Anti-HIV Drugs
§
SUMMARY OF
DRUG TARGETS
& ACTION.
( FIG. 45.1 – A Textbook
of Clinical
Pharm., 4th ed. )
a)
Nucleoside analogue
reverse transcriptase inhibitors.
ZIDOVUDINE (
AZT, ZDV,
Azidothymidine )
§
Analogue of
thymidine in
which 3’-OH
replaced by
N3 group.
§
Only licensed
for symptomatic
HIV-1 infection.
§
Mechanism
of action :
1.
Anabolically phosphorylated to ZDV-triphosphate
( intracellular t½ : 2 – 3 h ),
a competitive
inhibitor of
HIV-1 Reverse
Transcriptase ( HIV-1
RT ).
2.
When incorporated
into nascent
viral DNA,
ZDV-TP causes
chain termination.
- Human nuclear
DNA polymerases 100 X less
sensitive to ZDV-TP
inhibition, producing selective
effect on
viral replication.
§
Pharmacokinetics
:
- > 90 % absorbed
from gut.
- Plasma elimination
t½ 1 – 2
h.
- 25 – 40 %
of dose
undergoes presystemic metabolism
in liver.
§
Contra-indications
: Bone marrow
suppression.
§
Side-effects :
Bone marrow
suppression &
myopathy in
long-term.
Nausea &
vomiting.
Melanonychia.
§
Drug
interactions : probenecid &
atovaquone decrease
ZDV renal
excretion.
ganciclovir
+ ZDV
profound bone
marrow suppression.
§
Used in
HIV +ve pregnant
women : reduces HIV
transmission to
foetus / neonate by 60 %.
§
Other drugs
in this
class e.g.
didanosine ( ddI ),
zalcitabine ( ddC ),
lamivudine ( 3TC )
or d4T :
- Useful for
AZT-intolerant / failing patients.
- When used
in combination with ZDV
reduces the development
of resistance to
treatment.
b)
Non-nucleoside analogue reverse
transcriptase inhibitors.
- Used in
combination with
ZDV ( synergistic
action ).
- HIV rapidly
develops resistance to them
if used
as monotherapy.
NEVIRAPINE
§
Dose increased gradually
to minimize
potential for
it to cause
skin rashes
which can
be dose
limiting. Cause
> 50 % reduction
in viral
load during
8 weeks
of therapy.
§
Mechanism
of action :
Inhibit HIV
RT by
binding to
allosteric site
& causing
non-competitive inhibition,
reducing viral
DNA production.
§
Pharmacokinetics
:
- > 90 % bioavailability
with t½ of 25 –
30 h.
- Induces hepatic
cytochrome P 450
3A4 which
metabolises it.
§
Contra-indications
: breast-feeding.
§
Side-effects :
Skin rashes.
Nausea.
Drowsiness.
§
Drug
interactions : Oral contraceptives, other HIV
inhibitors – ↑ their clearance
& ↓
effectiveness.
c)
Anti-HIV protease
inhibitors.
- Causes the
most rapid
reduction of
HIV-1 replication.
- Used in
combinations because of synergy
with anti-HIV
RT inhibitors & reduced
resistance.
- HIV resistance
to 1
agent usually
means cross-resistance
to others
in group.
- Others in
the group
e.g. saquinavir,
ritonavir, nelfinavir.
INDINAVIR
§
Mechanism
of action :
1.
Competitive inhibitor
of HIV protease, preventing
cleaving of
gag & gag-pol
protein precursors
encoded by
HIV genome
in acutely
& chronically
infected cells,
arresting maturation
& blocking
infectivity of
nascent virions.
2.
Weakly active
against human
aspartyl-proteases.
§
Pharmacokinetics
:
- 65 % bioavailability
with t½ of 2 h.
- 60 – 65 %
protein bound.
- Metabolised
in the
liver. However,
it DOES NOT induce
but inhibits
hepatic cytochrome
P 450 3A4.
§
Contra-indications
: breast-feeding.
§
Side-effects :
Gastrointestinal upset
( fewer than
other protease
inhibitors ).
Hyperglycaemia.
Hepatic dysfunction.
Fat redistribution.
§
Drug
interactions : midazolam – increased
prolonged sedation.
terfenadine – risk
of arrhythmias.
ritonavir – increased
indinavir [ plasma ]
& thus
greater toxicity.
sildenafil – possibly
increased sildenafil
[ plasma ].
Changes in
anti-HIV therapy
§
Required because
of treatment
failure, poor
compliance, adverse
effects, potential
drug interactions.
§
ZDV resistance
occurs rapidly
& to
greater degree
in later
stages of
AIDS. Reduction
in susceptibility
of HIV
RT correlate
with acquired
mutations in
the gene
for RT
protein.
§
Alternative anti-HIV
therapy combinations :
|
INITIAL
TREATMENT REGIMEN
|
ALTERNATIVE
TREATMENT REGIMEN
|
|
ZDV +
didanosine +
indinavir
|
d4T +
3TC +
Nelfinavir
Ritonavir
+ Saquinavir
+ 3TC
|
|
d4T +
3TC +
indinavir
|
ZDV +
didanosine +
Nelfinavir / Nevirapine
Ritonavir
+ Saquinavir
+ ZDV
|
Future treatments
§
Integrase enzyme
inhibitors.
§
Anti-HIV vaccine.
§
tat inhibitors.
§
Interferons.
Prognosis
§
60 % progress
to AIDS
within 10 yr
of seroconversion.
10 % remain
well.
§
Median survival
from AIDS
diagnosis is
2 years.
|