Dental Antiviral and Antifungal Pharmacology Flashcards
virus in latin means:
poison
what is a virus
small, obligate parasites with DNA or RNA genomes
how do viruses work
viral genomes direct their own replication and the synthesis of other viral components using host cell machinery
- no metabolic activity of their own
- not alive themselves
who do viruses infect
- can infect all living organisms, commonly cause disease in humans
do viruses reproduce faster or bacteria
viruses
are viruses easier or more difficult to treat than bacteria
more difficult
what is the animal virus life cycle
- attachment: polypeptide binding sites (on envelope or capsid) interact with host cell receptors
- entry: receptor- virus complex enters host cell (endocytosis)
- replication: utilizing host cell metabolic processes, nucleic acids and proteins are synthesized and assembled into viral particles
- process varies (DNA vs RNA)
why do antiviral drugs have limited selective toxicity
- viruses mostly use host cell machinery, so very few unique targets
- most drugs block steps that take place within cells, increasing chances for cell toxicity
describe the viral attachment to host cell
- highly specific interaction first step in infection
what does enfuvirtide do
- anti-HIV drug
- viral attachment to host cell
- blocks folding of gp41 protein, prevents fusion of virus with host cell membrane
describe the uncoating of the virus
for most viruses, nucleic acid must leave the capsid for transcription or replication
what is amantadine and what does it do
- anti flu drug
- uncoating of virus
- blocks M1 receptor, preventing detection of pH outside of virus
describe the viral DNA/RNA synthesis and give examples
-enzymes needed for replication of viral nucleic acid are either unique targets (reverse transcriptase) or more sensitive than host enzymes to drugs
- inhibition of specific enzymes
- NRTIs (HIV), baloxavir (flu), remdesivir (COVID-19)
describe the inhibition of viral assembly and give examples
- proteins attached to host membrane
- HIV makes long precursor protein which is then cut into functional proteins by HIV protease
- protease inhibitors such as saquinavir, ritonavir, and indinavir block this step
describe the blocking of budding/release and give examples
- many viruses bud, taking host membrane with viral proteins embedded
- surface glycoproteins (neuraminidase) must remove terminal sialic acid residues from glycoproteins or new virions will attack on way out, and get stuck
- oseltamivir (Tamiflu): drugs inhibit neuraminidase; dont stop viral replication but prevent viral spread
describe the stimulation/assisting of immune system and give examples
- natural human peptides used as drugs
- interferon: inhibit protein synthesis, degrade viral RNA
- immunoglobulin
- monoclonal antibodies
what is the herpes simplex virus
- HSV-1 and HSV-2
- large DNA virus spread by direct contact due to viral shedding from saliva or blood
what is the infectious process of herpes simplex
infection through broken skin and inoculates nerve tissue- primary infection
when is herpes simplex active and latent
- herpes viruses remain latent for long periods of time without reproducing and avoid the immune response
- immune deficiency states, stress, irritating agents reactivate latent virus, trauma to the area of primary infection by dental procedures, extractions, lip injury
what are the prodromal symptoms of herpes simplex virus
pain, tingling, burning
where does herpes occur
on keratinized tissue
what is herpes simplex labialis
- a cold sore
- HSV type 1
- primarily oral
3% genital area
what is herpes simplex genitalis
- HSV type 2
- primarily genital
- 30% oral
what is the latency of herpes simples
- virus ascends (trigeminal) nerves- survives/persists
- hides from immune system in nerve cell bodies of ganglia
- virus lies dormant (for life) in nerve roots, intermittently reactivates. shed new virus through blisters
- herpes is never eliminated- only managed
what are the reactivation triggers for herpes simplex
- UV light
