what are therapeutic uses of acyclovir? administration? excretion? adverse reactions?
varicella-zoster (ZVZ), herpes virus (HSV)
topical, PO, IV
renal excretion
PO + topical -> well tolerated
IV-> risk of nephrotoxicity (neurologic toxicity if renal impaired)
what is mechanism of action of acyclovir?
inhibition of DNA replication -> inhibits viral replication
acyclovir is a prodrug, so it has to be activated through triphosphorylation
thymidine kinase adds the first P, and this can only be performed by virus cells NOT healthy cells
then there is cellular kinase to add 2 other groups of P
acyclovir + 3Ps incorporates itself within replicating DNA strands of virus to stop replication
what are therapeutic uses of ganciclovir? administration? excretion? adverse reactions?
cytomegalovirus infections (prevention + tx) -> immunocompromised pt + high relapse risk pt
IV -> low oral bioavailability
renal -> decrease dose if renal impaired
higher toxicity -> granulocytopenia and thrombocytopenia (monitor neutrophil + platelets) + teratogenic (avoid pregnancy 90 days post tx)
what is mechanism of action of ganciclovir?
inhibition of DNA replication -> inhibit viral replication
kind of same as acyclovir (prodrug as well)
needs triphosphorylation
what is the goal of chronic hep C therapy? what is old regimen vs new one?
cure the infection !!!
interferon-Alfa + ribavirin (always in combo) -> higher toxicity/lower efficacy
direct acting antivirals (DAAs): NS3/4A protease inhibitors + NS5A inhibitors + NS5B inhibitors (always in combo) -> lower toxicity + higher efficiency
what is mechanism of action of interferon alfa?
block viral entry + block mRNA synthesis + block assembly/release -> inhibit viral replication
when it binds to receptors, it induces changes in DNA transcription and translation -> formation of certain proteins that help fighting off viral infection
MAYBE look this up
what is efficacy interferon alfa? administration? adverse reactions?
30-40% normalize 1-year HCV-RNA, high relapse rate, SVR in 5-15% pt
IV (it is a protein, would be digested by stomach acid)
conventional formulation: 3x/week, short T 1/2
long acting formulation: 1x/week, long T1/2, higher efficacy/higher toxicity
high toxicity, flu-like syndrome (50%), neuropsychiatric effects
what is mechanism of action of ribavirin?
nucleoside analog with various actions -> inhibit viral replication (always combined to IFN-Alfa)
it can integrate itself within hep C virus -> causes mutations, can block replication....
MAYBE look this up
what is kinetics ribavirin? administration? adverse reactions?
T1/2 -> 6-12 days
PO
hemolytic anemia -> 10-13% patients, onset 1-2 wks, monitor Hb
fetal injury -> fetal death + malformations
what is mechanism of action of direct acting antivirals?
protease inhibitor, NS5A inhibitor, NS5B inhibitor -> inhibit viral replication
stops protein synthesis at multiple steps
NS5A: translation
NS5B: RNA replication
what is kinetics of direct acting antivirals? administration? adverse reactions?
CYP3A4 metabolism
PO
common: headaches, fatigue
serious: hepatotoxicity, skin hypersensitivity reactions
what are 2 treatment plans of chronic hep B therapy?
interferon alfa: higher toxicity + efficacy, more expensive
nucleoside analog: high relapse rate, requires post treatment monitoring
what are the current recommendations for chronic hep B therapy?
treat only high risk patients: moderate/advanced hepatic fibrosis, reduces risk of toxicity, cost + resistance development
what is therapeutic use of nucleoside analogs? administration? adverse reactions? efficacy? excretion?
hep B, HIV
PO
high relapse rate + resistance, serious: pancreatitis, lactic acidosis
very well tolerated
renal (decreased if renal impaired)
what is mechanism of action of nucleoside analogs?
inhibits reverse transcriptase (enzyme that allows RNA to go back to DNA) -> inhibit viral replication
a prodrug, needs triphosphorylation
incorporates itself into DNA
look this up
what are the 3 major target sites of influenza virus?
neuraminidase tetramer (NA)
haemagglutinin most antigenic trimer (HA)
ion channel tetramer (M2)
what is influenza virus really susceptible to?
antigenic shift: when protein subtypes specific for certain species change/combine and infect humans -> hard to have drugs ready for new strains
what is mechanism of action of neuraminidase inhibitor: oseltamivir?
inhibition of virion release -> inhibit viral replication
virion are baby viruses copied inside infected cells, they need to assemble + exit cell to go infect elsewhere
oseltamivir inhibits NA protein which results in virion being stuck inside cell
what is therapeutic use of neuraminidase inhibitor: oseltamivir? administration? adverse reactions? excretion?
influenza: Tx + prophylaxis
PO
common: nausea, vomiting, serious: anaphylaxis, resistance development (discontinue before flu shot)
renal
what is therapeutic use of paxlovid? administration? efficacy? adverse effects?
