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ANTI VIRAL DRUGS

EVELYN B. YUMIACO M.D.


SCHOOL OF MEDICINE
ANGELES UNIVERSITY FOUNDATION
VIRUS
• OBLIGATE INTRACELLULAR PARASITE
• DOUBLE OR SINGLE STRANDED RNA OR
DNA ENCLOSED IN A PROTEIN COAT
CALLED CAPSID
• CAPSID MAY HAVE ICOSAHEDRAL OR
HELICAL SYMMETRY COMPOSED OF
CAPSOMERS WHICH ARE MADE UP OF
PROTEINS
ENVELOPED HERPES VIRUS
CORE

GLYCO
PROTEIN DNA

ENVELOPE

CAPSID
CLASSIFICATION OF VIRUS
• DNA VIRUS
– POXVIRUS
– HERPES VIRIDAE
– ADENOVIRIDAE
– PAPOVAVIRIDAE
– PARVOVIRIDAE
– HEPADNAVIRIDAE
CLASSIFICATION OF VIRUS
• RNA VIRUS
– RETROVIRUS
– PICORNAVIRIDAE
– CALICIVIRIDAE
– TOGAVIRIDAE
– BUNYAVIRIDAE
– REOVIRIDAE
– ORTHOMYXOVIRIDAE
– PARAMYXOVIRIDAE
– RHABDOVIRIDAE
– ARENAVIRIDAE
– CORONAVIRDAE
– FLAVIVIRIDAE
STAGES OF VIRAL INFECTION

• VIRAL INTERACTION AT THE CELL


SURFACE
• VIRAL GENE EXPRESSION
• VIRAL ASSEMBLY AND EGRESS
DNA VIRUS INTERACTION AT THE CELL SURFACE

TRASCRIPTION INTO
VIRAL MRNA

VIRAL ATTACHMENT TRASFER OF VIRAL DNA


PENETRATION UNCOATING
AND ENTRY TO HOST NUCLEUS

SYNTHESIS OF VIRAL DNA

•STRUCTURAL PROTEIN
•VIRAL ENZYMES
•REGULATORY PROTEIN

PROTEIN
SYNTHESIS
AND PACKAGING

VIRAL RELEASE

PACKAGING AND
ASSEMBLY
RNA VIRUS INTERACTION AT THE CELL
SURFACE

RNA REPLICA

BINDING TO CELL
SURFACE
UNCOATING
HEMAGGLUTININ ENDOCYTOSIS ENDOSOME

M RNA V RNA

•STRUCTURAL
PROTEIN
•NON STRUCTURAL
PROTEIN
PROTEIN SYNTHESIS
AND PACKAGING

VIRAL RELEASE

PACKAGING AND
ASSEMBLY
CLASSIFICATION OF
ANTIVIRAL DRUGS
1. AGENTS THAT TREAT HERPES SIMPLEX
VIRUS AND VARICELLA ZOSTER
2. AGENTS THAT TREAT
CYTOMEGALOVIRUS
3. ANTI RETROVIRAL AGENTS
4. ANTIHEPATITIS AGENTS
5. ANTI INFLUENZA AGENTS
6. OTHER ANTIVIRAL AGENTS
AGENTS THAT TREAT HERPES
SIMPLEX VIRUS AND
VARICELLA ZOSTER
• ACYCLOVIR
• VALACYCLOVIR
• FAMCICLOVIR
• PENCICLOVIR
• DOCOSANOL
• TRIFLURIDINE
ACYCLOVIR
• APPROVED BY FDA IN 1982
• GUANINE DERIVATIVE
• MECHANISM
• INHIBITS VIRAL DNA SYNTHESIS
• COMPETITION WITH DEOXY GTP FOR
THE VIRAL DNA POLYMERASE
• CHAIN TERMINATION AFTER
INCORPORATION INTO VIRAL DNA
ACV
O VIRAL THYMIDINE KINASE
O ACTIVATION BY PHOSPHORYLATION
HN N HN N

H2N N ACYCLOVIR
N
H2N N MONOPHOSPHATE
N P OCH2

HOCH2
CELLULAR GMP KINASE
O
HN N ACYCLOVIR
H2N N N DIPHOSPHATE NON FUNCTIONAL COMPLEX
P P OCH2
5
CELLULAR PROTEIN KINASE P
O O
HN N ACYCLOVIR G
H2N N TRIPHOSPHATE
N
P P P OCH2 P
O
CG
O VIRAL DNA POLYMERASE O
P
DEOXY GUANOSINE TRIPHOSPHATE HN N P
O
H2N N N TA
COMPETITIVE INHIBITION O
P P P P
OCH2 O
ONCORPORATION INTO P
PRIMER STRAND O
CG
HO O
P
P
5
3

