Drugs Flashcards
Enfuvirtide
fusion inhibitor: Peptide binds specifically in the groove of a coiled coil in the gp41 protein
Requires subcutaneous injection twice a day.
Side effects include skin reactions at site of injection/ greater incidence of pneumonia. Resistance correlates with appearance of mutations in the N-terminal portion of gp41.
maraviroc
fusion inhibitor: Mechanism
• Blocks HIV entry by binding the human CCR5 coreceptor.
-Only works for HIV isolates that utilize CCR5 (CCR5-tropic). Not for those that use CXCR4.
Preference of CCR5 over CXCR4 may not be absolute, and it can change over course of
infection, particularly in late stages. Thus, never use maraviroc alone.
Pharmacodynamics
• Drug is metabolized by P450s so inducers and inhibitors of system may influence levels.
• Taken orally twice a day.
• Only 50% of patients eligible because of CXCR4-tropism.
Resistance
Due to the emergence of mutant strains that use CXCR4 to gain entry
Emtricitabine
nucleoside reverse
transcriptase
inhibitors: • Fluorinated cytidine analog of lamivudine with long t1/2.
• Clinically significant drug-drug (p450) interactions have not been identified.
• Can be taken as pill once a day
. Mechanistic details
1) Act as suicide substrates by poisoning RT chain elongation.
2) Drugs bind the active site of the HIV RT.
3) Selectivity because drugs do not bind well to nuclear DNA polymerases.
4) Drugs prevent acute infection but have little effect on infected cells.
. Pharmacodynamics
1) Taken orally and generally well absorbed from GI.
2) NRTIs are prodrugs that must be triphosphorylated by cytoplasmic enzymes.
3) Half-life is usually extended by transport into cell and subsequent phosphorylation.
Adverse reactions
1) NRTIs can poison host DNA polymerases, particularly mitochondrial polymerases,
which leads to potentially fatal lactic acidosis.
2) Each NRTI also has intrinsic side effects.
D. Resistance
1) Due to mutations in RT active site. Each NRTI has unique profile of resistance mutations.
2) Lamivudine resistance develops more rapidly than other NRTIs.
Tenofovir disproxil fumarate
reverse
transcriptase
inhibitors
. Mechanistic details
1) Act as suicide substrates by poisoning RT chain elongation.
2) Drugs bind the active site of the HIV RT.
3) Selectivity because drugs do not bind well to nuclear DNA polymerases.
4) Drugs prevent acute infection but have little effect on infected cells.
. Pharmacodynamics
1) Taken orally and generally well absorbed from GI.
2) NRTIs are prodrugs that must be triphosphorylated by cytoplasmic enzymes.
3) Half-life is usually extended by transport into cell and subsequent phosphorylation.
Adverse reactions
1) NRTIs can poison host DNA polymerases, particularly mitochondrial polymerases,
which leads to potentially fatal lactic acidosis.
2) Each NRTI also has intrinsic side effects.
D. Resistance
1) Due to mutations in RT active site. Each NRTI has unique profile of resistance mutations.
2) Lamivudine resistance develops more rapidly than other NRTIs.
**Synthetic adenosine analog with a phosphate. Technically a nucleotide RT inhibitor.
• Presence of first phosphate overcomes rate limiting phosphorylation step in CD4+ cells.
• Protective groups stripped in plasma before transport into cells.
• Drug acts by competing with dATP for binding HIV RT and then chain terminates.
• Interacts little with P450s thus few drug-drug interactions.
• Systemic use can cause nephrotoxicity and decrease in bone mineral density.
• Resistance develops slowly. The drug retains activity even with resistance to other NRTIs.
tenofovir alafenamide fumarate
reverse
transcriptase
inhibitors
. Mechanistic details
1) Act as suicide substrates by poisoning RT chain elongation.
2) Drugs bind the active site of the HIV RT.
3) Selectivity because drugs do not bind well to nuclear DNA polymerases.
4) Drugs prevent acute infection but have little effect on infected cells.
. Pharmacodynamics
1) Taken orally and generally well absorbed from GI.
2) NRTIs are prodrugs that must be triphosphorylated by cytoplasmic enzymes.
3) Half-life is usually extended by transport into cell and subsequent phosphorylation.
D. Resistance
1) Due to mutations in RT active site. Each NRTI has unique profile of resistance mutations.
2) Lamivudine resistance develops more rapidly than other NRTIs.
New derivative was developed to reduce side effects (albeit minimal) of tenofovir.
