis

53:44b virus and we won't have the nuclear

53:46machinery that it needs to be able to

53:48replicate make more proteins and perform

53:50all the nasty functions that it does

53:51that's a pretty cool thing so we have

53:53two different drug categories within

53:55this reverse transcriptase inhibitors

53:56and this is your nrtis that sounds

53:58familiar nucleoside reverse

54:00transcriptase inhibitors what do they do

54:02very simple it's very very simple guys

54:03think about it

54:05here

54:06we have our

54:08rna here's the pre-genomic rna we need

54:10to convert this into dna what does it do

54:13it reads the rna reads the actual

54:15nucleotides on the rna and then adds on

54:18nucleotides on the opposite the daughter

54:21strain in this case to make a new dna

54:23strand but it needs nucleotides to make

54:25dna off of the rna template guess what

54:27these nrtis act like they act like

54:30nucleotides they're nucleoside reverse

54:32transcriptase numbers and usually they

54:33don't have a hydroxyl group on the end

54:35so what happens is you try to add them

54:37on okay

54:38let's say that there's a you know you

54:40try to make a new strand here off of

54:41this you're trying to make a new strand

54:43what's going to happen is you have the

54:45nucleotides that are complementary here

54:46and they're just interacting perfectly

54:48but then this reverse transcriptase goes

54:50into its pocket grabs off a nrti and

54:53tries to add it on here adds it on

54:56when it adds it on

54:58guess what you can't add anything else

55:00to the actual strand because it has no

55:02hydroxyl group for you to add another

55:03nucleotide onto and so it terminates the

55:06formation of further dna you can't make

55:09dna you can't make the actual coding

55:10that you need for that virus to continue

55:12to replicate and cause all its nasty

55:13functions and so that's where these

55:15drugs come into play so the two nrtis

55:17that i really want you to remember that

55:19work to inhibit this particular enzyme

55:21here

55:22is lamivudine okay

55:25lamivudine

55:28and intakovir

55:31all right so lumidine and takavira the

55:33two big ones that i want you guys to

55:35remember now it's hard to uh you know

55:36there's no particular beautiful thing

55:38that's similar between these two that

55:40has a root word so it's unfortunate that

55:41you have to just remember it but the

55:43other ones the ntrtis they're basically

55:45just like nrtis they just are a

55:47nucleotide

55:48they just again they have the kind of a

55:50similar function just to the nrdis they

55:52basically terminate the formation of

55:53more dna off of your rna template

55:55because they won't allow for further

55:57growth of nucleotides or polymerization

55:59after them

56:00these ones are nucleotide reverse

56:03transcriptase numbers these are

56:04nucleocide

56:06so this is a defever and tanoff of here

56:08do you notice a similarity between both

56:09of these they both have fover in them so

56:12we can remember these by

56:15the fover okay so your ntrtis have the

56:19same function as the nrtis it's just

56:22they are nucleotides this is a

56:24nucleoside

56:25but they're pretty cool drugs now one of

56:28the big things that you have to remember

56:29with these particularly adephavir and

56:31tanofever you should actually watch out

56:33for something called fanconi syndrome

56:35this is extremely rare

56:37but it's something they may test you on

56:40on your boards so fanconi syndrome is

56:42this condition where it's a triad okay

56:44and again you see this with a defever

56:47a death of here and tenofovir

56:49and what happens with fanconi syndrome

56:53is it's a condition where

56:56where you excrete out three particular

56:58things into the urine

57:00you excrete out lots of phosphates you

57:02have what's called

57:04phosphaturia you excrete out a lot of

57:06glucose so you have glycosauria

57:09and you excrete out a lot of amino acids

57:11so you have amino acid urea so there's a

57:13lot of phosphates glucose and amino

57:15acids that are excreted into the urine

57:17this is called fanconi syndrome so

57:18remember that as a potential adverse

57:20effect whenever you're monitoring these

57:21patients for particular electrolyte

57:23abnormalities their glucose

57:24abnormalities and particularly amino

57:26acid abnormalities this can be seen with

57:28the defiver and alpha veer

57:30now

57:31that's these drugs working on that

57:33particular part of the pathway the next

57:34drug is a little interesting a little

57:36odd has a lot of different functions if

57:38you will here's what's really

57:40interesting you know the basic kind of

57:42immunology is whenever you have a virus

57:44that infects a particular cell so it

57:47infects these cells these cells are now

57:49viral infected when they're viral

57:51infected what they do is they try to

57:53alert nearby healthy cells that there is

57:56a virus in the proximity and it's

57:58causing a lot of problems and they

58:00release a particular molecule that we

