Drug Synergy Flashcards
How can using multiple drugs minimise drug toxicity?
Lower doses of individual agents can be used
Drugs may have different targets, limiting unwanted effects
How does HIV bind to and fuse with the host cell membrane?
Binds to CD4 and chemokine co-receptor (including CCR5 AND CXCR4) via gp120
Fuses with membrane via gp41
What is maraviroc? What is it used for clinically?
An allosteric modulator of CCR5, used to prevent HIV binding and entering host cells
What is enfuvirtide? What is it used for clinically?
A peptide that binds to gp41 to prevent HIV fusion with the host cell membrane in the treatment of HIV
What are the 2 classes of reverse transcriptase inhibitors used to treat HIV? What is the difference in their modes of action?
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
What is zidovudine (AZT)?
NRTI
What is nevirapine?
NNRTI
What is raltegravir? What is it used for clinically?
Inhibitor of the HIV integrase enzyme, which is responsible for integrating proviral DNA into the host genome
What is saquinavir? What is it used for clinically?
An inhibitor of the HIV protease enzyme, which is responsible for cleavage of polypeptide into mature viral enzymes and proteins
What is the limitation of drug monotherapy in the treatment of HIV?
Drug resistance develops (only of transient benefit)
What is HAART?
Highly Active Anti-Retroviral Therapy; “triple therapy” used to treat HIV
Give 3 examples of drug combinations used in HAART
2 x NRTIs + NNRTI
2 x NRTIs + PI
NRTI + NNRTI + PI
What is the benefit of using a combination of RTIs when treating HIV?
Each individual drug may be less than maximally active
If resistance emerges to 1, this does not mean resistance emerges to all
What is in the combined pill (polytherapy) used to treat HIV? What is the benefit of the combined pill?
Combined pill: tenofovir (NRTI), emtricitabine (NRTI), efavirenz (NNRTI)
May increase patient compliance
What is a bifunctional drug? What is the proposed benefit?
1 compound with 2 activities (e.g. NRTI linked to an NNRTI)
May produce synergistic activity (still experimental)
What is the benefit of using ritonavir with a PI?
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
What is NS5B?
An RNA-dependent RNA polymerase
What is sofosbuvir?
A prodrug which acts as a nucleotide inhibitor of NS5B
How does sofosbuvir act as a nucleotide inhibitor of NS5B?
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
What are some of the problems with using nucleotide inhibitors? How does sofosbuvir overcome this?
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
Give 2 examples of combination therapies for HCV. How is a decision made which to use?
Sofosbuvir + PEG-interferon + ribavarin
Sofosbuvir + ribavarin
Use is dependent on HCV genotype
What is the drawback of using combination therapy for HCV?
Cost: currently costs $70,000 (may be cost-benefit analysis - prevent further treatment down the line?)
How long is the course of combination therapy for HCV?
12- or 24-week depending on HCV genotype
What is the result of using a bacteriostatic and a bacteriocidal together?
Bacteriocidal requires some bacterial growth to work
Bacteriostatic inhibits bacterial growth
Effect is antagonistic
Name 2 bacterial organisms for which synergistic drug treatments are recommended
Enterococcus faecalis
Staphylococcus aureus
Explain what causes synergism when using an aminogylcoside with a penicillin
Penicillin prevents bacterial cell wall synthesis, which enhances aminoglycoside entry and therefore activity within the cell (where it inhibits bacterial protein synthesis)
What are the 3 ways in which an aminoglycoside may inhibit bacterial protein synthesis?
Blocks initiation
Blocks further translation and elicits premature termination
Incorporation of incorrect amino acid
Give an example of drug synergy used to treat non-specific fungal infections
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
Give an example of drug synergy used to treat fungal infection with Pneumocystis jiroveci
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
Give an example of a cancer chemotherapy combination treatment used for metastatic testicular cancer
Bleomycin
Etoposide
Cisplatin
What is the basis of synergy between cisplatin/bleomycin and etoposide?
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
What kind of synergy is achieved by adding ondansetron to a chemotherapy regime?
Ondansetron is an anti-emetic; achieves clinical (not mechanistic) synergy by countering side effects
List 6 classes of immunosuppressants and their cell targets
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
Give an example of a glucocorticoid
Prednisolone
Give 2 examples of a cytotoxic drug
Azathioprine Mycophenolate mofetil (MMF)
Give 3 examples of calcineurin inhibitors
Cyclosporin
Tacrolimus
Sirolimus
Give an example of an antibody used to target cytokine receptors or cytokines
Daclizumab (anti-IL2R/CD25)
Give an example of a T-lymphocyte depletion antibody
Anti-thymocyte globulin
Give an example of antibody that blocks T-cell co-stimulation
Abatacept (CTLA-4 fusion)
What kind of drug is used for induction of immunosuppression (e.g. prior to transplant)?
Often antibody-mediated T cell depletion
What combination of drugs is used to maintain immunosuppression?
Commonly calcineurin inhibitor, glucocorticoid and cytotoxic drug (e.g. MMF)
What is Targin and what is the basis of its action?
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