• New derivative is deprotected only in lymphoid cells. Thus, more stable in plasma.
• Importantly, lower concentrations of the drug can be used for same therapeutic effect
Efavirenz
non-nucleoside reverse
transcriptase
inhibitors
Mechanistic details
1) Non-NRTIs (NNRTIs) bind adjacent to the RT active site, inducing a conformational
change that blocks RT activity.
2) Does not require cellular activation (phosphorylation).
3) Acts on HIV-1 but not HIV-2.
B. Pharmacodynamics
1) Taken orally and well absorbed in GI.
2) Diffuses into cells.
C. Resistance
Resistance develops rapidly. NNRTIs are always prescribed in combination with other drugs.
D. Metabolism
1) NNRTIs interact with P450 CYP3A4 and either inhibit or induce P450 activity.
3) Some patients can undergo methadone withdrawal on nevirapine due to CYP3A induction.
E. Adverse effects
Rash, elevated liver enzymes,
**Selected on the basis of activity toward HIV-resistant to more common
NNRTIs.
Resistance
• Persistent activity of etravirine despite mutations in active site is based
on concept of “strategic flexibility” – the newer NNRTIs can
accommodate up to 3-4 mutations in the binding pocket through
‘‘wiggling’’ (torsional flexibility) and ‘‘jiggling’’ (ability to reposition).
Dosage and recommendations
• Dosing is twice-daily.
• The drug will likely be reserved for patients who have failed traditional
treatment protocols and developed resistance to NNRTIs.
Raltegravir
viral integrase
inhibitors
• Inhibits strand-transfer actions mediated by HIV viral integrase.
• Binds Mg2+ in the active site of Integrase-DNA complex.
• Drug displaces the 3hydroxyl ends away from reactive center.
• Does not interact with the P450 system.
Dosage and recommendations
• A first-line therapy.
• Extremely potent.
Resistance
Mutations map to the integrase.
Adverse effects – few
Low toxicity increases chances that patients will adhere to long-term treatment
protocols.
Dolutegravir
viral integrase
inhibitors
Does not require boosting by cobicistat.
• Remains active in patients who have become resistant to earlier integrase inhibitors.
• Coformulated as Triumeq with abacavir and lamivudine. Once daily dosing.
Elvitegravir
viral integrase
inhibitors
Elvitegravir:
• Similar mechanism and resistance profile as raltegravir.
Darunavir
protease
inhibitors
Efficacy
1) Lower plasma RNA levels 100-1000 fold within 4-12 weeks of therapy.
2) When combined with two nucleoside analogs, 60-95% of first-time patients achieve
viral levels below detection limit.
3) Failures (appearance of resistant virus) are due to poor patient compliance.
B. Resistance
1) Resistance conferred by mutations in protease gene.
2) Generally occurs in a stepwise manner. Initial mutations confer low level resistance
that causes virus to replicate inefficiently. Compensatory mutations compensate for
replication defects.
C. Adverse Effects
1) Changes in body fat distribution - lipodystrophy syndrome or pseudo-Cushings
syndrome
2) Hyperlipidemia from interference of PIs with normal lipid metabolism.
3) Worsening glycemic control in patients w/ pre-existing diabetes, and cases of new
onset diabetes.
Pharmacodynamics
1) Administered orally.
2) Metabolized by
P450 CYP3A4 in liver and in intestinal epithelial cells.
3) Substrates for multidrug efflux pumps, which limits intracellular concentration.
F. Drug Interactions
1) Many drug interactions tied to interactions of PIs with P450s (CYP3A4).
Examples:
Antifungal ketoconazole inhibits CYP3A4 and causes PIs to increase.
Rifampin causes CYP induction resulting in decrease of Protease inhibitors
General
• Active against some HIV isolates that are resistant to other PIs.
.
Pharmacodynamics.
• Inhibitor and substrate of CYP3A.
• Take orally 2x daily.
Atazanavir
protease
inhibitors
Efficacy
1) Lower plasma RNA levels 100-1000 fold within 4-12 weeks of therapy.
2) When combined with two nucleoside analogs, 60-95% of first-time patients achieve
viral levels below detection limit.
3) Failures (appearance of resistant virus) are due to poor patient compliance.
B. Resistance
1) Resistance conferred by mutations in protease gene.
2) Generally occurs in a stepwise manner. Initial mutations confer low level resistance
that causes virus to replicate inefficiently. Compensatory mutations compensate for
replication defects.