58:02naturally make in our body called

58:03interferons one of them is interferon

58:05alpha beta these are the big ones and

58:07what happens is the interferons they

58:08circulate through your bloodstream to

58:10nearby healthy cells

58:13nearby healthy hepatocytes that haven't

58:14been infected by a virus yet and they

58:16bind onto these cells and via particular

58:19sick second messenger systems they work

58:21to be able to

58:23stimulate the host cells dna to make

58:26particular types of proteins so it'll

58:29increase the particular production of

58:31proteins now these proteins that it

58:33makes are very significant one of the

58:36proteins that interferon alpha makes is

58:38is it makes proteins that'll actually

58:40act as antiviral peptides in other words

58:42they'll break they'll actually prevent

58:45protein synthesis they'll prevent the

58:47actual rna

58:49formation

58:50and they'll do something else so they'll

58:51do three particular things so what do

58:53interferon elephants do here's what i

58:54want you to remember there's three

58:55particular things that i want you to

58:56remember with interferon alpha

58:58one of the proteins is it increases

59:02antiviral peptides

59:04antiviral peptides and these antiviral

59:07peptides which are very very interesting

59:09here can do a couple particular things

59:12one is that these antiviral peptides can

59:14actually inhibit protein synthesis so

59:16particularly what they'll be able to do

59:18is they'll help to be able to inhibit

59:19this particular process so one of the

59:21things that you can say here is that if

59:22we were to kind of follow this it makes

59:23these particular proteins interferon

59:25alpha will inhibit the actual protein

59:27synthesis

59:29it also may prevent particularly

59:32this process of the rna okay so it might

59:35also be able to prevent the rna from

59:36being able to convert it into dna so

59:39there might be another particular

59:40function here where it may be able to

59:42inhibit this particular process by

59:44working on very specific enzymes and the

59:46second thing that it can do is it can

59:48also increase the expression of very

59:50specific molecules on the actual cell

59:53membrane and these are called

59:55mhc-1 complexes so it increases

59:58antiviral peptides one of them is it's

1:00:00going to inhibit protein synthesis

1:00:05okay of the actual viral proteins

1:00:07it may also inhibit

1:00:10viral

1:00:12rna formation and this the third thing

1:00:15that it can actually do is it can

1:00:17increase the expression of

1:00:20mhc1

1:00:22complexes now why is that important i'm

1:00:24glad you asked so you know whenever you

1:00:26have like a cell that's infected so

1:00:28here's our cell it's infected with a

1:00:29particular virus when it expresses these

1:00:32mhc-1 molecules so here's mhc1 molecules

1:00:36what that does is it'll express a piece

1:00:38of the actual virus on it

1:00:40and when we have immune system cells you

1:00:42know these these immune system cells

1:00:43called your cd8 positive t cells so

1:00:47these can be like your cytotoxic t cells

1:00:50they'll notice this and when they notice

1:00:52this they'll say oh boy something wrong

1:00:55here and i'm going to go ahead and

1:00:57release particular types of perforins

1:00:58and granzymes and kill this virus

1:01:01infected cell so that's how interferons

1:01:03work interferons are pretty intense they

1:01:05have ability to be able to increase

1:01:07antiviral peptides one of the ways is by

1:01:10inhibiting protein synthesis second way

1:01:12is inhibiting the viral rna activity

1:01:15third thing is increasing the expression

1:01:17of mhc-1 complexes which causes more

1:01:19cytotoxic t cells to come to the area

1:01:22and kill these virus-infected cells

1:01:24thereby preventing the replication

1:01:26formation and spread of the actual hpv

1:01:29virus

1:01:30pretty insane right yeah it's pretty

1:01:32cool so you can actually use interferons

1:01:34alpha in two ways

1:01:36you can use them one way to be able to

1:01:38work against hepatitis b virus but it

1:01:40also can be utilized in refractory

1:01:42hepatitis c virus so we'll talk about a

1:01:43little bit later

1:01:45but with interferon alpha what are the

1:01:47particular com complications adverse

1:01:49effects that you can see with this

1:01:50particular drug one of the things is

1:01:51this teratogenic so you want to be able

1:01:53to avoid this in someone who is pregnant

1:01:55so teratogenic is one particular thing

1:01:58and the other thing is it can actually

1:01:59suppress the bone marrow drop the

1:02:00production of your red blood cells so

1:02:02called anemia drop the production of

1:02:04your platelets thrombocytopenia and drop

1:02:05the production of your white blood cells

1:02:07leukopenia collectively this is called

1:02:11pancytopenia

1:02:12so you may see pancytopenia

1:02:16as a potential adverse effect of

1:02:17interference so avoid this in

1:02:19women who are pregnant and avoid this

1:02:21the potential patient who already has

