PHARMACOLOGY OF ANTIVIRALS AND ANTIFUNGALS Flashcards
- Capsid:
protein coat surrounding genetic material of a virus
- DNA polymerase:
an enzyme which catalyzes the process of DNA
replication
- Endocytosis:
ingestion/engulfing of materials (e.g. a virus) via the
cell membrane
- Envelope:
outermost lipid (fatty) layer which protects genetic
material when traveling between host cells; only present on some
viruses
- Host:
organism that is infected by a virus
- Incubation period:
time duration between exposure to the virus and
the appearance of symptoms
- Latency:
the ability a pathogenic virus to lie dormant within a cell
- Neuraminidase:
an enzyme found on the surface of influenza virus
which enables the virus to be released from the host cell
- Nucleocapsid:
core of a virus, made up of the genetic material and
the capsid
- Reverse transcriptase:
an enzyme used to generate
complementary DNA (cDNA) from an RNA template (reverse
transcription)
- RNA polymerase:
the enzyme which catalyzes the process of
transcription
- Transcription:
the synthesis of RNA from a DNA template
- Translation:
the synthesis of protein from RNA
- Virion:
a complete and free-living virus particle outside of its host;
the vehicle for transmission of the genome to the next host cell or
organism
What is a Virus?
* “Virus” in Latin means “poison”
* Small, obligate parasites with — genomes
* Viral genomes direct their own replication and the synthesis of other
viral components, using —
- No — of their own
- Not “—” themselves
* Can infect all living organisms; commonly cause — in humans
* — much faster than bacteria
* Much more difficult to — than bacteria
DNA or RNA
host cell machinery
metabolic machinery
alive
disease
Reproduces
treat
Characteristics of Viruses
DNA
(3)
- Herpesviruses
(chickenpox, shingles, cold
sores, infectious
mononucleosis) - Adenoviruses (sore throat)
- Papillomaviruses (warts)
Characteristics of Viruses
RNA
(4)
- Orthomyxoviruses
(influenza) - Paromyxoviruses
(respiratory tract infections) - Picornaviruses (colds)
- Retroviruses (HIV/AIDS)
Virus Life Cycle
General Steps:
(3)
- Attachment: Polypeptide binding sites (on envelope or
capsid) interact with host cell receptors - Entry: receptor-virus complex enters host cell (e.g.
endocytosis) - Replication: utilizing host cell metabolic processes,
nucleic acids and proteins are synthesized and
assembled into viral particles
* Process varies (DNA vs RNA)
Virus Life Cycle
General Replication Differences:
DNA Viruses
(4)
- Viral DNA enters host cell nucleus
- Host cell’s RNA polymerase
catalyzes transcription into mRNA - Translation of mRNA into virus-
specific proteins - Enzymes for further synthesis of
viral DNA - Structural proteins comprising
viral coat and envelope - Release of complete virions
- Via budding or host cell lysis
Virus Life Cycle
General Replication Differences:
RNA Viruses
(4)
- Enzymes within virion synthesize
mRNA from the viral RNA template
OR viral RNA serves as its own
mRNA - Translation into enzymes
(including RNA polymerase,
structural proteins) - Assembly of and release similar to
DNA viruses - NOTE: host cell nucleus usually
NOT involved in viral replication
Virus Life Cycle
General Replication Differences:
Retroviruses (RNA)
(5)
- Virion contains reverse
transcriptase enzyme (RNA-
dependent DNA polymerase)
complementary DNA - DNA copy integrated into host cell
genome (“provirus”) - Provirus DNA is transcribed into
new viral genome RNA and mRNA
for translation into viral proteins - Completed viruses released via
budding - NOTE: retroviruses often replicate
without killing host cell
Herpesviruses
(2)
- DNA viruses
- Responsible for cold sores, genital ulceration, chickenpox, shingles,
etc
Herpesviruses
* Eight Types Can Infect Humans:
- Herpes simplex viruses (HSV-1 and HSV-2)
- Varicella-zoster virus (VZV/HHV-3)
- Epstein-Barr virus (EBV/HHV-4)
- Cytomegalovirus (CMV/HHV-5)