TEMPLATE PRIMER
RESISTANCE
• ABSENCE OR PARTIAL PRODUCTION
OF VIRAL THYMIDINE KINASE- MOST
COMMON
• ALTERED THYMIDINE KINASE
SUBSTRATE SPECIFICITY
• ALTERED VIRAL DNA POLYMERASE
• MUTATION - RARE
PHARMACOKINETICS
• BIOAVAILABILITY (15-20% )10-30% DECREASE WITH
INCREASING DOSE
• UNAFFECTED BY FOOD
• CLEARED BY GF AND TS
• PLASMA T/2= 2.5 HRS (1.5-6) IN NORMAL RENAL
FUNCTION
• INCREASE IN NEONATES AND ANURIC PATIENTS
• CLEARED BY HEMODIALYSIS BUT NOT BY
PERITONEAL DIALYSIS
• <15% EXCRETED AS 9 CARBOXYMETHOXY METHYL
GUANINE
• DIFFUSES READILY IN ALL TISSUES AND BODY
FLUID
• CONCENTRATED IN MILK, AMNIOTIC FLUID AND
PLACETA
• PERCUTANOUS ABSORPTION IS LOW
• VALACYCLOVIR IS CONVERTED
COMPLETELY TO ACYCLOVIR
• DUE TO FIRST PASS METABOLISM
ADVERSE EFFECTS
• TOPICAL = MUCOSAL IRRITATION
• TRANSIENT BURNING WHEN APPLIED TO
GENITAL LESIONS
• ORAL
– ACYCLOVIR
• NAUSEA, DIARRHEA, RASH, HEADACHE
• RENAL INSUFFICIENCY (REVERSIBLE- CRYSTALLINE
NEPHROPATHY DUE TO RAPID INFUSION,
DEHYDRATION, DEC URINE FLOW) INFUSED OVER
ONE HOUR
• NEUROTOXICITY- ALTERED SENSORIUM, TREMOR,
MYOCLONUS, DELIRIUM ,SEIZURE, EPS
• NEUTROPENIA IN NEONATES
– VALACYCLOVIR (HIGH DOSE)
• CONFUSION, HALLUCINATION, NEPHROTOXICITY,
THROMBOCYTOPENIA,
DRUG INTERACTION
– SEVERE SOMNOLENCE AND LETHARGY
IF GIVEN WITH ZIDOVUDINE
– CYCLOSPORINE- NEPHROTOXIC
– PROBENECID PROLONG CLEARANCE
– ACYCLOVIR DECREASE THE RENAL
CLEARANCE OF OTHER DRUGS
INDICATION
1. HESPES SIMPLEX VIRUS
a. GENITAL HERPES (FIRST EPISODE)
• ACYCLOVIR 200 MG 5 X A DAY OR 400 MG TID
FOR 7-10 DAYS
• VALACYCLOVIR- 1000 MG BID 7-10 DAYS
• SHORTEN DURATION BY 2 DAYS
• LESION HEALING BY 4 DAYS
• VIRAL SHEDDING 7 DAYS
• TOPICAL LESS EFFECTIVE
b. RECURRENT
• CHRONIC ORAL ACYCLOVIR 400 BID
• VALACYCLOVIR 500-1000 OD
INDICATION
1. HESPES SIMPLEX VIRUS
a. GINGIVOSTOMATITIS
b. OROLABIAL
c. MUCOCUTANOUES LESIONS
INDICATION
1. VARIZELLA ZOSTER
WITHIN 24 HRS OF RASH ONSET
a. ACYCLOVIR 800 MG 5 X A DAY FOR 7 DAYS
a. REDUCE LESION
b. CRUSTING
c. DURATION OF FEVER
b. ACYCLOVIR 20 MG/KG QID FR 5 DAYS (CHILDREN)
a. DEC FEVER
b. DEC LESION
2. HERPES ZOSTER
1. 800 MG 5 X A DAY FOR 7 DAYS
2. REDUCE PAIN
3. INITIATE TREATMENT WITHIN 72 HRS AFTER RASH
AGENTS THAT TREAT
CYTOMEGALOVIRUS
• GANCICLOVIR
• VALGANCICLOVIR
• FOSCARNET
• CIDOFOVIR
GANCICLOVIR
• GUANINE NUCLEOSIDE ANALOG
• VALGANCYCLOVIR IS A PRODRUG
• MECHANISM
• INHIBIT VIRAL DNA SYNTHESIS
• PHSPHORYLATED BY VIRAL THYMIDANE
KINASE AND PHSOPHOTRANSFERASE
• ACTS AS A COMPETITIVE INHIBITOR OF
DOXYGUANOSINE TRIPHOSPHATE
• ORAL BIOAVILABILITY= 6-9% AFTER INGESTION
WITH FOOD
• VALGANCICLOVIR IS CONVERTED TO
GANCICLOVIR 61% BIOAVILABILITY FURTHER
INCREASED BY FOOD INTAKE COMPARABLE TO
IV DOSE
• FOOD INCREASES BIOAVIALBILITY TO 25%
• T1/2= 2-4 HRS
• 90% ELIMINATED UNCHANGED BY GF AND TS
ADVERSE EFFECTS
• GANCYCLOVIR
– MYELOSUPPRESSION (DOSE LIMITING TOXICITY)
– NEUTROPENIA
– THROM BOCYTOPENIA
– NEUROITOXICITY
– TERATOGENIC, EMBRYOTOXIC
• VALGANCYCLOVIR
– HEADACHE
– GIT DISTURBANCE
– NEUTROPENIA
– INFUSION RELATED PHALEBITIS
– RASH
– AZOTEMIA
– ANEMIA
– LIVER FUNCTION ABNORMALITIES
– NAUSEA
– VOMITING
– TERATOGENIC
INDICATION
• CYTOMEGALOVIRUS
FOSCARNET
• INHIBIT VIRAL NUCLEIC ACID SYNTHESIS
BY INTERACTING WITH HERPES VIRUS
DNA POLYMERASE
• REVERBLE BLOCKADE OF
PYROPHOSPHATE BINDING SITE OF VIRAL
POLYMERASE
• 100 X GREATER INHIBITORY EFFECT
AGAINST HERPESVIRUS DNA
POLYMERASE THAT CELLULAR DNA
POLYMERASE ALPHA
• 80% EXCRETED UNCHANGED IN
URINE
• NEPHROTOXIC
• HYPOCALCEMIA
• INCREASE SERUM CREATININE
• NEUROTOXIC
• ECG CHANGES
• ELEVATED LIVER FUNCTION TEST
CIDOFOVIR
• MECHANISM
• INHIBIT VIRAL DNA SYNTHESIS
• SLOWING AND TERMINATING CHAIN
ELONGATION
• LOW BIOAVIALBILITY
• EXCRETED BY KIDNEY
• PROBENECID INCREASES HALF LIFE
• NEPHROTOXIC
• MUTAGENIC, GONADOTOXIC,
EMBRYOTOXIC, ERATOGENIC
TRICYCLIC AMINES