1:02:22issues with anemia thrombocytopenia or

1:02:25leukopenia or monitor their cbc for any

1:02:29evidence of pancytopenia so again when

1:02:31we talk about hepatitis b viruses when

1:02:34we talk about the drugs that are

1:02:35targeting it one is the reverse

1:02:36transcriptase inhibitors your nrtis

1:02:38which is the lemividine and

1:02:40your uh particularly in tacovir and

1:02:43again the other one is the ntrtis these

1:02:45are nucleotides transcriptase inhibitors

1:02:47and this would be a definition of their

1:02:48big thing to watch out for these is

1:02:50particularly a death evaporation of air

1:02:52can cause fanconi syndrome

1:02:54the other one is interferon alpha

1:02:55increases the production of antiviral

1:02:57peptides that prevent protein synthesis

1:02:58inhibit the activity of the viral rna

1:03:00and increase the expression of mhc-1

1:03:02complex which cause increased cytotoxic

1:03:04t-cell activity to destroy these

1:03:06virus-infected cells

1:03:08the other thing is again watch out for

1:03:09in patients who are pregnant and watch

1:03:11out for any pancytopenia with

1:03:13interference okay now that we talked

1:03:14about that let's move on to the next one

1:03:16which is the antivirals against

1:03:17hepatitis c virus all right so we're

1:03:19almost done guys hang in with me okay we

1:03:21got hepatitis c virus and we'll finish

1:03:23hepatitis medication so with hepatitis c

1:03:25virus again same thing we know that you

1:03:28have the hepatitis c virus that's going

1:03:29to love to attack the liver cells so

1:03:32it's going to cause damage to the liver

1:03:33cause inflammation and again potentially

1:03:34increase the risk of a vital cell

1:03:35carcinoma now when the hepatitis c virus

1:03:38binds to the actual hepatocytes it uses

1:03:40like a plethora of receptors there's so

1:03:42many dang receptors like ldl receptor

1:03:44and srv1 there's just a plethora there's

1:03:46no reason to remember all these dang

1:03:48things remember that the hepatitis c

1:03:50virus though is an rna virus in

1:03:51comparison to hepatitis b which is a dna

1:03:53virus

1:03:55so

1:03:55when it binds with these particular

1:03:57proteins it uses these to be able to

1:03:58undergo an endocytosis mechanism to be

1:04:00brought into the cell

1:04:02once it's brought into the cell it has

1:04:04to uncoat once it uncoats it will then

1:04:06release

1:04:07its rna into the actual host cell

1:04:10cytoplasm so now where's my markers oh

1:04:12my gosh all of them are over here okay

1:04:14so once we have

1:04:16this rna get released

1:04:18here's my beautiful rna from the

1:04:20hepatitis c virus

1:04:21this rna

1:04:23is going to then go and bind with the

1:04:26ribosomes on our rough endoplasmic

1:04:27reticulum so see this is a rough

1:04:29endoplasmic reticulum and then on there

1:04:31they're going to have all these

1:04:31ribosomes studying all the on the edges

1:04:33of it

1:04:34this viral rna hepatitis c viral rna

1:04:36will then go and bind with these

1:04:39ribosomes

1:04:40once it binds with the ribosomes the

1:04:42ribosomes are then going to utilize the

1:04:43rna to do what translate it and make

1:04:46proteins but it makes these big big

1:04:49polyproteins so as a result i'm going to

1:04:51synthesize a bunch of polyproteins now

1:04:54these polyproteins that we synthesize

1:04:56actually from the actual viral mrna via

1:04:59this translation process so this again

1:05:00what is this called translation we know

1:05:02this right

1:05:04we're going to make a bunch of these

1:05:05polyproteins now there's a couple

1:05:07different polyproteins that we should be

1:05:08aware of first one that i want you to

1:05:10remember is called

1:05:11ns3

1:05:13then you have ns4a

1:05:18ns5a

1:05:20and then the last one is ns5b

1:05:27now these particular structures are

1:05:29making up this big thing called a

1:05:31polyprotein

1:05:33now this polyprotein

1:05:35we need to be able to break it down all

1:05:37right so once this protease works here

1:05:39it's going to break down this poly

1:05:40protein when it breaks down the

1:05:41polyprotein it breaks it into two

1:05:42components one is it breaks it into the

1:05:44different types of structural proteins

1:05:46so obviously these are the different

1:05:47like capsion burner proteins envelope

1:05:49proteins all of those things but it also

1:05:51breaks it into functional proteins so

1:05:52these are proteases and polymerases etc

1:05:55so we need both of these in order for

1:05:57the virus to be able to replicate in

1:05:59order for it to be able to function and

1:06:01obviously infect other cells so in order

1:06:04for us to be able to form these we have

1:06:05to cleave this polyprotein and this

1:06:08enzyme is integral into actually being

1:06:10able to cut this polyprotein and it

1:06:12loves to particularly work out the ns3

1:06:14site and the ns4h site it's called a

1:06:17produce but we actually know what we

1:06:18call this dang thing we call this an ns3

1:06:23for a protease i know it's ridiculous

1:06:27but that's what we call this little cube