SARS-Co-V-2 positive adults at high risk of severe complications
PO for 5 consecutive days, doses = 2x150mg nirmatrelvir + 100mg ritonavir
88% against hospitalization + death
best within 5 days of Sx onset
well tolerated
common: change in taste, GI distress, high risk of interaction with CYP3A4 drugs
inappropriate use: pre or post exposure prophylaxis, longer than 5 days, pregnancy
what is mechanism of action of paxlovid?
nirmatrelvir = protease inhibitor
ritonavir = inhibit nirmatrelvir metabolism (CYP3A4)
-> inhibit viral protein synthesis
nirmatrelvir only 1 that has effect on covid: blocks action of cysteine protease so mature protein cannot be made
ritonavir prevents CYP3A4 enzyme from breaking down nirmatrelvir
where does HIV attach itself?
CD4 (Tcells)
CCR5/CXCR4 (macrophages)
what is the goal of HIV therapy?
no cure, it is to keep the pt in the clinical latency stage, they can stay like this for life actually
what is the typical HIV clinical course?
rapid replication rate -> high reverse transcriptase error rate -> rapid mutation -> drug resistance -> antiretroviral tx similar strategy as for TB tx
what are 2 classifications of antiretroviral drugs (HIV drugs)?
drugs that inhibits HIV enzymes (NRTIs + NNRTIs + protease inhibitors)
drugs that block entry into cells
what are common kinetics of antiretroviral drugs?
PO available
relatively long half-life (10+ hours) (except enfuvirtide)
drug interaction warning: P450 induction/inhibition, additive ADRs, interactions w/antimicrobial Rx
efuvirtide: class? MoA? adverse reactions? significant interactions?
fusion inhibitors
prevents viral entry: when virus tries to get inside cell, it prevents fusion of protein of cell membrane
injection site reactions
unknown
maraviroc: class? MoA? adverse reactions? significant interactions?
CCR5 antagonists
prevents viral entry: inhibits binding of virus to CCR5 protein, useful for type of HIV that binds to CCR5
well tolerated, rare liver + cardiac toxicities
CYP3A4 metabolism
abacavir: class? MoA? adverse reactions? significant interactions?
nucleoside reverse transcriptase inhibitors (NRTI)
RNA-DNA conversion: blocks enzyme reverse transcriptase from switching HIV RNA to DNA
severe skin hypersensitivity reactions, screen for HLA-B*5701
alcohol
efavirenz: class? MoA? adverse reactions? significant interactions?
non-nucleoside reverse transcriptase inhibitors (NRRTI)
RNA-DNA: does not add itself within line of nucleosides to block additions it blocks from different site, stops enzyme from working at all
CNS related, severe rash, teratogenic
P450 interactions, increase warfarin, decrease oral contraceptives
raltegravir: class? MoA? adverse reactions? significant interactions?
integrase inhibitors
prevents viral replication: blocks activity of integrate enzyme which is responsible for getting virus DNA into our own DNA inside cell
best toxicity profile, rare liver impairments, insomnia, skin rash
less than others
saquinavir/ritonavir: class? MoA? adverse reactions? significant interactions?
protease inhibitor
prevents viral assembly: inhibit last step of breaking down protein to form new baby virus
hyperglycemia/diabetes exacerbation
many P450 inhibitors
what are the goals of ART?
cannot cure AIDS/HIV yet, can delay AIDS indefinitely if proper ART but is very intensive, difficult and very costly
goals:
max+long-term suppression of viral load
restoration/preservation of immune functions
improved QOL
reduction of HIV-related morbidities/mortality
prevention of HIV transmission
what is the lab test for ART viral suppression?
viral load count -> looking for viral load in blood
best clinical outcome predictor
viral load > 100,000 = poor prognosis
ART goal: decrease viral load as much as possible
minimum reached should be 4-5 months post-ART
what is the lab test for immune function?
CD4 T cell counts
guides initiation/modification to ART regimen
healthy range around 500-1600 cells/mm3
elevation post initiation indicates efficient ART
what are other lab tests useful for HIV?
