Chřipka - epidemiologie, diagnostika, léčba, profylaxe a prevence

Chřipka - epidemiologie, diagnostika, léčba, profylaxe a prevence

Antiviral drugs
Simplified viral structure
lipoprotein envelope
nucleic acid
protein capsule
Viral replication cycle
8. Viral shedding
1. Adhesion
7. New viruses assembling
2. Penetration
6. Late proteosynthesis
3. Uncoating
5. NAc synthesis 4. Early proteosynthesis
Targets of antiviral drugs
1. Viral adhesion: g-globulins, fusion inhibitors
2. Penetration: g-globulins, fusion inhibitors
3. Uncoating: cyclic amines
4. Early proteosynthesis: no drug yet
5. Nucleic acid synthesis: NRTI, NNRTI,
integrase inhibitors
6. Late proteosynthesis: Protease inhibitors (PI)
7. Viral assembling: neuraminidase inhibitors
8. Viral shedding: neuraminidase inhibitors
Classification of antiviral agents
M-channel protein
inhibitors
Nucleic acid
synthesis inhibitors
Cyclic amines
Amantadin, rimantadin,
tromantadin
Ribavirin
DNA synthesis
DNA polymerase
and DNA
synthesis
Cyclic
nucleosides
Acyclic
nucleosides
DNA polymerase
and reverse
transcriptase
Phosfonic acid
derivatives
Cyclic
nucleosides
Acyclic
nucleotides
Proteosynthesis inhibitors
(POL-protein)
Asp-protese (proteinase) inhibitors
Deoxypropyladenin,
arabinofuranosyl-adenin, vidarabin,
Pyrimidin
analogues
Purin analogues
Brivudin, trifluridin, idoxuridin
Purin
analogues
Pyrimidin
analogues
Didanosin, abacavir
Purin
analogues
Pyrimidin
analogues
Aciklovir, valacyklovir, penciklovir,
famciklovir, gancyklovir,
valgancyklovir
Foscarnet, fosfonet
Zidovudin, zalcitabin, stavudin,
lamivudin, sorivudin, alovudin,
fluorothiacytidin, emtricitabin
Tenofovir, adefovir, adefovir
dipivoxil
cidofovir
Non nenucleoside
analogues
Thiosemicarbasones
Nevirapin, delaviridin, efavirenz,
lovirid, capravirin, emivirin
Methisazon,
Ansamycins
Rifampicin
Peptides
Saquinavir, ritonavir, nelfinavir,
amprenavir, indinavir, lopinavir
Tipranavir
Non pepeptides
Neuraminidase inhibitors
Purin analogues
Zanamivir, oseltamivir
Antiviral drugs against herpetic
viruses
Acyclovir (UASN) Aciclovir (INN)
• DNA synthesis inhibitor
– Viral TK phosphorylation needed (200 x higher
affinity against viral in comparison to mammal
TK)
– Cellular enzymes convert acyclo-GMP to acycloGTP
– This process is 40 - 100 x more potent in infected
cells than in intact cells
Mode of action of acyclovir
Inhibition of viral DNA synthesis
Mode of action of acyclovir
Inhibition of viral DNA synthesis
Deoxyribonucleosides
Acyclovir
x
Acyclovir monophosphate
Acyclovir diphosphate
Acyclovir triphosphate
x
Viral thymidine kinase
Viral kinases or
cellular enzymes
Cellular enzymes
DNA/Acyclovir monophosphate
DNA polymerase
Deoxyribonucleoside
trifosphate Viral DNA polymerase
Acyclovir - pharmacokinetics (1)
 tmax (oral)
1,5 - 2,5 h
 Oral bioavailability
15 - 20 %
 Distribution
 Kidney
1000% plasma conc.
 Liver, heart, lungs 130%
 CSF
50%
 Maternal milk
325% mater. plasma conc.
Acyclovir - pharmacokinetics (2)
 t 0,5
 Adults 2 - 3 h (i.v.)
 Newborn 2,5 - 5,0 h
 Maternal milk 2,8 h (p.o.)
