Download Mech196-Antiviralagents - UNT Health Science Center

MOD
10 am June 9, 2003
Dr. Luedtke
Ryann McClennen
Page 1 of 10
ANTIVIRAL DRUGS
I. Background
A. Viruses are consisting of
a. Nucleic acid (RNA or DNA)
b. Protein coat or capsid
B. Some Viruses may also contain
a. Antigenic viral glycoproteins
b. enzymes for replication
c. single or double stranded nucleic acid
“Built for speed NOT comfort”
C. Examples
a. DNA viruses
poxvirus (small pox), Herpesvirus (chicken pox, shingles, herpes),
adenovirus (sore throat, conjunctivitis), papillomavirus (warts)
b. RNA viruses
orthomyxoviruses (influenza), paramyxoviruses (measles, mumps), rubella
virus (german measles, rhabdoviruses (rabies), retrovirus
(AIDS, T-cell Leukemia), arenavirus (meningitis, Lassa fever),
hepadnavirus (serum hepatitis), arbovirus (arthropod-borne
encephalitis)
D. General Viral life cycle represents certain points for antiviral therapy
II. Antiviral Drugs
A. General
a. Viruses share the metabolic processes of host cells, therefore, difficult
to find selective antiviral drugs.
b. Generally, by the time viral infection becomes diagnosed viral
replication is advanced and chemotherapy is difficult.
c. For many life-threatening viral infections, there is no cure and the
antiviral drugs simply improve quality of life (AIDS and Herpes)
d. Best strategy is prevention
B. Purine and Pyrimidine Analogues –Commonn Mechanism of action that
inhibits viral nucleic acid synthesis.
C. HIV and AIDS
a. 1st figure 10 yo from 1995
b. WHO estimated that in 1993 13 million individuals would be
infected with HIV.
In 2000
36.1 million people world wide were infected and living with AIDS
world wide
3 million people died of AIDS in 2000
21.8 million people have died of AIDS
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>750,000 total AIDS cases had been reported in the USA
82% males
17% females
1% children
c. Course of HIV Infection
1. virus interacts with CD4 and chemokine receptors
2. Symptoms: fever, headache, swollen lymph, rash
3. increase in number of viral particles in the blood
4. wide spread dissemination of viral particles in the body
5. after several weeks, viremia is reduced
6. after clinical latency symptoms of AIDS appears,
including:
a. opportunistic infection
b. neurological disease
c. bone marrow depression
d. cancer
e. chronic GI infections/severe weight loss
f. cardiovascular and kidney damage
g. death
d. RNA retrovirus replication
1. virion contains reverse transcriptase,
2. viral encoded DNA integrates into the host genome a as
provirus
3. virally coded DNA is transcribed into genomic RNA and
mRNA
4. translation of viral proteins
5. virus is released by budding
6. virus can replicate without killing the host cell
7. some RNA retroviruses transform normal cells to malignant
cells
Anti-AIDS Drugs (know generic name NOT common name i.e. Know
Zidovudine not just AZT)
Nucleoside Reverse Transcriptase Inhibitors (NRTI)
1. Zidovudine (AZT) - azido (N3) thymidine analogue (nucleotide
analogue)
Clinical Use
i. reduces the incidence of opportunistic infections stabilizes weight,
reverses HIV-associated dementia and reduces viral burden
ii. delays the onset of AIDS in HIV-positive patients.
AZT alone delays the progression of the disease, but does not alter the median survival
time. Poorly tolerated by patients and ineffective in late stage of AIDS
iii. reduces the risk of transmission of the virus from HIV mothers to
fetus (66% reduction of risk).
iv. After specific exposures to the HIV virus (i.e., after accidental
needle-stick injury)
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AZT given as prophylactic therapy with lamivudine (3TC) and a protease inhibitor.
The effectiveness of this strategy in preventing HIV transmission is unclear.
Mechanism
i. analogue of the pyrimidine thymidine
ii. phosphorylated by cellular enzymes to the triphosphate derivative
(Must be modified to be activated)
iii. inhibitor of reverse transcriptase.
iv. mammalian alpha DNA polymerase is not effected however
mitochondria gamma DNA is effected.
Administration
i. i.v and oral (60-80% bioavailability)
ii. Glucuronidation in the liver causes inactivation.
iii. Probenecid inhibits hepatic inactivation/ renal excretion.
iv. Agents which undergo glucuronidation may alter AZT metabolism (i.e.
St. John’s Whart enhances the metabolism of AZT)
Side Affects
anemia, neutropenia (agranulocytosis)/ long term administration GI
disturbances, paresthesia, skin rash, insomnia, fever, headache
abnormalities of liver function and myopathy
Resistance
The therapeutic response to AZT wanes with long-term use.