- Herpesvirus type 6 (HBLV/HHV-6)
- Herpesvirus type 7 (HHV-7)
- Kaposi’s sarcoma herpesvirus (KSHV/HHV-8)
Herpes Simplex Viruses (HSV-1 &
HSV-2)
* *Manifestations:
* HSV-1
(2)
* HSV-2
(1)
- Primary infection: pharyngitis,
gingivostomatitis - Recurrent infection: herpes labialis
- Typically genital manifestations
Herpes Simplex Viruses (HSV-1 &
HSV-2)
* Highly Contagious:
(3)
- Transmission via direct contact
- Sharing food utensils/drinks
- Oral-genital contact
Herpes Simplex Viruses (HSV-1 &
HSV-2)* HSV Development
Exposure
Primary Infection
Latency
Reactivation
Exposure
Entry typically via direct contact
with infected person’s:
* Skin
* Mucous membranes
* Bodily fluids
Primary
Infection
Clinical illness may occur
Virus travels to nerve
ganglia and establishes
latency
Latency
Virus remains inactive/dormant,
but still present within nerve
cells
No symptoms
Reactivation
Virus travels to
skin or mucous
membranes:
* Cold sores
* Fever blisters
* Genital
lesions
Herpes Simplex Viruses (HSV-1 &
HSV-2)
* Potential Triggers for Reactivation:
(5)
- Immunosuppression
- Stress
- Sunlight
- Fever
- Trauma to area of primary infection
- Dental procedures; extraction
- Lip injury
Herpes Simplex Viruses (HSV-1 &
HSV-2)
Prodromal symptoms: (3)
pain, tingling, burning
Herpes
Simplex
Viruses
(HSV-1 &
HSV-2)
Treatment
(5)
Acyclovir (Zovirax)
* Valacyclovir (Valtrex)
* Penciclovir (Denavir)
* Famciclovir (Famvir)
* Docosanol (Abreva)
Herpes
Simplex
Viruses
(HSV-1 &
HSV-2)
Therapeutic management considerations:
(4)
- Primary vs reactivated infection
- Severity
- Site of infection
- Frequency of recurrences
Herpes Simplex Viruses: Therapeutics
Acyclovir (Zovirax)
*Preparation(s)
Oral: capsule (200 mg), tablet (400 or 800 mg), suspension (200 mg/5
mL)
Topical: 5% cream, 5% ointment
Herpes Simplex Viruses: Therapeutics
Acyclovir (Zovirax)
Mechanism of Action
Converted to acyclovir monophosphate (via thymidine kinase) and
triphosphate (via other enzymes) to target viral DNA synthesis
Monophosphate: incorporates into viral DNA chain termination
Triphosphate: competitive inhibition and inactivation of viral DNA
polymerase
Herpes Simplex Viruses: Therapeutics
Acyclovir (Zovirax)
Dosing (Adult)
Primary infection: acyclovir 400 mg PO 3x/day OR 200 mg PO 5x/day x 7-
10 days
Recurrent: Acyclovir 400 mg PO 3x/day x 5 days OR (if topical) Apply to
affected area topically 5x/day x 4 days
*Requires renal dose adjustment
Herpes Simplex Viruses: Therapeutics
Acyclovir (Zovirax)
Drug-Drug
Interaction(s)
Tizanidine
Herpes Simplex Viruses: Therapeutics
Acyclovir (Zovirax)
Adverse Effects
GI upset, malaise; Local pain (topical)
Valacyclovir (Valtrex)
*Preparation(s)
Oral: tablets (500 mg or 1000 mg)
Valacyclovir (Valtrex)
Mechanism of
Action
Prodrug which is rapidly converted to acyclovir
[See acyclovir MOA]
Valacyclovir (Valtrex)
Dosing (Adult)
Primary infection: valacyclovir 1 gram PO twice daily x 7-10 days
Recurrent: valacyclovir 2 grams PO 2x/day x 1 day
*Requires renal dose adjustment
Valacyclovir (Valtrex)
Drug-Drug
Interaction(s)
Tizanidine
Valacyclovir (Valtrex)
Adverse Effects
GI upset, headache
Valacyclovir (Valtrex)
Miscellaneous
Following maternal administration of valacyclovir, acyclovir is detectable in cord
blood and amniotic fluid; Pregnancy Category B
Higher than serum concentrations present in breast milk (caution)
DDIs: Acyclovir and Valacyclovir
Oral acyclovir and oral valacyclovir are weak –inhibitors
May increase serum concentration of —
Risk Rating:
CYP1A2
tizanidine
D Consider therapy modification
If therapy cannot be modified, monitor for increased adverse
reactions of tizanidine
(3)
- Hypotension
- Bradycardia
- Drowsiness
Thymidine Kinase
- Phosphorylates thymidine and other nucleoside
analogs - Herpesviruses have their OWN viral thymidine kinase
(TK) enzyme which works much more efficiently than
human TK - Preferentially phosphorylates antiherpetic drugs (e.g.