 CSF 28,0 h (i.v. inf. + probenecid)
 Renal elimination 45 - 79% (i.v. dose)
Valaciclovir and other esters
Valaciclovir – mode of action
• ACV selective activation of viral thymidin
kinase (TK)
• Cellular TK does not activate ACV (ACV
itself does not have cytotoxic effects)
• ACV triphosphate is 100 x more potent
then penciclovir triphosphate
• ACV is obligate chain terminator on the
level of guanosine
Valaciclovir - metabolism
Valaciclovir p.o.
55% absorption
45% into GIT as ACV
Valaciclovir hydrolase
Valin
1% nonmetabolised VCV
55% ACV bioavailability
Comparative kinetics
Parameter
tmax (h)
t0,5 (h)
F (%)
pen/fam
1,0
2,2
0/77
aciclo/vala
1,5
3,1
15/55
Single dose kinetics
• Fast conversion of VCV into ACV = first
pass effect
• Absorption not influenced by food
• t0,5 – 2,6 - 3,0 h
Repeated dose kinetics
Antivirals against herpetic viruses incl. CMV
Generic
Brand
Aciklovir
Zovirax, Herpesin, Virolex, Aciclovir
Valaciklovir
Valtrex
Famciklovir
Famvir
Ganciklovir
Cymevene
Cidofovir
Vistide
Valganciklovir
Valcyte
Methisoptinol
Isoprinosine
Local antivirals against herpetic viruses
and warts (verrucae)
Generic
Brand
Aciklovir
Zovirax, Herpesin, Virolex, Aciclovir
Penciklovir
Vectavir
Tromantadin
Viru-Merz
Podofylotoxin
Wartec (condylomata/bradavice)
Imikvimod
Aldara
Postherpetic neuralgia
Valaciclovir
•
•
•
•
•
Prodrug of acyclovir
Higher bioavailability = higher efficacy
Effective also against less sensitive viruses
Dosage (3 x 1 000 mg/d)
Safety – more than 35 000 000 treatment
cures with active compound – acyclovir
Valaciclovir - summary
•
•
•
•
Ester
Fast conversion to acyclovir (99%)
3 – 5times higher bioavailability vs. ACV
No change in bioavailability (food, age, co
morbidity)
• Active only after conversion of VCV to ACV
• Conversion (hydrolysis) - ACV + valin
(essential amino acid)
Acyclic nucleoside phosphonates
cidofovir and adefovir
Acts independently on viral thymidinkinase
– direct metabolism by cellular enzymes
Direct conversion into diphospho
derivatives
Interaction with viral DNA
Main indication:
Cidofovir: CMV, HSV, papiloma viruses
Adefovir: HBV see hepatitis
Antiviral drugs against HIV viruses
HIV virus
Lipid bilayer
Zidovudine (azidothymidine, AZT)
Zidovudine – highly effective antiretroviral
compound.
Nonselective phosphorylation into MP- DPTP by cellular TK and nonspecific kinases
Zidovudine TP - inhibits substrate of viral
reverse transcriptase with100 x higher affinity
to HIV RT than cellular DNA and polymerase.
AZT – pharmacokinetics and dosage
Kinetics
 Oral bioavailability
 t0,5
 Elimination route
 Metabolism
 5´glucuronid in urine
 Protein bound
 CSF/Plasma ratio
60 - 80%
1,1 - 1,5 h
GF a Ts
5´glucuronide
adults 60-80%, children 45%
35 - 40%
0,5 - 0,8 (in interval 1 - 4h)
Dosage
 Adults 500 mg/day (in 2 doses)
 Children 720 mg/m2/day (in 4 doses)
AZT – adverse events (AEs)
Hematotoxicity (long term use of high dosages
- follow blood count)
Lactate acidosis connected with hepatomegaly
and steatosis (LFT check – AST, ALT needed)
Mutagenity (significant chromosomal
aberrations not proved)
Cancerogenity (in high doses in animals)
Gravidity (only when clearly indicated)
Lamivudine (3-thiacytidine)
• Lower toxicity in vitro than zalcitabine a didanosine
• Oral bioavailability – 80%
• No myelotoxicity
• No mitochondrial toxicity in concentration inhibiting
•
•
viral replication
Effective in HIV and HBV
Combination with other antiretroviral drugs and
interferon possible
Abacavir (ABC)
Higher generation RTI,
More potent than current antiretroviral
drugs (tricyclic guanosine derivative).