C. Adverse Effects
1) Changes in body fat distribution - lipodystrophy syndrome or pseudo-Cushings
syndrome
2) Hyperlipidemia from interference of PIs with normal lipid metabolism.
3) Worsening glycemic control in patients w/ pre-existing diabetes, and cases of new
onset diabetes.
Pharmacodynamics
1) Administered orally.
2) Metabolized by
P450 CYP3A4 in liver and in intestinal epithelial cells.
3) Substrates for multidrug efflux pumps, which limits intracellular concentration.
F. Drug Interactions
1) Many drug interactions tied to interactions of PIs with P450s (CYP3A4).
Examples:
Antifungal ketoconazole inhibits CYP3A4 and causes PIs to increase.
Rifampin causes CYP induction resulting in decrease of Protease inhibitors
An azapeptide with a distinct structure and resistance profile. As effective as previous
protease inhibitors. However, once daily dosing with fewer untoward effects on lipid
profiles.
Certain antacids, and proton pump inhibitors, interfere with absorption.
Take with food.
Drug is degraded in liver and can cause many drug interactions because it is processed
by CYP3A4. Side effects include hyperbilirubinemia w/ or w/o jaundice or scleral
icterus.
Ritonavir
protease
inhibitors
Efficacy
1) Lower plasma RNA levels 100-1000 fold within 4-12 weeks of therapy.
2) When combined with two nucleoside analogs, 60-95% of first-time patients achieve
viral levels below detection limit.
3) Failures (appearance of resistant virus) are due to poor patient compliance.
B. Resistance
1) Resistance conferred by mutations in protease gene.
2) Generally occurs in a stepwise manner. Initial mutations confer low level resistance
that causes virus to replicate inefficiently. Compensatory mutations compensate for
replication defects.
C. Adverse Effects
1) Changes in body fat distribution - lipodystrophy syndrome or pseudo-Cushings
syndrome
2) Hyperlipidemia from interference of PIs with normal lipid metabolism.
3) Worsening glycemic control in patients w/ pre-existing diabetes, and cases of new
onset diabetes.
Pharmacodynamics
1) Administered orally.
2) Metabolized by
P450 CYP3A4 in liver and in intestinal epithelial cells.
3) Substrates for multidrug efflux pumps, which limits intracellular concentration.
F. Drug Interactions
1) Many drug interactions tied to interactions of PIs with P450s (CYP3A4).
Examples:
Antifungal ketoconazole inhibits CYP3A4 and causes PIs to increase.
Rifampin causes CYP induction resulting in decrease of Protease inhibitors
Truvada
Emitricitabine + tenofovir disoproxil fumarate: inhibits reverse transcriptase
Triumeq
Dolutegravir, abacavir and lamivudine. Once daily dosing.
• Avoid in HLA-B*5701 positive patients because of potential abacavir sensitivity.
Stribild
once-a-day combo pill
(Stribild) containing elvitegravir/cobicistat/emtricitabine//tenofovir disproxil fumarate
• Cobicistat boosts elvitegravir half-life by inhibiting CYP3A4 metabolism. Cobicistat
has no anti-viral activity of its own.
• Caution required regarding cobicistat, CYP3A4 and drug-drug interactions.
Genvoya
Elvitegravir/cobicistat/emtricitabine,/tenofovir alafenamide
Protease inhibitors
First drugs mimicked peptides and resembled phenylalanine-proline cleavage site.
3) Each is an analog of the transition state. A tertiary alcohol often with a recognizable phenylalanine.
4) All viral protease inhibitors bind the active site reversibly. In general, the protease inhibitors make
many contacts with enzyme. Reduces ease in acquiring resistance.
5) No cross reaction with other proteases - serine cysteine, or metalloproteases.
acyclovir
herpes CMV nucleoside analog
Mechanism
• Guanosine derivative, viral DNA replication inhibitor
• Monophosphorylation by viral thymidine kinase (HSV-TK).
• Di and tri phosphorylation by host enzymes.
• Phosphorylation traps drug within infected cells (40-100 fold enrichment).
• The triphosphate form competes with dGTP to bind viral DNA polymerase.
• Also acts as chain terminator.
Resistance
• Resistance due largely to mutations in HSV-TK but also viral DNA polymerase.
•
Pharmacodynamics
• Available in oral, topical, and IV formulations.
Adverse reactions
• Generally well tolerated when taken orally.
• Nausea, diarrhea, rash, headache.
• IV acyclovir is limited by renal insufficiency and CNS effects. Use slow infusion rate.
