Title: Antiretroviral Agents Pharmacology Introduction: Antiretroviral agents play a crucial role in the management of human immunodeficiency virus (HIV) infections. HIV is a retrovirus that attacks the immune system, specifically the CD4 cells (T cells), leading to a weakened immune system and increased susceptibility to various infections. Antiretroviral therapy (ART) aims to suppress viral replication, maintain or restore immune function, and improve overall quality of life. This note provides a detailed overview of the pharmacology of antiretroviral agents. Classification of Antiretroviral Agents: Antiretroviral agents are classified into several classes based on their mechanism of action: a. Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs): - Examples: Zidovudine, Lamivudine, Tenofovir. - Mechanism: They inhibit reverse transcriptase, an enzyme essential for viral DNA synthesis, by acting as faulty substrates. b. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs): - Examples: Efavirenz, Nevirapine, Rilpivirine. - Mechanism: They bind directly to reverse transcriptase, causing conformational changes that inhibit its activity. c. Protease Inhibitors (PIs): - Examples: Atazanavir, Darunavir, Ritonavir. - Mechanism: PIs interfere with the protease enzyme, hindering the cleavage of viral polyproteins and preventing the maturation of infectious viral particles. d. Integrase Strand Transfer Inhibitors (INSTIs): - Examples: Raltegravir, Elvitegravir, Dolutegravir. - Mechanism: INSTIs block the integrase enzyme, preventing the integration of viral DNA into the host genome. e. Entry Inhibitors: - Examples: Enfuvirtide, Maraviroc. - Mechanism: Enfuvirtide inhibits the fusion of viral and cellular membranes, while Maraviroc blocks the CCR5 receptor, preventing viral entry into the cell. Pharmacokinetics: a. Absorption: Antiretroviral drugs can be taken orally, and their absorption may be affected by food. For instance, some PIs are better absorbed with food, while others should be taken on an empty stomach. b. Distribution: Antiretrovirals distribute widely in the body, including the central nervous system. Some drugs have specific formulations to enhance their penetration into sanctuary sites. c. Metabolism: Many antiretrovirals undergo hepatic metabolism, primarily through the cytochrome P450 system. Drug interactions may occur, influencing the metabolism of co-administered medications. d. Excretion: Renal excretion is a significant route for some antiretrovirals. Dosing adjustments are necessary in patients with renal impairment. Resistance: a. Mechanisms: HIV has a high mutation rate, leading to the emergence of drug-resistant strains. Resistance can result from mutations in the viral genome, reducing drug binding or increasing the efficiency of viral replication. b. Prevention: Combination therapy, or highly active antiretroviral therapy (HAART), is employed to reduce the risk of resistance. This involves using

1. Antiviral Agents
(Antiretroviral Drugs) -Prajwal Waman Ghatol

2. 01.
Introduction
These are drugs active against human
immuno-deficiency virus (HIV) which is a
retrovirus. They are useful in prolonging
and improving the quality of life and
postponing complications of acquired
immunodeficiency syndrome (AIDS) or
AIDS-related complex (ARC), but do not
cure the infection. The clinical efficacy of
anti-retrovirus drugs is monitored primarily
by plasma HIV-RNA assays and CD4
lymphocyte count carried out at regular
intervals.
Prajwal Ghatol

3. 02.
Introduction
HIV is a single stranded RNA retrovirus which
uniquely carries out reverse transcription of pro-
viral DNA from viral RNA (normally RNA is
transcripted from DNA) with the help of a viral
RNA-dependent DNA polymerase (reverse
transcriptase). The primary cell type attacked by
HIV is the CD4+ helper T-lymphocytic, but later
macrophages and some other cell types may also be
infected. When population of CD4 cells declines
markedly (<200 cells/~1L), cell mediated immunity
(CMI) is lost and opportunistic infections abound, to
which the victim ultimately succumb , unless
treated. Because the HIV genome integrates with the
host DNA, eradication of the virus from the body of
the victim appears impossible at present.
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4. Over the past 35 years, a number of virus
specific targets have been identified and
drugs for these developed. We now have
drugs which effectively suppress HIV
replication and restore CMI for variable
periods of time. The two established targets
for anti-HIV attack are:
(a) HIV reverse transcriptase: Which
transcripts HIV-RNA into pro-viral DNA.
(b) HIV protease: Which cleaves the large
virus directed polyprotein into functional
viral proteins.
Introduction
03.
Prajwal Ghatol

5. In addition, some newer targets being
exploited are:
• Fusion of viral envelope with plasma
membrane of CD4 cells through which HIV-
RNA enters the cell.
• Chemokine coreceptor (CCR5) on host
cells which provide anchorage for the
surface proteins of the virus.
• HIV-integrase: Viral enzyme which
integrates the pro-viral DNA into host DNA.
Introduction
04.
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6. Classification Prajwal Ghatol