1:06:29pink enzyme and what it does it'll

1:06:31actually work to be able to cut this

1:06:32poly protein particularly at the sites

1:06:34in the different structural and

1:06:35functional proteins we actually do have

1:06:37drugs that we can utilize to target that

1:06:39preventing the cleavage there we'll talk

1:06:40about that in just a second

1:06:42but you know what else is really

1:06:43interesting

1:06:44this ns5a and this ns5b have very

1:06:47interesting functions

1:06:48ns5a there's still some kind of debate

1:06:50exactly what it does there's a thought

1:06:52process but ns5b we definitely know what

1:06:55it does

1:06:56and what happens here is it's really

1:06:57really interesting

1:06:59is you take rna right so we have the rna

1:07:02that the virus is actually going to be

1:07:04shedding into the actual cell and what

1:07:06happens is we think that the ns5a and we

1:07:08definitely know that the ns5b are

1:07:11particular enzymes that are utilized to

1:07:15be able to replicate

1:07:17and make more of the rna so these are

1:07:20particular proteins that we may utilize

1:07:22to make more

1:07:23of the hcv rna so very very important so

1:07:27what if i had very particular drugs that

1:07:29i can use to inhibit the ns5a will i be

1:07:32able to make more of this rna no

1:07:35what if i have a drug that can inhibit

1:07:36the ns5b will i be able to use that is

1:07:39actually you know what the ns5b is it's

1:07:40actually rna-dependent rna polymerase

1:07:42that's why we know it definitely is

1:07:44involved in this so it takes rna and

1:07:46makes more rna if i inhibit that

1:07:48particular protein will i be able to

1:07:50make more rna no will i be able to make

1:07:52more virus no so this is why these are

1:07:54two important drug sites and then this

1:07:56protease is an important drug site now

1:07:59once i actually have all of these

1:08:01structural functional proteins plus my

1:08:03rna what can i do

1:08:05i can send this rna

1:08:08i can send these different types of

1:08:11proteins all my structural functional

1:08:13proteins and send it to the golgi

1:08:15apparatus from the golgi apparatus we'll

1:08:17package it make a new

1:08:19virus replicate more of these little

1:08:21suckers and then exocytose them out to

1:08:23go and infect other cells

1:08:26my question here is

1:08:27what are the actual drugs

1:08:29that are actually going to target this

1:08:31protease what are the drugs that are

1:08:32going to target this ns5a what are the

1:08:34drugs are going to target this ns5b and

1:08:36then we'll finish off talking about this

1:08:38last enzyme that has a little

1:08:39interesting weird function that doesn't

1:08:40really completely correlate with the

1:08:42life cycle we'll talk about that one

1:08:43next all right so let's talk about these

1:08:45groups here so we have one particular

1:08:46group called a protease inhibitors so

1:08:48these are protease inhibitors that

1:08:49actually are directly acting so it will

1:08:51inhibit this ns3 4a protease preventing

1:08:56the cleavage of this polyprotein in the

1:08:57different types of structural functional

1:08:58proteins and again it targets like right

1:09:00here at that site so if we utilize

1:09:02particular drugs such as cemeprovere

1:09:04peretoperia

1:09:07see they're so dang hard to remember

1:09:08these dang names right

1:09:10i don't even bother doing that you know

1:09:12what i look for what's the common theme

1:09:14within all of these preview go with that

1:09:17so if we have previer we see that within

1:09:20these protease inhibitors we know which

1:09:22type of group we're going to talk about

1:09:23in comparison to all these other ones

1:09:25now

1:09:26what these drugs really are

1:09:28interestingly doing again is just don't

1:09:30forget here's your protease it works on

1:09:32this polyprotein you have the

1:09:34four different components here right the

1:09:35ns3

1:09:38ns4a

1:09:39and s5a

1:09:42ns5b it's working to cleave this actual

1:09:46protein at this particular ns34a site

1:09:49making your different types of

1:09:50structural proteins making your

1:09:51different types of functional proteins

1:09:53so if we can inhibit this actual

1:09:55protease will inhibit the actual

1:09:57cleavage and prevent the formation of

1:09:59structural functional proteins which are

1:10:00integral to making more virus so again

1:10:03protease inhibitors semeprovere pareto

1:10:05prevail

1:10:07glycoprevia just remember the previers

1:10:10okay

1:10:11now the next one is the ns5a inhibitors

1:10:13remember i told you that there's kind of

1:10:15a question theory about how they

1:10:16actually work one of the big things that

1:10:18we know about these is that there is at

1:10:20least from what we understand is that

1:10:22this again here we have the ns3

1:10:25ns4a here right here is going to be the

1:10:28ns5a and then here is your ns5b

1:10:31we utilize this ns5a they believe to be

1:10:33able to act as a some type of integral

1:10:35protein that's needed to make more rna

1:10:39the other thing that we see here is that

