1

6. ANTIVIRAL DRUGS

Dr. Racha KARAKY

Pharmacology

Faculty of Pharmacy
4th year – S2
 Outline
2

 Drugs for Herpesvirus infections

 Drugs for influenza

 Drugs for hepatitis

 Drugs for HIV infection (antiretroviral drugs)

 Introduction
3

 Viruses are obligate intracellular parasites that use the

host cell’s metabolic pathways for reproduction

 General mechanisms of action

 Antimetabolites of endogenous nucleosides and prevent the
replication of viral nucleic acid.
 Inhibition of the entry, uncoating, or release and spread of
the virus.

 Other targets for antiviral therapy are currently being

investigated.
4 Drugs for Herpesvirus infections
 Introduction
5

 All herpesviruses are DNA viruses.

 The most common examples are
 Herpes simplex virus (HSV)
 Varicella-zoster virus (VZV)
 Cytomegalovirus (CMV)

Virus Infection
HSV herpes genitalis  genital herpes infection
herpes labialis  infection of the lips and mouth
herpetic keratoconjunctivitis  infection of the cornea and conjunctiva
herpetic encephalitis  less common, potentially fatal disease.
VZV Chickenpox = varicella
Shingles = herpes zoster results from activation of latent VZV in dorsal root ganglia
 skin lesions + pain + postherpetic neuralgia (complication)
CMV Immunocompetent individuals  usually asymptomatic
Symptomatic CMV / retinitis, esophagitis, and colitis  immunocompromised patients
 Replicative cycle of Herpesvirus
6
 Anti-Herpesvirus agents
7

Anti-Herpes virus drugs

Nucleoside analogues Foscarnet

Acyclovir Penciclovir Ganciclovir

Cidofovir
Valacyclovir Famciclovir Valganciclovir
 Mechanism of action : Nucleoside
8
analogues
 Nucleoside analogues are prodrugs
 Initially converted to monophosphate metabolites by a virus-encoded
thymidine kinase  conversion occurs only in infected host cells 
selective toxicity
 Host cell kinases subsequently convert the monophosphates to active
triphosphate metabolites  compete with endogenous nucleoside
triphosphates  competitively inhibit viral DNA polymerase  prevent
viral DNA synthesis
 Mechanism of action : Nucleoside
9
analogues
 Nucleoside analogues are prodrugs

Some nucleoside analogues (e.g., acyclovir) are incorporated into nascent viral
DNA and cause DNA chain termination because they lack the 3'-hydroxyl group
required for attachment of the next nucleoside
Other analogues (e.g., ganciclovir and penciclovir) inhibit viral DNA polymerase but do
not cause DNA chain termination.
 Mechanism of action : Nucleoside
10
analogues
 Resistance : Nucleoside analogues
11

 Three mechanisms:
 Impaired production of viral thymidine kinase (most
common)
 Altered thymidine kinase substrate specificity (e.g.,
phosphorylation of thymidine but not acyclovir)
 Altered viral DNA polymerase (rare)

 Resistant variants are present in native virus

populations and in isolates from treated patients.
 Acyclovir & Valacyclovir
12

 Acyclovir ZOVIRAX (p.o., IV, topical)

 Valacyclovir VALTREX (p.o.)

 Valacyclovir  ester prodrug of acyclovir (completely

hydrolyzed into acyclovir)

 Mechanism : nucleoside analogs

 Suicide inactivation  terminated DNA template containing
acyclovir binds the viral DNA polymerase  irreversible
inactivation

 Spectrum :
 Clinically useful antiviral spectrum is limited to herpesviruses
 HSV-1 > HSV-2 >> VZV or EBV >>> CMV
 Acyclovir & Valacyclovir
13

 PK
 Bioavailability : acyclovir 20% ; valacyclovir 70%
 Valacyclovir hydrolyzed into acyclovir by first-pass intestinal and
hepatic metabolism
 Wide distribution (including CNS)
 t1/2 of acyclovir ~2.5 hours
 Principal route of elimination : Renal excretion of unmetabolized
acyclovir by glomerular filtration and tubular secretion

