Pharmacology: Test 4: Antiviral Drugs Lec 66 And 67

Front 1

Penetration and Uncoating: AMANTADINE, RIMANTADINE

Back 1

Interfere w/ VIRAL UNCOATING.

propylaxis in Influeza A, and reduce sx if tx w/in initial 48 hrs.

Inhibits viral uncoating by blocking viral membrane protein, M2 proton channel.

Rapidly adsorption, secreted unmetabolized in urine T1/2 20hrs

NOT EFFECTIVE against H5N1.

15% resistance.

Front 2

Penetration and Uncoating: DOCOSANOL

Back 2

saturated fatty alcohol, INHIBITS FUSION OF VIRAL ENVELOPE to cell membrane

Effective for tx of HERPES LABIALIS (HSV 1)

Front 3

Penetration and Uncoating: ENFUVIRTIDE

Back 3

36 residue synth peptide, based on seq of HIV gp41, BLOCKS FUSION OF THE HIV VIRION TO LYMPHOCYTE.

Adverse eff: hypersensitivity and pneumonia

Front 4

Assembly and Release: Neuraminidase inhibitor: Zanamivir and Oseltamivir (Tamiflu)

Back 4

prophylaxis and tx of Influenza A and B ifxn. Reduce sx if given within 48 hrs.

Front 5

Assembly and Release: Neuraminidase inhibitor: Zanamivir and Oseltamivir (Tamiflu)-- Mech of action

Back 5

inhibits viral neuraminidase, thereby inhibiting cleavage of sialic aid from glycoproteins, glycolipids and oligosaccharides.

So, end result is: blocks budding of new virus, slows viral spread through respiratory tract

Zanamivir: inhalation; may cause bronchospasm and decrease lung funxn.

oseltamivir: a prodrug, oral admin; nausea and vomiting in >10% pts

SOME EFFECTIVENSS AGAINST H5N1

Front 6

Humanized Monoclonal Ab: PALIVIZUMAB

Back 6

against the F PROTEIN of RSV

approved for prophylactic tx of RSV infxn in high-risk infants
Side effects: Fever, Pneumonia

Front 7

Viral Nucleic Acid Synthesis: TRIFLURIDINE

Back 7

thymidine analogue, in which 3 H in the 5-methyl group been replaced with fluorines, which inhibits THYMIDYLATE SYNTHETASE and feedback inhibits other steps in PYRIMIDINE BIOSYNTHESIS

Front 8

Viral Nucleic Acid Synthesis: TRIFLURIDINE -- Pharmacology

Back 8

rapidly metabolized by nucleotideases, so useful in METABOLICALLY INACTIVE sites i.e. eye

For tx of Herpetic Conjuctive Keratitis

Selectivity due to differential rate of viral and DNA cellular synthesis

Front 9

Viral Nucleic Acid Synthesis: RIBAVIRIN

Back 9

synthetic nucleoside containing 1,2,4 traizole carboxamide fused to a ribose ring moiety.

The phosphorylated form pertub intracellular nucleotide pools; monophophate inhibit INOSINE monophosphate dehydrogenase (essential for synthesis of GMP).

Tx: for RSV infxn in children (inhalation) and combo with IFN in Hep C.

Adv: some incidence of reversible anemia

Front 10

Viral Nucleic Acid Synthesis: ACYCLOVIR, VALACYCLOVIR (valtrex), Penciclovir, famciclovir

Back 10

guanosine analogue, having acyclic side chain instead of ribose moiety.

Effective: HSV1, HSV2, VZV

Drug of choice for herpes encephalitis, and varicella (chickenpox) in adolescents and adults.

Front 11

Viral Nucleic Acid Synthesis: ACYCLOVIR, VALACYCLOVIR (valtrex), Penciclovir, famciclovir -- Mech of Action

Back 11

Acyclovir is phosphorylated by THYMIDINE KINASE (TK). The triphosphate form is an extremely potent INHIBITOR of VIRAL DNA POLYMERASE.

Acyclovir also doesn't have 3'-OH, so incorporation in nascent DNA would result in chain termination.

