Antiinfective agents

1. Antiviral agents
Sept, 2022

2. Introduction
• Viruses are obligate intracellular parasites,
–the replication of viruses depends on
synthetic processes of the host cell.

3. – Common viruses:
– Herpes viruses:
– Herpes simplex virus (HSV); has two types- HSV 1 and HSV
2
– Herpes simplex infection causes blisters in the skin or mucous
membranes of the mouth, lips or genitals:
– HSV 1- oral herpes
– HSV2- Genital herpes
– Varicella Zoster Virus (VZV)-chicken pox and shingles
(herpes zoster)
– Cytomegalovirus
– A common virus particularly among immuno-compromised
patients and infants

4. –Influenza virus- causes respiratory
illness (flu)
–Hepatitis viruses- cause inflammation
of the liver; Include- Hepatitis A Virus
(HAV), Hepatitis B Virus (HBV),
Hepatitis C Virus (HCV), and others
–Human Immunodeficiency Virus (HIV)

5. • Antiviral drugs act at several stages of viral replication:
– viral entry,
– nucleic acid synthesis,
– late protein synthesis and processing,
– and in the final stages of viral packaging and virion release
(Figure 49–1).
• Most anti-herpes and anti- HIV drugs are structurally
similar to naturally occurring compounds.
• The selective toxicity of antiviral drugs usually depends
on greater susceptibility of viral enzymes to the
inhibitory actions of the drugs than host cell enzymes.

6. Antiviral agents: classification
• Antiviral drugs:
• Drugs for herpes:
– Acyclovir
– Ganciclovir
– Foscarnet
– Drugs for influenza:
• Amantadine
• Zinamivir
– Drugs for HBV and HCV:
• IFN- alpha
• Lamivudine
• Ribavirin

7. • Antiretroviral drugs:
– Drugs for HIV
• Reverse transcriptase inhibitors: nucleoside and non-
nucleoside
• Protease inhibitors
• Fusion inhibitors
Antiviral agents: classification

8. Antiherpes drugs
• Drugs:
– Acyclovir
– Valacyclovir (prodrug)
– Penciclovir
– Famciclovir (prodrug)
• Mechanism of action
– Activated by viral thymidine kinase (TK) to forms
that inhibit viral DNA polymerase

9. • Clinical use:
– Treatment and prophylaxis for Herpes Simplex Virus
Infection (HSV-I, HSV-2) and Varicella Zoster Virus (VZV)
– None of these drugs is active against TK– strains
• Pharmacokinetics:
– Acyclovir: Topical, oral, and IV
– Penciclovir: Topical
– Famciclovir and valcyclovir: Oral
• Adverse effects:
– Oral forms cause nausea, diarrhea, and headache
– IV acyclovir may cause renal and CNS toxicity

10. Drugs for cytomegalovirus
• Drugs:
– Ganciclovir
– Valganciclovir (prodrug of ganciclovir)
– Cidofovir
– Foscarnet
• Mechanism of action:
– Ganciclovir requires activation to a form inhibiting
DNA polymerase;
– No viral bioactivation of cidofovir and foscarnet is
required
• Clinical use
– Treatment of CMV infections in immunosuppression
(eg, AIDS) and organ transplantation

11. • Pharmacokinetics:
– Ganciclovir: Oral, IV, intraocular forms
– Valganciclovir: Oral
– Cidofovir and foscarnet (IV)
• Adverse reactions:
– Ganciclovir: Bone marrow suppression, hepatic and
neurologic dysfunction
– Cidofovir and foscarnet: Nephrotoxicity
– Foscarnet: CNS effects (headache, hallucinations, and
seizures) and electrolyte imbalance

12. Antihepatitis drugs
• Drugs:
– Interferon- (IFN- alpha)
– Adefovir-dipivoxil
– Entecavir
– Lamivudine
– Ribavirin
– Telbivudine
– Tenofovir
• Mechanism of action
– IFN alpha;
• Degrades viral RNA via activation of host cell RNAase;
– The others inhibit HBV DNA polymerase

13. • Clinical use
– Suppressive treatment of HBV (all drugs except ribavirin);
– Treatment of HCV (ribavirin +/– IFN-)
• Pharmacokinetics:
– IFN-alpha: Parenteral
– Adefovir, entacavir, lamivudine, and ribavirin: Oral
– Ribavirin: Inhalational
• Adverse reactions
– IFN-alpha: Alopecia, myalgia, depression, flu-like syndrome
– Adefovir: lactic acidosis, renal and hepatic toxicity
– Ribavirin: Anemia, teratogen

14. Anti-influenza drugs
• Drugs:
– Amantadine
– Rimantadine
– Oseltamivir
– Zanamivir
• Mechanism of action
– Amantadine and rimantidine: block M2 proton
channels (proteins present in viral membrane),
preventing viral uncoating
– Oseltamivir and zanamivir: inhibit neuraminidase,
preventing viral cleavage and release

15. • Clinical use
– M2 blockers are virtually obsolete;
– others are used in:
• Prophylaxis against most current flu strains; used to shorten
symptoms
• Pharmacokinetics:
– All given orally except zanamivir, which is inhalational
• Adverse reactions
– Oseltamivir: Gastrointestinal effects
– Zanamivir: Bronchospasm in asthmatics

16. Antiretroviral Drugs
Classes:
• Reverse transcriptase inhibitors (nucleoside
and non nucleoside)
• Protease inhibitors
• Entry inhibitors

17. Antiretroviral Drugs

18. • Further learning resources on HIV replication:
– https://www.youtube.com/watch?v=8sipX86JfUw
– Katzung- Basic and Clinical Pharmacology, Figure
49–4.

