Antivirals and Antifungals PDF

AntiViral AntiFungal Pharm II Anti-infective Drugs AntiViral Drugs AntiFungal Drugs Other Pharmacology II Diane T. Adamczyk, OD Diane T. Adamczyk, OD/Copyright © 2024 1 1 AntiViral AntiFungal Pharm II Viral Overview Diane T. Adamczyk, OD/Copyright © 2024 2 2 AntiViral AntiFungal Pharm II Virus: Over...

AntiViral AntiFungal Pharm II Anti-infective Drugs AntiViral Drugs AntiFungal Drugs Other Pharmacology II Diane T. Adamczyk, OD Diane T. Adamczyk, OD/Copyright © 2024 1 1 AntiViral AntiFungal Pharm II Viral Overview Diane T. Adamczyk, OD/Copyright © 2024 2 2 AntiViral AntiFungal Pharm II Virus: Overview > Virus: O b lig a te parasites cannot multiply outside the living cells L a c k cell wall and cell membrane Consists of proteins and nucleic acids A r e either double or single stranded D N A or RNA (nucleic acids) That is encased in protein c o a t (capsid) Diane T. Adamczyk, OD/Copyright © 2024 3 Viruses are very different than bacteria in structure Drugs preventing the growth of viruses then the MOA of action is different Obligate parasites need us to live on à so they can proliferate and grow They cannot multiple outside of living cells They don’t have a cell wall or cell membrane It is a clump of proteins and nucleic acid (what a virus is) but can be double or single stranded and encased in a protein capsule There are DNA and RNA viruses 3 AntiViral AntiFungal Pharm II Herpes Virus DNA core Capsid-surrounds core Tegumentbetween (nucleus)capsid and envelope Consists of viral enzymes Envelope-outer layer of virion Composed of glycoproteins; Appear as short spikes embedded in envelope Diane T. Adamczyk, OD/Copyright © 2024 4 Herpes is the biggest virus we will discuss It is a DNA virus so its genetic material is DNA the capsid is what surrounded the core of genetic material à It is b/w the nucleus and the envelope on the envelope there are glycoproteins that stick out and are like short spikes embedded in the envelope Antivirals are going after whatever the genetic material is and stopping it from replicating its own DNA 4 AntiViral AntiFungal Pharm II Quick Review of the Basics…. Nucleoside: Nucleotide: Purine (adenosine or guanosine) O R Pyrim idine (cytosine, thym ine, uracil) base PLUS Sugar (ribose or deoxyribose) Nucleoside + phosphate group Nucleic acid: bonded together nucleotides (e.g. DNA) Function nucleotide: structural unit for DNA/RNA and part of cell function. Function nucleic acid: storage and expression of genetic inform ation (e.g. DNA, RNA) Diane T. Adamczyk, OD/Copyright © 2024 5 The end result is DNA or RNA Purines are A and G and pyrimidines are C, T, and U When something is a guanosine analog we know it is mimicking the genetic material The base is attached to a sugar à ribose is what it can be attached to or deoxyribose Deoxyribose then DNA and ribose then RNA Together these make nucleosides à purine or pyrimidine plus a sugar The nucleoside goes through a phosphorylation stage and with a phosphate you get a nucleotide Base (purine or pyrimidine) + sugar (ribose or deoxyribose) = nucleoside + phosphate = nucleotide The nucleotide are bonded together and so you get a nucleic acid A virus is a clump of genetic material so if you look at herpes it is a DNA virus 5 AntiViral AntiFungal Pharm II Viral Replication 1 Virus binds to host cell 2 Viral particle penetrates host cells 3 Duplication of viral DNA or RNA 4 New viral particle released 5 Cell death or survival (latency) Diane T. Adamczyk, OD/Copyright © 2024 6 Obligate parasite cannot survive on its own The spikes on the outer aspect of the virus attaches to the host cell and the virus attached and injects its genetic material into the host cell By entering the host cell it is able to replicate and so you get duplication of the genetic material and so when it duplicates it is ready