Front 12

Viral Nucleic Acid Synthesis: ACYCLOVIR, VALACYCLOVIR (valtrex), Penciclovir, famciclovir -- Selectivity

Back 12

drug phosphorylated by TK which cellular enzymes lack. Thus only infected cells accumulate the triphosphate

Front 13

Viral Nucleic Acid Synthesis: ACYCLOVIR, VALACYCLOVIR (valtrex), Penciclovir, famciclovir -- Pharmacology

Back 13

Valacyclovir (Valtrex) is a prodrug form of acyclovir: Converted to acyclovir during first pass. Thus, oral admin yeiled 5x greater conc. REDUCES TRANSMISSION OF HSV-2 BY 50%.

Penciclovir: acyclovir analogue, for Herpes labialis (cold sores). It has prodrug form too (FAMCICLOVIR) for tx of herpes labialis and genital herpes.

Front 14

Viral Nucleic Acid Synthesis: ACYCLOVIR, VALACYCLOVIR (valtrex), Penciclovir, famciclovir -- Toxicity

Back 14

Oral: GI distress
IV: cause renal dysfunction.

Front 15

Viral Nucleic Acid Synthesis: Ganciclovir, valganciclovir

Back 15

also a acyclic guanine nucleoside analog, cosely related to cylcovir.

FOR CMV: inhibits CMV DNA Polymerase.

Catalyzed by CMV encoded UL97 PHOSPHOTRANSFERASE. Also, phosphorylated to some extent by cellular kinase (so more toxic)

Therefore, cause granulocytpenia and thrombocytopenia.

Limit use to severe infxn in immunosuppressive pts and CMV retinits.

Ganciclovir can be given as OCULAR implant.

valganciclovir is a PRODRUG form that is orally active.

Front 16

Nucleoside Reverse Transcriptase Inhibitor: Zidovudine (AZT)

Back 16

A synthetic thymidine analog in which 3'-OH replaced with azido group. Prolongs lives of AIDS pts and decrease mother to fetus transmission.

Front 17

Nucleoside Reverse Transcriptase Inhibitor: Zidovudine (AZT) -- Mech of action

Back 17

Triphosphate competes w/ dTTP for binding to RT, when incorporated into viral DNA, nascent chains are terminal due to absence of 3'-OH.

Selectivity based on 100x greater affinity of viral RT for AZT than thymidine than is host DNA POL

Front 18

Nucleoside Reverse Transcriptase Inhibitor: Zidovudine (AZT) -- Pharmacology

Back 18

well oral absorbtion, cleared rapidly (hepatic) t1/2 One hr.

Can slow metab and excretion with PROBENICID, ACETAMINOPHEN, and ASPIRIN.

Effective conc. in CNS reached.

Front 19

Nucleoside Reverse Transcriptase Inhibitor: Zidovudine (AZT) -- Toxicity and Resistance

Back 19

Resistance to AZT and other NRTIs due to mutations in HIV RT gene.

Tox: anemia, neutropenia. POTENTIAL TO INDUCE LACTIC ACIDOSIS as a result of mitochondrial toxicity.

Front 20

Nucleoside Reverse Transcriptase Inhibitor: OTHER NRTI's.

Back 20

didanosine (ddl): deoxyadenosine analog

lamivudine (3TC), emtricitabine: approved for Hep B tx

stavudine (d4T), zalcitabine (ddC):

abacavir: guanosine analog, less toxic than AZT

Entecavir: guanine nucleoside analog; Telbivudine: a thymidine analog ;; Inhibit Hep B RT and HBV DNA POL. Not effective against HIV.

Front 21

Nucleotide reverse transcriptase inhibitor: TENOFOVIR DISOPROXIL

Back 21

acyclic nucleoside phophonate that when converted to the 'diphosphate' inhibits HIV RT.

The lack of req't for nucleoside kinase activity provides for antiviral activity in RESTING CELLS.

Can increase conc. of didanosine , so when used in combo, increased risk of pancreatitis

Front 22

Nucleotide reverse transcriptase inhibitor: CIDOFOVIR

Back 22

another acyclic nucleoside phosphonate.