acyclovir) - Human cellular TK is much less likely to be able to
activate antiherpetic drugs - Drug remains inactive in normal uninfected cells
- Effective HSV treatment with minimal side effects to
the host - Viral thymidine kinase is the key to selective toxicity
Penciclovir: Efficacy
- Penciclovir 1% cream vs. matching
placebo cream - 3,057 immunocompetent patients
initiated treatment - Penciclovir: n = 1,516
- Placebo: n = 1,541
- Penciclovir recipients’ lesions healed
31% faster than placebo patients - HR 1.31; 95% CI (1.20 to 1.42); P=
0.0001) - Significant benefit when initiated in
both early (p = 0.001) and later (p =
0.0055) stages - Effective at speeding healing and
pain relief by ~1 day
Orthomyxoviruses
(3)
- RNA viruses
- Responsible for causing influenza
- Four generate infect vertebrates
- Four generate infect vertebrates
- Influenza A (most virulent, “seasonal flu”)
- Influenza B (“seasonal flu”)
- Influenza C (milder)
- Influenza D (infect swine, cattle, sheep – NOT humans)
Influenza A
* Divided into subtypes based
on surface proteins:
(2)
* Subtypes N1 - N11
* Subtypes known to infect
humans:
(2)
* Known to cause …
- Hemagglutinin (HA or H)
- Subtypes H1 - H18
- Neuraminidase (NA or N)
- Hemagglutinin subtypes:
H1, H2, and H3 - Neuraminidase subtypes:
N1 and N2
global
influenza pandemics
Influenza A and B
(4)
- Cause acute viral respiratory disease or “seasonal flu”
- Affect individuals of all ages worldwide
- Primarily respiratory droplet transmission person-to-person
(sneezing, coughing, etc.) - Some airborne and indirect contact transmission
- Incubation period: average ~2 days (range 1-4 days)
Influenza A and B
* Manifestations (not comprehensive):
(2)
- Fever, nonproductive cough, myalgia, malaise, chills, sore
throat, nausea, congestion, headache, fatigue - Varies based on infecting strain and severity
Influenza A and B
* Management:
(2)
- Oseltamivir (Tamiflu)
- Baloxivir marboxil (Xofluza)
Influenza A and B
* Therapeutic management considerations:
(3)
- Treatment vs. post-exposure prophylaxis
- Severity
- Onset of symptoms (48-hour window)
Retroviruses
(2)
- RNA viruses
- Responsible for causing acquired immunodeficiency syndrome
(AIDS), T-cell leukemia
- Retroviruses with implications in Dentistry
- HIV-1
(2) - HIV-2
(2)
- Most common; higher rate of transmission
- Worldwide
- Also causes immune suppression; less virulent
- Endemic in West Africa
Human Immunodeficiency Virus
(HIV)
* Virus that causes HIV infection
(2)
- If left untreated, may caused AIDS (most advanced stage)
- Attacks and destroys immune system’s CD4 T-cells
Human Immunodeficiency Virus
(HIV)* Manifestations:
* Acute: (7)
* Range of severity
* Median duration:
fever, fatigue, myalgia, skin rash (commonly with
trunk involvement), headache, pharyngitis, cervical
adenopathy
~14 days
HIV Transmission
(4)
- Anal or vaginal intercourse
- Oral sexual activity
- Exposure to infected blood
- Sharing of needles or syringes (injecting drugs,
tattooing, etc) - Accidental percutaneous injury
- Pregnancy, childbirth, or breastfeeding
Post-Exposure Prophylaxis (PEP)
Treatment to prevent HIV infection following potential exposure
Indications:
(2)
Administer ASAP - Ideally within – hours of exposure
Example regimens:
* Bictegravir + TAF + Emtricitabine
* Dolutegravir + TAF + Emtricitabine
* Dolutegravir + TDF + Emtricitabine