 Adverse effects
 Very well tolerated
 Local use  mucosal irritation and transient burning (genital
application)
 Orally  nausea, diarrhea, rash, or headache
 High doses : CNS signs (confusion and hallucinations) & nephrotoxicity
 IV  renal insufficiency and CNS side effects (dose-limiting)
 Famciclovir & Penciclovir
14
 Famciclovir FAMVIR (p.o.)
 Penciclovir (topical)
 Famciclovir = prodrug  penciclovir (nucleoside analogue)
 Penciclovir versus acyclovir
 Same spectrum of activity
 Competitive inhibitor of viral DNA polymerase
 Potency = 1/100 acyclovir
 present in much higher concentrations and for more prolonged periods in infected
cells than acyclovir
 has a 3'-hydroxyl group  not an obligate chain terminator but does inhibit DNA
elongation
 Cross resistance between drugs (same mechanisms of resistance)
 Same adverse effects (p.o.)
 No clinically relevant drug interactions

 PK
 Bioavailability p.o. : famciclovir 75% ; penciclovir 5%
 Penciclovir : Renal clearance as unchanged form
 Ganciclovir & Valganciclovir
15

 Ganciclovir CYMEVEN (IV)

 Valganciclovir VALCYTE (p.o.)
 Valganciclovir = prodrug  Ganciclovir (nucleoside analogue)
 Spectrum : all herpes viruses and especially active against CMV
 Competitive inhibitor of DNA  cessation of DNA chain elongation
 Intracellular ganciclovirTP t1/2 >24 hours  QD
 Cross resistance with acyclovir and cidofovir
 PK
 Oral bioavailability: ganciclovir 6-9%, Valganciclovir 61%
 >90% of ganciclovir eliminated unchanged by renal excretion

 Adverse effects
 Dose-limiting toxicity = myelosuppression (reversible after D/C)
 Oral valganciclovir : headache and GI disturbance (i.e., nausea, pain, and diarrhea)

 Zidovudine, cytotoxic agents, nephrotoxic agents  risk of myelosuppression

 Cidofovir
16
 Nucleoside analogue (IV)
 Large spectrum of activity  herpes, papilloma, polyoma, pox, and
adenoviruses
 Phosphorylated by cellular but not virus enzymes 
 Less selective toxicity towards uninfected cells
 May inhibit acyclovir- or ganciclovir- resistant strains including deficient or altered
thymidine kinase (TK)
 Competitive inhibitor of DNA polymerases
 Resistance : mutations in viral DNA polymerases
 PK
 Prolonged intracellular t1/2  once a week administration
 > 90% cleared unchanged in the urine

 Adverse effects
 Dose-limiting toxicity : nephrotoxicity ( by probenecid and saline prehydration )
 Topical  dose-related application-site reactions (e.g., burning, pain, and pruritus)

 Approved for the treatment of CMV retinitis in HIV-infected patients

 Foscarnet
17

 Pyrophosphate analog
 Spectrum : all herpesviruses & HIV
 Effective against most ganciclovir-resistant CMV and acyclovir-resistant HSV and
VZV strains.

 Mechanism of action
 Direct interaction with herpesvirus DNA polymerase or HIV reverse transcriptase
 Noncompetitive binding to pyrophosphate-binding site of viral polymerase 
prevents cleavage of the pyrophosphate from nucleoside triphosphates  blocks
viral nucleic acid synthesis

 Resistance : mutations in the viral DNA polymerase

 PK
 IV administration (very low oral bioavailability)
 Wide distribution including CNS
 > 80% excreted unchanged in the urine
 Terminal t1/2 = 3-4 days
 Foscarnet
18

 Adverse effects
 dose-limiting toxicities = nephrotoxicity and symptomatic
hypocalcemia (due to chelation of the drug with divalent
cations)
 Neurotoxicity : headache, tremor, irritability, seizures, and
hallucinosis
 Hematologic toxicity : anemia, leukopenia
 Cardiotoxicity

 Indications
 CMV retinitis in AIDS patients, including ganciclovir-resistant
infections
 Acyclovir-resistant HSV and VZV infections
19 Drugs for influenza
 Introduction
20

 Influenza is one of the most common causes of infectious disease–related

deaths
 Caused by orthomyxoviruses = RNA virus
 Vaccines are the primary means of prevention
 Replicative cycle :
 The surface of influenza virus A is decorated with three proteins: an M2 ion channel
protein, the lectin haemagglutinin and the enzyme neuraminidase (sialidase)
 Virus adheres to the target host cell by using its surface glycoprotein haemagglutinin
to recognize glycoconjugates
 After endocytosis, the M2 protein of influenza virus allows an influx of hydrogen ions
into the virion interior  dissociation of the RNP (ribonuclear protein) segments 
release into the cytoplasm (uncoating).
 Host-cell machinery is engaged to produce the necessary viral components.
 Subsequent viral protein synthesis and particle assembly in the host cell prepares the
virion progeny for the budding process to exit the host cell.
 The action of neuraminidase enables the host-cell-surface aggregated virion
progeny to elute away from the infected cell and seek new host cells to infect
 Replicative cycle of influenza cycle
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 Anti-influenza drugs
22

