Review of Pharmacology - 9E (2015)

Review of Pharmacology
Chemotherapy B: Antimicrobials for Specific Conditions
Abacavir increases the risk of
myocardial infarction particularly
in patients having HLA B*5701
allele. Testing of this allele
should be done before starting
abacavir.
Drugs having activity against
both HIV and HBV
L – Lamivudine
E – Emtricitabine
T – Tenofovir
• Zalcitabine has unique toxicity to cause oral ulceration and stomatitis It is least effective
NRTI. It also result in peripheral neuropathy and pancreatitis.
• Abacavir increases the risk of myocardial infarction. It may cause severe hypersensitivity
reaction particularly in patients having HLA B*5701 allele. Testing of this
allcle should be done before starting abacavir.
• All NRTIs are excreted by the kidney (require dose adjustment in renal failure)
except abacavir which gets metabolized by alcohol dehydrogenase. Hypersensitivity is
the major adverse reaction of abavacir (should not be restarted).
• All NRTIs may cause lactic acidosis, hepatomegaly and steatosis by inhibiting mammalian
mitochondrial DNA polymerase. Risk factors are obesity and pre-existing liver
dysfunction.
b. Nucleotide RTI
Tenofovir is a nucleotide and does not require bioactivation by kinases. It is excreted mainly by
the kidney and renal impairment including a Fanconi like syndrome with hypohosphatemia may
occur. Oral bioavailability of tenofovir increases with meals (decreased for other NRTIs). It is well
tolerated and flatulence is only significant side effect. It is also effective against hepatitis B.
Note:
• Lamivudine, emtricitabine and tenofovir have activity against hepatitis B virus.
• Thymidine analog NRTIs (zidovudine and stavudine) and protease inhibitors are associated with
lipodystrophy syndrome characterized by hyperlipidemia, hypercholesterolemia, glucose intolerance
and fat re-distribution.
• Strains of HIV resistant to lamivudine (due to MI84V substitution) appear to have enhanced sensitivity
to other NRTIs.
• Zidovudine is most likely to cause anemia whereas zidovudine and didanosine are most likely to
cause neutropenia
• Stavudine (followed by zidovudine) are most likely to cause lipoatrophy
• Zidovudine and didanosine are most likely to cause peripheral neuropathy.
Didanosine has maximum risk of causing pancreatitis
c. NNRTIs
These drugs inhibit reverse transcriptase by acting at a site (allosteric site) different from
that of NRTIs. These are selective for HIV-1 and have no activity against HIV-2. Resistance to
these drugs develops very rapidly. Drugs in this group are efavirenz, nevirapine, etravirine and
delavirdine. Skin rash is an adverse effect of all of these drugs and nevirapine can cause Steven
Johnson syndrome and toxic epidermal necrolysis. Delavirdine and efavirenz should be avoided in
first trimester of pregnancy. Nevirapine is used in pregnancy to prevent vertical transmission
(single oral dose of 200 mg to mother during labour and single 2 mg/kg oral dose to neonate
within 3 days after birth). It decreases transmission to 13% as compared to 21.5% by zidovudine.
However because of hepatotoxicity and less effectiveness of nivaprine, it is not preferred for this
indication. Efavirenz is neurotoxic and side effects may range from lack of concentration to
vivid dreams to delusions and mania.
• Etravirine is a recently approved NNRTI. This second generation NNRTI is
effective against HIV resistant to first generation NNRTI (Efavirenz, nevirapine and
delavirdine). Another recently approved second generation NNRT1 is rilpivirine.
Note:
• NNRTI donot cause lipodystrophy
• Nevirapine and efavirenz are CYP 450 enzyme inducers whereas delavirdine is enzyme inhibitor.
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Protease inhibitors
Protease helps in the maturation of infectious virions and inhibitors of this enzyme can be used in
the treatment of HIV infections (by inhibiting the post-translational modification of viral proteins).
• Oral bioavailability of indinavir is decreased by food. It can cause crystalluria and
kidney stones. To prevent renal damage, good hydration must be maintained. It can
also cause asymptomatic hyperbilirubinemia.
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