Viral resistance due to mutation of reverse transcriptase.
Increasing viral load due to immunosuppression
2. Zalcitabine (ddC) - synthetic cytosine nucleoside analogue.
Used in combination with AZT.
Mechanism
i. inhibitor of reverse transcriptase.
ii. activated in T cells by a different phosphorylation pathway than
AZT (Selectively unique to T-cells)
Administration
oral
Side affects
i. dose-related neuropathy
ii. GI disturbances, headache, mouth ulcers, nail changes, edema of
lower limbs and general malaise.
3. Lamivudine (3TC)-2'-deoxy-3'-thiacytidine (3TC)
Clinical Use
AIDS in combination with zidovudine (AZT).
Mechanism
i. a dideoxynucloside terminates the synthesis of the proviral DNA
ii. inhibiting reverse transcriptase
Administration
oral
Side Affects
pancreatitis can develop in pediatric patients
Resistance
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resistance to AZT develops more slowly
when given in combination
with 3TC (decrease rate of mutations)
4. Didanosine (ddI) – purine dideoxynucleotide ananlogue
Clinical Use
Switching to didanosine after AZT therapy has been shown to be
beneficial in AIDS therapy.
Mechanism
i. phosphorylated in the host to a triphosphate
ii. chain terminator and inhibitor of viral reverse transcriptase
Administration
Oral- rapidly adsorbed (even better with antacids) Increased
Bioavailability
Side Affects
i. dose-related peripheral neuropathy and pancreatitis
ii. headache and GI disturbances, insomnia, skin rash,bone marrow
depression and alteration of liver function
Resistance
After prolonged therapy, but is less than AZT
NonNucleoside Reverse Transcriptase Inhibitors (NNRTI)
1. Nevirapine (BI-RG-587; Viramune)
Clinical Use
i. Treatment of AIDS and AIDS related symptoms
ii. Prevention of transmission of HIV virus from infected mothers to
newborns
A study of African HIV compared the effects of AZT and Nevirapin on the ability to
prevent HIV-1 transmission for mothers to newborns during birth.
AZT
Nevirapine
Infection % 25%
13%
Cost
$1,000
$4
Mechanism
i. Binds to the lipohilic pocket of RT to allosterically distort the
polymerase active site.
ii. Acts synergistically with NRTIs
Side Effects
Rash (16%) within 6 weeks of treatment on trunk, face and
Extremities, fever, fatigue headach nausea
Resistance
Rapid if given alone, Decreased rate of resistance if given with NRTIs
2.Delavirdine (BHAP U-90152)
Mechanism
i. Binds to the lipohilic pocket of RT to allosterically distort the
polymerase active site.
ii. Acts synergistically with NRTIs
iii. Inhibits the P-450 system, so decreases the metabolism of protease
inhibitors. (Don’t worry about this, but it effects any other drugs in
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system)
Side Effects
Rash (not as sever as with Nevirapine)
Resistance
Rapid if given alone, Decreased rate of resistance if given with NRTIs
Second Generation NNRTI currently approved by the FDA. Experimental evidence
indicates that the resistance to second generation NNRTIs may occur less rapidly.
(Second generation NNRTI – Efavirenz) (NOT on Drug List)
Protease Inhibitors (First to extend life span)
Clinical Use
Treatment of HIV
Mechanism
i. Inhibition of HIV-1 protease.
HIV-1 protease is an member of the aspartyl class of proteases and is
essential for the final stage of viral formation.
ii. Gag-pol 160-kDA precursor protein undergoes autocatalytic
cleavage to form HIV-1 proteases. The active enzyme then hydrolyses
the precursor protein to generate the proteins required for viral
formation. The proteases inhibitors interfere with this viral
formation leading to immature, noninfectious virions. (Inhibits large
protein therefore non-infective viron)
In vitro studies indicate that the combination of reverse transcriptase
inhibitors and protease inhibitors is at least additive and usually synergistic.
1. Indinavir (Crixivan)
Side Effects
increase bilirubin without other hepatic abnormalities and nephrolithiasis
due to crystallization of drug in urine
Resistance
resistance emerges rapidly at suboptimal doses. essential to administer the
protease inhibitors at maximum tolerated doses and in combination with
reverse transcriptase inhibitors.
2. Nelfinavir (Viracept)
Side Effects
diarrhea, asthenia, headache and moderate hypertension
3. Ritonavir (Norvir)
Side Effects
nausea, vomiting and diarrhea elevated hepatic aminotransferase and
triglyceride levels
4. Saquinavir (Invirase)
Side Effects
mild diarrhea, abdominal discomfort and nausea
low bioavailability (4-5%)/ metabolized by P-450
co-administration with rifamycin or cabamazepine can further decrease plasma
concentrations
Resistance
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resistant variants emerge in 45% of patients after 1 yr appears to be due to
a single amino acid mutation at either position 48 or 90.