Anti-influenza drugs

Inhibitors of viral Neuraminidase

uncoating (and assembly) inhibitors

Amantadine Oseltamivir
Rimantadine Zanamivir
 Amantadine & Rimantadine
23

 Amantadine SYMMETREL (p.o.)

 Potency : rimantadine = 4-10x amantadine
 Spectrum : influenza A viruses (prophylaxis & treatment)
 Mechanism of action
 Interfere with function of the M2 protein (ion channel) 
prevent acidification of influenza type A virus and the fusion
of viral membranes and endosomes required for uncoating
and transfer of viral nucleic acid into the host cell cytoplasm
 Resistance
 Mutation in the RNA sequence encoding for the M2 protein
 Resistant isolates typically appear in the treated patient within
2-3 days of starting therapy (cross resistance for both)
 Amantadine & Rimantadine
24

 PK
 Well absorbed orally
 Wide distribution
 Rimantadine : metabolic clearance
 Amantadine : Renal excretion

 Adverse effects
 Minor dose-related CNS and GI effects
 CNS :
 Nervousness, difficulty concentrating, insomnia, loss of appetite or
nausea
 Amantadine > rimantadine
 Appears mainly in elderly & concomitant ingestion of antiH1 and
psychotropic drugs
 Neuraminidase
25

 The viral surface glycoprotein (hemaglutinin) binds to sialic

acid residues on the surface of respiratory epithelial cells.
 This interaction is necessary for initiation of infection.
 After viral replication in the host cell, virions are similarly
bound to these host cell glycoproteins

 Neuraminidase catalyzes reactions that promote viral

spreading and infection.
 First, it enables the release of virions from the surface of
infected cells after viral replication.
 Second, it inactivates respiratory tract mucus that would otherwise
prevent spreading of virions through the respiratory tract.

 Neuraminidase accomplishes this by cleaving sialic acid

residues attached to cells/ mucus proteins
 Neuraminidase inhibitors
26
 Neuraminidase inhibitors
27

 Oseltamivir TAMIFLU (p.o.)

 Zanamivir RELENZA (inhalation)
 Inhibit the neuraminidases of influenza A and B viruses
 Mechanism of action
 Conformational change within the enzyme's active site  inhibits its
activity  viral aggregation at the cell surface and reduced virus
spread within the respiratory tract

 Resistance
 Hemagglutinin and/or neuraminidase mutations

 Neuraminidase inhibitors
 Are useful for prophylaxis & treatment during outbreaks
 Can shorten the duration of illness in infected persons if administered
less than 3 days after the onset of symptoms, preferably within the first
48 hours.
 Can prevent complications
 Neuraminidase inhibitors
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 PK
 Oseltamivir : prodrug  active carboxylate by esterases in
the GI tract and liver
 Oral bioavailability (carboxylate)= 80%
 Oral bioavailability of zanamivir is low (<5%)  oral
inhalation
 Renal clearance

 Adverse effects
 Oseltamivir : GI irritation  nausea, abdominal discomfort,
and emesis ( when ingested with food)
 Zanamivir : Wheezing and bronchospasm  not
recommended for treatment of patients with underlying
airway disease (e.g., asthma or COPD)
29 Drugs for hepatitis
 Introduction
30

 Hepatitis B = HBV  DNA virus (hepadnaviruses)

 Transcribed into DNA that can be integrated into host chromosomal DNA
 lifelong chronic infection in ~10% of patients.
 Chronic infection  Active hepatitis  fibrosis and cirrhosis
 incidence of hepatocellular carcinoma
 Interferon  ribavirin  high rate of adverse effects
 Nucleoside or nucleotide analog polymerase inhibitors (anti-HIV)

 Hepatitis C = HCV  RNA virus (flaviviruses)

 Untreated  progressive hepatocellular injury with fibrosis and eventual
cirrhosis
 Chronic HCV is also a major risk factor for hepatocellular carcinoma
 Current standard of care = combination of peginterferon alfa and
ribavirin  high cure rate