CH3

CHNH2

NH2

AMANTADINE RIMANTADINE
MECHANISM
1. INHIBIT EARLY STEP IN VIRAL
REPLICATION – VIRAL UNCOATING
2. ALTER HEMAGGLUTININ PROCESSING
IN VIRAL ASSEMBLY
• ACTS ON INFLUENZA A M2 PROTEIN
• RESISTANCE IS UNCOMMON <1-2.5 %
KINETICS
• AMANTADINE AND RIMANTADINE
– WELL ABSORBED
– LARGE VOLUME OF DISTRIBUTION
– EXCRETED IN BREAST MILK
– EXCRETD UNMETABOLIZED IN THE URINE
THROUGH GF AND TS
• AMANTADINE T1/2 12-18 HRS
• RIMANTADINE T1/2- 24-36 HRS
• 60-90% EXCRETED AS METABOLITE
ADVERSE EFFECTS
• GIT
• CNS
– LIGHT HEADEDNESS
– DIFFICULTY IN CONCENTRATING
– INSOMINA
– LOSS OF APPETITE
– NAUSEA
• NEUROTOXIC IF TAKEN WITH ANTIHISTAMINE AND
ANTICHOLINERGIC
– DELIRIUM
– HALLUCINATION
– SEIZURE
– CARDIAC ARRYTHMIA
– COMA
– PSYCHIATRIC SYPTOMS
• TERATOGENIC
INDICATION
• PREVENTION AND TREATMENT OF
INFLUENZA A VIRUS
• SEASONAL PROPHYLAXIS
OSELTAMIVIR
• OSELTAMIVIR PHOSPHATE
– ETHYL ESTER PRODRUG
• OSELTAMIVIR CARBOXYLATE
– POTENCY SIMILAR TO ZANAMIVIR
OSELTAMIVIR
• NEURAMINIDASE
– IS FOUND IN THE SURFACE OF THE VIRUS
– AID IN THE EFFICIENCY OF THE RELEASE OF
VIRUS FROM INFECTED CELLS
• OSELTAMIVIR MECHANISM
– INTERACTION WITH NEURAMINIDASE LEAD
TO CONFORMATIONAL CHANGE WITHIN THE
ENZYMES ACTIVE SITE INHIBITING ITS
ACTIVITY
KINETICS
• OSELTAMIVIR PHOPHATE IS ABSORBED
RAPIDLY AND CLEAVED BY ESTERASE IN
THE LIVER AND GIT TO OSELTAMIVIR
CARBOXYLATE
• BIOAVAILABILITY 80%
– PHOSPHATE 1/2 1-3 HRS
– CARBOXYLATE 6-10 HRS
• TIME TO PEAK- 2.5 -5 HRS
• PROBENECID DOUBLES THE HALF LIFE
UNWANTED EFFECTS
• GIT
• NAUSEA
• EMESIS
• HEADACHE
• NON TERATOGENIC
• SAFETY IS NOT GUATRANTEED
INDICATION
• INFLUNEZA A AND B
RETROVIRUS
REPLICATIVE CYCLE OF HIV

