10. antiviral and antiparasitic agents

varicella-zoster (ZVZ), herpes virus (HSV)

topical, PO, IV

renal excretion

PO + topical -> well tolerated

IV-> risk of nephrotoxicity (neurologic toxicity if renal impaired)

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

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)

inhibition of DNA replication -> inhibit viral replication

kind of same as acyclovir (prodrug as well)

needs triphosphorylation

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

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

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

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

T1/2 -> 6-12 days

PO

hemolytic anemia -> 10-13% patients, onset 1-2 wks, monitor Hb

fetal injury -> fetal death + malformations

protease inhibitor, NS5A inhibitor, NS5B inhibitor -> inhibit viral replication

stops protein synthesis at multiple steps

NS5A: translation

NS5B: RNA replication

CYP3A4 metabolism

PO

common: headaches, fatigue

serious: hepatotoxicity, skin hypersensitivity reactions

interferon alfa: higher toxicity + efficacy, more expensive

nucleoside analog: high relapse rate, requires post treatment monitoring

treat only high risk patients: moderate/advanced hepatic fibrosis, reduces risk of toxicity, cost + resistance development

hep B, HIV

PO

high relapse rate + resistance, serious: pancreatitis, lactic acidosis

very well tolerated

renal (decreased if renal impaired)

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

neuraminidase tetramer (NA)

haemagglutinin most antigenic trimer (HA)

ion channel tetramer (M2)

antigenic shift: when protein subtypes specific for certain species change/combine and infect humans -> hard to have drugs ready for new strains

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

influenza: Tx + prophylaxis

PO

common: nausea, vomiting, serious: anaphylaxis, resistance development (discontinue before flu shot)

renal

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

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

CD4 (Tcells)

CCR5/CXCR4 (macrophages)

no cure, it is to keep the pt in the clinical latency stage, they can stay like this for life actually

rapid replication rate -> high reverse transcriptase error rate -> rapid mutation -> drug resistance -> antiretroviral tx similar strategy as for TB tx

drugs that inhibits HIV enzymes (NRTIs + NNRTIs + protease inhibitors)

drugs that block entry into cells

PO available

relatively long half-life (10+ hours) (except enfuvirtide)

drug interaction warning: P450 induction/inhibition, additive ADRs, interactions w/antimicrobial Rx

fusion inhibitors

prevents viral entry: when virus tries to get inside cell, it prevents fusion of protein of cell membrane

injection site reactions

unknown

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

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

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

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

protease inhibitor

prevents viral assembly: inhibit last step of breaking down protein to form new baby virus

hyperglycemia/diabetes exacerbation

many P450 inhibitors

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

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

CD4 T cell counts

guides initiation/modification to ART regimen

healthy range around 500-1600 cells/mm3

elevation post initiation indicates efficient ART

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

start it REGARDLESS of clinical phase or CD4 count

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

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)

initiate therapy ASAP

accelerated clinical course (increased risk of toxicity and opportunistic infections)

similar therapeutic regimen + goals

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

TB, pneumocystis pneumonia, herpes simplex virus, cytomegalovirus retinis, candidasis

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)

much cheaper than lifetime ART + ART is not available everywhere

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

it is on the rise

adults: azithromycin or doxycycline

infants: eryhtromycin

rapid resistance development !!

preferred: cerftriaxone IM + azythromycin or doxycycline PO

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

acyclovir (Sx management only)

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

superficial mycoses -> treated w/ OTC

sytemic mycoses -> occur most when immunocompromised, Tx characterized by: high resistance, prolonged therapy, increased toxicity

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

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

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

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

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

inhibits ergosterol synthesis

inhibits growth + kills fungi

broad -> systemic + superficial mycoses

alternative to amphotericin B: less toxicity + PO

cardiac suppressions -> decrease inotropic action

hepatotoxicity -> very rare

CYP3A4 inhibition -> frequent interactions (digoxin, warfarin...)

vivax malaria -> mild Sx but high relapse rate (hypnozoites hidden in liver)

falciparum malaria -> severe Sx but no relapse risk

easy to kill

hard to kill

do not respond to current Rx

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)

moderate attacks: chloroquine

severe attacks: IV quinidine gluconate

relapse prevention: primaquine (P vivax only)

prophylaxis: chloroquine

moderate attacks: artemether/lumefantrine

severe attacks: IV quinidine gluconate

relapse prevention: primaquine (P vivax only)

prophylaxis: atovaquone/proguanil

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

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)

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

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

actions/uses: organophosphate cholinesterase inhibitor

kills lice + eggs

kinetics: harmless since quickly metabolized

adverse effects: bad smell + mild scalp irritation

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

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