Ios 11 Exam 1 Dlp Kuma

Front 1

Name the guanosine analog anti-HIV drug

Back 1

abacavir (Ziagen®) - ABC

Front 2

How is abacavir Metabolised?

Back 2

98-99% metabolized in liver (alcohol dehydrogenase).

Front 3

What test should a patient test negative for before beginning abacavir?

Back 3

Pharmacogenetic test screens for predisposition (HLA-B5701) for Hypersensitivity reaction (~3-5%). Multi-symptom (rash, GI, pharyngitis, fever). If diagnosed, NEVER RECHALLENGE.

Front 4

What is the significance of low or high activity against mitochondrial DNA polymerase gamma and what level of activity does abacavir have?

Back 4

Activity against mitochondrial DNA polymerase gamma causes many side effects. The higher the activity the more prevalent the side effects.
Low activity versus mitochondrial DNA polymerase gamma.

Front 5

What is the active form of abacavir?

Back 5

carbovir-TP

Front 6

What factors determine parmacological success in HIV therapy?

Back 6

* The activity of the drug regimen * Must be combination therapy * Adverse drug-drug or drug-food interactions. * Adherence to the drug regimen. * Patient specific factors (ultra-fast metabolizers, poor drug absorbers, etc) * Viral/immunological factors (huge viral burden; drug resistance)

Front 7

What is the goal of HIV therapy?

Back 7

"The goal of therapy is to suppress HIV replication as much as possible, for as long as possible

Front 8

What are consequences of inadequate drug activity?

Back 8

* Developement of HIV drug resistance * HIV produces about 109 viruses/day. * HIV is an RNA virus with a relatively high chance for genetic error (genetic mutation) with each replication cycle . * Therefore, when HIV replicates in the presence of sub-optimal drug pressure, the virus can efficiently select for mutants (resistant) that have an advantage in the presence of drug.

Front 9

Genotypic vs. phenotypic drug resistance

Back 9

* Testing available to determine susceptability of certain HIV strains to Anti-viral agents. * Genotypic mutations associated with drug resistance can be detected. * Phenotypic resistance can be determined by comparison to wild-type virus. The closer the test strain is to the wild-type the less resistant it is.

Front 10

How are NRTI's activated?

Back 10

* NRTIs are nucleoside analogs which must be activated by phosphoralation by human kinases to the active triphosphate form.

Front 11

What is the MOA of Nucleoside analogs?

Back 11

Competitively inhibit reverse transcriptase and terminate chain elongation if incorporated.

Front 12

What is the blackbox warning for Nucleoside analogs and which agents carry this warning?

Back 12

All have black-box warning for lactic acidosis

Front 13

How are NRTI's eliminated?

Back 13

Most NRTIs are excreted/secreted by the kidney

Front 14

T or F: Cross-resistance is not possible between Nucleoside analogs, because it takes several resistance mutations to confer high-level resistance.

Back 14

False: HIV usually needs several resistance mutations to confer high-level resistance; cross-resistance possible

Front 15

Compare Pharmacokinetic half-lives: parent drug in plasma and triphosphate in cells

Back 15

Triphosphate forms have longer T1/2 than the parent drug. Dosing is based on the triphosphate forms.

Front 16

What kind of nucleoside analog is didanosine (Videx®) - ddI?

Back 16

Inosine analog that converts to adenosine

Classified as an adenosine analog

Front 17

How active is didanosine against mitochondrial DNA polymerase gamma?

Back 17

Highly active:

Mitochondrial toxin (2nd worst): lactic acidosis, peripheral neuropathy, pancreatitis

Front 18

NRTIs side effects

Back 18

Considered mitochondria poisons:

Body-fat changes
Peripheral neuropathy
Pancreatitis
Lactic acidosis/hepatosteatosis
Newer NRTIs appear to be safer

Front 19

Which anti-HIV drug is Acid sensitive, old formulations in Mg/Ca buffers; new formulation enteric coated beads and should be taken on a empty stomach?

Back 19

didanosine

Front 20

What is the differentiating side effect of Emtricitabine?

Back 20

Discoloration of palms and soles in non-Caucasians

Front 21

What is Emtricitabine's place in therapy?

Back 21

First line with tenofovir

Front 22

What type of nucleoside analog is Emtricitabine?

Back 22

Cytosine

Front 23

Is Emtricitabine FDA approved to treat hepatitis B?

Back 23

Emtricitabine has activity versus hepatitis B but no FDA approved indication.

Front 24

Can two analogs of the same nucleoside be used together?