RNA REPLICA

ATTACHMENT
CD4
AND FUSION PENETRATION
RECEPTORS
AND UNCOATING

REVERSE TRANSCRIPTASE

M RNA V RNA

•STRUCTURAL
PROTEIN
•NON STRUCTURAL
PROTEIN
PROTEIN SYNTHESIS
AND PACKAGING

VIRAL RELEASE

PACKAGING AND
ASSEMBLY
ANTI RETROVIRAL AGENTS
• NRTI (NUCLEOSIDE REVERSE
TRANSCRIPTASE INHIBITOR)
– ABACAVIR
– DIDANOSINE
– ERMTRICITABINE
– LAMIVUDNE
– STAVUDINE
– TENOFOVIR
– ZALCITABINE
– ZIDOVUDINE
ZIDOVUDINE
• SYNTHETIC THYMIDINE ANALOG
• BROAD SPECTRUM COVERAGE FOR
– HIV 1
– HIV 2
– HTLV I AND II
• ACTIVE AGAINST MONOCYTIC AND
LYMPHOBLASTIC CELL LINES
• LESS ACTIVE AGAINST CHRONICALLY INFECTED
CELLS
• NO IMPACT ON CELLS ALREADY INFECTED WITH
HIV
• MORE POTENT AGAINST ACTIVATED THAN
RESTING LYMPHOCYTES
MECHANISM OF ACTION
• CONVERTED TO Z MONO PHOSPHATE
– COMPETITIVE INHIBITOR OF CELLULAR THYMIDYLATE
KINASE

• CONVERTED TO Z DI PHOSPHATE
• CONVERTED TO Z TRI PHOSPHATE
– INHIBIT DNA POLYMERASE ALPHA
– INHIBIT MITOCHONRIAL POLYMERASE GAMMA

• REVERSE TRANSCRIPTASE INHIBITOR


• RESISTANCE
– MUTATION IN REVERSE TRANSCRIPTASE
THYMIDINE ANALOG MUTATION (TAMs)
KINETICS
• ABSORBED RAPIDLY WITH PEAK PLASMA
CONCENTRATION WITHIN 1 HOUR
• ELIMINATION T1/2 3-4 HRS
• DOSE : 300 MG BID
• UNDERGO RAPID FIRST PASS METABOLISM
• BIOAVAILBILITY 64%
• FOOD SLOWS DOWN ABSORPTION
• NOT BOUND TO PLASMA PROTEIN
• CROSS BBB
• DETECTABLE IN MILK, SEMEN, FETAL TISSUE,
MALE GENITAL TRACT
ADVERSE EFFECT
• ACUTE ADVERSE EFFECT
– FATIGUE, MALAISE, MYALGIA, NAUSEA, ANOREXIA,
HEADACHE, INSOMINIA
– BONE MARROW SUPPRESSION
– ANEMIA
• erythropoietin
– NEUTROPENIA
• GMCSF
• CHRONIC USE
– SKELETAL MUSCLE ATROPHY (DUE TO DEPLETION OF
MITOCHONDRIAL DNA)
– HEPATIC TOXOCITY
– LACTIC ACIDOSIS
– NAIL HYPERPIGMENTATION
DRUG INTERACTION
• DRUG WHICH INCREASE PLASMA
CONCENTRATION OF AZT
– PROBENECID
– FLUCONAZOLE
– ATOVAQUONE
– VALPROIC ACID
• STAVUDINE COMPETES FOR
INTRACELLULAR PHOSPHORYLATION
INDICATION
• ADULTS AND CHILDREN WITH HIV INFECTION
• PREVENT MOTHER TO CHILD TRANSMISSION
• POST EXPOSURE PROPHYLAXIS IN HIV EXPOSED
HEALTH CARE PROFESSIONAL
• MORE EFFECTIVE WHEN COMBINED WITH OTHER
DRUGS
• RECOMMENDATION IS TO COMBINE WITH
– PI + 1 NUCLEOSIDE ANALOG
– 2 NUCLEOSIDE ANALOG
– NNRTI + NUCLEOSIDE ANALOG
REPLICATIVE CYCLE OF HIV