- friction, trauma
- fever, illness
- stress
- steroids
- immunosuppressants
what approach for the management of HSV-1 depends on:
- primary HSV-1 infection or reactivation
- severity of symptoms
- site of infection
- frequency of recurrences
what are the systemic agents used for management of HSV-1
- acyclovir, famiciclovir, valacyclovir
- famciclovir and valacyclovir better oral bioavailability than acyclovir: longer half life, dosed less frequently, more expensive
- excellent safety for all three medications: selectively converted to active compounds within virally infected cells
- acyclovir is the only intravenous agent
describe DNA nucleoside analogs
- drugs are structural analogs of nucleosides- building blocks of DNA and RNA
- good anti viral drugs- block viral nucleic acid synthesis
- are selectively toxic prodrugs. only viruses with viral thymidine kinase are affected
what is the key to selectivity with thymidine kinase
- changes nucleosides into a nucleotides by adding 1st phosphate
- thymidine kinase is less active in normal nerve cells
- herpesvirus has its own viral thymidine kinase that is very active
- selectively toxic because the drug is phosphorylated by the viral thymidine kinase only. drug is activated in infected cells only
viral thymidine kinase works _____ than host cell thymidine kinase
100x faster
what stops DNA polymerase/synthesis with nucleoside antivrial drugs
false nucleotide
what is the dosing of herpes simplex virus with acyclovir
acyclovir 400mg PO TID for 5 days or 200mg PO five times a day for 7-10 days
what herpes drug needs to be adjusted for dose with kidney disease
acyclovir
what is the drug interaction with acyclovir
tizanidine
what is the MOA of valacyclovir
prodrug which is rapidly converted to acyclovir
what is the dosing with valacyclovir
1 gram PO BID 7-10 days but if recurrent infection only 2 grams PO BID for one day
what is the drug interaction with valacyclovir
tizanidine
can pregnant women take herpes simplex therapeutics
yes acyclovir and valacyclovir
what is the MOA of the drug-drug interaction with acyclovir and valacyclovir
- they are weal CYP1A2 inhibitors
- may increase serum concentration of tizanidine
- risk rating D -> consider therapy modification
- if therapy cannot be modified, monitor for increase adverse reactions of tizanidine such as hypotension, bradycardia, drowsiness
what is the MOA of famiciclovir
prodrug which is rapidly converted to active penciclovir
what is the dosing for famciclovir
250mg TID or 500mg BID for 7-10 days
for recurrent ifnections 1500mg single dose
what are the drug interactions with famciclovir
none and safe in pregnancy
topicals are _____ than oral agents
less effective
describe the 1% penciclovir cream and dose
- recurrent: apply q2h x 4 days (x9 times a day)
- best topical to date
- cream should not be applied to mucocutaneous tissue
describe the 5% acyclovir cream or ointment and dose
- topical ointment has not demonstrated much benefit in adult non immunocompromised patients
- recurrent: apply 5 times daily for 4 days
- ointment appropriate for mucocutaneous tissues
- buccal tablet: apply one 50 mg tablet as a single dose to the upper gum region (canine fossa)
what is the OTC treatment for herpes labialis and describe it
- n-docosanol (Abreva)
- used in cosmetics as thickener, ointment, emollient
- inhibits fusion between human cell membrane and viral envelope
- applied 5x daily beginning within 12 hours of onset
- safe and somewhat effective
what type of virus is the HIV virus
RNA retrovirus
what is the MOA of HIV
- transforms its RNA into DNA, reversing the natural process
- requires reverse transcriptase (viral DNA polymerase)
- main target of HIV:T- cells (CD4) and macrophages
- host- where the virus harbors and replicates
- in the host cytoplasm:
-1st step: viral RNA transcribed into a double- stranded DNA - 2nd step: Viral DNA incorporated into T-cells DNA
what are the oral health care considerations for the HIV patient
- HIV patients are often referred for routine and preventative dental care