to leave the host cell as viral entities From the host it either goes out and dies eventually or stays latent For herpes it becomes latent in the nerve ganglion We see the manifestations of herpes simplex in the primary infection than secondary à primary is when you first have manifestations so it can be a conjunctivitis in relation to the eye, then it stays latent in the nerve ganglion until it becomes reactivated and in herpes simplex it can be reactivated to things like immunosuppression, exposure to sun, your period and when it is reactivated it goes back down to the original site and with the ocular structures its repeat manifestations it shows up in the cornea Herpes zoster which is a family of the herpes viruses, it manifests pustules/vesicles initially as chicken pox or you can get a vaccine for it so the body has immunity to it and in the original infectious stage then it shares the same nerve ganglion as herpes simplex You need a greater decrease in immunity for zoster to manifest 6 Simplex can reactivate easily so like even less sleep can activate it For zoster you really need a hit to your immunity so something like HIV or cancer treatment but of course people without these can still get it It could be that as we get older our immune system decreases so it is easier to reactivate it 6 AntiViral AntiFungal Pharm II Viral Life Cycle (DNA/Herpes) > Nucleoside triphosphates are incorporated into new viral genomes by viral or cellular polymerase HS: Generation of deoxyribonucleoside triphosphates involves phosphorylation of nucleosides via the salvage pathway by viral thymidine kinase; Viral DNA polymerase then adds deoxyribonucleoside triphosphates to the growing DNA genome Diane T. Adamczyk, OD/Copyright © 2024 7 Start with a nucleoside and after the first phosphorylation you need viral specific enzyme specially thymidine kinase (specific for viral) à you need this specific enzyme to get the first phosphorylation and then the host comes in The host enzymes is what helps you go from monophosphate to diphosphate to triphosphate The first change is viral enzyme driven and the rest are host enzyme driven Salvage pathway is the name for what you are using the thymidine kinase for Last stage after the triphosphate you need the viral DNA polymerase in order to incorporate the viral DNA into the growing genome 7 AntiViral AntiFungal Pharm II Viral Life Cycle (HIV) https://aidsinfo.nih.gov/understanding-hiv-aids/glossary/1596/life-cycle (accessed 2-4-20) Diane T. Adamczyk, OD/Copyright © 2024 8 HIV is a different virus as it is a retrovirus so it starts off as RNA so there is a conversion inside the host from the RNA to DNA so there is a number of stages where the virus binds to host cell and injects its genetic material but there is an added step of the reverse transcriptase where you turn the RNA into DNA and so you get replication and it gets released into the body 8 AntiViral AntiFungal Pharm II AntiViral Overview Diane T. Adamczyk, OD/Copyright © 2024 9 9 AntiViral AntiFungal Pharm II AntiViral Pathway into Viral Life Cycle (Viral DNA/Herpes) > Nucleoside triphosphates are incorporated into new viral genomes by viral or cellular polymerase Generation of deoxyribonucleoside triphosphates involves phosphorylation of nucleosides by viral thymidine kinase; Viral DNA polymerase then adds deoxyribonucleoside triphosphates to the growing DNA genome R o le of host kinase Diane T. Adamczyk, OD/Copyright © 2024 10 There is a pathway from nucleotide to viral DNA and then integration into genome so he antivirals come in and trick the virus into thinking it is its own nucleoside but really it’s a different monophosphate say acyclovir monophosphate and not its own So interrupting replication of the viral DNA 10 AntiViral AntiFungal Pharm II AntiVirals (Herpes) Diane T. Adamczyk, OD/Copyright © 2024 11 11 AntiViral AntiFungal Pharm II Oral Antiviral Agents Acyclovir (Zovirax) Valacyclovir (Valtrex) Famciclovir > Use: > Herpes Zoster > Herpes Simplex > Bell’s Palsy (off label) > Acute Retinal Necrosis (off label) - this can come from many viruses but herpes Virus causes devastating effect on cornea Diane T. Adamczyk, OD/Copyright © 2024 12 These are the oral antivirals Found that the oral agents are able to get on the ocular surface and fight off the virus when it is in its epithelial form and there are topical agents that can be used 12 AntiViral AntiFungal Pharm II AntiVirals Nucleosides: acyclovir, valacyclovir, famciclovir Chemical structure is close to purine nucleoside deoxyguanosine –DNA component Under action of thymidine kinase produced by viruses, nucleosides block DNA polymerase necessary for viral DNA replication Treat HS 1 and 2, Varicella-zoster, epstein-barr, cytomegalovirus Diane T. Adamczyk, OD/Copyright © 2024 13 These are nucleosides à chemical structures are close to purine nucleoside deoxyguanosine which is important to make the DNA structure so the antiviral mocking it The thymidine kinase phosphorylates it and it ended up blocking the DNA polymerase Acyclovir and valacyclovir impact the DNA polymerase and the viral structure falls apart CMV is something we all have but when our immune system goes out of sync then it cannot suppress the CMV HSV 1 and 2 is something latent in us but our immune system keeps it in check 13 AntiViral AntiFungal Pharm II M e d ic a l P h a r m a c o lo g y C h a p te r 36: A n tiv ira l D rugs/http://w w w.pharm acology2000.com /Antiviral/antiviral400.htm # Antiviral_D rugs Diane T. Adamczyk, OD/Copyright © 2024 14 Acyclovir mimics the genetic material/the building block of DNA Valacyclovir is a prodrug of acyclovir By definition, a prodrug has an enzymatic rxn that takes valacyclovir and transfers it into acyclovir Famciclovir is the prodrug of Penciclovir The viral thymidine kinase phosphorylates Acyclovir to get the acyclovir monophosphorylate and then the cellular kinase creates acyclovir triphosphate but it will effect the DNA polymerase which helps to incorporate the triphosphate into the developing strand it also prevents the development of the strand from developing à normally it will interlock but the acyclovir triphosphate is not the real thing so the real viral strand isn’t being able to be made and there will be viral DNA strand early termination Here the drug mimics what the virus is normally doing 14 AntiViral AntiFungal Pharm II Acyclovir (Zovirax) Oral Antiviral Agents Valacyclovir (Valtrex) Famciclovir Caution in those with renal impairment Those at risk of renal disease: check BUN and creatinine before high dose Diane T. Adamczyk, OD/Copyright © 2024 15 Be careful of these oral agents and they should have the BUN and creatinine check à they are markers for how well the kidneys are working If pts kidneys aren’t great to start, think of other drugs to use 15 AntiViral AntiFungal Pharm II Antiviral Drugs Acyclovir > Activity: HSV, VZV > > Selective against herpes (low toxicity) Guanosine (nucleoside) analog Only partially absorbed by human GI tract > > The bioavailability at therapeutic doses is limited at 20% > Therefore needs to be administered in high doses and at higher frequency Diane T. Adamczyk, OD/Copyright © 2024 16 Acyclovir main thing is going against Herpes and zoster It’s a pharmaceutical version of guanosine For acyclovir there are two steps of action b/c it shows that you have acyclovir triphosphate and you need the viral DNA polymerase to help it enter the growing chain and it entering the growing chain will break the chain b/c it will not allow it to continue to develop It has two areas that it goes after à affects viral DNA polymerase which is needed to incorporate the triphosphate into the