1:10:41it may be involved particularly in

1:10:43allowing for the rna

1:10:45and some of these actual proteins

1:10:48to be taken to the golgi which is

1:10:50important for assembly so there's two

1:10:52particular things that we think may be

1:10:54important here one is it's going to be

1:10:56involved in rna replication

1:10:59making more rna

1:11:02and also it's important in viral

1:11:05assembly

1:11:09so if we give ns5a inhibitors le dip

1:11:12severe vopatosphere

1:11:14to cladosphere

1:11:16these drugs are going to inhibit

1:11:19this particular protein from undergoing

1:11:21rna replication to make more hcv rna and

1:11:24inhibit the viral assembly of this

1:11:26actual protein of these particularly hcv

1:11:28viruses all right you guys notice like a

1:11:30very interesting thing here between all

1:11:31of these la dip severe velpatosvir the

1:11:33cladosphere do you guys notice a common

1:11:35like root term between all of these you

1:11:37see there's as veer as vir as vir that's

1:11:40the way i would want you guys to

1:11:41remember the ns5

1:11:44a inhibitors so remember previer at the

1:11:47end for proteus inhibitors as veer at

1:11:49the end for ns5a inhibitors

1:11:51the next drug if you just want to look

1:11:53here we'll actually hit this part two

1:11:54ns5b inhibitors we'll talk about what it

1:11:56does in just a second we already kind of

1:11:57have a good idea but remember how you

1:11:59look here so phosphavir de zabovir what

1:12:02do you notice as a kind of a common

1:12:03theme between both of these it's the

1:12:05beuver right so they both have

1:12:08buver

1:12:10at the end so again

1:12:11previer protease asvir ns5a buvir and

1:12:15s5b inhibitors

1:12:17now again here is going to be your ns3

1:12:20ns4a and s5a and here is going to be

1:12:23your ns5b

1:12:25remember this actually acts as a rna

1:12:29dependent

1:12:31rna polymerase meaning it takes rna and

1:12:34makes more

1:12:35rna so we can utilize this particular

1:12:38enzyme we definitely know that this is

1:12:40utilized to be able to make more

1:12:42rna if we utilize a particular drug such

1:12:45as one of these buvers it'll actually

1:12:47help to inhibit the formation of more

1:12:49hcv rna thereby inhibiting the formation

1:12:52of more hcv viruses this is a very very

1:12:55good drug now you're probably wondering

1:12:58okay how in the heck am i supposed to

1:13:00remember which one of these i actually

1:13:01use do i always use a protease inhibitor

1:13:03do i use an ns5a do i use an ns5b it's

1:13:06actually really complicated and believe

1:13:07it or not it depends upon the genotype

1:13:10and there's like so many different

1:13:11genotypes of the hepatitis c but we'll

1:13:13have a link down in the description box

1:13:14to that below and we'll also talk about

1:13:15in a case but

1:13:17i want you to remember there are so many

1:13:18different genotypes that the type of

1:13:20genotype is that actual type of genotype

1:13:24determines which type of drug

1:13:25combination you use so you may be

1:13:27utilizing a protease inhibitor plus an

1:13:28ns5a inhibitor or a protease inhibitor

1:13:31plus an ns5b inhibitor one of the very

1:13:33common combos that you'll actually see

1:13:35oftentimes is just super expensive is

1:13:37actually an ns5b and an ns5a inhibitor

1:13:40combination and that's usually so

1:13:42phosphavir and ledipsevere but again it

1:13:44depends upon the genotype and we'll have

1:13:46a little link on that it just goes way

1:13:48too beyond the lecture here to really go

1:13:49into that much detail about all the

1:13:51different genotypes but again i think

1:13:53now that you have a basic understanding

1:13:54of the mechanism of action and the drug

1:13:56categories let's now move up now and

1:13:58talk about this other random drug here

1:14:00called rib of iron all right so the next

1:14:01one is ribavia ribavia is pretty

1:14:03interesting so

1:14:04this drug here

1:14:06it's primarily to be honest with you we

1:14:08only use this uh in refractory hepatitis

1:14:12c virus so really it's it's primarily

1:14:14only used in like your refractory

1:14:17refractory

1:14:20hcv all right and and really if we do

1:14:23utilize this in refractory hcv it's

1:14:25dependent upon the particular type of

1:14:26like genotype of the virus

1:14:28but really it's a part of a triple

1:14:30therapy so we only utilize this drug as

1:14:32a part of a triple therapy and more of

1:14:34your really resistant refractory

1:14:36hepatitis c viruses and so it'll be a

1:14:38combo of rib of iron

1:14:41so would be three drugs rib of iron will

1:14:43be one of them

1:14:45the second one will be sophosphavir

1:14:47which was a

1:14:48buver that was an ns5b inhibitor so

1:14:50again we'll put

1:14:51ns5b inhibitor in this is going to be

1:14:54so phosphavir

1:14:56here we'll put down so

1:14:58fosbuver

1:15:00and the last one is actually believe it

1:15:02or not interferon alpha remember i told

1:15:04you that interferon alpha can treat both

1:15:06hepatitis b virus but it also can be