- range of oral manifestations can occur due to immunodeficient status or antiretroviral therapy
- challenges with access to oral health services
what are the oral complications of HIV
- oral candidiasis
- oral hairy leukoplakia
- oral kaposi’s sarcoma (human herpes virus 8)
- oral viral infections (HSV)
- ulcerative disease
- malignancy
- dental caries, gingivitis, periodontitis
- more severe manifestations of periodontal disease (linear gingival erythema, necrotizing ulcerative gingivitis and necrotizing ulcerative periodontitis
what determines what infections occur in HIV
CD4 count
what is the normal CD4 count
greater than 1000
aids defining opporunistic infections start to appear at CD4 count of:
less than 750
which infections first occur in HIV
candida, TB, bacterial infections
with the opportunisitc infection of pneumocystic jiroveci pneumonia with HIV what is the CD4 count that warrants prophylaxis and what is the prophylaxis
- less than 200
- sulfamethoxale- trimethoprim (bactrim) 1 DS tablet daily
with the opportunisitc infection of toxoplasmosis with HIV what is the CD4 count that warrants prophylaxis and what is the prophylaxis
- less than 100
- sulfamethoxale- trimethoprim (bactrim) 1 DS tablet daily
with the opportunisitc infection of mycobacterium avium complex with HIV what is the CD4 count that warrants prophylaxis and what is the prophylaxis
- less than 50
- azithromycin 1200mg once weekly
what are the HIV targets in treatment
- fusion inhibitors
- protease inhibitors
- reverse transcriptase inhibitors
- integrase inhibitors
how many NRTIs are used together
2
describe nucleoside reverse transcriptase inhibitors
- incorporated into viral DNA stops further transcription to DNA
- interrupt the virus from duplicating
- nucleoside analogs converted by host cell thymidine kinase to nucleototides
what are the NRTIs
- Abacavir
- Lamivudine
- Tenofovir
what are the combination NRTIs for once daily dosing
- Epzicom
- Truvada
what do non- nucleoside transcriptase inhibitors (NNRTI) do
directly binds/blocks reverse transcriptase enzyme
what are the disadvantages of NNRTI
- highest incidence of resistance ~18%
- high cross resistance in entire class - requires only a single mutation
- CYPP450 inducers
what are the advantages of NNRTI
- daily dosing (long half lives)
- no interference with food
- do not increase TG, less severe side effects vs PIs
- can use in renal disease
NNRTIs block the infection of new cells by HIV with these drugs:
- Efravirenz (Sustiva, EFV)
- Rilpivirine (Edurant, RPV)
what do protease inhibitors do
- blocks last stage of virus production - new protein production
- prevents HIV assembly
- all are CYP 3A4 substrates
what are the drugs that are protease inhibitors
- atazanvir (reyataz, ATV)
- fosamprenavir (Lexiva, FOS)
- Prezcobix = Darunavir + cobicistat
describe protease inhibitors
- often boosted
- strong inhibitors of CYP3A4 added to boost levels of PI’s/NNRTI’s
- Ritonavir and cobicistat are strong CYP3A4 inhibitors that are added
- less frequent dosing, same efficacy
- less resistance: unboosted resistance ~5%/year
- boosted resistance <1%/yr
what are the adverse effects of protease inhibitors
- insulin resistance
- hyperglycemia
- diabetes
- hyperlipidemia
- lipodystrophy
- hepatotocivity
- increased risk of bleeding **
- PR internal prolongation
what are the oral adverse effects of protease inhibitors per drug
- fosamprenavir (Lexiva) - perioral numbness, taste changes
- atazanavir (Reyataz) - Dental pain, taste changes
- ritonavir (Norvir) -taste changes
what do integrate strand transfer inhibitors do
- bind integrase enzyme, block viral DNA integration into host cell DNA
describe integrate strand transfer inhibitors
- no major side effects
- preferred for initial therapy: high efficacy, low adverse effect profile, minimal drug interactions
what drugs are integrase strand transfer inhibitors
- Dolutegravir (trivicay)
- Bictegravir (biktarvy)
what is the initial treatment for HIV
- combination of INSTI and 2 NRTIs is preferred for most patients: 2 NRTIs and 1 INSTI