- Occupational exposure
- Non-occupational exposure:
72
Pre-Exposure Prophylaxis (PrEP)
- Preventative strategy to prevent transmission of HIV for those who
are at high risk but are currently HIV negative
Pre-Exposure Prophylaxis (PrEP)
* Risk Factors (NOT comprehensive):
(3)
- Those in a sexual relationship with HIV-positive partner
- Drug-using behaviors
- Recent sexually transmitted infections (e.g. syphilis, gonorrhea)
Pre-Exposure Prophylaxis (PrEP)
* Pre-treatment evaluation and testing:
(2)
- HIV, HBV, STI testing
- Renal function, osteoporosis, lipid testing
Pre-Exposure Prophylaxis (PrEP)
* Example Regimens:
(2)
- Tenofovir disoproxil fumarate-emtricitabine
- Tenofovir alafenamide-emtricitabine
Reduction of HIV Transmission
(6)
Antiretroviral
Therapy (ART)
and Viral
Suppression
Post-exposure
prophylaxis
Pre-exposure
prophylaxis
(PrEP)
Testing and early
diagnosis
Safe sex
practices
Avoid sharing
needles/syringes
HIV Life Cycle
(7)
- Binding
- Fusion
- Reverse Transcription
- Integration
- Replication
- Assembly
- Budding
Antiretroviral Therapy (ART)
(4)
- The routine use of a combination of HIV medication classes to
treat or prevent HIV - Recommended for all patients with HIV, regardless of CD4
count - NOT a cure
- Potential for resistance; adherence is KEY
ART
* Goals:
(4)
- Reduce morbidity and mortality associated with HIV
- Restore and preserve immunologic function
- Suppress plasma HIV viral load
- Prevent HIV transmission
HIV Drug Classes
(9)
- Nucleoside Reverse Transcriptase Inhibitors (NRTI)
- Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)
- Protease Inhibitors (PI)
- Integrase Strand Transfer Inhibitors (INSTI)
- Fusion Inhibitors
- CCR5 Antagonists
- Attachment Inhibitors
- Post-Attachment Inhibitors
- Capsid Inhibitors
NRTIs
* Nucleoside reverse Transcriptase Inhibitors
* MOA:
block and prevent reverse transcriptase enzyme from accurately
copying its RNA into complementary DNA( cDNA)
NRTIs
Adverse Effects:
(2)
- Common: N/V/D, upset stomach, headache
- Serious: bone marrow suppression (and associated increased risk of
bleeding or oral ulcers), peripheral neuropathy, pancreatitis,
lipoatrophy, hepatic steatosis, lactic acidosis
NRTIs
* Contraindications:
- Abacavir and moderate or severe hepatic insufficiency
NRTIs
* DDIs: Minimal
- Tenofovir products and high-dose or multiple NSAIDs May enhance
nephrotoxic effects of tenofovir - Category D: Consider Therapy Modification
NRTIs
* Examples:
- Abacavir (Ziagen)
- Abacavir-Lamivudine (Epzicom)
- Abacavir-Lamivudine-Zidovudine (Trizivir)
- Didanosine (Videx)
- Emtricitabine (Emtriva)
- Lamivudine (Epivir)
- Stavudine (Zerit)
- Tenofovir alafenamide-Emtricitabine (Descovy)
- Tenofovir disoproxil fumarate (Viread)
- Tenofvoir disoproxil fumarate-Emtricitabine (Truvada)
- Zidovudine (Retrovir)
- Zidovudine-Lamivudine (Combivir)
NNRTIs
* Non-nucleoside reverse transcriptase inhibitors
* MOA:
block and prevent reverse transcriptase enzyme from accurately
copying its RNA into complementary DNA (cDNA)
* Binding occurs in a pocket further away from active site
NNRTIs
* Adverse Effects:
(3)
- Common: rash, GI upset, elevated liver enzymes, metabolic changes
(cholesterol) - Sedation (benzodiazepines, barbiturates, opioids, etc) used in dental procedures
may need adjustment if liver toxicity is present - Serious: QT prolongation and neurologic/psychiatric side effects with efavirenz