For tx of ganciclovir and foscarnet-resistant CMV retinitis.

Highly nephrotoxic , may be used for tx of small pox for small pox vaccine reactions

Front 23

Nucleotide reverse transcriptase inhibitor: ADEFOVIR

Back 23

for tx of Hep B, nephrotoxic.

Front 24

Non-nucleoside reverse transcriptase inhibitors: DELAVIRIDINE

Back 24

rash, fatigue, nausea etc

Front 25

Non-nucleoside reverse transcriptase inhibitors: NEVIRAPINE

Back 25

hepatotoxicity, epidermal necrolysis, STEVEN'S JOHNSON

Front 26

Non-nucleoside reverse transcriptase inhibitors: efavirenz

Back 26

nightmares, neuropsychological effects. NOT USED DURING PREGNANCY.

Front 27

Non-nucleoside reverse transcriptase inhibitors: delviridine, nevirapine, efavirenz

Back 27

These are all used in combo chemotherapy.

Front 28

Other inhibitors of viral DNA Synthesis: FORSCARNET

Back 28

inhibits HSV and CMV encoded DNA PL and HIV encoded RT

Effective against ganciclovir-resistant CMV retinitis in AIDS pts

acyclovir-resistant herpes simplex in AIDS pts

Nephrotoxic and symp hypocalcemia

Front 29

Protein Synthesis/proteolysis inhibition: HIV PROTEASE INHIBITORS

Back 29

Long List: amprenavir/fosamprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir

Front 30

Protein Synthesis/proteolysis inhibition: HIV PROTEASE INHIBITORS

Back 30

bind to the catalytic site of the HIV encoded Protease cleavage of multiprotein gag-pol precursor into mature viral protein products

Front 31

Protein Synthesis/proteolysis inhibition: HIV PROTEASE INHIBITORS ... Pharmacology

Back 31

should only be used in combo which includes one or more nucleoside analogs. Use of two different PI is more effective than a single inhibitor.

Inducers of CYP3A4 i.e. rifampin signif. decrease serum conc. of PIs.

Front 32

Protein Synthesis/proteolysis inhibition: HIV PROTEASE INHIBITORS -- drug Resistance

Back 32

result of mutation in HIV protease gene.

Front 33

Protein Synthesis/proteolysis inhibition: HIV PROTEASE INHIBITOR -- Toxicities

Back 33

Use of PI assoc. w/ LIPODYSTROPHIES. Increased total LDL, TGs and decreased HDL. Increase Hyperglycemia and MI.

Ritonavir-containing combo of protease inhibitors if used with Rifampin, can lead to drug induced HEPATITIS.

Front 34

Protein Synthesis Inhibitor: INTERFERON

Back 34

a glycoprotein with broad in vitro spectrum antiviral activity.

Interferon Alpha (2a, 2b, n1 and alfacon-1) approved for Chronic Hep B and C and malignancies.

IFN alpha nad n3 used for condyloma acuminata.

Tx of Hep C in combo with Ribavirin.

IFN alfa-2b reduces frequency of chronic infection.

Front 35

Protein Synthesis Inhibitor: INTERFERON -- Mech of action

Back 35

effect exerted at level of viral protein synthesis:

Two IFN induced enzymes participate in inhibition of viral protein synth:
1. Induction of DS RNA-dependant protein kinase (PKR) that selectively phosphorylate protein synth factor eIF2.

2. inductin of RNA-dependant 2'-5' oligoadenylate synthetase, which produces enzymes that activate a potent RNase that degrades viral message.

IFN also reduces inflammatory cytokine expression in pts with Hep C.

Front 36

Protein Synthesis Inhibitor: INTERFERON -- Pharmacology

Back 36

admin IM or IV; t1/2 if 2 hrs, biologic half life much longer

PegIFN have longer half life (45 hrs) and requires less freq administration

Front 37

Protein Synthesis Inhibitor: INTERFERON -- Toxicities

Back 37

bone marrow supression (granulocytopenia, thrombocytopenia) and neurotoxicity, acute toxicities incl. flu like sx, alopecia, depression, and GI distress.