- 3 drugs from at least 2 different classes of medication
- first line treatment variation: 2 NRTIs and 1 PI
multiple agents in treating HIV are ____ used
always
what drug for HIV is known as the backbone of therapy
NRTIs
what are the most common single tablet regimens for HIV
- bictegravir - TAF- Emtricitabine = Biktarvy
- Dolutegravir - Abacavir- Lamivudine = Triumeq
- Dolutegravir - Lamivudine (Dovato)
what is the post exposure of HIV prophylaxis
- cleanse intact skin with soap and water, open wounds with antiseptic, and mucosal by flushing with lots of water
- start PEP < 2 hours
what body fluids are of concern in Post exposure prophylaxis with HIV
- semen, vaginal, other body fluids contaminated with visible blood
what body fluids are not considered infectious unless they contain blood with HIV
- feces
- nasal secretions
- saliva
- gastric secretions
- sputum
- sweat
- tears
- urine
- vomut
what is the risk of exposure with HIV
HIV transmission in .33% following percutaneous expsure
what is the drug regiment for post exposure prophylaxis for HIV
- tenofovir- emtricitabine (Truvada) plus dolutgravir (trivicay)
- tenofovir- emtricitabine (Truvada) plus raltegravir (Isentress)
- 4 weeks of therapy
what is influenza A
- obligate intracellular parasite
- replicates inside host respiratory cells
what are the two major surface glycoprotein antigens in influenza A and what do they do
- hemagluttinin (H)- cell attachment
- neuraminidase (N)- maturation and release
what is the treatment for influenza A
- neuraminidase inhibitors (INfluenza A and B): zanamavir (relenza), oseltamivir (Tamiflu)
- endonuclease inhibitors (influenza A and B): baloxavir marboxil (Xofluza)
what are the indications, mechanism of action, and examples of neuraminidase inhibitors
- indications: prophylaxais and treatment of influenza A and B
- MOA: prevent the release of new virions from the cell surface, binds the surface antigen neuraminidase, on influenza A and B viruses preventing release of new viruses, neuraminidase releases virus from cell surface
- Oseltaminir (Tamiflu)
- Zanamivir (Relenza)
what is the dosing for Tamiflu
- tx: 75mg by mouth BID for 5 days
- prevention: 75 mg PO QD for 7 days following exposure
- begin within 48 hours of symptoms or exposure
what do endonuclease inhibitors do
- inhibits initiation of mRNA and transcription of viral RNA
what is an example of endonuclease inhibitors
baloxavir marboxil (Xofluza)
what is the dosing of baloxavir marboxil (Xofluza)
- less than 80 kg: 40 mg as single dose within 48 hours of symptoms or exposure
- more than 80 kg: 80mg as a single dose within 48 hours of symptoms or exposure
fungus are mainly seen as:
opportunistic or superinfections
describe the difference between cutaneous fungal infections and systemic fungal infections
- cutaneous: common, chronic, seldom dangerous
- systemic: difficult to diagnose, treat and often lethal
visible fungal infections of the mouth can tell you:
- immune status
- drugs that are taking
describe the selective toxicity in treating fungal infections
- rigid cell walls contain chitin and the cell membrane contains ergosterol
- selectiv toxicity achieved by targeting ergosterol
what are the medically important fungal groups
- molds (dermatophytes)
- yeasts (candida, cryptococcus, aspergillus)
describe dermatophytes
- subgroup of molds that live on skin
- normla inhabitants of skin, contagious, spread by contact
- produce keratinases that dissolve keratin
- hyphal filaments penetrate into keratin
- invades hair shafts and nail beds
dermatophyte (tinea) infections affect:
keratinized tissues
what are the 3 common pathogenic dermatophytes
- trichophyton
- epidermophyton
- microsporum
what are the Tinea disease/ “cutaneous mycoses”
- tinea capitis- scalp - common in children
- tinea corporis - body
- tinea pedis- athletes foot
- tinea cruris - groin
- tinea unguium - toenails (onychomycosis)
what are allymines and examples
- binds/inhibits squalene epoxidase: squalene precursors build up and are also toxic aiding toxicity, requires actively growing fungi
