1. Review on Infectious Diseases and Management
Jamaluddin Shaikh, Ph.D.
School of Pharmacy, University of Nizwa

2. What is Virus?
Intracellular parasites that use many of the host cell’s biochemical mechanisms and products to sustain their viability
A mature virus (virion) can exist outside a host cell and retain its infective properties
For reproduction virus must enter the host cell, take over the host cell’s mechanisms for nucleic acid and protein synthesis, and direct the host cell to make new viral particles
Two types of virus
DNA virus
RNA virus

3. DNA Virus DNA viruses and the diseases that they produce:
Adenoviruses (colds, conjunctivitis)
Hepadnaviruses (hepatitis B)
Herpesviruses (shingles)
Papillomaviruses (warts)
Poxviruses (smallpox)

4. RNA Virus RNA viruses and the diseases that they produce:
Arenaviruses (meningitis)
Orthomyxoviruses (influenza)
Paramyxoviruses (measles, mumps)
Picornaviruses (polio, meningitis, colds)
Rhabdoviruses (rabies)
Rubella virus (German measles)
Retroviruses (AIDS)

5. Overview of Antiviral Therapy
Basic approaches are used to control viral diseases:
1.Vaccination
2. Antiviral chemotherapy
3. Stimulation of host resistance mechanisms
Antiviral Therapy: Vaccination
Used to prevent:
measles, rubella, mumps, poliomyelitis, yellow fever, smallpox, chickenpox, and hepatitis B
Vaccines have little or no use once the infection has been established

6. Antiviral Chemotherapy
The chemotherapy of viral infections may involve interference with any or all of the steps in the viral replication cycle
Disadvantage:
Because viral replication and host cell processes are so intimately linked, the main problem in the chemotherapy of viruses is finding a drug that is selectively toxic to the virus

7. Viral Infections Types of viral infections HIV infection Herpes
Influenza
Hepatitis

8. HIV Infection
HIV, a family of mammalian retroviruses evolved to establish chronic persistent infection with gradual onset of clinical symptoms
Humans and chimpanzees are the only known hosts for these viruses
HIV is a typical retrovirus with a small RNA genome of 9300 base pairs

9. Drug Used to Treat HIV Infection
Each class of anti-HIV drug has a different mechanism of action and combinations are used in the therapy of HIV/AIDS
Combination treatment is known as highly active antiretroviral therapy (HAART)
A HAART combination would involve two nucleoside reverse transcriptase inhibitors with either a non-nucleoside reverse transcriptase inhibitor or one or two protease inhibitors

10. Drug Used to Treat HIV Infection
Two main classes of anti-HIV drug:
Reverse transcriptase inhibitors
nucleoside reverse transcriptase inhibitors
non-nucleoside reverse transcriptase inhibitors
Protease inhibitors
Fusion inhibitors
Integrase inhibitors

11. Nucleoside Reverse Transcriptase Inhibitor (NRTI)
This class includes
zidovudine
abacavir
lamivudine
didanosine
zalcitabine
stavudine

12. NRTI: Zidovudine An analogue of thymidine
Given to the parturient mother and then to the newborn infant it can reduce mother-to-baby transmission by more than 20%
Administered orally twice daily
Most of the drug is metabolized to the inactive glucuronide in the liver, only 20% of the active form being excreted in the urine
Adverse effects: Anemia, GI disturbances, skin rash, insomnia, fever, headaches, abnormalities of liver function, confusion, anxiety, and depression

13. NRTI: Abacavir A guanosine analogue
It is proved to be more effective than most other nucleoside reverse transcriptase inhibitors
Well absorbed after oral administration and is metabolised in the liver to inactive compounds
CSF level is 33% of that in the plasma
Adverse effects: Generalised hypersensitivity reaction (rare but potentially fatal), skin rashes and GI disorders

14. NRTI: Lamivudine An analogue of cytosine Given orally
Well absorbed, mostly excreted unchanged in the urine
CSF level is 20% of the plasma concentration
Used alone it could select for HIV mutants that are resistant to several nucleoside reverse transcriptase inhibitors
Also used in the therapy of hepatitis B infection
Adverse effects: Generally mild and include headache and GI disorders

15. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)
This class includes
efavirenz
nevirapine

16. NNRTI: Efavirenz Plasma half-life is about 50 hours
It is 99% bound to plasma albumin and its CSF concentration is ∼1% of that in the plasma
Inactivated in the liver
Adverse effects: Mild and consist mainly of CNS symptoms (dizziness, confusion, dysphoria), skin rashes, and GI disorders

17. NNRTI: Nevirapine Nevirapine is given orally
Bioavailability is >90%
CSF level is 45% of that in the plasma
Metabolized in the liver and metabolite is excreted in the urine
Can prevent mother-to-baby transmission of HIV if given to the parturient mother and the neonate
Adverse effects: Rash occurs in about 17% of patients, if not carefully monitored, this may develop in some cases into life-threatening skin conditions