Back 24

No, Phosphorylation antagonism occurs.

Front 25

What dtug is Emtricitabine very similar to?

Back 25

Lamivudine (Epivir®) - 3TC

Very similar to 3TC in terms of resistance and activity (me too).

Front 26

What nucleoside is Lamivudine (Epivir®) - 3TC
an analog of?

Back 26

Cytosine

likely antagonistic with FTC

Front 27

What level of activity versus mitochondrial DNA polymerase gamma does Lamivudine have?

Back 27

Very well tolerated (low activity versus mitochondrial DNA polymerase gamma

Front 28

How many genetic mutations does an HIV strain require to gain resistance to lamivudine (3TC)?

Back 28

Just one HIV mutation at base 184 in HIV-RT gene causes many fold resistance to 3TC.

Front 29

What nucleoside is Stavudine (Zerit®) - d4T an analog of?

Back 29

Thymidine analog (antagonistic phosphorylation with ZDV)

Front 30

What level of activity does Stavudine (Zerit®) - d4T have against mitochondrial DNA polymerase gamma?

Back 30

Mitochondrial toxin (3rd most active): peripheral neuropathy, pancreatitis (rarely), lactic acidosis

Even so this drug is initially well-tolerated.

Front 31

What side effect is characteristic of Stavudine (Zerit®) - d4T?

Back 31

Fat-loss of the limbs, buttocks, and face.

Front 32

Which anti-HIV drug is a nucleotide analog and what is it an analog of?

Back 32

Tenofovir (Viread®) - TDF

Pro-drug adenosine-MP analog

Front 33

What is tenofovir's role in therapy?

Back 33

First line agent

Front 34

What level of activity does Tenofovir (Viread®) - TDF have against mitochondrial DNA polymerase?

Back 34

Well tolerated, low activity versus mitochondrial polymerase gamma.

Front 35

Is tenofovir indicated for HBV?

Back 35

Yes (same dose)

Front 36

What toxicity do you need to be on the look-out for with tenofovir?

Back 36

renal toxicity (rare)

Front 37

What other anti-HIV agents does tenofovir have a drug interaction with?

Back 37

Plasma drug-drug intrxns (e.g. reduce ddI dose; atazanavir).

Front 38

Which NRTI has the longest TP half-life?

Back 38

tenofovir

Front 39

What nucleoside is Zalcitabine (Hivid®) - ddC an aanolog of?

Back 39

Cytosine analog (antagonistic phosphorylation with FTC/3TC)

Front 40

What side effects are characteristic of Zalcitabine (Hivid®) - ddC?

Back 40

Severe side effects (mouth ulcers, peripheral neuropathy).

Considered most poisonous to mitochondria.
Peripheral neuropathy (33%)
Pancreatitis
Lactic acidosis/liver failure

Front 41

Is Zalcitabine (Hivid®) - ddC still available?

Back 41

No, distribution ceased 12-31-06.

So....why did I make notecards for this drug...I dunno

Front 42

What was the first HIV drug and when was it released?

Back 42

Zidovudine (Retrovir®) - AZT, ZDV
1987

Front 43

What was Zidovudine (Retrovir®) - AZT, ZDV originally used for?

Back 43

Rarely used for leukemia/lymphoma

Front 44

What side-effects are unique to Zidovudine?

Back 44

Cytopenia
Myopathy (rarely)
Headache, nausea

Front 45

What nucleoside is Zidovudine an analog of?

Back 45

Thymidine analog (antagonistic phosphorylation with d4T)

Front 46

E.L., a 51 y.o. patient with uncomplicated chronic HIV-infection, is ready to start antiretroviral therapy. What tests should be considered regarding nucleoside analog selection?

Back 46

HLA-B5701

Front 47

What does HLA-B5701 test for?

Back 47

Predisposition for hypersensitivity reaction to abacavir

Front 48

MAO of Non-nucleoside reverse transcriptase inhibitors NNRTIs

Back 48

“Butterfly drugs”.
NON-competitively inhibit reverse transcriptase by binding to a “pocket” adjacent the active site. A conformational change causes enzyme dysfunction.

Front 49

Side effects of NNRTIs

Back 49

Hypersensitivity, hepatitis/rash (allergens)
Nevirapine is most often associated with the severest cases.

Front 50

Metabolism of NNRTIs

Back 50

Metabolized by various enzymes in the liver (CYP 3A4 and 2B6). Cause induction or inhibition interactions with 3A4. Long plasma half-lives (24 to 48 hours).

Front 51

How difficult is it for a strain of HIV to become resistant to NNRTIs?