Cross Resistance- to indinavir and ritonavir can also occur, but requires 3 to 11
amino acid changes
AIDS Drugs are given in combination
1st choice
2 NRTIs + Protease Inhibitor
2nd choice
2 NRTIs + NNRTI
3rd choice
NTRI + NNRTI + PI
E. Herpes Simplex Virus
a. General
1. HSV-1 and HSV-2
2. DNA virus.
3. Humans are the only host
4. A sexually transmitted disease generally not seen before
puberty.
5. 500,000 cases per year
b. HSV-1
1. Oral involvement HSV-1 is found in oral mucosa and oral
cavity; Found in sensory neurons causes recurrent lesions
known as cold sore or fever blisters
2. Ocular involvment can infect cornea of the eye immune
response leads to scarring, clouding and blindness; Antibodydependent complement-medicated lysis of infected cells of the
cornea
c. HSV-2
1. Genital Herpes -- both HSV-1 and HSV-2 are sexually
transmitted HSV-2 is the major cause of genital herpes
2. Maternal – fetal transmission HSV-2 can be spread to fetus
during delivery resulting in encephalitis and disseminated
herpes infections [ 6% of children become infected; 60% of
infected newborns will die likely due to an immature immune
system]
d. Pathogenesis of Genital HSV
1. Initial infection
Onset 5 days after sexual contact
First episode ends 20-30 days
Initial symptoms generally more severe than recurrent
episodes
2. Recurrence
pain and itching
4-5 days
lesions
10-14 days
Reoccurring lesions 4-5/ year
Anti-Herpes Drugs
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1. Acyclovir (Zovirax)
Clinical Use
a. varicella-zoster (VZV) infections (shingles)
i. orally if immunocompotent
ii. i.v. for immunocompromised patients
b. herpes simplex infection (genital herpes, mucocutaneous herpes and
herpes encephalitis)
i. prophylactic treatment in immunocompromised patients
ii. prophylactic treatment in patient with recurring genital infection with
herpes virus.
c. varicella (chicken pox) in immunocompromised hosts
Mechanism
i. Acyclovir is converted to the monophosphate by thymidine kinase (viral
enzyme)
ii. The monophosphate is converted to the triphosphate by mammalian
kinases.
iii. Acyclovir-triphosphate inhibits viral DNA-polymerase
(30x more selective at herpes virus enzymes than at host enzymes)
Side Affects
i. local inflammation during i.v injection
ii. renal dysfunction if given i.v. too rapidly
iii. nausea and headache
Resistance
Herpes simplex virus isolates that are resistant to acyclovir have been
obtained from immunocompromised patients.
Mutations in the viral genes for thymidine kinase or DNA polymerase
2. Valacyclovir (Valtrex)
Clinical Use
similar to acyclovir
Mechanism
i. an L-valyl ester of acyclovir. (PRO DRUG)
ii. almost completely metabolized to acyclovir.
iii. higher bioavailability than acyclovir. (More efficient at getting the
drug into the system)
Administration
Oral
Side Affects
Generally well tolerated.
Side effects are generally similar to acyclovir.
3. Vidarabine (Vira-A) - adenine arabinoside purine nucleotide (alanine
perinucleotide analogue)
Clinical Use
i. herpes simplex virus in neonates
ii. Herpes associated encephalitis
iii. varicella-zoster virus infections in AIDS patients
iv.* second-line drug after Acyclovir.* With Resistance to Acyclovir
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Mechanism
i. phosphorylated by cellular kinases to a triphosphate
ii. The triphosphate inhibits of viral DNA polymerase.
Administration
slow i.v. administration or topically
Side Affects
i. nausea, vomiting and diarrhea
ii. neurotoxicity late in therapy with high doses/reversible
iii. bone marrow disturbances have been reported
iv. can be carcinogenic
(Acyclovir is generally more effective for herpes with less toxicity,
therefore it is the first choice. However, Vidarabine is a second choice
drug for HSV resistant to acyclovir. Foscarnate is also used and is more
effective and less toxic)
4. Idoxuridine (Herplex) - pyrimidine analogue of thymidine
Clinical Use
herpes simplex and varicella-zoster infections in eye
Mechanism
i. idoxuridine is phosphorylated by cellular kinases
ii. the triphosphate derivative is incorporated into both viral and host
DNA.