19. Antiretroviral Drugs
Nucleoside/nucleotide reverse transcriptase
inhibitor (NRTIs)
– Abacavir
– Didanosine
– Emtricitabine
– Lamivudine
– Stavudine
– Tenofovir
– Zalcitabine
– Zidovudine

20. • Mechanism of action
– Inhibit HIV reverse transcriptase after
phosphorylation by cellular enzymes;
– cross-resistance common, but incomplete
• Pharmacokinetics:
– Duration of action usually longer than half-life;
– most undergo renal elimination especially,
didanosine, emtricitabine, lamivudine, stavudine,
tenofovir, and zidovudine

21. • Adverse reactions:
– Zidovudine: Bone marrow suppression
– Abacavir: Hypersensitivity
– Didanosine: Pancreatitis
– Stavudine, zalcitabine: Peripheral neuropathy, Lactic
acidosis with hepatic steatosis
• Drug interactions:
– Most NRTIs are not extensively metabolized by
hepatic enzymes such as the CYP450 isoforms,
• so they have few interactions that concern their
pharmacokinetic characteristics

22. • Nonnucleoside reverse transcriptase
inhibitors (NNRTIs)
– Delavirdine
– Efavirenz
– Etravirine
– Nevirapine
• Mechanism of acion:
– Inhibit HIV reverse transcriptase; no
phosphorylation required;
– cross-resistance between NNRTIs but not with
NRTIs

23. • Pharmacokinetics
– All current NNRTIs are metabolized via CYP450 isozymes;
– Etravirine may induce formation of CYP3A4, but inhibits
other CYP450s
• Adverse reactions:
– Delavirdine, nevirapine: Rash, increased liver enzymes
– Efavirenz: Teratogenicity
• Interactions:
– Inducers of CYP450 isozymes (eg, phenytoin, rifampin) and
inhibitors (eg, azoles, PIs) alter NNRTI duration of action

24. Protease inhibitors (PIs)
– Atazanavir
– Darunavir
– Fosamprenavir
– Indinavir
– Nelfinavir
– Ritonavir
– Saquinavir
– Tipranavir

25. • Mechanism of action
– Inhibit the action of the enzyme protease which is
involved in viral protein processing;
– cross-resistance between PIs is common
• Pharmacokinetics
– Elimination mainly via metabolism by CYP450
isozymes; they act as substrates and inhibitors of
P450
– Fosamprenavir is a prodrug forming amprenavir, a
substrate and inducer of CYP450

26. • Adverse reactions:
– GI distress and diarrhea associated with:
• Atazanavir,
• fosamprenavir,
• lopinavir,
• nelfinavir,
• saquinavir:
– Atazanavir: Peripheral neuropathy
– Amprenavir: Rash
– Indinavir: Hyperbilirubinemia and nephrolithiasis

27. • Effects on Carbohydrate and Lipid Metabolism
– The use of PIs in HAART drug combinations has led
to the development of disorders in carbohydrate
and lipid metabolism:
• hyperglycemia and insulin resistance or hyperlipidemia,
• altered body fat distribution;
– Buffalo hump (accumulation of fat on the back of the neck),
gynecomastia,
– truncal obesity
– facial and peripheral lipodystrophy.

28. • Interactions:
– Ritonavir and other PIs can inhibit CYP450
metabolism of many drugs including:
• antihistamines,
• antiarrhythmics,
• HMG-CoA reductase inhibitors,
• oral contraceptives
• sedative-hypnotics
– Drugs known to induce or inhibit CYP450 isoforms
may alter the plasma levels of PIs

29. Entry inhibitors
– Enfuvirtide
– Maraviroc
• Mechanism of action
– Enfuvirtide: Blocks fusion between viral and cellular
membranes
– Maraviroc: CCR5 receptor antagonist
• Pharmacokinetics:
– Enfuvirtide- given as a subcutaneous injection;
undergoes extrahepatic hydrolysis
– P450 metabolism (maraviroc)

30. • Adverse reactions:
– Enfuvirtide: Hypersensitivity
– Maraviroc: Muscle/joint pain, diarrhea, and
increased liver enzymes
• Interactions:
– Inducers and inhibitors of CYP450 alter
elimination of maraviroc;
• no effects on enfuvirtide

31. Bibliography
– Anthony J. Trevor, Bertram G. Katzung & Susan B.
Masters (2013) Pharmacology- Examination And
Board Review 10th ed., McGraw Hill, Lange
– Katzung B.G (2007) Basic & Clinical Pharmacology,
11th ed, McGraw Hill, Lange