Most important drugs that are used in influenza,herpes and AIDS

1. M.A.A.Al-Maqrashi
Anti-viral Drug MOA Pharmacokinetics Uses A.E[Anti-Influenza]
Releaseinhibitors
oseltamivir
selectively inhibit
neuraminidase
- orally
- Prodrug that is hydrolyzed by liver to its active form.
- excreted unchanged in urine
- prophylactic for: Inf A &
B
- within 24 to 48 hours
after the infection:
decrease the intensity
and duration of
symptoms.
- vomiting: alleviated by
taking it with food.
zanamivir
- inhaled orally
- excreted unchanged in urine
- Irritation of the RT:
Not used by asthma pt.
Uncoatingblockers
amantadine
interfere with
the function of the viral
M2 protein
- orally
- crosses BBB
- excreted unchanged in the urine
- Treatment &
Prophylaxis for: Inf A
- Supplement with
vaccine until developing
Ab response
CNS related:
- insomnia
- Excitability
- ppt. to seizure &
psuchosis
- anorexia
- Rimantadine causes
fewer CNS reactions.
- Amantadine in
pregnancy: epilepsy &
renal dysfunction
rimantadine
- orally
- does not cross BBB
- metabolized by the liver
- metabolites and the parent drug are excreted in urine
[Anti-Herpes]
Acyclovir
DNApol.inhibitors
- competes with
deoxyguanosine
triphosphate
- incorporated into
the
viral DNA, causing
premature DNA
chain termination
- monophosphorylated
in the cell by the
herpesvirus-specific
enzyme thymidine kinase
converted to the di- and
triphosphate forms by the
host cell kinases.
- guanosine analog
- orally, IV or Topical
- penetrate BBB
- excreted mainly
unchanged in urine
- valacyclovir: acyclovir
prodrug with better oral
bioavailability
- HSV, HZV, VZV or EBV
- Drug of choice for HSV
encephalitis.
- commonly used in:
genital herpes infection
- Prophylaxis in
transplant pts.
- Topical: local irritation
& phlebitis
- Oral: diarrhea, nausea,
and vomiting
- transient renal
dysfunction
- Tremors & delirium
Ganciclovir
- Acyclovir analog
- only IV: poor oral
absorbtion
- crosses BBB
- excreted unchanged in
urine
- valganciclovir: G.prodrug
with better oral
bioavailability
- treatment of CMV
retinitis in
immunocompromised
pts
- CMV prophylaxis in
transplant pts.
-severe, dose-dependent
neutropenia.
- CNS toxicity
foscarnet
- competes with
deoxyguanosine
triphosphate
- Inorganic pyrophosphate.
- does not require activation.
- IV only: poor oral absorption
- enters bone matrix and it is slowly released
- excreted unchanged in urine
- immunocompromised
pts:
- CMV retinitis in
- acyclovir-resistant
HSV infections.
- headache & fever
- diarrhea & nausea
- nephrotoxicity &
seizure:
Hypo- Ca2+
, Mg2+
, K+
,
PO4
2-

2. M.A.A.Al-Maqrashi
[Anti-Retroviruses]
Binding/entryinh. Maraviroc
blocks the CCR5
coreceptor
[ test to determine viral
tropism is required]
- well absorbed orally
- metabolized by CYP3A4 enzyme:
Interactions with CYP3A4 inducers/inhibitors
- against HIV-1
- inconclusive data about
the effect against HIV-2
Well toleratedFusioninhibitors
Enfuvirtide
binds to gp41,
preventing the
conformational change &
fusion.
- polypeptide
- SC only
- clearance by proteolytic hydrolysis
- against HIV-1
- low activity against HIV-
2
related to the injection:
- pain
- erythema
- induration
- nodules
Rarely:
- Abscess
- hypersensitivity
Nucleoside
Reverse
Transcriptase
Inhibitor
[NRTIs]
- activated by
phosphorylation to tri-P
- Compete with normal
nucleosides 
incorporated within viral
DNA by RT  termination
of DNA chain
- well-absorbed orally
- metabolized in liver [not by CYP450 enzymes]
- renal excretion:
Dose adjustment in renal dysfunction [except.
Abacavir]
- inhibition of mitochondrial DNA polymerase cause:
- Mitochondrial toxicity
- Lactic acidosis
- Liver toxicity
[least in Lamivudine]
Zidovudine
[AZT]
- pyrimidine analog
- well-absorbed orally
- crosses BBB
- metabolized in liver
- metabolites excreted in urine
- prophylaxis in
individuals exposed to
HIV infection
- delay onset of
opportunistic infection
- prevent maternal/fetal
transmission
- Headache: common
- toxic to bone marrow
[Myelosuppression]
- anemia
- neutropenia.
- not combine with
stavudine: similar
toxicity
Abacavir
[ABC]
- guanosine analog
- well-absorbed orally
- metabolized in liver
- inactive metabolites excreted in urine
- GI upsets
- headache
- dizziness
- hypersensitivity [can be fatal]
presence of the HLA-B*5701 genetic
screening test
Non-Nucleoside
Reverse
Transcriptase
Inhibitor
[NNRTIs]
- not activated by phosphorylation
- highly selective, noncompetitive inhibitors of HIV-1 RT
bind to HIV RT at an allosteric hydrophobic site adjacent to the active site,
inducing a conformational change that results in enzyme inhibition.
- against RT of HIV-1 only
- not active against HIV-2

3. M.A.A.Al-Maqrashi
cont.[Anti-Retroviruses]
Efavirenz
[EFV]
- Orally
- better on an empty stomach to reduce adverse CNS effects.
- High PPB
- Long t0.5 > 40 hs  taken once/day
- crosses BBB
- Potent inducer of CYP450 enzymes.
- Hypersensitivity rash
- dizziness & headache
- vivid dreams
- dysphoria
- depression
- elevated liver enzymes
- not used in pregnancy  use Nevirapine
Integrase
Inhibitors
- inhibiting the insertion of proviral DNA into the host cell genome:
By ocuuping the active site of the enzyme is occupied  integration process is halted.
- chelation interactions with antacids resulting in significant reductions in bioavailability.
- not CYP450 substrate  minimal interaction
Well tolerated
Raltegravir
- not CYP450 substrate  minimal interaction
- evidence of viral replication despite ongoing antiretroviral drug therapy.
Esp. with treatment-experienced pts
Common:
- diarrhea
- nausea
- Rhabdomyolysis
- depression with
suicidal thoughts
Protease Inhibitors
reversible
inhibitors of the HIV-1
protease
(which is
the viral enzyme
responsible for cleavage of
the viral polyprotein into
structural / functional
prot.
- High-fat meals ↑the bioavailability of some PIs
Opposite effect with indinavir
- High PPB. Exp. Indinavir
- highly metabolized: substrates for the CYP3A4. & short
t0.5
Exp. Nelfinavir
Indinavir has shortest t0.5
- excreted in urine, mainly metabolites
- Dosage adjustments in renal & liver impairment.
-drug Interaction:
PIs are substrate & inhibitors for CYP450
- against HIV-1
- inconclusive data about
the effect against HIV-2
- common: nausea,
vomiting, and diarrhea
- chronic use:
1- Disturbances in
metabolism: DM,
↑TAG & cholesterol
2- Lipodystrophy:
fat redistribution
loss from extremities,
accumulation in
abdomen, breast and
the base of the neck
buffalo hump
- nephrolithiasis &
hyperbilirubinemia
Esp. indinavir
Ritonavir
- used as a pharmacokinetic enhancer or “booster” of other PIs.
- potent inhibitor of CYP3A  ↑ t0.5
- not affective with Nelfinavir