No activity against hepatitis B and C viruses
Synergy with zidovudine and nevirapine
Abacavir (ABC) – mode of action
• ABC is prodrug
• Phosphorylation is needed to generate
•
effect
Resulting antiretroviral substance carbovir TP (carbocyclic GTP) action:
–dGTP competitive inhibition
(deoxyguanosine-TP)
–DNA chain termination by means of
incorporation of false nucleoside analogue
Abacavir (ABC) – mode of action
Intracellular activation
2´deoxyguanosine and abacavir
dG
dGMP
dGDP
dGTP
RT
ABC
ABC-MP
CGMP
CGDP
CGTP
RT
Proviral DNA
Abacavir (ABC) – pharmacokinetics
• Good absorption and bioavailability
•
•
•
•
(F=83%)
Good CNS penetration (30 - 44%)
Low plasma protein binding (49%)
Metabolism – 1st step: ADH, 2nd step:
glucuronidation
No P-450 interactions
Abacavir (ABC) – KI
• Contraindications
–moderate – severe liver dysfunction
–terminal stage of renal failure
• Cave: in 3% patients hypersensitivity
(very serious!!!)
–Be alert in first 2 month of treatment!
Trizivir – combo: abacavir + lamivudine + zidovudine
Srovnání farmakokinetiky
abacavir
F = 83 %
Vd = 0,8 l/kg
t1/2 = 1,5 h
lamivudin
F = 85 %
Vd = 1,3 l/kg
t1/2 = 6,0 h
zidovudin
F = 70 %
Vd = 1,6 l/kg
t1/2 = 1,1 h
Plasma/CSF = 0,35
Cmax = 3,0 g/l
Tmax = 1,5 h
D = 300 mg
Plasma/CSF = 0,06
Cmax = 1,5 g/l
Tmax = 0,75 h
D = 150 mg
Plasma/CSF = 0,60
Cmax = 1,8 g/l
Tmax = 0,5 h
D = 300 mg
Activation of abacavir, lamivudine and
zidovudine (3 different modes of action)
ABC adenosin
phosphotransferase
3TC (also ddC)
deoxycitidin
kinase
AZT (also d4T)
thymidin
kinase
ABC MP
cytosolic
enzymes
Carboxyl GMP
Carboxyl GDP
3TC MP
AZT MP
3TC DP
AZT DP
deoxycitidin
MP kinase
Purin
nucleoside
DP kinase
3TC TP
Carboxyl GTP
thymidilat
kinase
pyrimidin
nucleoside
DP kinase
AZT TP
Protease inhibitors (PI) – mode of action
HIV-1, (2) protease inhibition
Inhibition prevents gag-pol polyprotein
cleft

structural genes: gag, pol, env - encoding
structural proteins
Resulting virus is immature and noninfectious
Protease inhibitors - comparison
INN
amprenavir
nelfinavir
indinavir
ritonavir
saquinavir
Brand
Agenerase
Viracept
Crixivan
Norvir
Invirase
Efficacy
+++
+++
+++
+++
+
Dosage
2xd
3xd
3xd
2xd
3xd
Tbl./d - Nos
Tolerance
12-16
+++
9
+++
6
++
12
+
12
+++
IT.-p-450*
IT.-food
++
-
++
++
++
+++
+++
++
+
-
CNS penetr. +
-
-
-
-
x-resist.
