Drug Synergy

Question 1

How can using multiple drugs minimise drug toxicity?

Answer 1

Lower doses of individual agents can be used

Drugs may have different targets, limiting unwanted effects

Question 2

How does HIV bind to and fuse with the host cell membrane?

Answer 2

Binds to CD4 and chemokine co-receptor (including CCR5 AND CXCR4) via gp120
Fuses with membrane via gp41

Question 3

What is maraviroc? What is it used for clinically?

Answer 3

An allosteric modulator of CCR5, used to prevent HIV binding and entering host cells

Question 4

What is enfuvirtide? What is it used for clinically?

Answer 4

A peptide that binds to gp41 to prevent HIV fusion with the host cell membrane in the treatment of HIV

Question 5

What are the 2 classes of reverse transcriptase inhibitors used to treat HIV? What is the difference in their modes of action?

Answer 5

Nucleoside/nucleotide RT inhibitors (NRTIs): competes with viral RNA genome for binding to RT
Non-nucleoside RT inhibitors (NNRTIs): allosteric modulator of RT, inhibits its action

Question 6

What is zidovudine (AZT)?

Answer 6

NRTI

Question 7

What is nevirapine?

Answer 7

NNRTI

Question 8

What is raltegravir? What is it used for clinically?

Answer 8

Inhibitor of the HIV integrase enzyme, which is responsible for integrating proviral DNA into the host genome

Question 9

What is saquinavir? What is it used for clinically?

Answer 9

An inhibitor of the HIV protease enzyme, which is responsible for cleavage of polypeptide into mature viral enzymes and proteins

Question 10

What is the limitation of drug monotherapy in the treatment of HIV?

Answer 10

Drug resistance develops (only of transient benefit)

Question 11

What is HAART?

Answer 11

Highly Active Anti-Retroviral Therapy; “triple therapy” used to treat HIV

Question 12

Give 3 examples of drug combinations used in HAART

Answer 12

2 x NRTIs + NNRTI
2 x NRTIs + PI
NRTI + NNRTI + PI

Question 13

What is the benefit of using a combination of RTIs when treating HIV?

Answer 13

Each individual drug may be less than maximally active

If resistance emerges to 1, this does not mean resistance emerges to all

Question 14

What is in the combined pill (polytherapy) used to treat HIV? What is the benefit of the combined pill?

Answer 14

Combined pill: tenofovir (NRTI), emtricitabine (NRTI), efavirenz (NNRTI)
May increase patient compliance

Question 15

What is a bifunctional drug? What is the proposed benefit?

Answer 15

1 compound with 2 activities (e.g. NRTI linked to an NNRTI)

May produce synergistic activity (still experimental)

Question 16

What is the benefit of using ritonavir with a PI?

Answer 16

Ritonavir is a PI which also (even at low doses) is a potent inhibitor of CYP3A4, which metabolises other PIs
This means that the administration of ritonavir with another PI will enhance efficacy, improve dosing regimen and reduce resistance when compared to the use of a single PI alone

Question 17

What is NS5B?

Answer 17

An RNA-dependent RNA polymerase

Question 18

What is sofosbuvir?

Answer 18

A prodrug which acts as a nucleotide inhibitor of NS5B

Question 19

How does sofosbuvir act as a nucleotide inhibitor of NS5B?

Answer 19

Drug has a phosphate attached along with a protective coating which helps the drug to enter the cell
Once inside the cell, the protective coating is removed
2 more phosphates are added
Triple phosphorylated drug can now be picked up by NS5B to inhibit viral RNA replication

Question 20

What are some of the problems with using nucleotide inhibitors? How does sofosbuvir overcome this?

Answer 20

Takes a long time for the triple phosphorylation of the drug to occur; drug can be eliminated before this occurs
Sofosbuvir already has 1 phosphate and only needs 2 more; this speeds the process up

Question 21

Give 2 examples of combination therapies for HCV. How is a decision made which to use?

Answer 21

Sofosbuvir + PEG-interferon + ribavarin
Sofosbuvir + ribavarin
Use is dependent on HCV genotype

Question 22

What is the drawback of using combination therapy for HCV?

Answer 22

Cost: currently costs $70,000 (may be cost-benefit analysis - prevent further treatment down the line?)