1:15:08utilized in hepatitis c virus remember

1:15:11what this one did increases antiviral

1:15:13peptides to inhibit protein synthesis

1:15:14inhibits the viral rna activity and also

1:15:17increases the expression of mhc-1

1:15:18complexes for cytotoxic t-cells okay

1:15:21remember tradogenic and

1:15:23for adverse effects but either way when

1:15:25we talk about this actual triple combo

1:15:28we utilize riboviron in the triple combo

1:15:30now what does it do

1:15:31it inhibits a very particular type of

1:15:33enzyme this enzyme is called ionosine

1:15:37monophosphate

1:15:39dehydrogenase

1:15:40so this enzyme basically what it does it

1:15:42helps to be able to make

1:15:44uh guanine nucleotides okay so it helps

1:15:47to be able to take and make

1:15:49something called guanine nucleotides now

1:15:51guanine nucleotides are important for

1:15:52being able to make more

1:15:54rna so it's a nucleotide you need this

1:15:57in order to be utilized by ns5a and ni5b

1:16:00to be able to add on so for example if i

1:16:03take this rna and i want to make more

1:16:04rna i need nucleotides to be able to

1:16:06make rna if i give a drug like riboviron

1:16:10what ribovirin does is

1:16:12is it actually works to inhibit this

1:16:14ionoscene monophosphate adenosine 5-fall

1:16:17it's actually ionosine 5-phosphate

1:16:19ionosine 5-phosphate

1:16:21ionosine

1:16:235-phosphate dehydrogenase either way

1:16:26it's an enzyme it inhibits it from being

1:16:28able to make guanine nucleotides if i

1:16:31don't make guanine nucleotides am i

1:16:33going to be able to utilize these to

1:16:34make rna no can i make rna then no and i

1:16:37hit with the rna replication and

1:16:38formation thereby inhibiting the virus

1:16:41from being able to replicate and form so

1:16:44a rib of iron is particularly going to

1:16:45be utilized to inhibit

1:16:47this particular enzyme the ionosine

1:16:495-phosphate dehydrogenase that inhibits

1:16:52the guanine nucleotides that are being

1:16:54formed that inhibits you from being able

1:16:56to utilize the ns5a ns5b to convert the

1:17:01rna to make more

1:17:03you're going to inhibit the formation of

1:17:05further

1:17:06rna okay

1:17:08pretty straightforward concept for this

1:17:10guy now one of the big things is that

1:17:12adverse effects of these drugs produce

1:17:14inhibitors ns5a inhibitors ns5b

1:17:15inhibitors they're actually relatively

1:17:17well tolerated not a ton of like toxic

1:17:19effects of these you got to be careful

1:17:21if a patient has like decompensated

1:17:22cirrhosis that you don't really want to

1:17:24give these drugs but for the most part

1:17:26riboviron is really the only one that

1:17:28can have some kind of nasty adverse

1:17:29effects and the big thing to remember

1:17:31here is it's terratogenic

1:17:33so you don't want to give this to a

1:17:34person who is pregnant

1:17:36and then the other thing here

1:17:38or someone who's you know again don't

1:17:40give us someone who's pregnant but the

1:17:41other thing here is hemolytic anemia

1:17:42it's been shown to be able to increase

1:17:44the risk of hemolytic

1:17:46anemia

1:17:48so these would be the big things that i

1:17:49would want you guys to remember about

1:17:50the hepatitis c virus drugs the direct

1:17:53acting antivirals and again primarily

1:17:56adverse effects here is rhyme of iron

1:17:57hemolytic anemia tyradogenic but don't

1:17:59utilize these drugs like a decompensated

1:18:00cirrhosis that's pretty much the big

1:18:02thing but relatively well tolerated all

1:18:04right so that covers the mechanism of

1:18:05action that covers the drug names that

1:18:07covers the indications that covers the

1:18:09adverse effects for the antihepatitis

1:18:11medication so let's now move on to the

1:18:12last big category which is the

1:18:14anti-herpes medications so the

1:18:16anti-freeze medications with these again

1:18:18when we talk about the herpes viruses

1:18:19like the family there's a bunch of these

1:18:20things that we can talk about obviously

1:18:22the one that we know is in your hsv

1:18:24could be one particular one so if we

1:18:25were talking about these hi hsv you get

1:18:28your varicella zoster virus

1:18:30your cmv these are the big ones that we

1:18:32actually should know because there's

1:18:32antivirals that i can actually treat

1:18:34these particular diseases with

1:18:37now the question that we have to be able

1:18:38to understand here is what kind of

1:18:39infections do these actually cause so

1:18:42what kind of tissues are they hitting

1:18:43right so herpes simplex viruses and

1:18:46varicella zosovirus particularly tend to

1:18:48attack very specific types of tissues so

1:18:50we see like herpes simplex viruses

1:18:52attacking

1:18:53for example we can see herpes simplex

1:18:55viruses attacking like the skin so you

1:18:56can see particularly like mucocutaneous

1:18:58lesions with hsv one and you can also

1:19:01see this with hsv

1:19:03too so for example herpes labials with

1:19:05the herpes simplex 1 you can see the

1:19:07genital lesions with herpes simplex 2.