- fungicidal against dermatophytes only: weak fungistatic activity against candida, little drug interaction potential, few side effects
- terbinafine
- naftifine
what is the most common fungal infection in the mouth
candida
c albicans normal habitat is:
the human oral cavity
what are the symptoms of oropharyngeal candidiasis (thrush)
- cottony feeling in the mouth, loss of taste, and/or painful eating and swallowing
- many pts are asymptomatic
- immunosuppressed patients with thrush often have concomitant candida esophagitis
what is the treatment for oropharyngeal candida albicans
- 10 day duration
- clotrimazole troches (one 10mg troche dissolved slowly 5 times a day)
- miconazole mucoadhesive buccal tabs (50mg 1 daily apply to mucosal surface over canine fossa)
- nystatin swish and swallow (400,000 to 600,000 units four times daily)
what is the treatment for esophagitis candida albicans
- fluconazole - 400mg as a loading dose and then 200-400 my daily for 14-21 days given orally
what is the pros and cons of using clotrimazole (Mycelex)
- pro: highly effective
- cons: ease of use (5x a day), expensive, drug interactions, irritating to mucosa, alters taste, contains sugar
what are the pros and cons of miconazole (oravig)
pros: ease of use (daily troche) , highly effective, tasteless, no sugar
- cons: expensive, drug interactions possible
what are the pros and cons of nystatin
- pro: no drug interactions, inexpensive, not irritating to mucosa
- con: ease of use (QID), ease of use (swish contact time) , less effective, high sugar content
what is angular cheilitis and what is it caused by
- acute or chronic inflammation of lateral commisures
- caused by excessive moisture and maceration from saliva
what is the treatment and possibility of angular cheilitis
- tx: topical barriers keep moisture out, prevent reoccurences
- barrier creams (zinc oxide paste) or petroleum
- may have candida superinfection: clotrimazole ointment BID 1-3 weeks
what is the MOA of Azoles
- inhibit cytochrome P450 14 alpha demethylase
what are the first generation azoles
imidazoles
what are the examples of imidazoles
- miconazole, clotrimazole: not taken systemicaly
- clotrimazole and miconazole oral formulations less cariogenic, better tolerated vs nystatin
what is the dosage and instructions for miconazole
50mg (1 tablet) applied to upper gum once daily for 7-14 days
- apply in morning after brushing. alternate sides of mouth with each application; do not crush, chew, or swallow. avoid chewing gum while in place
- if the tablet does not adhere to gum or falls off within 6 hours of application, same tablet should be repositioned immediately
- exposure time is important: goal entirety of waking hours
what is the dosage and instructions for clotrimazole
-10mg (1 troche) dissolved slowly 5 times daily for 7-14 days
- metabolized in lover - 3A4. contraindicated in liver disease
- avoid combination with benzos; HIV
- oral troche for management of oral candidiasis
- patient ed: 5 times daily, swallow the saliva. no eating or drinking for 30 minutes following medication
- dissolves over 30 minutes and remains in saliva for up to 3 hours
what are the second generations of azoles
triazoles
what are examples of triazoles
- fluconazole, itrconazole, voriconazole, posaconazole, isavuconazole
describe triazoles
- first line drugs for systemic fungal infections
- fewer drug drug interactions and expanded spectrum
- still metabolized via the cytochrome P450 enzyme system
- all azole agents are both metabolized by and slow down hepatic cytochrome P450 activity
- safer side effect profiles than ketoconazole for systemic use
what are triazoles used for in dentistry
esophageal candidiasis or refractory resistant oral candidiasis
why is resistance a big problem with triazoles
there are 2 mechanisms- efflux pumps and altered binding site on demethylase
describe fluconazole (diflucan)
- high absorption after oral administration with high distribution into all tissues
- long half-life allows for once daily dosing