growing strand but also has an effect into the growing strand b/c if any of it enters the growing strand it stops the growing strand from developing more Acyclovir is going against the viral aspect of things It is partially absorbed by the GI abstract so only 20% absorbed which is fairly low Acyclovir b/c its bioavailability is very low it is administered in higher doses and more frequency Prodrug will differ since it has a better bang for its buck 16 AntiViral AntiFungal Pharm II Antiviral Drugs Acyclovir 2 mechanisms that results in viral DNA chain termination: > Com petitively inhibits a n d inactivates viral DNA polym erase > Incorporates into a n d term ination of grow ing viral D N A chain Pharmacology > ACV (guanosine analog) >>> > Isselectively phosphorylated by herpes specific (HSV/HZV) thymidine kinase to ACV monophosphate >>> > Subsequent formation of ACV triphosphate by cellular enzymes>>> > ACV triphosphate inactivates/Inhibits (herpes) viral DNA polymerase and > Incorporates into causing chain termination Diane T. Adamczyk, OD/Copyright © 2024 17 17 AntiViral AntiFungal Pharm II Antiviral Drugs Acyclovir > Clinical Use: > Primary and recurrent episodes of genital herpes > Primary varicella (chickenpox) > Herpes zoster > Off label: > HSV k e ra titis > A c u te retinal n e cro sis > H erpes zoster o p h th a lm icu s > Bell p a lsy > HSV p ro p h y la x is Diane T. Adamczyk, OD/Copyright © 2024 18 When there is widespread retinitis which can be caused by many different viruses, acyclovir is FDA approved for a bunch of viruses but there are off label uses as well Jere the HSV keratitis à typically if you wanted to give something locally then that may be best but with oral antivirals they seem to work very good at topical manifestations at HSV keratitis 18 AntiViral AntiFungal Pharm II Antiviral Drugs Acyclovir > Adverse Reactions > Safe > Nausea, vomit, diarrhea > HA > Skin rash > Caution in renal impairment and dehydration > ACV resistance: 1% prevalence, but immunocompromised ~5% Diane T. Adamczyk, OD/Copyright © 2024 19 Acyclovir is a safe drug Biggest caution is renal impairment Pt need to drink a lot of water b/c of dehydration There is resistance being built to it Safe to use while pregnancy and breastfeeding 19 AntiViral AntiFungal Pharm II Acyclovir Treatment in Active HSV Keratitis Oral acyclovir 400 mg 5 times daily for treatment of HSV epithelial keratitis Does not prevent stromal disease during active keratitis Does not benefit stromal keratitis inpatients receiving topical Viroptic and steroids Diane T. Adamczyk, OD/Copyright © 2024 20 20 AntiViral AntiFungal Pharm II > Purpose: To describe the clinical and virological profiles of patients with herpes simplex keratitis (HSK) caused by acyclovir-resistant (ACVR) strains of herpes simplex virus 1 (HSV-1). Acyclovir-resistant HSV-1 keratitis: a concerning and emerging clinical challenge. Am J Ophthal 2022 Diane T. Adamczyk, OD/Copyright © 2024 > Background: > ACV 400 mg BID causes 2 fold decrease in recurrences > Valacyclovir (prodrug of ACV) 500 mg QD can replace ACV > ACV resistance may be due to mutations in thymidine kinase or viral DNA polymerase > Conclusions: > Suspect resistance in cases with highly frequent recurrences despite ACV prophylaxis > Resistance is more likely in patients with long-standing disease and multiple recurrences > Resistance develops more rapidly in immunocompromised 21 This article looked at the profile of pts of those with HSK caused by acyclovir resistant herpes simplex virus They found that if someone has recurrences of HSV and you decide you want to put them on prophylactic oral treatment and they have HSK once a year then do you need prophylactic treatment and probably not. But if they get recurrences more often then may clinically decide to put them on prophylactic tx Once you