+
+++
+++
+
+
•Enzyme inhibitors – AE : Lipid spectrum abnormities up to influence on adipogenesis
•New PI: Atanzavir, Fosamprenavir, Tipranavir
NNRTI – efavirenz
NNRTI (noncompetitive)
Does not inhibit DNA polymerase
Protein bound - 99,5 - 99,8%
Metabolism - CYP 3A4 a CYP 2B6
Enzyme inducer – after repeated dose
shorter elimination half live
Frequent interactions similar as in PIs
NNRTI – delaviridine and nevirapine
Nevirapine: bioavailability 90%, t 0,5 27 h,
metabolism – P-450, enzyme inducer decreasing concentrations of PIs and
contraceptives …
Delaviridine: bioavailability 85%, t 0,5 5,8 h,
metabolism – P-450, enzyme inhibitor increasing concentration of antiepileptics,
astemizole, cizapride … (Contraindication!!!)
Differencies in mode of action
between NRTI and NNRTI
NNRTI
Intracellular activation
not needed
Allosteric inhibition
noncompetitive
Enzyme conformation
changes - inactivation
NRTI
Phosphorylation to
nucleoside 3-P
Competitive substrate inhibitor
on catalytic subunit
Nucleotide sequence
synthesis termination
HIV-1 reverse transcriptase inhibition
Antivirals against HIV viruses (RTIs)
Generic
Brand
Zidovudine
Retrovir
Stavudine
Zerit
Didanosine
Videx
Lamivudine
Epivir/Zeffix
Abacavir
Ziagen
Tenofovir disoproxil
Viread
Emtricitabine
Emtriva
Antivirals against HIV viruses (PIs)
Generic
Brand
Saquinavir
Invirase, Fortavase
Ritonavir
Norvir
Indinavir
Crixivan
Nelfinavir
Viracept
Amprenavir
Agenerase
Lopinavir
Kaletra
Fosamprenavir
Antivirals against HIV viruses (NNRTIs)
Generic
Brand
Efavirenz
Stocrin, Sustiva
Nevirapine
Viramune
Antiviral drugs against Hepatitis B and C
viruses
Antivirals against Hepatitis B and C viruses
Generic
Brand
Lamivudine
Zeffix/Epivir - Hep. B
Adefovir dipivoxil
Hepsera - Hep. B
Ribavirin
Rebetol, Copegus - Hep. C in combination
with IFN
Interferons – immunomodulating cytokines
•
•
•
Interferon alpha
Interferon beta
Interferon gama
•
Mode of action
–
–
–
–
–
(IFN alpha) – leucocyte
(IFN beta) – fibroblast
(IFN gamma) – T-lymphocyte
Antiproliferative – slow down transition from G1 to S phase
Immunomodulating effects – increased expression of cytotoxic lymphocytes,
macrophages and NK-cells,
Increase of expression of main histocompatible complex needed for induction
of cytotoxic reaction
Viral inhibition replication inductors
Antitumor activity – oncogen expression decrease c-myc, v-myc…
1. IFN binding on membrane receptor
2. Internalization of the complex
3. Initiation of intracellular steps
Interferons – immunomodulating cytokines
• Adverse events
– Anti-platelet effects and suppression of
granulopoesis (Decrease in platelet count limiting factor for application)
– Flu-like syndrome (2 – 4 h after application, lasts
4 – 8 h)
– Less frequent AEs
•
•
•
•
Hypotension, BP fluctuation, arrhythmias
Interferon pneumonia
Autoimmune symptoms
Proteinuria
Passive immunization –
immunoglobulins
• Aim – immediate short term protection
(acquired)
– Antisera (heterologous) – immunoglobulins from
purified immunized animal sera
– Homologous immunoglobulins – produced by B
lymphocytes as humoral response to
heterologous antigen
• Normal human Ig
• Specific Ig
Immunoglobulin structure
F(ab)2
VH
Fab
CH1
1
2
3
VL
–S–S–
–S–S–
CL
Papain
CH3
C = constant
domain (link with
complement, link with
Fc receptor of
immunocompetent
cells …)
1-3 – hypervariable part
(antigenic specificity)
CH2
Pepsin
V = variable
domain (antigenic
variability)
Fc
VL-VH = Fv (link to
antigen)
m, d, a, g, e = isotype of