 Hepatitis A = HAV  RNA virus (picornaviruses)

 Antihepatitis drugs
31

Hepatitis C Hepatitis B

Interferon Interferon

Ribavirin Ribavirin

Entecavir
Nucleoside Lamivudine
analogues Telbivudine
Clevudine

Nucleotide Adefovir
analogues Tenofovir
 Ribavirin REBETOL
32

 Purine nucleoside analog (p.o., IV, inhalation)

 Mechanism of action
 Intracellular phosphorylation is mediated by host cell enzymes
 Ribavirin monophosphate inhibits purine metabolism by inhibiting
inosine monophosphate dehydrogenase (IMPDH)  deficiency of GTP
 Block the synthesis of viral DNA and RNA
 Block activity of GTP-dependent enzymes
 Ribavirin triphosphate
 Competitively inhibits the GTP-dependent 5' capping of viral mRNA
 Inhibits viral-dependent RNA polymerases and reverse transcriptase
 Large spectrum of activity
 RNA  orthomyxoviruses (influenza), paramyxoviruses (measles, mumps,
parainfluenza virus, respiratory syncytial virus), arenaviruses
(meningitis, Lassa fever), flaviviruses (West Nile meningoencephalitis,
yellow fever, hepatitis C),
 DNA  hepadnaviruses (hepatitis B [HBV])
 Ribavirin REBETOL
33

 PK
 Oral bioavailability ~50%
 Wide distribution
 Hepatic metabolism and renal excretion of ribavirin and its
metabolites are the principal routes of elimination

 Adverse effects
 Inhalation  transient wheezing, and occasional reversible
deterioration in pulmonary function
 Oral  hemolytic anemia
 Antagonizes the antiviral effect of zidovudine

 Specifically approved for the treatment of severe RSV

infection and chronic HCV (+ interferon).
 34

ANTIRETROVIRAL DRUGS
 Introduction
35

 Human immunodeficiency viruses (HIV) are lentiviruses = retrovirus

 Establish chronic persistent infection with gradual onset of clinical
symptoms
 Humans and nonhuman primates are the only natural hosts
 2 major families : HIV-1& HIV-2
 Both share similar in vitro sensitivity to most antiretroviral drugs
 Exception : non-nucleoside reverse transcriptase inhibitors (NNRTIs) &
Enfuvirtide are HIV-1-specific

 Drugs prevent infection of susceptible cells but do not eradicate the

virus from cells that already harbor integrated proviral DNA.
 Highly active antiretroviral therapy (HAART) = combined use of two
or more drugs from different classes  markedly reduce viral loads
and improve survival in HIV-positive individuals.
 Replicative cycle
36

120

Polyproteins
 Replicative cycle
37

 Viral replication begins when glycoprotein 120 on the

surface of HIV-1 binds to the CD4 antigen on the surface of
HIV-specific helper lymphocytes (CD4 cells).

 Binding of gp120 to CD4 causes a conformational change in

gp120, enabling it to interact with the chemokine co-
receptor (CCR5 or CXCR4) on the lymphocyte surface.

 These events expose a virus fusion protein, glycoprotein 41,

which undergoes a conformational change so it can insert a
hydrophobic tail into the host cell membrane and bind host
cell integrins, leading to fusion of the viral and host cell
membranes, uncoating and transfer of the viral genome
into the cytoplasm.
 Replicative cycle
38

 Once HIV enters the CD4 cell, viral RNA serves as a template to
produce a complementary doubled-stranded DNA in a reaction
catalyzed by viral reverse transcriptase (RNA-dependent DNA
polymerase).

 The viral DNA then enters the host cell nucleus and is incorporated
into the host genome in a reaction catalyzed by HIV integrase.

 Eventually the viral DNA is transcribed and translated to produce

large, nonfunctional polypeptides called polyproteins.

 These polyproteins are packaged into immature virions at the cell

surface.