take the pt off the prophylactic tx the recurrences can come back though Resistance happens more rapidly to those who are more immunosuppressed 21 AntiViral AntiFungal Pharm II Acyclovir Treatment in Herpes Zoster > Should be started within 72 hours of skin lesions, maximum efficacy 48 hours > 800 mg 5 x/ daily for 7 days for HZO Diane T. Adamczyk, OD/Copyright © 2024 22 When dealing with zoster, it happens more on the thoracic dermatome but for ocular it can happen as shown There will be Hutchinson's sign à follows the dermatome and be on one side of the face Tx should be within 72 hrs of when the lesions start Greatest effect is done ASAP Efficacy of treating after 72 hrs decreasing tremendously! 22 AntiViral AntiFungal Pharm II Acyclovir Treatment For Herpes Herpes zoster: 800 mg 5 x/day (7 days) Diane T. Adamczyk, OD/Copyright © 2024 Herpes Simplex keratitis: 400 mg 5x/day (7 days) Prophylactic: 400 mg BID 23 Don’t need to know the dose But known that when treat simplex vs zoster, the frequency is the same but zoster dose is twice as simplex (know this) 23 AntiViral AntiFungal Pharm II Bell Palsy > Prescribe oral steroids within 72 hours of symptom onset > New onset: steroids and oral antiviral (not antiviral alone) > Etiology: viral etiology suspected; exact mechanism unknown > Inflammation and edema causing compression > Oral steroid > Prednisolone 50 mg for 10 days OR > Prednisolone 60 mg for 5 days with 5 day taper > Initiate within 72 hours (benefit after 72 hours less clear) Otolaryngology–Head and Neck Surgery149(3S) S1–S27 American Academy of Otolaryngology—Head and NeckSurgery Foundation 2013 Diane T. Adamczyk, OD/Copyright © 2024 24 Saying that when a pt develops bells palsy you cant use an antiviral alone but you MUST use in combination with a steroid 72 hours is the time frame! With bells palsy there is edema on the nerve causing the palsy which is why you need an oral steroid You need an oral steroid with an antiviral Need an steroid with antiviral like acyclovir within 72 hours! 24 AntiViral AntiFungal Pharm II Acyclovir Treatment Summary > HSV keratitis (off label) > 400 mg 5x/day > Prophylactic: 400 mg BID > Herpes zoster ophthalmicus (off label) > 800 mg 5x/dy x 7 days > Bell palsy (new onset) (off-label) > 400 mg 5x/day for 10 days in combination with corticosteroids (not alone) > Begin within 3 days of symptom onset Diane T. Adamczyk, OD/Copyright © 2024 25 25 AntiViral AntiFungal Pharm II Antiviral Drugs Valacyclovir (Valtrex) > Pharmacology > Prodrug of acyclovir > L-valyl (valine) ester of acyclovir > Metabolized to acyclovir > H igher b ioa v a ila b ility th a n a cy clo v ir b y 3-5 fo ld c o m p a r e d to oral A C V > R a p id ly c o n v e r te d to A C V after oral co n su m p tio n > H igher p la sm a A C V co n ce n tra tio n s th a n oral A C V , c o m p a r a b le to IV A C V > Unlike A C V b ioa v a ila b ility o f 10-20% b e c a u s e o f lo w absorption , v a la cy clo v ir’s (A C V ) b ioa v a ila b ility > 5 0 % > This results in e.g. V A L BID vs A C V 5 x /d a y E.g. Treatment effect for HZ: > 800mg ACV 5x/day=VAL 500mg BID (or 250mg QID) > Caution: renal disease and dehydration Diane T. Adamczyk, OD/Copyright © 2024 26 Valacyclovir is a prodrug of acyclovir Other than the conversion from prodrug to regular drug, you are dealing with acyclovir The prodrug is different b/c it has high bioavailability than oral acyclovir This means you don’t need to take it as frequently as acyclovir since there is greater bioavailability It is rapidly converted to acyclovir and there are greater plasma concentrations of it It is comparable to IV acyclovir Same cautions for renal disease and dehydration Can be used for pregnancy and breastfeeding 26 AntiViral AntiFungal Pharm II Antiviral Drugs Valacyclovir (Valtrex) > Clinical use: > HSgenital > HZ > Off label: > HSV p ro p h y la x is > HZO > A c u te retinal n e cro sis > Bell Palsy (n e w o n se t) Diane T. Adamczyk, OD/Copyright © 2024 27 27 AntiViral AntiFungal Pharm II Reported that more than 95% of Valacyclovir is converted to ACV The high bioavailability of Valacyclovir is similar to IV ACV Diane T. Adamczyk, OD/Copyright © 2024 28 You take valacyclovir and it geos through the lumina esterase and enters the dipeptide transporter or acyclovir but either way get acyclovir entering the systemic circulation 28 AntiViral AntiFungal Pharm II Antiviral Drugs Valacyclovir (Valtrex) > Caution: renal disease and dehydration Diane T. Adamczyk, OD/Copyright © 2024 29 29 AntiViral AntiFungal Pharm II Antiviral Drugs Valacyclovir (Valtrex) > Dosage: > HS keratitis: 500 mg TID > HZ:1000mg TIDs(within 72 hours, max efficacy w/in 48 hours) > HS prophylactic: 500mg QD > Bell Palsy (new onset) (off label) > Adjunctive with corticosteroid > 500 mg TIDx 7 days (within 72 hours of onset) Diane T. Adamczyk, OD/Copyright © 2024 30 Needed to take less times than acyclovir HSV dose is half of zoster dose 30 AntiViral AntiFungal Pharm II Antiviral Drug: Famciclovir > Pharmacology > Prodrug of penciclovir > PCV=nucleoside analogue, similar mechanism of action as ACV > Effective against some ACV-resistant HSV strains > Selectively inhibits herpes DNA synthesis > Interferes with action of viral DNA polymerase > Rapidly absorbed and converted > Bioavailability 77% vs ACV 20% > Longer half life compared to ACV = less frequent dosages Diane T. Adamczyk, OD/Copyright © 2024 31 Famciclovir is a prodrug for penciclovir It is a nucleoside analog and has a similar mechanism than acyclovir Effective against acyclovir resistant simplex strains Like acyclovir and valacyclovir this also interferes with the viral DNA polymerase It prevents the viral DNA from forming but it effects ONLY the viral DNA polymerase (whereas acyclovir ahs two way) 31 AntiViral AntiFungal Pharm II Antiviral Drug: Famciclovir > Clinical use: > HS > HZ > Off label: > HSV prophylaxis > HZO > Acute retinal necrosis > Bell Palsy (new onset) Diane T. Adamczyk, OD/Copyright © 2024 32 32 AntiViral AntiFungal Pharm II Antiviral Drug: Famciclovir > Caution: Renal Impairment Diane T. Adamczyk, OD/Copyright © 2024 33 For famciclovir you need to weigh risk and benefit for it 33 AntiViral AntiFungal Pharm II Antiviral Drug: Famciclovir > Dosage: > HSkeratitis: 250 mg TIDx 7-10 days > HZ:500 mg tid x 7 days (72 hrs onset, max efficacy w/in 48h) > Bell’s Palsy: 500mg tid x 7 days (within 3 days of onset) with oral steroid Diane T. Adamczyk, OD/Copyright © 2024 34 The dosing is twice that for zoster but amount per day is the same 34 AntiViral AntiFungal Pharm II > Acyclovir > HSV keratitis: 400mg 5x/day > P rop h y la ctic: 400 mg BID > HZ:800 mg 5x/day X 7 days > Valacyclovir (Valtrex) > Prodrug of acyclovir Oral AntiViral Treatment Summary > HSKeratitis: 500 mg TIDx 7 days > P rop h y la ctic: 500m g Q D > HZ:1000mg TIDx 7 days > Famciclovir > Prodrug of penciclovir > HSKeratitis: 250 mg TIDx 7 days > P ro p h y la ctic consider: 250m g B ID > HZ:500 mg TIDx 7 days Note for all HZ: Ø Start within 72 hours of skin lesions, Ø Max effect w/in 48 hours Diane T. Adamczyk, OD/Copyright © 2024 35 For zoster you need to get it within 72 hours to get max effect, better sooner than later! 35 AntiViral AntiFungal Pharm II Acyclovir (Zovirax) Oral Antiviral Agents Caution Valacyclovir (Valtrex) Famciclovir Caution in those with renal impairment Those at risk of renal disease: check BUN and creatinine before high dose Diane T. Adamczyk, OD/Copyright © 2024 36 Need to check BUN and creatine If they come in with renal problems then consult with physician before putting them on it 36 AntiViral AntiFungal Pharm II AntiVirals (HIV and CMV) Diane T. Adamczyk, OD/Copyright © 2024 37 37