• No evidence of teratogenic or carcinogenic effects despite nucleoside structure.
cidofovir
herpes CMV cytidine nucleotide analog (already has a single phosphate)
Mechanism
• Taken up by both infected and noninfected cells.
• Two additional phosphates added by host enzymes.
• Active drug competes with dCTP for binding viral enzyme.
• Also chain terminates.
Resistance
• Resistance due to mutations in viral DNA polymerase.
Pharmacodynamics
• Diphosphate compound has t1/2 of 17-65 hours. Infrequent dosing an advantage.
• Initial phosphate on drug means it has low oral bioavailability
Adverse effects
Probenecid blocks tubular transport of cidofovir, thereby reducing renal clearance and
associated nephrotoxicity.
Dose dependent nephrotoxicity. Must monitor renal function.
• Concurrent administration with other nephrotoxic agents should be avoided.
•
• Probenecid causes GI distress – take w/food, anti-emetics, antihistamines, or acetaminophen.
topical nucleoside
analogs for herpes, cytomegalovirus
herpes CMV nucleoside analog
trifluridine and vidarabine, Too toxic for anything other than ophthalmic use.
foscarnet
Herpes, CMV drug
Mechanism
-structurally just looks like only a diphosphate, doesn’t bind human nuc polymerase
• Blocks viral DNA polymerase, viral RNA polymerase, and HIV RT directly.
• Drug binds these enzymes in pocket that typically holds triphosphates and prevents cleavage.
• Works 100 fold better on viral than on host polymerases.
Resistance
• Resistance associated with appearance of mutations in viral DNA polymerase.
• Activity remains against ganciclovir and cidofovir resistant strains.
Pharmacodynamics
• Oral availability is low. Given by IV.
• Taken up slowly by cells but does not undergo much intracellular metabolism.
Adverse effects
• Dose-limiting effects are nephrotoxicity and changes in the levels of Ca2+ and phosphate.
• Penile ulcerations due to high levels of ionized drug in urine.
• CNS toxicities (25% of patients) including headache, hallucinations, and seizures.
amantadine
influenza viral exit
inhibitors
Mechanism
• Virus enters cell by endocytosis. Particles arrive in endosomes, which are then acidified.
• Low pH causes cleavage of hemagglutinin on viral surface and activation of the viral M2
ion channel.
• Amantadine and rimantidine bind to the M2 protein and block the unsheathing process.
Resistance
• Most circulating strains were resistant to these drugs in the 2014-15 season. The warning
is still in effect.
• Not effective against influenza B.
• Resistance emerges upon mutation of M2.
Pharmacodynamics
• Well absorbed by oral administration
• Very large Vd
• Amantidine excreted unmetabolized in urine. Levels rise with renal insufficiency
Adverse effects
• Minor dose-related GI problems.
• CNS disturbances - nervousness, lightheadedness, difficulty concentrating
(less so w/ rimantadine)
rimantidine
influenza viral exit
inhibitors
Mechanism
• Virus enters cell by endocytosis. Particles arrive in endosomes, which are then acidified.
• Low pH causes cleavage of hemagglutinin on viral surface and activation of the viral M2
ion channel.
• Amantadine and rimantidine bind to the M2 protein and block the unsheathing process.
Resistance
• Most circulating strains were resistant to these drugs in the 2014-15 season. The warning
is still in effect.
• Not effective against influenza B.
• Resistance emerges upon mutation of M2
Pharmacodynamics
• Well absorbed by oral administration
• Very large Vd
*• Rimantidine is metabolized by hydroxylation, conjugation and glucuronidation
before excretion..
Adverse effects
• Minor dose-related GI problems.
• CNS disturbances - nervousness, lightheadedness, difficulty concentrating
(less so w/ rimantadine)
zanamivir
influenza viral exit
inhibitors
Neuramidase inhibitors
*Zanamivr is an inhaled drug to overcome low oral bioavailability of zanamivir is low.
• Viral neuramidase cleaves sialic residues from receptors on surface of virus and host cells.
• Uncleaved sialic residues bind viral hemagglutinin causing viral particles to aggregate.
• These drugs are sialic acid, transition-state analogs that inhibit viral neuraminidase activity.
• Therefore, the drugs reduce viral escape from infected cells, preventing infection of others.
• The drugs work on neuraminidase of both influenza A and B viruses.
• Resistance to drug appears with mutations in the neuraminidase gene or hemagglutinin.
oseltamivir
influenza viral exit
inhibitors
Neuramidase inhibitors
* Oseltamivir is a prodrug that is taken orally. Activated by esterases in GI or liver
• Viral neuramidase cleaves sialic residues from receptors on surface of virus and host cells.