and rilpivirine
- Rilpivirine must be administered with a full meal to
increase absorption
NNRTIs
* Examples:
(5)
- Doravirine (Pifeltro)
- Efavirenz (Sustiva)
- Etravirine (Intelence)
- Nevirapine (Viramune)
- Rilpivirine (Edurant)
Protease Inhibitors (PIs)
* MOA:
block protease enzyme to prevent new (immature) HIV from
becoming a mature virus that can infect other CD4 cells
* CYP3A4 substrates
* Often “boosted” by pharmacokinetic enhancers
PIs
* Adverse Effects:
(2)
- Many are agent-specific
- Class effects: insulin resistance, hyperglycemia, diabetes, hyperlipidemia,
lipodystrophy, hepatotoxicity, increased risk of bleeding, PR interval
prolongation
PIs
* Oral adverse effects:
(3)
- Fosamprenavir - Perioral numbness (lips), taste changes
- Atazanavir - Dental (tooth) pain, taste changes
- Ritonavir - Taste changes
Protease Inhibitors
* Examples:
- Atazanavir (Reyataz)
- Atazanavir-Cobicistat (Evotaz)
- Darunavir (Prezista)
- Darunavir-Cobicistat (Prezcobix)
- Fosamprenavir (Lexiva)
- Indinavir (Crixivan)
- Lopinavir-Ritonavir (Kaletra)
- Nelfinavir (Viracept)
- Saquinavir (Invirase)
- Tipranavir (Aptivus)
INSTIs
* Integrase stand transfer inhibitors
* MOA:
block integrase enzyme, preventing insertion of HIV viral DNA into the
DNA of the host CD4 cell, thus preventing replication
INSTIs
* Adverse Effects:
- Generally well tolerated
- Increased weight gain, insomnia, dizziness
- Pertinent adverse effects related to dentistry:
- Osteopenia/osteoporosis
- Xerostomia (dry mouth)
- Oral ulcers, mucosal irritation
- Altered taste
- Increased risk of bleeding
INSTIs: DDIs
- Raltegravir PLUS:
- Proton pump inhibitors (omeprazole, pantoprazole, etc) may
increase concentrations of raltegravir - Category B: No Action Needed
INSTIs
* Examples:
- Cabotegravir (Apretude)
- Dolutegravir (Tivicay)
- Raltegravir (Isentress)
- Elvitegravir (within combination products)
- Bictegravir (within combination products)
Other Drug Classes
* CCR5 Antagonists
* Example:
* Attachment Inhibitors
* Example:
* Post-Attachment Inhibitors
* Example:
* Capsid Inhibitors
* Example:
Maraviroc (Selzentry)
Fostemsavir (Rukobia)
Ibalizumab-uiyk (Trogarzo)
Lenacapavir (Sunlenca)
Pharmacokinetic Enhancers
* MOA:
Inhibit enzymes (CYP3A4) that metabolize other antiretroviral drugs
to “boost” concentrations and effectiveness
* ↑ concentration, ↑ PK profile, ↑ effectiveness
* Allows for ↓ doses used and ↓ associated drug toxicity
Pharmacokinetic Enhancers
* Adverse Effects:
- Common: GI upset
- Pertinent adverse effects in dentistry:
- Ritonavir: Metallic or bitter taste, oral ulcers or inflammation, perioral numbness/tingling,
increased bleeding risk (if DDI with anticoagulants) - Dry mouth
Pharmacokinetic Enhancers
* Examples:
- Ritonavir (Norvir)
- Cobicistat (Tybost)
Single-Tablet Regimens
* Examples:
- Bictegravir-TAF-Emtricitabine (Biktarvy)
- Darunavir-Cobicistat-TAF-Emtricitabine (Symtuza)
- Dolutegravir-Abacavir-Lamivudine (Triumeq)
- Dolutegravir-Lamivudine (Dovato)
- Dolutegravir-Rilpivirine (Juluca)
- Doravirine-TDF-Lamivudine (Delstrigo)
- Efavirenz-TDF-Emtricitabine (Atripla)
- Elvitegravir-Cobicistat-TAF-Emtricitabine (Genvoya)
- Elvitegravir-Cobicistat-TDF-Emtricitabine (Stribild)
- Rilpivirine-TAF-Emtricitabine (Odefsey)
- Rilpivirine-TDF-Emtricitabine (Complera)