heavy chains (IgM,
IgD, IgA, IgG, IgE)
Active immunisation – vaccination
• Aim – long term prevention (post vaccination
immunity)
– Vaccines
• Alive
– Heterologous – smallpox (variola) - (eradicated)
– Attenuated
» Viruses (polio, measles, mumps, rubella, yellow fever)
» Bacteria (BCG)
• Inactivated
– Viruses (flu)
– Bacteria (whooping cough, cholera)
– Inactivated anatoxins (toxoids) - (diphtheria, tetanus)
Anti flu antivirals
Mixovirus influenzae
M2
Flu – etiology
• Flu viruses - 3 types
– Orthomyxoviridae: Myxovirus influenzae A, B, C
• Different structure
– A – cause of large epidemics and/or pandemic
– in humans and other mammals and birds
– B and C – typically in humans only
Flu virus
Neuraminidase
Polymerase
Haemagglutinin
RNA
Matrix protein
Lipid bilayer
Ribonucleoprotein
M2 channel protein not depicted
Haemagglutinin (HA)
Principal antigenic determinant of A and B flu
virus
Responsible for adhesion to receptor and
endocytosis, contains sialic acid
Continuous development of new variants
(shift) essential for survival
Neuraminidase (NA)
One of essential glycoproteins (antigenic
determinants) of A and B flu virus
NA inhibition prevent viral shedding
Viral ion channels
M2 channels in flu A virus only
Responsible for uncoating after virus
entry in to the cell
Replication cycle of flu virus
release of progeny v irions
atta chment
ass embly of
new virus
partic le s
entry
endos om al
ves ic le
cyt oplasm
prote in
synthes is
Ô
release
from vesicle
RNA
replic ation
in nucleus
new RNA
genom es
respira tory
cell s urfac e
Antigenic shift
• Antigenic shift – new virus in 10 – 30y
interval (e.g. H5N1)
• Combination of human and animal flu antigens
probably in pigs in SE Asia
• Source water birds and poultry
• Type A flu - No antibodies against new
antigenic variant!!!
Antigenic drift
• Antigenic drift – small antigenic changes
(point mutations)
• Typical for flu B virus
• Flu C virus responsible only for sporadic
disease
Shift and drift
mechanism
Flu virus in RTI
1 Adhesion
1
2
3
2 Replication
3 Shedding
Respiratory tract is the main target of flu viruses
Flu management
Vaccination
Prevention
Antiviral drugs
Treatment
Causative
 Antiviral drugs
Symptomatic
 Symptomatic treatment
Flu treatment
Causative – antiviral drugs
Cyclic amines - M2 channel protein inhibitors,
flu A only. Issue - resistance
Amantadin
Rimantadin
Neuraminidase inhibitors – flu A and B.
Oseltamivir
Zanamivir
NA inhibitors
Prophylactic and therapeutic use in A and
B flu
Mode of action – selective NA inhibitor.
Prevention of viral shedding.
Zanamivir inhalation device
Mouthpiece
Piercing Needle
Rotadisk
Cover
Inhalation Powder
Zanamivir – lung deposition
Zanamivir – adverse events
4
3,5
3
2,5
% patients
2
1,5
1
ORL bleeding
ORL infection
vertigo
vomitus
sore throut
sinusitis
cough
bronchitis
headache
zanamivir
placebo
nausea
diarrhoea
nasal symptoms
0,5
0
Oseltamivir
• Oral form - prodrug
• Bioavailability 80 %
• Metabolism - liver esterases to carboxylate =
active substance – NA inhibitor
• Renal elimination
Anti flu antivirals
Generic
Brand
Rimantadin
Maridin
Oseltamivir
Tamiflu
Zanamivir
Relenza
New trends
New trends
• Herpetic protease inhibitors
• HIV fusion inhibitors (CD4 molecule on
lymphocyte) (chemokin co-receptor
antagonists - 5, CCR5)
– Prevention of HIV adhesion and fusion with cell
membrane close to gp 41 and gp 120.
– No cross resistance with RTI and PI.
• HIV integrase inhibitors
– Prevention of integration of bihelical HIV DNA into
host genome