• Uncleaved sialic residues bind viral hemagglutinin causing viral particles to aggregate.
• These drugs are sialic acid, transition-state analogs that inhibit viral neuraminidase activity.
• Therefore, the drugs reduce viral escape from infected cells, preventing infection of others.
• The drugs work on neuraminidase of both influenza A and B viruses.
• Resistance to drug appears with mutations in the neuraminidase gene or hemagglutinin.
interferons
Interferons - human proteins with antiviral, immunmodulating, and antiproliferative actions
• Three types of interferons made: α, β, and γ.
• IFN activate JAK-STAT signal transduction pathway, activating IFN responsive genes.
• Yields two dozen gene products that contribute to anti-viral defense (see figure).
• IFN-induced major histocompatability antigens enhance the lytic effects of cytotoxic T
lymphocytes, which may contribute to antiviral actions of IFN.
Pharmacodynamics
• IFN is linked to polyethylene glycol (PEG), which increases its half-life from 2-3 to 54
hours. Allows less frequent injections.
• Peg-IFN/ribavirin only effective in about 50% of HCV patients! 48 week treatment!
Adverse effects – MANY!!!!!
• Up to 1/3 of people taking IFNs must stop early due to side effects.
• Dose-limiting toxicities are myelosuppression with granulocytopenia and thrombocytopenia.
• Neurotoxicity, autoimmune disorders, hepatotoxicity.
• Psychiatric disorders including depression which can be treated with anti-depressants.
• Contraindicated for hepatic decompensation, autoimmune disease, severe heart disease,
kidney disease, poorly controlled psychiatric conditions.
• Acute influenza-like syndrome beginning several hours after injection. Symptoms resolve
and tolerance gradually develops. Treat febrile response with antipyretics.
Drug interactions
**• IFN reduces P450 metabolism of other drugs (eg. IFN increases levels of theophylline)
PEG-IFN is considered a first-line treatment for HBV
tenofovir
HBV nucleoside analogs
Tenofovir (tenofovir disproxil fumarate)
• Synthetic adenosine analog with a phosphate. Technically a nucleotide RT inhibitor.
• Presence of first phosphate overcomes rate limiting phosphorylation step in CD4+ cells.
• Protective groups stripped in plasma before transport into cells.
• Drug acts by competing with dATP for binding HIV RT and then chain terminates.
• Interacts little with P450s thus few drug-drug interactions.
• Systemic use can cause nephrotoxicity and decrease in bone mineral density.
• Resistance develops slowly. The drug retains activity even with resistance to other NR
entecavir
HBV nucleoside analogs
General
• Guanosine nucleoside analog recently approved by FDA for HBV.
• Prodrug is triphosphorylated inside cells
Comparison to other drugs
• Drug is chain terminator for HBV RT.
• Inhibits both first and second strand synthesis.
• 3’-hydroxyl allows additional bases to be added before termination.
• ***Distortion of DNA end blocks further synthesis.
• Long half-life allows once-daily dosing.
• Entecavir only suppresses HBV. It does not eradicate chronic HBV infections. Rebounding occurs
when treatment stopped. Therefore, treat for life. Expensive and ultimate possibility of resistance.
Resistance
• Resistance requires two mutations. Thus, not much resistance seen yet.
• Lamivudine (for HIV) was first drug of this class for HBV and it is still in wide-spread use.
However, resistance emerges rapidly, and this accelerates cross-resistance to entecavir.
Few adverse effects
• Headache, fatigue, dizziness, nausea
ribavirin
HCV nucleoside analogs
Guanosine analog that is phosphorylated by host enzymes.
• Multiple targets conspire to lower cellular GTP levels (synthesis
inhibitor). Also inhibits viral mRNA capping and RNA virus replication.
Pharmacodynamics
• Absorbed by GI nucleoside transporters. Food helps.
• Avidly enters cells thus yielding a large Vd.
• t1/2 = 30-40 hours initially, but 200-300 at steady state.
• Eliminated by hepatic metabolism and renal excretion of both drug and its metabolites.
Adverse effects
• 10% of patients experience dose-dependent hemolytic anemia.
• Psychiatric side-effects.
• Teratogenic in animals. Keep away from pregnant patients and health care providers.
• Aerosolized ribavarin may cause mild conjunctival irritation, rash transient wheezing…
• Dose-dependent hemolytic anemia.