Front 38

Antisense Oligonucleotides: FOMIVIRSEN

Back 38

antisense oligonucleotide complementary to immediate-early transcriptional unit (IE2) of CMV.

It binds to IE2 mRNA resulting in decreased expression of IE-encoded proteins.

Administered IV to treat CMV retinitis in AIDS pts.

Front 39

Antifungal: Polyenes; NYSTATIN, AMPHOTERICIN B

Back 39

characterized by conjugated double bond system with a macrolide ring. Ring is closed by internal ester or lactone.

Effective against Histoplasma capsulatum, cryptococcus neoformans, blastomyces dermatidis, coccodiodes immitis, candida, and spororthrix schenkii.

Front 40

Antifungal: Polyenes; NYSTATIN, AMPHOTERICIN B -- Mech of ACtion

Back 40

polyenes bind tightly to sterols (ergosterol) in serum and cell membrane. This causes membrane disturbance and leakage in the cell components and altered membrane transport.

Front 41

Antifungal: Polyenes; NYSTATIN, AMPHOTERICIN B --- Selectivity

Back 41

fungal membrane sterol is ergosterol instead of cholesterol. These drugs have greater affinity for ergosterol than cholesterol

Front 42

Antifungal: Polyenes; NYSTATIN, AMPHOTERICIN B --Pharmacology

Back 42

extremely insoluble, and poorly absorbed orally.

Nystatin virtually insoluble; used for superficial and GI infection.

Amp B more potent than nystatin and soluble enough for IV administration and distributed to all body components. Excreted in urine.

Front 43

Antifungal: Polyenes; NYSTATIN, AMPHOTERICIN B -- Toxicity

Back 43

Amp B: principal side effect Renal Fxn, decrease in GFR

Liposomal prep are available with decreased toxicity, but more expensive.

Front 44

Antifungal: AZOLES

Back 44

This includes fluconazole, itraconazole, ketoconazole, posoconazole, voriconazole

effective in tx of variety of superficial and systemic fungal infxn.

Front 45

Antifungal: AZOLES -- Mech of action

Back 45

inhibition of 14-ALPHA-DEMETHYLASE, a Cyt p450 involved in Ergosterol biosynthesis, thus resulting in membrane with altered permeability.

Selectivity: fungal sterol biosynthesis more sensitive to inhibition than mammalian (However, Ketoconazole does inhibit other mammalian p450 and reduce adrenal and gonadal steroid biosynthesis.)

Front 46

Antifungal: AZOLES -- some specific

Back 46

Miconazole: exclusively topical form.

Ketoconazole, fluconazole, itraconazole: suitable for oral use

Itraconazole: suitable for nails** and dermatophytosis

Voriconazole: invasive aspergillosis

Fluconazole: good CNS penetration, tx of AIDS associated cryptococcal meningitis, and candida esophagitis.

Posoconazole: for fluconazole and itraconazole-resistant candidiasis.

No renal toxicitiy, metabolism is mainly HEPATIC.

Front 47

Antifungal: AZOLES -- Toxicities

Back 47

gynecomastia, Ketoconazole inhibit other mammalian p450s and reduce adrenal and gonadal steroid biosynthesis.

Itraconazole can precipitate CHF in susceptible pts.

Front 48

Antifungal: AZOLES -- Resistance

Back 48

overproduction of 14-alpha-demethylase (gene amplification) and efflux via MDR-like efflux pump.

Front 49

Antifungal: Allylamines: TERBINAFINE

Back 49

Inhibits fungal SQUALENE EPOXIDE

when used topically, effective against crusi, pedis, corporis.

Orally: efective tx of cutaneous tinea infxn, cutaneous candidiasis.

As effective as GRISEOFULVIN for tx tinea cruris and corporis. MORE effective for onychomycosis and moccasin type tinea pedis.

hepatic metabolism

Tox: alopecia, contact dermatitis, hepatotoxity