INSERTION IN THE HOST GENE


ATTACHMENT
CD4
AND FUSION PENETRATION TRANSCRIPTION
RECEPTORS
AND UNCOATING INTO VIRAL DNA

RT

M RNA V RNA

•STRUCTURAL
PROTEIN
•NON STRUCTURAL
PROTEIN
PROTEIN SYNTHESIS
AND PACKAGING
PROTEASE

VIRAL RELEASE

PACKAGING AND
ASSEMBLY
ANTI RETROVIRAL AGENTS
• NNRTI (NON NUCLEOSIDE REVERSE
TRANSCRIPTASE INHIBITOR)

– DELAVIRDINE
– EFAVIRENZ
– NEVIRAPINE
NON NUCLEOSIDE REVERSE
TRANSCRIPTASE INHIBITORS (NNRTI)

• BIND TO A HYDROPHOBIC POCKET IN THE p66


SUBUNIT OF THE HIV -1 REVERSE
TRANSCRIPTASE
• INDUCE A CONFORMATIONAL CHANGE IN THE
ENZYME THUS REDUCING ITS ACTIVITY
• NON COMPETITIVE INHIBITOR
• DOES NOT REQUIRE INTRACELLULAR
PHOSPHORYLATION
• ACTIVE AGAINST
• HIV-1 BUT NOT HIV 1
EFAVIRENZ
• ADVERSE EFFECTS
• RASH
• STEVEN JOHNSON SYNDROME
• PSYCHIATRIC SIDE EFFCTS
• VIVID DREAMS
• PSYCHOSIS
• INSOMNIA
• ELEVATED HEPATIC TRANSAMINASE
• ELEVATED CHOLESTEROL
• FALSE POSITVE TEST FOR MARIJUANA
• FETAL MALFORMATION
NEVIRAPINE EFAVIRENZ DELAVIRDINE

ORAL 90-93 50 85
BIOAVAILBILITY

EFFECT ON INC 17-28%


MEALS

PLASMA T1/2 25-30 40-55 2-11

PROTEIN BINDING 60 99 98

METABOLISM CYP3A4> CYP2B6> CYP3A4


CYP2B6 CYP3A4
RENAL <3% <3% <3%
EXCRETION

INHIBITION BY
CYP3A NO YES YES
ANTI RETROVIRAL AGENTS
• PROTEASE INHIBITOR
– AMPRENAVIR
– ATAZANAVIR
– FOSMAPRENAVIR
– INDINAVIR
– LOPINAVIR
– RITONAVIR
– NELFINAVIR
– RINTONAVIR
– SAQUINAVIR
– TIPRIANIVIR
PROTEASE INHIBITOR
• COMPETITIVELY INHIBITS VIRUS
ASPARTYL PROTEASE
• PREVENTS MATURATION OF VIRUS
TO ITS MATURE FORM
REPLICATIVE CYCLE OF HIV

RNA REPLICA

ATTACHMENT
CD4
AND FUSION PENETRATION TRANSCRIPTION
RECEPTORS
AND UNCOATING INTO VIRAL DNA

RT

M RNA V RNA

•STRUCTURAL
PROTEIN
MATURE VIRUS •NON STRUCTURAL
PROTEIN
PROTEIN SYNTHESIS
AND PACKAGING
PROTEASE

VIRAL RELEASE

PACKAGING AND
ASSEMBLY
ADVERSE EFFECT
• METABOLIC DRUG INTERACTION
• PI ARE INDUCERS OF CYP3A4 AND
GLUCORONOSYL S TRANSFERASE
ANTI RETROVIRAL AGENTS
• ENTRY INHIBITOR
– ENFUVIRTIDE
• HIV DERIVED PEPTIDE
• DEVELOP AS A VACCINE
• INHIBIT MEMBRANE FUSION
GUIDELINES
• COMBINATION THERAPY TO
PREVENT RESISTANCE
• EMPHASIS ON REGIMEN
CONVENIENCE, TOLERABILITY,
ADHERENCE
• NEED FOR LIFE LONG TREATMENT

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