 An enzyme called HIV protease cleaves the polyproteins into

smaller, functional proteins in a process called viral maturation as
the virions are released into the plasma.
 Antiretroviral drugs
39

Antiretroviral agents

Nucleoside and Non-nucleoside HIV Fusion and

nucleotide reverse reverse protease Entry Integrase
transcriptase inhibitors transcriptase inhibitors inhibitors inhibitors
inhibitors

Saquinavir
Zidovudine Indinavir
Didanosine Ritonavir
Nevirapine
Stavudine Nelfinavir
Delavirdine Maraviroc
Zalcitabine Tenofovir Fosamprenavir Raltegravir
Efavirenz Enfuvirtide
Lamivudine Lopinavir
Etravirine
Emtricitabine Atazanavir
Abacavir Tipranavir
Darunavir
40 Fusion and Entry inhibitors
 Mechanisms of action
41

 Maraviroc
 Chemokine receptor antagonist  targets a host protein
 Binds to the host cell CCR5 receptor to block binding of viral gp120
 Active only against CCR5-tropic strains of HIV
 Has no activity against viruses that are CXCR4-tropic or dual-tropic.
 Retains activity against viruses that have become resistant to
antiretroviral agents

http://www.youtube.com/watch?v=oneYI0fhGa0
 Enfuvirtide
 Large peptide that binds to HIV-1 viral glycoprotein 41 protein
 Inhibits fusion of the viral and cell membranes mediated by gp41
and CD4 interactions
 Retains activity against viruses that have become resistant to
antiretroviral agents
42
Fusion inhibitors: Enfuvirtide (T-20) is a 36 amino acid peptide derived from the extracellular
domain of gp41 (transmembrane segment) of the HIV-1 envelope. After gp120 binds to a CD4+
cell, the transmembrane (TM) domain undergoes a conformational change that includes unfolding,
which
43 results in the 'spring-loaded' formation of coiled-coil helices in preparation for viral entry.
Enfuvirtide binds to the transmembrane domain and prevents fusion to the host cell and viral entry.
 Resistance
44

 Maraviroc : two resistance pathways

 Shiftin tropism to CXCR4- or dual/mixed-tropism
predominance
 Retain CCR5-tropism but gain resistance to the drug
through specific mutations in the V3 loop of gp 120
that allow virus binding in the presence of inhibitor

 Enfuvirtide
 Specific mutations in the enfuvirtide-binding domain of
gp41
 Maraviroc
45

 PK
 Administered orally
 Metabolized by CYP3A4  t1/2 of 10.6 hours

 Adverse effects
 Generally well tolerated
 Hepatotoxicity (allergic)
 CCR5 inhibition might interfere with immune function  clinical
significance ??

 Approved for use in HIV-infected adults who have baseline

evidence of predominantly CCR5-tropic virus
 Enfuvirtide
46

 PK
 Peptide  administered SC
 t1/2 = 3.8 hours  BID

 Adverse effects
 Injection-site reactions : pain, erythema, and induration at the site
of injection in 98% of patients
 minimized by rotating injection sites
 Higher incidence of lymphadenopathy and pneumonia  2
possible mechanisms
 Drug-related immune dysfunction
 Effects from another mechanism ?

 Given the cost, inconvenience, and cutaneous toxicity of this

drug, enfuvirtide generally is reserved for patients who have
failed all other feasible antiretroviral regimens.
47 Inhibitors of reverse transcriptase
 Mechanism of action
48

 Nucleoside reverse transcriptase inhibitors (NRTIs)

 Small amounts of the NRTIs are converted to their active triphosphate
metabolites by host cell kinases.
 The triphosphate metabolites (nucleotides) compete with the
corresponding endogenous nucleoside triphosphates for incorporation
into viral DNA in the reaction catalyzed by reverse transcriptase.
 Once incorporated into DNA, the NRTIs cause DNA chain termination
(as acyclovir)
 The NRTIs also inhibit host cell DNA polymerase to varying degrees 
toxic effects (e.g., anemia).

 Nonnucleoside reverse transcriptase inhibitors (NNRTIs).

 Unlike the NRTIs, NNRTIs bind directly to reverse transcriptase and
disrupt the catalytic site  do not require phosphorylation for activity.

