1F. Antiviral Drugs - Drug Mechanisms

Front 1

What is Zidovudine also called?

Back 1

AZT

Front 2

How is Zidovudine administered?

Back 2

-Oral
-IV

Front 3

What is Zidovudine's mechanism?

Back 3

Thymidine nucleoside analog that inhibits reverse transcriptase and blocks nucleic acid synthesis; it is a chain terminator.

Front 4

What gives Zidovudine specificity against HIV-infected cells?

Back 4

It is activated by Host thymidine kinase phosphorylation by cells in S-phase - only those actively replicating ie infected cells.

Front 5

How does AZT act as a chain terminator?

Back 5

It has an azeto N3 instead of a 3'OH needed for incorporation of the next nucleoside.

Front 6

What is the use of Zidovudine?

Back 6

HIV in kids/adults

Front 7

How is Zidovudine metabolized and excreted?

Back 7

By glucuronidation in the liver and excreted in urine

Front 8

What happens when drugs that inhibit glucuronyl transferase are given to patients on AZT?

Back 8

The metabolism of AZT shifts to a P450 mechanism which produces a toxic amine that damages the bone marrow.

Front 9

So what is the contraindication to giving AZT/Zidovudine?

Back 9

When a patient is on a Glucuronyl transferase inhibiting drug

Front 10

What are the 2 main side effects of AZT?

Back 10

-BM suppression (reduced WBC/RBC counts)
-Myopathy after prolonged use

Front 11

What are the other 2 nucleoside RT inhibitors?

Back 11

-Lamivudine
-Tenofovir

Front 12

Which is the most preferred NRTI to give for HVI?

Back 12

Tenofovir

Front 13

What is the mechanism of Lamivudine?

Back 13

Nucleoside analog inhibitor of RT that must be phosphorylated by cell enzymes to be active.

Front 14

How is Lamivudine used?

Back 14

In synergistic combos with AZT

Front 15

Why is Lamivudine given along with Zidovudine?

Back 15

Because HIV strains that resist Lamivudine will be sensitive to Zidovudine, and vice versa.

Front 16

What happens when Lamivudine is given in synergistic combo with AZT?

Back 16

It makes it difficult for HIV to become resistant to both drugs simultaneously.

Front 17

And for what other viral infection is Lamivudine used as a treatment?

Back 17

Hep B

Front 18

How is Lamivudine administered? Excreted?

Back 18

Admin: oral
Excreted: renal unchanged

Front 19

How does Lamivudine effect the body normally?

Back 19

Well tolerated

Front 20

What are 2 side effects that Lamivudine can have?

Back 20

-Nausea
-Diarrhea

Front 21

How is Tenofovir similar to AZT?

Back 21

It inhibits RT by competing for incorporation into DNA and causes chain termination.

Front 22

How is Tenofovir DIFFERENT from AZT?

Back 22

It is a NucleoTide prodrug that is hydrolyzed to tonofovir monophosphate, then phosphorylated by cell enzymes.

Front 23

What does the active form of Tenofovir then do?

Back 23

Inhibits RT by competing with dATP for incorporation into DNA to terminate chain elongation.

Front 24

What is Tenofovir's use?

Back 24

Combination therapy for HIV Patients

Front 25

How is Tenofovir administered/excreted?

Back 25

Admin: oral
Excretion: Renally via Glomerular filtration and active secretion

Front 26

So what is a contraindication to giving Tenofovir?

Back 26

Severe renal disease

Front 27

Why is Tenofovir one of the preferred drugs for treating HIV?

Back 27

Because it is really well tolerated and has few side effects.

Front 28

What are 2 side effects that all NRTIs have in general?

Back 28

-Lactic acidosis
-Hepatic steatosis

Front 29

Why do the nucleoside/NT RT inhibitors cause lactic acidosis and hepatic steatosis?

Back 29

Because they inhibit Mitochondrial polymerase gamma which leads to mitochondrial damage and deficiencies in metabolism.

Front 30

What is the NONnucleoside inhibitor of RT?

Back 30

Efavirenz

Front 31

What is a major difference of Efavirenz compared to the NRTIs? (aside from being a non-nucleoside inhibitor)

Back 31

It doesn't require phosphorylation to be active

Front 32

What is the use of Efavirenz?

Back 32

Multi-drug therapy for HIV

Front 33

What is an advantage of Efavirenz?

Back 33

It only requires 1/day dosing

Front 34

What are 3 side effects of Efavirenz?

Back 34

-Rash
-CNS/psychiatric symptoms
-NIGHTMAREs

Front 35

What % of patients on Efavirenz actually get nightmares?

Back 35

50%

Front 36

What are the 2 protease inhibitors to know of for HIV treatment? Which is the preferred one?

Back 36

-Lopinavir - preferred
-Ritonavir

Front 37

What protease do the protease inhibitors inhibit?

Back 37

Aspartic Protease - the enzyme that cleaves the gag-pol polyprotein product of viral RNA translation.

Front 38

How do the protease inhibitors act on the Aspartic protease?

Back 38

By competitive inhibition of its active site.

Front 39

What is the result of competitive inhibition of Aspartic protease in HIV infected cells?

Back 39

Viral particles are produced, by they are non-infectious.

Front 40

How are the Protease inhibitors used?

Back 40

In combination with RT inhibitors for HIV 1 and 2

Front 41

What effect do the PI + NRTI or NNRTI combos have?