HIV drug resistance: expensive/long/low-reliability, use only if failure of initial ART/slow progression/pregnant pt
allergy to abacavir: HLA-B*5701 (gene) screening (+ = allergy)
maraviroc indication: if HIV binds to CCR5
what indicates we should start treatment of HIV in adults/adolescents?
start it REGARDLESS of clinical phase or CD4 count
what is the progression of treatment of HIV in adolescents/adults?
ART initiation: 2 NRTIs + 1 integrase inhibitor (diff classes), choice depends on lab tests
Change regimen: ONLY if Tx failure or drug toxicity
adherence program: increase efficacy and decrease resistance
what are the treatment characteristics of HIV for pregnant pt?
ART benefits > risks of fetal harm
preconception counselling: education (contraception + HIV risks), optimize overall health status, monitor for opportunistic infections
during labour: C section at 38 weeks recommended + Zidovudine IV 3h prior (transmission risk around 0)
what are the treatment characteristics of HIV for infant/child pt?
initiate therapy ASAP
accelerated clinical course (increased risk of toxicity and opportunistic infections)
similar therapeutic regimen + goals
what are characteristics of opportunistic infections?
main cause of death of patients living with HIV
risk increases as CD4 count decreases (especially below 200)
ART decreases risk of infections, prolongs lifespan
what are examples of opportunistic infections?
TB, pneumocystis pneumonia, herpes simplex virus, cytomegalovirus retinis, candidasis
what is pre-exposure prophylaxis for HIV ? who is it recommended for ? what are the instructions?
tenofovir/emtricitabine combination (Truvada) -> decreases transmission by 44-73%
high risk individuals: known HIV + partner, sexually active in group with high HIV prevalence, injectable drug substance use disorder
when suspected/known exposure, initiate within 1-2h (no later than 72h)
regimen = Truvada + integrase inhibitor
risk of infection decrease ONLY (does not do anything else)
why is HIV vaccines a priority mission?
much cheaper than lifetime ART + ART is not available everywhere
what are obstacles of HIV vaccines?
HIV infects THE very cell boosted by vaccines -> could accelerate spread rather than prevent it
must stimulate BOTH humeral + cell-mediated immunity -> cell mediated vaccines = live vaccines
what is happening with STI incidence?
it is on the rise
what is treatment for chlamydia?
adults: azithromycin or doxycycline
infants: eryhtromycin
what is treatment for gonorrhoea?
rapid resistance development !!
preferred: cerftriaxone IM + azythromycin or doxycycline PO
what is treatment for syphilis?
all penicillins except if allergic -> cephalosporins
primary, secondary or latent: 1 IM penicillin G dose
tertiary or latent: penicillin G IM x3 doses
neuropyshilis: IV penicillin G for 10-14 days
what is treatment for herpes simplex?
acyclovir (Sx management only)
what is the goal of fungal pathogen treatment? what are the challenges?
target elements of fungal cells that human cells don't have
fungal cells more complex than bacteria/virus (more resistant)
more similar to human cells as evolved later
what are 2 types of fungal infections?
superficial mycoses -> treated w/ OTC
sytemic mycoses -> occur most when immunocompromised, Tx characterized by: high resistance, prolonged therapy, increased toxicity
what is MoA of amphotericin B? what is effect? what does it treat?
interacts hydrophobic ally with ergosterol found in fungal cell membrane which forms a pore which cause leakage of cellular contents
kills fungi
broad spectrum: progressive + systemic mycoses
what are adverse effects of amphotericin B?
toxicity is almost certain w/ IV (it is such a big polar molecule)
nephrotoxicity -> renal impairment in almost all patients -> minimize via 1L saline injection on admin days + monitor kidneys every 3-4 days
infusion reactions -> release of pro-inflammatory cytokines, frequent fever/nausea/headaches, Sx occur few hrs post admin
-> NSAIDs can decrease reaction but will increase nephrotoxicity
-> glucocorticoid for extreme cases but immunocompromised increased mycotic infections
what are characteristics of administration of amphotericin B? interactions?
very poor GI absorption so must be given IV
unknown excretion
very long T ½ -> detected 1 year post Tx
negative interaction: potentiation of other nephrotoxic drugs
postive interaction: potentiation of another anti fungal (flucytosine) -> can reduce dose of amphotericin B, reducing toxicity
what is MoA of flucytosine? what is effect? what does it treat?