Question 23

How long is the course of combination therapy for HCV?

Answer 23

12- or 24-week depending on HCV genotype

Question 24

What is the result of using a bacteriostatic and a bacteriocidal together?

Answer 24

Bacteriocidal requires some bacterial growth to work
Bacteriostatic inhibits bacterial growth
Effect is antagonistic

Question 25

Name 2 bacterial organisms for which synergistic drug treatments are recommended

Answer 25

Enterococcus faecalis | Staphylococcus aureus

Question 26

Explain what causes synergism when using an aminogylcoside with a penicillin

Answer 26

Penicillin prevents bacterial cell wall synthesis, which enhances aminoglycoside entry and therefore activity within the cell (where it inhibits bacterial protein synthesis)

Question 27

What are the 3 ways in which an aminoglycoside may inhibit bacterial protein synthesis?

Answer 27

Blocks initiation Blocks further translation and elicits premature termination Incorporation of incorrect amino acid

Question 28

Give an example of drug synergy used to treat non-specific fungal infections

Answer 28

Flucytosine inhibits fungal DNA synthesis, but under normal conditions relies on cytosine permease to gain entry to the cell Amphotericin binds to ergosterol (found selectively in fungal cell membranes) to disrupt the membrane, which allows more ready access by flucytosine

Question 29

Give an example of drug synergy used to treat fungal infection with Pneumocystis jiroveci

Answer 29

Drugs targeting 2 points on the same DNA synthesis pathway Sulfonamides (e.g. sulfmethoxazole) inhibit dihydropteroate, which converts PABA to folate Trimethoprim inhibits dihydrofolate reductase, which converts folate to tetrahydrofolate

Question 30

Give an example of a cancer chemotherapy combination treatment used for metastatic testicular cancer

Answer 30

Bleomycin Etoposide Cisplatin

Question 31

What is the basis of synergy between cisplatin/bleomycin and etoposide?

Answer 31

Cisplatin/bleomycin repairs DNA damage/strand breaks Etoposide inhibits topoisomerase (normally inserts breaks in DNA to allow transcription), inhibiting DNA ligation and inducing cell apoptosis

Question 32

What kind of synergy is achieved by adding ondansetron to a chemotherapy regime?

Answer 32

Ondansetron is an anti-emetic; achieves clinical (not mechanistic) synergy by countering side effects

Question 33

List 6 classes of immunosuppressants and their cell targets

Answer 33

Glucocorticoids: block cytokine stimular for T cell proliferation Cytotoxic drugs: block DNA synthesis to prevent cell division Calcineurin inhibitors (and related compounds): blocks signal leading to transcription of various genes related to proliferation Antibodies targeting cytokine receptors or cytokines Antibodies leading to T cell depletion (bind to cell surface markers to allow targeting of T cells) Antibodies blocking co-stimulation

Question 34

Give an example of a glucocorticoid

Answer 34

Prednisolone

Question 35

Give 2 examples of a cytotoxic drug

Answer 35

``` Azathioprine Mycophenolate mofetil (MMF) ```

Question 36

Give 3 examples of calcineurin inhibitors

Answer 36

Cyclosporin Tacrolimus Sirolimus

Question 37

Give an example of an antibody used to target cytokine receptors or cytokines

Answer 37

Daclizumab (anti-IL2R/CD25)

Question 38

Give an example of a T-lymphocyte depletion antibody

Answer 38

Anti-thymocyte globulin

Question 39

Give an example of antibody that blocks T-cell co-stimulation

Answer 39

Abatacept (CTLA-4 fusion)

Question 40

What kind of drug is used for induction of immunosuppression (e.g. prior to transplant)?

Answer 40

Often antibody-mediated T cell depletion

Question 41

What combination of drugs is used to maintain immunosuppression?

Answer 41

Commonly calcineurin inhibitor, glucocorticoid and cytotoxic drug (e.g. MMF)

Question 42

What is Targin and what is the basis of its action?

Answer 42

A combination drug that include oxycodone and naloxone Oxycodone is an opioid analgesic, which acts as a u receptor agonist Naloxone is a u receptor antagonist which has poor bioavailability (not absorbed well and undergoes 1st pass metabolism) and therefore exerts its effect in the GIT to prevent opioid-induced constipation