1:19:10for the other thing is it may also

1:19:11attack the esophagus and cause hsv

1:19:14esophagitis the other thing is it can

1:19:16attack the actual meninges in the brain

1:19:18tissue and so you may see hsv

1:19:21encephalitis meningitis and you know

1:19:24varicella zoster virus varicella zoster

1:19:26virus is really interesting because what

1:19:28can happen is it can actually become you

1:19:30can get an infection it can travel along

1:19:31to the actual nerve stay there until you

1:19:34actually have some type of issue where

1:19:35you're immunosuppressed you have some

1:19:36type of stressor or anything like that

1:19:38and it can become reactivated come down

1:19:39and lead to shingles so you can get

1:19:41shingles with varicella zoster virus

1:19:44the other thing is cmv so cmv has the

1:19:47ability to cause infections particularly

1:19:49to the esophagus and cause esophagitis

1:19:51it can attack the lungs and cause

1:19:53pneumonia so you can get cmv pneumonia

1:19:56and it can also attack the actual retina

1:19:58and lead to cmv retinitis and so you can

1:20:01see how these viruses can attack various

1:20:04tissues but the question is is how does

1:20:06this virus

1:20:08affect the tissue in other words how

1:20:09does it get in how does it utilize the

1:20:11actual host cell's particular machinery

1:20:13to make more viruses and replicate and

1:20:15is there any particular

1:20:17enzymes or any particular targets within

1:20:20that life cycle of the cmv vcv or hsv

1:20:22virus that we can target to prevent them

1:20:25from replicating prevent them from

1:20:27shedding prevent them from causing nasty

1:20:29effects

1:20:30in these actual diseases so let's talk

1:20:32about that

1:20:33all right so either way one of these

1:20:34viruses they bind onto the host cell

1:20:35wherever this host cell may be

1:20:37again it could be any of these tissues

1:20:39once they bind what happens okay they

1:20:41bind onto these particular receptors

1:20:43once they bind they get taken into the

1:20:45cell via endocytosis then via the

1:20:48uncoding they release what particular

1:20:51structure

1:20:52well you know most of these viruses are

1:20:53dna viruses and so what happens is

1:20:55they'll release their actual dna

1:20:58into the host cell

1:21:00once the dna is released into the actual

1:21:03host cell it'll then actually get taken

1:21:04into the actual nucleus

1:21:06once it's taken into the nucleus it'll

1:21:09utilize

1:21:10particular enzymes you know these

1:21:13viruses also contain particular like

1:21:15what's called

1:21:16nasty viral dna polymerases so it'll

1:21:20also release not just this dna but it

1:21:22also release particular enzymes and

1:21:24proteins that are essential to its

1:21:25replication so here's the viral dna

1:21:28the viral dna will then be utilized by

1:21:30this very special enzyme you know what

1:21:31this enzyme is called this is actually a

1:21:33dna

1:21:35polymerase but it's important to

1:21:37remember that this is actually a viral

1:21:38dna polymerase so what it's going to do

1:21:41is it's actually going to take this

1:21:42viral dna and do what

1:21:44make more dna so what's going to happen

1:21:47is i'm actually going to take from this

1:21:50i'm going to utilize this enzyme and i'm

1:21:51going to

1:21:53stimulate

1:21:55more formation of viral

1:21:58dna so now i'm just going to have tons

1:22:01and tons

1:22:02of this actual viral dna as a result

1:22:04here of this enzyme now what can happen

1:22:07is i can take some of this actual viral

1:22:09dna and utilize particular rna

1:22:12polymerases so i can utilize particular

1:22:14rna polymerases and from this i can make

1:22:17something called rna so this is all dna

1:22:20all of this is

1:22:22viral dna that we're just replicating

1:22:24utilizing the viral dna polymerase but i

1:22:26can utilize maybe specific types of

1:22:29rna polymerases to make rna

1:22:33once i make this rna this messenger rna

1:22:35this type of viral messenger rna it can

1:22:38then get taken out of the actual nucleus

1:22:40and then go to the ribosomes

1:22:42from the ribosomes the ribosomes can use

1:22:44this actual viral mrna and do what

1:22:47synthesize particular types of proteins

1:22:50so it can synthesize all the proteins

1:22:52that are integral to making the actual

1:22:54viruses the herpes viruses these could

1:22:56be different types of structural

1:22:58proteins these could be different types

1:22:59of functional proteins

1:23:01but all of these are very very important

1:23:03to remember so what are we going to make

1:23:04as a result a bunch of different types

1:23:05of protein structural

1:23:07and subsequently functional proteins

1:23:11and these proteins that we're going to

1:23:12make are going to be needed to

1:23:13incorporate to make a new virus what

1:23:16will we do we'll send these to the golgi

1:23:19apparatus and then from the golgi

1:23:21apparatus will take these proteins

1:23:22combine it with the nucleic acid and

1:23:24make a new virus that virus will then be

1:23:27put into a vesicle butted off of the

1:23:29golgi and then fuse with the cell

1:23:31membrane and when it fuses with the cell

1:23:33membrane it'll release the virus via

1:23:35exocytosis

1:23:37now this is the protein component we

1:23:39have the proteins that are important to

1:23:40the virus where we need the nucleic acid

1:23:42well we've utilized this viral dna

1:23:44polymerase to make tons and tons of dna

1:23:46so then guess what i'm going to do i'm

1:23:48going to push this dna that i replicated

1:23:50out

1:23:51and i'm going to push this into the

1:23:52actual

1:23:54cytoplasm and then i'm going to

1:23:56transport this to the golgi apparatus

1:23:58and incorporate it with all these

1:23:59proteins to make a new virus and then

1:24:01release it via exocytosis

1:24:04so you know what we can do

1:24:06the primary area that we should target

1:24:08the most important area that is the

1:24:10target site here is going to be taking

1:24:12the viral dna and making more viral dna

1:24:14that seems to be the biggest point so i

1:24:16should have drugs that target this viral

1:24:18dna polymerase or in some way target the

1:24:21formation of new dna because if i can

1:24:23inhibit that formation of doing dna i

1:24:25won't be able to use the viral dna to

1:24:27make rna i won't be able to take the dna

1:24:29and incorporate it into making a new

1:24:31virus so this is really important so i

1:24:33might be able to come up with ways to

1:24:34stop making dna if i have less dna i

1:24:37have less rna less proteins and i have

1:24:39less of the virus as well so let me

1:24:41think about a particular drug category

1:24:43that i can do that with

1:24:44that's going to be this first one the

1:24:45viral dna polymerase inhibitor and we'll

