T2 - Micro - Virology - Pharm 2 - Hiv Drugs

Front 1

what's a typical HAART cocktail consist of?

Back 1

two nucleoside analogue reverse transcriptase inhibitors (NRTI) and either a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor.

Front 2

when do we begin HIV treatment?

Back 2

debated - but definitely before the CD4 count goes below 250, most say before 350.

note that if it's started at 350, median survival is 32 years.

Front 3

reverse transcriptase inhibitors - what step do they stop?

specifically, how do nucleoside analogues work?

what are the major side effects?

Back 3

reverse transcription. no double stranded DNA is produced, so nothing can move to the nucleus and get incorporated into the host chromosome.

note there are two kinds - nucleoside and non-nucleoside.

the nucleosides work by COMPETATIVE INHIBITION - for the RT enzyme. Out compete the dNTP's that are natural, lead to CHAIN TERMINATION.

when talking about nucleoside reverse transcriptase inhibitors, immediately think myelosuppression - neutropenia, severe anemia, lactic acidosis and severe hepatomegaly. Recall that RT inhibitors also screw up mitochondrial replication, leading to screwed up muscles and WBC's.

NOTE - nucleoSide inhibitors have 3 activation steps done by host nucleoside kinases, nucleoTide inhibitors require 2

Front 4

NRTI's - what do they require?

Back 4

the nucleoside analogues require 3 phosphorylations by host nucleoside kinases.

nucleoTide analogues require 2 phosphorylations by host kinases.

Front 5

what are the main NRTI side effects?

Back 5

they can inhibit mitochondrial DNA synthesis (polymerase gamma) - this leads to mitochondrial toxicity = MYOPATHY.

don't forget neutropenia, severe anemia, hepatosplenomegly,
cardiomyopathy is seen most often with AZT.

Front 6

what are our NRTI's:

name the side effects again:

Back 6

zidovudine (AZT)

stavudine (D4T)

lamivudine

didanosine (DDI)

(Z-LSD)

remember that side effects include myopathy, neutropenia and severe anemia, lactic acidosis and severe hepatomegaly.

Front 7

First NRTI - Zidovudine - details:

Back 7

aka AZT.

oral. renal clearance.

No Zidovudine + Stavudine combo = antagonism.

Front 8

Lamivudine?

Back 8

aka 3TC.

nothing underlined.

Front 9

Stavudine?

Back 9

(D4T) - causes DOSE RELATED PERIPHERAL NEUROPATHY.

do not give with AZT (zidovudine)

Front 10

Didanosine?

Back 10

causes FATAL and NONFATAL Pancreatitis.

Front 11

What's our NtRTI?

Back 11

nucleoTide reverse transcriptase inhibitor = TENOFOVIR.
advantage - because it's a "tide", the first, rate limiting step doesn't have to happen. so it works faster.

NO BBB CROSSING.

underlined things - causes lactic acidosis, fanconi syndrome, protenuria, tubular necrosis.

does not cross BBB.

good in resistant strains, especially lamivudine.

also available as part of a single pill cocktail - -plus emtrictabine.

also with atazanavir + ritonavir + tenofir.

also atripla is tenofovir plus emtrictabine plus efavirenz.

Front 12

How do NNRTI's work? Side effects? Clearance?

Back 12

non-nucleoside reverse transcriptase inhibitors - these use NON-COMPETATIVE inhibition of reverse transcriptase. DO NOT REQUIRE ACTIVATION. Bind directly to HIV-1 RT.

can cause HYPERSENSITIVITY, with serious and life threatening skin rashes (stevens johnson!) - all underlined.

note - no activity towards HIV-2! Long halflife.

Generally cleared by P450.

Front 13

which are our NNRTI's?

Back 13

Nevirapine, Efavirenz, and Delaviradine. NED.

Front 14

Nevirapine - go

Back 14

underlined:
fatal hepatoxcisity

rash.

remember that the NNRTIs can cause hypersensitivity and stevens johnson - this is no exception

also the fact that it induces P450 and also is eaten by it, means that it's killing itself.

Remember that p450 here is associated with liver toxicity.

substrate of and inducer of p450.

Nevirapine is given in pregnancy in africa - remember the other NNRTI's are teratogenic, this is the only safe one.

Front 15

Efavirenz - go

Back 15

induces p450. No pregnancy use! don't use with saquinavir.

psychiatric symptoms and teratogenic.

Front 16

Delaviridne - go

Back 16

no use with pregnancy.

teratogenic. Liver function abnormalities.

Inhibits p450 (rest induce)

eaten up by p450 too.

don't forget to NOT GIVE WITH ANTACIDS.

Front 17

protease inhibitors - how do they work? Drugs? How are they cleared? Side effects?

Back 17

prevent large precursor protein molecule from being cleaved - get faulty viral packages.

ALL THIS CLASS IS EATEN UP BY P450.

Also can inhibit.

drugs include: saquinavir, indinavir, nelfinavir, amprenavir, lopinavir, plus ritonavir, and maybe atazanavir, darunavir


Protease inhibitors are our bad for diabetics form - they cause lipodystrophy, fat redistribution, buffalo humps, bleeding, central obesity.

Front 18

Indinavir?

Back 18

not urine soluble, can crystalize and cause KIDNEY STONES.

substrate/inhibitor of p450.

Front 19

Lopinavir/Ritonavir?

Back 19

Ritonavir inhibits p450 SO much that it's often given with these other drugs. it's a crappy antiviral, but it definitely increases the concentration and effectiveness of the others. Given with lopinavir commonly.

given at low dose (at high dose, ritonavir has the worst side effects).

works with all PI's, except nelfinavir.

Front 20

Saquinavir?

Back 20

underlined - also given with ritonavir to keep its concentration high.

Front 21

how do entry inhibitors work? what are our drugs?

Back 21

two classes - one that stops entry into CD4 cells by messing with fusion of the two membranes.

and also can screw with the binding of COreceptors (CCR5 only one right now).

one in each class - fusion inhibitor = Enfuvirtide

CCr5 inhibitor = Maraviroc

Front 22

Enfuvirtide?

Back 22

Kept only for salvage therapy. Expensive. Need to be resistant to NRTI and PI. Sub Q injection.

Front 23

Maraviroc?

Back 23

taken twice daily, MUST be taken with other HIV drugs. Kept for people with resistant strains.

only good against virus that uses the CCr5 coreceptor.

Front 24

Integrase inhibitor?

Back 24

Rategravir - not in drug list? salvage therapy. It gets viral load down fast.

Front 25

what are our drug complications, generally?

Back 25

NRTI's cause mito toxicity, PI's cause insulin resistance syndrome.

HAART's linked with lipodystrophy syndrome and cardiovascular disease.

lipodystrophy syndrome = lipoatrophy and hyperadiposity - loss and gain of fat.

heart disease - high LDL and low HDL happens on drugs. PI's main culprits.

all associated with hepatitis.

Front 26

what if someone gets preggers? what about teenagers?

Back 26

try to avoid new treatment for 10-12 weeks.

NEVER USE EFAVIRENZ ever throughout pregnancy.

teenagers use tanner staging.

Front 27

what do you do for people who fail therapy?

Back 27

salvage - try to use as many new drugs as possible. Or, mega haart - with five drugs.