- significant excretion via kidney- dose adjustment when adminsitered to renal impairment
- strong inhibitor of CYP2C19 and a moderate inhibitor of CYP2C9 and CYP3A4: caution with benzos and warfarin
- pregnancy category C- drug excreted in breastmilk. do not use in pregnancy and breastfeeding
when is fluconazole used in dentistry and what is the dosage
- esophageal candidiasis or refractory, resistant oral candidiasis
- 200mg tablet, or 400mg once then 200mg PO daily x 14 days
what other triazoles are used clinically
- voriconazole
- posaconazole
what are drugs that stimulate metabolism of azoles
- 3A4 inducers: rifampin, phenytoin, carbapenzamine, phenobarbital
what is the MOA of polyenes
- binds ergosterol in fungal cell membrane
- forms pores in cell membrane
- cell contents leak out
- fungal cell death
what do polyenes do
- binds to ergosterol in fungal membranes. fungicidal
what is a medication that is a polyene and describe it
- amphotericin B: broad spectrum fungicidal for IV use
- 1st line IV drug for most systemic yeasts: histoplasmosis, aspergillosis, crypto
- standard tx: cryptococcal meningitis
- severe, potentially lethal side effects (dose dependent nephrotoxicity)
describe nystatin
- broad spectrum antifungal
- no GI absorption - entirely excreted in feces
- pregnancy category B (safe)
- topical only for mucocutaneous candidiasis
- length of contact - 2minutes
- suspension , high sucrose concentration
- alterantive to clotrimazole/miconazole
what is the pt counseling for nystatin
- swish in mouth
- hold in mouth for as long as possible
- no eating or drinking for 30 minutes
what are the indications for magic mouthwash
- aphthous stomatitis
- recurrent aphthous ulcers
- chemo induced oral mucositis
is there a standard formula for magic mouthwash
no
what are the most common magic mouthwash ingredients
- diphenhydramine (benadryl) >90%
- viscous lidocaine 90%
- magnesium hydroxide/aluminum hydroxide (maalox) 80%
- nystatin 30%
- corticosteroids 10%
- tetracyclines 10%
what is diphenhydramine used for in magic mouthwash
- antihistamine/reduce inflammatory process: limit pain sensation, reduce swelling and erythema
- may be useful for trauma, food allergens or infections
what does viscous lidocaine do in magic mouthwash
- topical anesthetic
- relieves pain associated with irritated oral/pharyngeal mucous membranes
ingesting too much viscous lidocaine can lead to:
arrhythmias
what does magnesium hydroxide do in magic mouthwash
- antacid- maalox and mylanta
- primarily used as vehicle to enhance coating of other ingredients within the mouth
what is nystatin used for in magic mouthwash
- fungicidal polyene for mucocutaneous candidiasis
- nonabsorbable by oral route
- not appropriate for RAU or mucositis without fungal etiology
- use if active oral candidiasis infection in concert with RAU or mucositis
what are corticosteroids used for in magic mouthwash
- hydrocortisone, dexamethasone, betamethasone, beclomethasone
- reduce inflammatory process: limit pain sensation, reduce swelling and erythema
- limited evidence for use/controversial
what helps pain/oral irritation in magic mouthwash
- diphenhydramine -analgesic
- viscous lidocaine- analgesic
- magnesium hydroxide - vehicle
- 1:1:1 ratio
what helps oral mucocutaneous candidiasis in magic mouthwash
- diphenhydramine -analgesic
- nystatin- antifungal
- magnesium hydroxide - vehicle
- 1:1:1 ratio
what is the administration of magic mouthwash
- 2 tablespoons (30mL) every 4-6 hours
- swish and spit to avoid systemic side effects
what are the side effects of magic mouthwash
- taste disturbances (49%)
- burning and/or tingling in the oral cavity (29%)
- drowsiness or any central nervous system adverse effects (11%)
- GI symptoms- constipation, diarrhea and nausea (11%)
describe the evidence for magic mouthwash
limited and controversial
what are the indications for each ingredient in magic mouthwash
- diphenhydramine for all indications
- maalox for all indications
- lidocaine for pain
- nystatin for candidiasis
- avoid steroids