Administration
topically dissolve in dimethylsulfoxide (DMSO) [Solvent very toxic
therefore only used as topical]
Side Affects
i. irritation (due to DMSO)/ contact dermatitis
ii. used topically only it is a mutagen and too toxic for systemic use
F. Cytomegalovirus
a. Ubiquitous DNA herpesvirus
b. Most infections during normal childhood and adulthood are
asymptomatic.
c. Immunosuppressed patients, such as organ or bone marrow
transplant patients or patients on cancer chemotherapy,
CMV may be reactivated resulting in interstitial pneumonia.
d. AIDS patients, CMV often disseminates to visceral organs causing
chorioretinitis (inflammation of the choriod and retina),
gastroenteritis and neurological disorders
1. Ganciclovir (Cytovene) - synthetic guanosine nucleoside purine analogue.
It is structurally similar to Acyclovir.
Clinical Use
a. 100 x more active than acyclovir for cytomegalovirus (CMV)
b. life-threatening or sight-threatening CMV infections in
immunocompromised patients.
c. prevent CMV infection in transplantation patients
*In AIDS patients*
It is difficult to administer ganciclovir and AZT simultaneously
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because they both cause granulocytopenia.
Mechanism
i. initial phosphorylation of ganciclovir is performed by a protein kinase
encoded by CMV
ii. Ganciclovir is converted to the triphosphate
iii. The triphosphate competes with guanosine triphosphate
for incorporation into viral DNA
Not broken down rapidly, persists in cell for 18-20 hours.
Administration
i.v.
Side Affects
i. bone marrow suppression
ii. severe myelosuppressive if given with zidovudine
iii. potentially carcinogenic and teratogenic
2. Foscarnet (Foscavir) - a non-nucleoside analogue, an inorganic pyrophosphate
analogue
Clinical Use
Second-line drug for CMV eye infection in immunocompromised patients
Mechanism
i. inhibits viral DNA polymerase
ii. binds to the pyrophosphate-binding site
Administration
i.v.
Side Affects
serious nephrotoxicity/ reversible/ kidney dialysis.
Resistance
CMV strains resistant to foscarnet reported
G. Lassa Fever
a. West African arenovirus hemorrhagic fever transmitted from rodents to
humans.
b. Symptoms are fever associated with hemorrhagic manifestations, shock,
neurological disturbances and bradycardia.
c. Diagnosis is suggested by recent travel to West Africa and clinical
symptoms. Any patient suspected of being infected should be
isolated/public health authorities notified.
d.Due to high risk of the spread of infection from fluids and excreta,
routine laboratory studies are best deferred until diagnosis and specimen
disposition is resolved
1.Ribavirin (Virazole) - adenosine/guanosine analogue.
Clinical Use (DRAMATIC advance in treatment)
i. Used to treat viral respiratory infections including influenza, respiratory
syncytial virus (RNA paramyxovirus)
ii. Used to treat early stages of Lassa fever, an arenovirus infection.
Reduces to 9% a case-fatality; rate previously at 76%.
Mechanism
alters both viral DNA and viral mRNA synthesis.
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Administration
i.oral
ii.aerosol (influenza and respiratory infections)
iii.i.v. for Lassa fever
Side Affects (Very Toxic)
i.teratogenic, embryotoxic and oncogenic
ii.anemia ( dose-related and reversible)
H. Hepatitis Virus - hepatitis means inflammation of the liver
a. Hepatitis A: self-limiting/ asymptomatic
b. Hepatitis B:
1. acute -fatigue and nausea
2. increasing liver involvement
3. jaundice/ darkening of urine
4. chronic hepatitis leading to liver failure
c.Hepatitis C:
1. mild symptoms at onset
2. longterm infection can lead to chronic liver disease
3. most common reason for liver transplantation in the USA
Hepatitis C risk factors
1. injection of illicit drugs
2. sexual partners with HCV
3. living in prison or juvenile detention centers
4. body-piercing or tattoos
5. health care workers exposed to infected blood
6. newborns of HCV-infected mothers
Anti-Hepatitis Drugs
HBV interferon α2b
HCV interferon α2b & Ribavirin
1. Interferon (IFN) (α, β and γ interferon) are inducible proteins synthesized by
mammalian cells.
2. Interferons are involved in cell growth, regulation and modulation of the
immune response.
Clinical Usage
α-2b-IFN - hepatitis B and C, Kaposi sarcomas & hairy cell leukemia
Mechanism
i. Thought to induce host enzymes that inhibit the translation of viral
mRNA.
ii. Receptors of IFN may be cell surface gangliosides, which cause
inhibition of viral replication.
Side Affects
i. Common fever, lassitude, headache and myalgia (muscle pain).
ii. bone marrow suppression, cardiovascular changes, rashes, alopecia,
alter thyroid & renal function.
iii. exacerbate autoimmune diseases such as thyroiditis
iv. acute, reversible hearing loss and/or tinnitus.