prodrug activated by cytosine deaminase (absent from millions of cells so very selective for fungus) + amphotericin B helps it get through cell membrane
inhibition of DNA synthesis and cell division -> incorporates itself into DNA elongation chain
inhibits GROWTH (does not kill)
narrow -> candida species + C.neoformans
what are characteristics of administration of flucytosine? adverse reactions?
always combined w/ amphotericin B -> it increases flucytosine entry into fungal cells + combined to decrease resistance development
bone marrow suppression -> reversible thrombocytopenia
hepatotoxicity -> mild + reversible, serious liver damage rare
what is MoA of azoles? what is effect? what does it treat?
inhibits ergosterol synthesis
inhibits growth + kills fungi
broad -> systemic + superficial mycoses
alternative to amphotericin B: less toxicity + PO
what are adverse reactions of azoles? interactions?
cardiac suppressions -> decrease inotropic action
hepatotoxicity -> very rare
CYP3A4 inhibition -> frequent interactions (digoxin, warfarin...)
what are 2 types of malaria and their Sx + relapse?
vivax malaria -> mild Sx but high relapse rate (hypnozoites hidden in liver)
falciparum malaria -> severe Sx but no relapse risk
are blood spores easy to kill? hepatic parasites? sporozoites?
easy to kill
hard to kill
do not respond to current Rx
what are the therapeutic objectives of malaria therapy?
acute Tx: drugs target blood spores
relapse prevention: initiate post-dip from malarial region -> target hepatic hypnozoites
prophylaxis: before travelling to malarial region -> prevents only blood infection (not hepatic)
what are drug selections for malaria therapy if chloroquine sensitive?
moderate attacks: chloroquine
severe attacks: IV quinidine gluconate
relapse prevention: primaquine (P vivax only)
prophylaxis: chloroquine
what are drug selections for malaria therapy if chloroquine resistant?
moderate attacks: artemether/lumefantrine
severe attacks: IV quinidine gluconate
relapse prevention: primaquine (P vivax only)
prophylaxis: atovaquone/proguanil
what are characteristics of chloroquine?
best Rx vs malaria: 1st choice agent
has some antiviral + anti-inflammatory properties
MoA:
1. parasite digests host cells Hb to obtain essential AA
2. process releases heme (toxic to parasite)
3. parasite polymerizes heme to nontoxic hemozin
4. drug prevents polymerization, lysis of both parasite + RBC
kinetics: excellent Po absorption, 1x week
toxicity: well tolerated acute Tx, vision impairments (retinopathy), GI distress
what are characteristics of primaquine?
therapeutic usage: relapse prevention ONLY, targets P vivax in liver
MoA: inhibit ETC + increase ROS within parasite mitochondria
toxicity: G6PD-deficiency hemolysis (screen for mutation prior to Tx)
what are characteristics of artemether/lumefantrine?
therapeutic usage: best option vs multi drug resistant P.falciparum, combination prolong duration (decrease resistance development)
MoA: artemether -> prodrug that releases ROS species
lumefantrine -> works like chloroquine
kinetics: artemether -> fast absorption -> short T1/2
lumefantrine -> slow absorption -> long T1/2
toxicity: QT prolongation
what are characteristic of ectoparasiticide permethrin?
actions/uses: disrupt AP propagation via Na+ channel activation
1% formulation -> best for lice
5% -> best for scabies
resistance: inefficient in 5% of pt for head lice
kinetics: topical, <2% absorbed + quickly eliminated
adverse effects: only mild redness + itching
what are characteristic of ectoparasiticide malathion?
actions/uses: organophosphate cholinesterase inhibitor
kills lice + eggs
kinetics: harmless since quickly metabolized
adverse effects: bad smell + mild scalp irritation
what are different lice infestations + their characteristics?
head: human head-to-head transmission only
Tx: OTC 1% permethrin
remove dead + remaining live lice w/comb few days later
body: live on clothes/bedding, only skin to feed
Tx: wash clothes + bedding, apply permethrin or malathion
combination w/trimethoprim or sulfamethoxazole if resistance
pubic: sexual intercourse transmission
Tx: 1% permethrin or 0.5% malathion lotion
should wash clothes/bedding
what are scabies? Sx? Tx?
lesions caused by females burrowing eggs within skin
severe itching + scratching -> leads to secondary infections
transmission via intimate contact or infected clothing
Tx: wash all body w/permethrin 5% cream
itching persists 1-2 weeks post Tx