Back 41

Significant decreases in the viral load measured in blood.

Front 42

What are some downsides to using multi-drug therapy?

Back 42

-Complexity of regimen increased
-Patients will fail due to noncompliance

Front 43

What is the main difference between Lopinavir and Ritonavir?

Back 43

Ritonavir is more toxic and too toxic to be given alone; so it is used along with Lopinavir

Front 44

How is Lopinavir/Ritonavir administered?

Back 44

Orally but poorly absorbed

Front 45

What are 4 toxic side effects of ALL PI's, including Lopinavir?

Back 45

-Diabetes (onset or exacerbate)
-Lipid metabolism altered
-Lipodystrophy, fat redistribn
-Alters metabolism of many drugs via Cyp3A inhibition

Front 46

Why is Ritonavir given in combo with Lopinavir?

Back 46

To boost its levels by inhibiting Cyp3A metabolism

Front 47

What is a side effect unique to Lopinavir?

Back 47

Diarrhea

Front 48

What is a side effect unique to Ritonavir?

Back 48

Circumoral parasthesia

Front 49

What is circumoral parasthesia?

Back 49

Numbness around the mouth

Front 50

What drugs are used for treating HIV when the NRTI's/NNRTI's and PI's don't work?

Back 50

Fusion inhibitors, integrase inhibitors, and CCR5 antagonists

Front 51

What is the fusion inhibitor?

Back 51

Enfuvirtide

Front 52

How is Enfuvirtide administered?

Back 52

Via subcutaneous injections 2x daily

Front 53

What is the mechanism of Enfuvirtide?

Back 53

Inhibits fusion of HIV1 and CD4+ cell membranes

Front 54

How does Enfuvirtide inhibit the fusion of HIV1 to Thelpers?

Back 54

By binding the gp41 subunit of the HIV glycoprotein

Front 55

What is Enfuvirtide NOT effective in treating?

Back 55

HIV2

Front 56

What is Enfuvirtide used for?

Back 56

Treating HIV1 in txmt experienced patients that resist other multiple regimens.

Front 57

How will resistance to the other HIV drugs effect Enfuvirtide efficacy?

Back 57

It won't - there isn't cross-resistance between Enfuvirtide and other HIV drugs

Front 58

What are the 2 major downsides to Enfuvirtide?

Back 58

-Subcut injections only
-High Cost $$

Front 59

What are 4 side effects of Enfuvirtide? What is the MOST COMMON one?

Back 59

-Local Injection site Rxn - 98%
-Diarrhea
-Nausea
-Fatigue

Front 60

What allows for Enfuvirtide to treat HIV that resists the other HIV drugs?

Back 60

Its completely different mechanism of action

Front 61

What is the CCR5 antagonist and what is it used for?

Back 61

Maraviroc - treatment of CCR5 tropic HIV strains late in disease, in patients resistant to other HIV drugs.

Front 62

What is the mechanism of Maraviroc's action?

Back 62

It is an antagonist of the CCR5 coreceptor for HIV-1 only

Front 63

What is Maraviroc NOT effective in treating?

Back 63

CXCR4-tropic HIV

Front 64

What does antagonism of the CCR5 chemokine receptor allow Maraviroc to do?

Back 64

Block entry of HIV1 into the host cell

Front 65

How is Maraviroc administerd?

Back 65

Orally 2X daily

Front 66

What affects the dose of Maraviroc?

Back 66

Other drugs that inhibit Cyp3A

Front 67

What are 2 documented side effects of Maraviroc (though it's a new drug with little data)?

Back 67

-Hepatotoxicity
-Cardiovascular events (MI)

Front 68

What drug is the Integrase inhibitor?

Back 68

Raltegravir

Front 69

What is Raltegravir used for?

Back 69

Treatment of HIV1 in tx experienced patients whose virus is resistant to other drugs.

Front 70

How is Raltegravir administered?

Back 70

Orally, 2x daily

Front 71

Against what virus is Raltegravir effective?

Back 71

HIV 1 only!!!

Front 72

What is the mechanism of Raltegravir's action?

Back 72

Inhibition of HIV-1 integrase activity, preventing integration of its DNA into the genome

Front 73

What is a possible side effect of Raltegravir? What is more common?

Back 73

Myopathy
More common: n/v, fever, HA

Front 74

So how are drugs used in general for treating HIV?

Back 74

In combinations of 3/more per patient

Front 75

What is the multidrug approach to treating HIV called?

Back 75

HAART - highly active anti-retroviral therapy

Front 76

What is the main thing to remember about HAART?

Back 76

It is combinations of different drugs with DIFFERENT MECHANISMS.

Front 77

What 3 drugs make up the most commonly used initial regimen for treating HIV?

Back 77

-AZT/Zidovudine (NRTI)
-3TC/Lamivudine (NRTI)
-Efavirenz (NNRTI)

Front 78

What are 2 things that must be taken into account when treating HIV?

Back 78

-Viral load in the patient
-Immune status (CD4 counts)

Front 79

Why should you take into account the immune status when determining Anti-HIV treatment?

Back 79

Because of the toxic side effects - its better to wait on them until the immune status is deteriorated; not too early.

Front 80

What is a downside to giving HAART too early in an HIV pos patient?

Back 80

Side effects result, and also resistance develops