Back 51

A key feature with this class is that HIV needs only ONE resistance mutation to confer high-level resistance to all agents in this class (except etravirine).

Front 52

Available Non-nucleoside analog reverse transcriptase inhibitors

Back 52

delavirdine (Rescriptor®) - DLV
efavirenz (Sustiva®) - EFV
etravirine (Intelence) - ETV
nevirapine (Viramune®) - NVP

Front 53

NNRTIs and NRTIs work on the same enzyme (reverse transcriptase). Will they be antagonistic together?

Back 53

No because they have two different binding sites.

Front 54

delavirdine (Rescriptor®) - DLV

Back 54

* Low activity.
* 8 hour half-life. TID dosing.

* Major substrate/inhibitor of CYP 3A4. Drug interactions. Rarely used as a “booster”.

* Side effects: rash/hepatitis (rarely severe).

Front 55

efavirenz (Sustiva®) - EFV

Back 55

* Most active agent in this class.
* 36 hour half-life.
* Metabolized by liver/gut (CYP 2B6). Inducer of CYP3A4; drug interactions.
* CNS perturbations in 50% of pts (subsides after several weeks). * Rash/hepatitis rarely severe
* Avoid in pregnancy (neural tube issues) (category D)

Front 56

etravirine (Intelence) - ETV

Back 56

* For experienced patients.
* Metabolized by 3A4, 2C9, and 2C19. Inducer of CYP3A4 and inhibitor of 2C9 and 2C19.
* Typically requires 2 or more resistance mutations.
* Rash (sometimes severe).

Front 57

nevirapine (Viramune®) - NVP

Back 57

* Intermediate activity.
* Metabolized by liver/gut (CYP 2B6). Inducer of CYP3A4; drug interactions.
* Blackbox warning for hepatitis and rash (Stevens-Johnson syndrome).
Auto-induces; MUST give 200mg qd (half-dose) lead-in for 14 days to reduce risk of rash/hepatolysis. Frequent monitoring recommended for 4 to 6 weeks.

Front 58

maraviroc (Selzentry)

Back 58

CCR5-inhibitor
* Inhibits HIV binding with CCR5 co-receptor.

* Experienced and naïve(?) patients. A “tropism” test is needed to determine whether the HIV strain uses CCR5 (instead of CXCR4 or both).
* Black box warning for hepatitis/hypersensitivity. Increased upper respiratory infections noted.

* Metabolized by CYP3A4. Dosing changes for interactions.

Front 59

Enfuvirtide (Fuzeon)

Back 59

gp41 fusion Inhibitor
* Inhibits gp41-mediated entry of HIV into cells.
* It is a linear 36 amino-acid synthetic molecule. It must be given SQ (arm, stomach, leg) bid.
* Toxicity is generally injection site reactions (~100%) – also an increase in bacterial pneumonia.
* Drug interactions are not expected. It is cleared by peptide catabolism and amino-acid recycling.
* Reserved for salvage therapy in combination with multiple other agents.
* Up to $20,000 per year.

Front 60

How is Enfuvirtide different from all the rest?

Back 60

Enfuvirtide is significantly larger and more complex than all the other AVR drugs

Front 61

When presented with a maraviroc prescription, what should you verify in the patient’s record?

Back 61

That a tropoism test has been performed to determine whether her HIV strain binds to CCR5 or CXCR4

Front 62

HIV Integrase Inhibitors

Back 62

Integrase Inhibitor – Raltegravir (Isentress)

Front 63

Protease inhibitor mechanism of action

Back 63

* Peptide analogues (peptidomimetics)-
* Competitively inhibit HIV protease by
mimicking the poly-protein (gag-pol) cleavage site: The resulting virion is immature, dysfunctional, non-infectious, and rapidly cleared from the body.

Front 64

Protease Inhibitors side effects

Back 64

Nausea, bloating, and diarrhea
High blood lipids & hyperglycemia

Front 65

Integrase Inhibitor – Raltegravir (Isentress)

Back 65

* Well-tolerated. Some GI SEs. Creatine kinase increases noted.

* Metabolized by UGT1A1 (bilirubin conjugating enzyme). Few, but some interactions; atazanavir, rifampin. Antacids may bind drug (caution, more research needed).

* Extremely potent strand transfer inhibitor. Approved for experienced and naive patients.


* Like any antiviral drug, resistance possible; more info needed.