1:24:47talk about some other interesting ones

1:24:48called guanosine analogues let's move on

1:24:50to those so now with the first category

1:24:52here is your viral dna polymerase

1:24:53inhibitor so again it's pretty

1:24:54straightforward they're going to inhibit

1:24:56this particular enzyme if we inhibit

1:24:58this particular enzyme here what are we

1:25:00going to do we're going to inhibit the

1:25:02actual viral dna that we brought into

1:25:03the actual host cell prevent us from

1:25:05making more dna if we inhibit the

1:25:07formation of more dna we're going to

1:25:09inhibit the actual dna that can be

1:25:11incorporated into the

1:25:13herpes virus plus on top of that if we

1:25:15don't have as much of this dna we won't

1:25:17be able to transcribe as much of it as

1:25:20less mrna less proteins again in

1:25:22combination with less dna that we've

1:25:24replicated we won't be able to make any

1:25:26more viruses so this is the particular

1:25:28groups that i want you to remember that

1:25:29inhibit the viral dna polymerase now

1:25:32what are the drugs that we can utilize

1:25:34here the first one is called

1:25:38sedophobia then the second one here is

1:25:41called phoscarnate

1:25:43now these drugs will inhibit this

1:25:46particular enzyme what the boards may

1:25:48try to test you on here is saddafi fair

1:25:51acts directly binds onto the actual dna

1:25:54polymerase and inhibits it but the

1:25:55phoscarnit may act like an analog that

1:25:58inhibits this enzyme and it's important

1:26:01to remember this because they will ask

1:26:02you this on the board likely is it's a

1:26:04pyrophosphate

1:26:09but again the basic concept here is that

1:26:12it is still inhibiting the viral dna

1:26:15polymerase from making more dna

1:26:18it's just this one is directly going to

1:26:20inhibit it this one is going to act like

1:26:21an analog that will inhibit that enzyme

1:26:23now big thing to remember here is

1:26:25indications for these particular drugs

1:26:27we obviously know that we're utilizing

1:26:28it to treat particular types of herpes

1:26:30infections but it's very important that

1:26:32you remember that we utilize this in cmv

1:26:35infections

1:26:37and particularly cmv infections that

1:26:40were resistant to maybe ganciclovir so

1:26:43ganciclovir is one of the guanosine

1:26:44analogs and we'll talk about that a

1:26:46little bit but cmv infections that maybe

1:26:48are resistant

1:26:51to

1:26:52something called gan

1:26:54cyclovir

1:26:56and this would be our infections like

1:26:57like cmv pneumonia cmv retinitis cmv

1:27:00esophagitis that ganciclovir wasn't able

1:27:03to actually treat so we would give

1:27:04sadafavir or phoscarnet

1:27:07the other one is we can use this in a

1:27:10cyclovir

1:27:14resistant

1:27:17hsv infections

1:27:19so acyclovir is again one of the other

1:27:21types of guanosine analogs

1:27:24and we

1:27:25very very commonly utilize in hsv

1:27:27infections

1:27:28but

1:27:29if patients have some type of resistance

1:27:31to the acyclovir such as n

1:27:33a hsv

1:27:35mucocutaneous lesions such as herpes

1:27:37labialis or genital lesions or

1:27:39meningitis encephalitis or some type of

1:27:41shingles virus or on top of that

1:27:43esophagitis and they're not responding

1:27:44to a cyclovir we can try things like

1:27:46sadofa verifoscarnet so that'll be the

1:27:49primary indications for these drugs okay

1:27:52we know the mechanism of action we know

1:27:53the indications what are the adverse

1:27:56effects that you should watch out for

1:27:57with these particular drugs one of the

1:27:59big things is that sedophobia has been

1:28:00shown to be able to produce something

1:28:02called crystal induced nephropathy okay

1:28:04that might sound familiar remember one

1:28:05of the other drugs over there with the

1:28:07uh we talked about that a little bit ago

1:28:09with the hiv medications the indenavir

1:28:11so it was one of those particular types

1:28:12of protease inhibitors this also can

1:28:14produce a crystal

1:28:17induced nephropathy

1:28:20and this can lead to acute kidney injury

1:28:22so one of the big things is to remember

1:28:24this one and it's just it's just also

1:28:26just naturally nephrotoxic too so with

1:28:29this particular drug you want to be very

1:28:30very careful with saddafire now one of

1:28:33the things that we can actually do with

1:28:34saddafivir to reduce the crystal

1:28:36inducing property they may ask you this

1:28:37on the exam is you want to give this

1:28:39with lots of iv fluids and also give

1:28:42this with something called probenicid

1:28:44and it may help to be able to reduce the

1:28:46crystal induced nephropathy with this

1:28:47drug this may be a question they could

1:28:48ask you on the exam

1:28:51the other one is the phoscarnic so

1:28:52phosparnate has been shown to

1:28:54potentially increase the risk of

1:28:55seizures

1:28:56but the exact mechanism is still kind of

1:28:59questionable but it's believed that it

1:29:01may produce massive electrolyte

1:29:03imbalances so it may produce alterations

1:29:06in calcium it may produce ulcer

1:29:08alterations in phosphate it may produce

1:29:10alterations in potassium and it may

1:29:12produce alterations in magnesium

1:29:14particularly they've been seen to cause

1:29:16hypomagnesemia hypokalemia it may cause

1:29:18increase or decrease calcium and

1:29:20increase and decrease of phosphorus so

1:29:22again you can see these particular

1:29:24electrolyte abnormalities and it's

1:29:26believed to be that these electrolyte

1:29:27abnormalities may potentially produce

1:29:29increased metabolic abnormalities that

1:29:31precipitate seizures that we can see

1:29:34primarily with phoscarnit

1:29:37so phoscarnet i want you to remember

1:29:38seizures via electrolyte abnormalities

1:29:41sadofovir crystal induced nephropathy

1:29:44but again you can try to reduce that by

1:29:45giving lots of iv fluids and probenicid

1:29:48during giving that type of drug

1:29:50all right this would be the viral dna

1:29:51polymerase inhibitors now

1:29:53we move on to our guanosine analogs

1:29:56the guanosine analogs are very very

1:29:57interesting drugs let's talk about the

1:29:59actual category there's a lot of other

1:30:01ones i just want you to remember the

1:30:02most common ones and these are getting

1:30:04your cyclovirs so for example you have

1:30:06something called a cyclovir

1:30:09and then there's another one called val

1:30:12acyclovir it's just kind of one of the

1:30:14pro drugs for this one as well but i

1:30:16think one of the big things to remember

1:30:18for these actual drugs here

1:30:21is acyclovir valcyclovir those are

1:30:23probably one of the big ones to be able

1:30:24to remember there is another one that we

1:30:26utilize here and we're going to talk

1:30:27about this one and this is called