7. Nucleoside Reverse Transcriptase Inhibitors [NRTIs]
These drugs, after entering HIV-infected
cells, are converted to their active
triphosphate forms by cellular kinases
and competitively inhibit HIV reverse
transcriptase. They get incorporated into
the growing viral DNA and cause
termination of chain elongation of
proviral DNA.
Prajwal Ghatol

8. This deoxiguanosine analogue requires a virus specific
enzyme for conversion to the active metabolite that
inhibits DNA synthesis and viral replication.
Acyclovir is preferentially taken up by the virus infected
cells. Because of selective generation of the active
inhibitor in the virus infected cell and its greater
inhibitory effect on viral DNA synthesis, acyclovir has low
toxicity for host cells: a several hundred-fold
chemotherapeutic index has been noted.
Zidovudine, a thymidine analogue, was the first antiretroviral drug approved for the treatment of
HIV infection. It is the prototype drug of NRTIs. Zidovudine is effective against HIV-1 and HIV-2. It
protects the uninfected cells from HIV, but has no effect on HIV-infected cells. Zidovudine is orally
effective. It is well absorbed from the GI tract, metabolized in liver by glucuronide conjugation and
excreted in urine. It crosses placental and BBB and is also secreted in milk.
Zidovudine
(Azidothymidine [AZT])
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9. Adverse Effects of
Zidovudine
Bone marrow suppression, anaemia and neutropenia
are the common side effects. Nausea, vomiting,
abdominal discomfort, headache and insomnia are
commonly seen during the initial stages of therapy.
Long- term therapy may cause hepatotoxicity,
myopathy with fatigue and lactic acidosis.
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10. Drug-Drug interactions
1. Zidovudine X paracetamol: Both are metabolized by glucuronide
conjugation. Paracetamol competes and interferes with glucuronide
conjugation of zidovudine. This leads to a rise in the plasma
concentration of zidovudine and its toxicity.
2. Azoles X zidovudine: Azole antifungal agents are hepatic microsomal
enzyme inhibitors. They inhibit the metabolism of zidovudine. This
leads to an increase in plasma concentration of zidovudine resulting in
its toxicity.
3. Zidovudine X stavudine: They should not be combined together
because they compete for intracellular phosphorylation.
Prajwal Ghatol

11. This deoxiguanosine analogue requires a virus specific
enzyme for conversion to the active metabolite that
inhibits DNA synthesis and viral replication.
Acyclovir is preferentially taken up by the virus infected
cells. Because of selective generation of the active
inhibitor in the virus infected cell and its greater
inhibitory effect on viral DNA synthesis, acyclovir has low
toxicity for host cells: a several hundred-fold
chemotherapeutic index has been noted.
Zidovudine is used in combination with other antiretroviral drugs for the
treatment of HIV-infected patients. It is also used for postexposure
prophylaxis (PEP) and to prevent vertical transmission of HIV.
NRTIs
Prajwal Ghatol

12. This deoxiguanosine analogue requires a virus specific
enzyme for conversion to the active metabolite that
inhibits DNA synthesis and viral replication.
Acyclovir is preferentially taken up by the virus infected
cells. Because of selective generation of the active
inhibitor in the virus infected cell and its greater
inhibitory effect on viral DNA synthesis, acyclovir has low
toxicity for host cells: a several hundred-fold
chemotherapeutic index has been noted.
NRTIs
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13. Non-Nucleoside Reverse Transcriptase Inhibitors [NNRTIs]
NNRTIs are highly active against HIV-1
but have no effect on HIV-2. They
directly and noncompetitively inhibit HIV
reverse transcriptase enzyme. There is
no cross-resistance with the NRTIs.
They are used in combination with
NRTIs in the treatment of AIDS. Adverse
effects are skin rashes, fever, nausea,
pruritus and CNS disturbances like
head- ache, confusion, insomnia, bad
dreams and amnesia.
Prajwal Ghatol

14. This deoxiguanosine analogue requires a virus specific
enzyme for conversion to the active metabolite that
inhibits DNA synthesis and viral replication.
Acyclovir is preferentially taken up by the virus infected
cells. Because of selective generation of the active
inhibitor in the virus infected cell and its greater
inhibitory effect on viral DNA synthesis, acyclovir has low
toxicity for host cells: a several hundred-fold
chemotherapeutic index has been noted.
NNRTIs
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15. Protease Inhibitors
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16. Protease Inhibitors
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17. Entry or Fusion Inhibitors
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18. Integrase Inhibitors
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19. Antiretroviral Therapy
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20. Antiretroviral Therapy
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21. Antiretroviral Therapy
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22. Prophylaxis of HIV Infection
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23. Prajwal Ghatol

24. Thank you!