Front 66

Protease inhibitor Class Characteristics:

Back 66

* Peptidomimetics - competitively inhibit HIV Protease.
* Adverse effects
- Increased blood lipids & glucose
- Gastrointestinal intolerance
* Pharmaceutics issues
- Formulation/dissolution/bioavailability issues
* Liver metabolized - drug-food & drug-drug interactions w/ CYP3A4. Complex (inducing and inhibiting properties)
- Ritonavir POTENTLY inhibits 3A and is thus used to “boost” other PIs
* HIV usually needs several resistance mutations to confer moderate to high-level resistance

Front 67

Available Protease Inhibitors

Back 67

amprenavir (Agenerase®) and fosamprenavir (Lexiva™)- AMP
atazanavir (Reyataz™) - ATZ
darunavir (Prezista™) - DRV
Indinavir (Crixivan®) - IDV
Lopinavir / ritonavir (Kaletra®) - LPV
nelfinavir (Viracept®) - NLF
Ritonavir (Norvir®) - RTV
Saquinavir (Fortovase®; Invirase®) - SQV
Tipranavir (Aptivus®) - TPV

Front 68

amprenavir (Agenerase®) and fosamprenavir (Lexiva™)- AMP

Back 68

* Amprenavir capsules not manufactured anymore (only fosamprenavir).

* Amprenavir solution w/ propoylene glycol (Not for kids (<4 y.o.), pregnant women, pts with hepatic/renal failure)

* Side effects
- Circumoral parasthesias
- Rash (contains sulfa)

* Dose recommendations for severe liver disease.

Front 69

atazanavir (Reyataz™) - ATZ

Back 69

* Tenuous QD drug (7 hour half-life) -- frequently “boosted” w/ ritonavir.

* Needs acid for dissolution: Interaction with antacids.

* Very little effects on lipids.

* Side effects
- hyperbilirubinemia via inhibition of UGT-1A1
- GI distress

Front 70

darunavir (Prezista™) - DRV

Back 70

* Must be boosted with ritonavir (600mg/100mg twice daily and 800mg/100mg once daily).

* Usual PI side effects
Cholesterol/lipids
GI distress
Hepatitis
Rash

* Best option for drug resistant HIV.

Front 71

Indinavir (Crixivan®) - IDV

Back 71

* Rarely used anymore. “Boosted” w/ ritonavir.

* Side effects
- Dry skin
- Kidney stones
- Extra hydration
needed to keep
renal tubules
clear (1.5L/day).

Front 72

Lopinavir / ritonavir (Kaletra®) - LPV

Back 72

* Co-formulated with ritonavir for “boosting” (800/200mg once or 400/100mg twice daily)

* Recommended in pregnant women.

* Side effects
Usual GI distress
Increased blood lipids/glucose

Front 73

nelfinavir (Viracept®) - NLF

Back 73

* Rarely “boosted” w/ ritonavir because of non-3A4 routes of metabolism

* lower activity

* Side effects
Diarrhea (preemptively treat)

Front 74

Ritonavir (Norvir®) - RTV

Back 74

* NOT used by itself anymore; essentially always used low dose as a “booster”

* Drug interactions

* Side effects
GI upset
Circumoral parasthesias
Hypertriglyceridemia
Liver dysfunction
Hyperinsulinemia

Front 75

Saquinavir (Fortovase®; Invirase®) - SQV

Back 75

* Invirase formulation had 4% bioavailability (F). Can only be used boosted.

* Side effects
Mild GI upset, bloating
New information about QT and PR effects.

Front 76

Tipranavir (Aptivus®) - TPV

Back 76

* Only for drug resistant virus.

* Must be dosed with ritonavir.

* Major drug interaction profile. Probably major inducer of P-gp.

* Prominent Side effects
Sulfonamide - rash
GI upset, bloating
Hyperlipidemia
Liver toxicity
Rare intracranial bleed

Front 77

What is P-glycoprotein?

Back 77

* Active drug efflux pump found in BBB, gut, lymphocytes, renal, TBB, tubules, thymus, etc
* Protects body/cells from xenobiotics: Reduces bioavailability and enhances clearance.
* All protease inhibitors are substrates and/or inhibitor/inducers of P-gp.

Front 78

Food affects on protease inhibitor AUCs

Back 78

NELFINAVIR(-3x)
INDINAVIR (~77%)
NELFINAVIR (-3x)
ATAZANAVIR (-70%)
TIPRANAVIR (~30%)DARUNAVIR (~30%)

Front 79

Protease Inhibitor boosting:

Back 79

* Most protease inhibitor use involves ritonavir “boosting” of another protease inhibitor.* Darunavir, tipranavir, saquinavir (Invirase), and lopinavir MUST be given with ritonavir.