 Because they act by different mechanisms, the NRTIs and NNRTIs

exhibit synergistic inhibition of HIV replication when they are given
concurrently.
 Mechanism of action
49

Conversion to triphosphate
metabolites  block
replication of the viral
genome both by
competitively inhibiting
incorporation of native
nucleotides and by
terminating elongation
of nascent proviral DNA
because they lack a 3'-
hydroxyl group

NNRTIs = noncompetitive
inhibitors  induce a
conformational change in
the three-dimensional
structure of the enzyme
that greatly reduces its
activity
 NRTIs : Agents
50

Pyrimidines analogues Purines analogues

 Thymidine analogues  Guanosine analogues

 Zidovudine ZIDOVIR  Abacavir ABAMUNE
 Stavudine STAVIR

 Cytidine analogues  Adenosine analogues

 Emtricitabine  Didanosine DINEX
 Lamivudine ZEFFIX  Tenofovir TENVOR
 NRTIs
51

 All must be triphosphorylated except tenofovir (only 2 phosphorylations)

 Spectrum of activity
 All inhibit both HIV-1 and HIV-2
 Emtricitabine, lamivudine, and tenofovir are active against hepatitis B virus
 Tenofovir is active against herpesviruses

 Selective toxicity
 Affinity : HIV reverse transcriptase > host cell DNA polymerases ( Lamivudine)
 Triphosphate forms are are capable of inhibiting human DNA polymerase- =
mitochondrial enzyme  toxicities from the inhibition of mitochondrial DNA
synthesis  anemia, granulocytopenia, myopathy, peripheral neuropathy, and
pancreatitis
 Phosphorylated emtricitabine, lamivudine, and tenofovir have low affinity for DNA
polymerase-   devoid of mitochondrial toxicity.

 Resistance (multiple step)

 Occurs slowly by comparison to NNRTIs and first-generation protease inhibitors
 Cross-resistance confined to drugs having similar chemical structures
 NRTIs : resistance
52
 NRTIs : PK
53

 All NRTIs can be given orally (didanosine is acid-labile)

 ZDV can also be given IV
 Most of the parent compounds are eliminated rapidly from the
plasma, with elimination half-lives of 1-10 hours,
 Exception of tenofovir: t1/2 ~14-17 hours
 Phosphorylated metabolites are eliminated from cells much more
gradually than the parent drug is eliminated from the plasma with
estimated t1/2 for intracellular triphosphates range from 2 to 50
hours NRTIs are dosed once or twice daily.
 Eliminated primarily by renal excretion  dosage should be
reduced in renal impairment
 Exceptions : Zidovudine and abacavir are cleared mainly by hepatic
glucuronidation

 Not major substrates for hepatic CYPs  no clinically significant

PK drug interactions
 NRTIs : adverse effects
54
 NRTIs differ in their major toxicities
 ZDV produces bone marrow suppression and can cause anemia and
neutropenia + nail hyperpigmentation (chronic administration)
 Didanosine and stavudine can cause pancreatitis, and peripheral neuropathy
 Didanosine and stavudine should not be combined !!!
 Abacavir causes fatal hypersensitivity reactions
 Tenofovir produces renal impairment in some patients.
 Lamivudine : safest drug ! (nausea, headache)
 Emtricitabine : low toxicity
 Specific agents
55

 Zidovudine : use in pregnancy  preventing mother-to-child

transmission of HIV infection ( risk of perinatal transmission
of HIV by 67%)

 Zidovudine + acyclovir  Severe somnolence and lethargy

 Zidovudine + stavudine : antagonism
 Stavudine and zidovudine compete for intracellular
phosphorylation and should not be used concomitantly

 Lamivudine : mainly used in hepatitis B infections

 Abacavir
 Fatal hypersensitivity syndrome (2-9%): fever, abdominal pain,
GI distress, rash, malaise, fatigue: immediate D/C of the drug
 Patients with one of these symptoms should be observed
 NNRTIs
56

 Efavirenz EFAVIR (the most potent)

 Nevirapine VIRAMUNE
 Delavirdine
 Etravirine
 Noncompetitive inhibitors of reverse transcriptase
 Do not require metabolic activation
 Narrow spectrum  only active against HIV-1
 High selective toxicity  no activity against host cell DNA polymerases
 Resistance
 Susceptible to high-level drug resistance caused by single-amino-acid
changes in the NNRTI-binding pocket
 Resistance appears rapidly (few days or weeks if monotherapy)
 Cross resistance except for etravirine
 These agents are potent and highly effective but must be combined with at least
two other active agents to avoid resistance.
 NNRTIs : PK
57

 NNRTIs have good oral bioavailability

 Highly lipophilic  wide distribution
 Extensively metabolized before undergoing fecal and renal
excretion.
 Nevirapine and delavirdine  CYP3A4
 Efavirenz  CYPs 2B6 and 3A4
 Long t1/2 = 24 to 72 hours

 CYP-related Drug interactions

 Efavirenz, etravirine, and nevirapine  inducers of CYPs
enzymes including CYP3A4
 Delavirdine  CYP3A4 inhibitor
 NNRTIs : adverse effects
58

 Moderately well tolerated

 Rash is the most common effect
 If mild, drugs can be continued or restarted if D/C
 Efavirenz  CNS or psychiatric side effects (53%)
 Dizziness, impaired concentration, dysphoria, vivid or disturbing
dreams, and insomnia
 Generally become more tolerable and resolve within the first 4
weeks of therapy.
 Nevirapine  hepatotoxic ( hepatic transaminases in 14%
of patients)
59 Integrase inhibitor
 Integrase activity
60

 Integrase incorporates the viral DNA formed by reverse

transcriptase into the DNA of CD4 cells through a
multistep process.
 Integrase removes the last nucleotide from both 3´ ends
of the viral DNA strand to enable formation of a
preintegration complex of viral DNA, integrase, and
other viral and host cell proteins.
 This complex is able to pass from the cell cytoplasm into
the nucleus
 Integrase randomly incorporates viral DNA into the host
chromosome by DNA strand transfer = formation of
covalent bonds between host and viral DNA
61
 Raltegravir ISENTRESS
62

 Blocks the catalytic activity of the HIV-encoded integrase, thus

preventing integration of virus DNA into the host chromosome
 Raltegravir prevents DNA strand transfer by binding divalent
cations in the catalytic core of integrase that are required for
interaction of the enzyme with host cell DNA.
 Resistance : mutations in integrase gene
 Potent activity against both HIV-1 and HIV-2
 Given orally
 Not a substrate/inducer/inhibitor for CYP  no drug
interactions
 Eliminated mainly via glucuronidation  possibility of drug
interactions
 Adverse effects : Headache, nausea, and asthenia
63 HIV protease inhibitors
 PIs : agents
64

 Saquinavir
 Indinavir CRIXIVAN
 Ritonavir RITOMUNE
 Nelfinavir
 Lopinavir KALETRA
 Fosamprenavir
 Atazanavir
 Tipranavir
 Darunavir
 PIs : Mechanism of action
65

HIV protease cleaves the gag- PIs = competitive inhibitors

pol (group-specific antigen
polymerase) polyprotein to
provide functional viral proteins
and is essential for the
maturation of the virus.

Protease inhibitors (PIs) bind

the active site of the enzyme
and inhibit proteolytic activity
 production of immature,
noninfectious viral particles.

Active against HIV-1 & HIV-2

gag  major structural proteins

pol  3 enzymes : reverse transcriptase,
integrase, and protease.
 PIs : resistance
66

 Speed of resistance : NNRTIs > PIs > NRTIs

 Median time ~ 3-4 months
 Resistance to PIs is associated with the accumulation
of mutations resulting in amino acid substitutions in
the viral protease structure.
 Varying degrees of cross-resistance occur between
different PIs
 Cross-resistance between PIs and reverse
transcriptase inhibitors is rare.
 PIs : PK
67

 PIs are given orally

 High interindividual variability

 Extensively metabolized by cytochrome P450 enzymes before undergoing
fecal excretion.
 All are metabolized predominantly by CYP3A4 (except nelfinavir)
 Saquinavir metabolized by intestinal & liver CYP3A4   bioavailability
with grapefruit juice (inhibitor of intestinal CYP3A4)
 t1/2 = 1.8 to 10 hours  dosed once or twice daily

 Substrates for Pgp  limited penetration in CNS

 CYP3A4 inhibitors  Drug interactions

 Ritonavir by far the most potent inhibitor  usually combined with other
PIs to increase their plasma levels and duration, and this is known as boosted
therapy
 Ritonavir moderate inducer of CYP3A4, glucuronosyl S-transferase, and
possibly other hepatic enzymes
 PIs : adverse effects
68

 GI side effects including nausea, vomiting, and diarrhea are common

(generally resolve within 4 weeks of starting treatment)
 All PIs can cause lipid accumulation in tissues (lipodystrophy) and
hyperlipidemia, insulin resistance and diabetes, elevated liver
function test results, and drug interactions.
 Ritonavir appears to produce the highest incidence of adverse
effects
 Atazanavir is better tolerated that most other PIs and has a lower
propensity to cause diarrhea, lipodystrophy, and hyperlipidemia.
 Indinavir  crystalluria & nephrolithiasis ( fluid intake)

, unconjugated hyperbilirubinemia