18. Protease Inhibitors This class includes saquinavir Nelfinavir
ritonavir

19. Protease Inhibitors Reversible inhibitors of the HIV aspartyl protease
Most protease inhibitors have poor oral bioavailability
Metabolism is extensive, and very little of the protease inhibitors are excreted unchanged in the urine
Adverse effects: Commonly cause nausea, vomiting, and diarrhea
Drug interactions: A common problem for all protease inhibitors, because they are not only substrates but also potent inhibitors of CYP isozymes

20. Fusion Inhibitors
Enfuvirtide is one of the drugs belongs to this group
Prevent HIV from binding to or entering human immune cells. For HIV to gain entry into the host cell, it must fuse its membrane with that of the host cell. This is accomplished by changes in the conformation of viral transmembrane glycoprotein gp41, which occurs when HIV binds to the host cell surface. Enfuvirtide binds to gp41 preventing the conformational change
Given subcoutenously
Most adverse effects are related to injection including pain, erythema, induration and nodules

21. Integrase Inhibitors
Raltegravir is one of the drugs belongs to this group
Integrase inhibitor interferes with the integrase enzyme, which HIV needs to insert its genetic material into human cells

22. Herpes Virus
Infection with herpes simplex virus type 1 (HSV-1) typically causes diseases of the mouth, face, skin, esophagus, or brain
Herpes simplex virus type 2 (HSV-2) usually causes infections of the genitals, rectum, skin, hands
Both cause serious infections in neonates

23. Antiherpes virus Agents
Except a few, all are purine or pyrimidine analogs that inhibit viral DNA synthesis
Few antiherpes virus agents
acyclovir
penciclovir
ganciclovir

24. Acyclovir
A guanosine derivative with a high specificity for herpes simplex and varicella-zoster viruses
Given orally, intravenously or topically
Widely distributed, reaching concentrations in the CSF that are 50% of those in the plasma
Excreted by the kidneys, partly by glomerular filtration and partly by tubular secretion
Adverse effects: Renal dysfunction has been reported when acyclovir is given intravenously; also nausea and headache can occur

25. Influenza Virus
Influenza is responsible for several thousand deaths each year
Individuals over the age of 65, and patients with long-term health problems are at highest risk for severe influenza and complications
Yearly vaccination can prevent influenza infection and minimize the severity of symptoms in those who do contract this disease
However, infection can occur in immunized persons, because influenza viruses mutate rapidly

26. Anti-influenza Agents
Neuraminidase inhibitors
oseltamivir
zanamivir
Inhibitors of viral uncoating
amantadine
rimantadine

27. Neuraminidase Inhibitors
Neuraminidase enzyme is essential to the life cycle of the influenza virus
These drugs selectively inhibit viral neuraminidase
These drugs are effective against both Type A and Type B influenza viruses
Oseltamivir is an orally active prodrug that is rapidly hydrolyzed by the liver to its active form
Zanamivir, on the other hand, is not active orally and is either inhaled or administered intranasally
Both drugs are eliminated unchanged in the urine

28. Inhibitors of Viral Uncoating
The therapeutic spectrum of the amantadine and rimantadine is limited to influenza A infections
Both drugs reduce the duration and severity of systemic symptoms if started within the first 48 hours after exposure to the virus
Treatment is particularly useful in high-risk patients who have not been vaccinated and during epidemics

29. Inhibitors of Viral Uncoating : Pharmacokinetics
Both drugs are well absorbed orally
Amantadine distributes throughout the body and readily penetrates into the CNS, whereas rimantadine does not cross the blood-brain barrier to the same extent
Amantadine is not extensively metabolized, and excreted into the urine and may accumulate to toxic levels in patients with renal failure
Rimantadine is extensively metabolized by the liver, and both the metabolites and the parent drug are eliminated by the kidney

30. Inhibitors of Viral Uncoating : Adverse Effects
The side effects of amantadine are mainly associated with the CNS. Minor neurologic symptoms include insomnia, dizziness, and ataxia. The drug should be employed cautiously in patients with psychiatric problems, renal impairment, or epilepsy
Rimantadine causes fewer CNS reactions, because it does not efficiently cross the blood-brain barrier
They should be used with caution in pregnant and nursing mothers, because they have been found to be embryotoxic and teratogenic in rats

31. Hepatic Virus Infections
Hepatitis viruses thus far identified as A, B, C, D, and E each have a pathogenesis specifically involving replication in and destruction of hepatocytes
Hepatitis B and hepatitis C are the most common causes of chronic hepatitis, and are the only hepatic viral infections for which therapy is currently available

32. Antihepatic Viral Agents
Oral therapy includes
lamivudine
adefovir
telbivudine

33. Adefovir: Mechanism of Actions
An acyclic phosphonate nucleotide analog of adenosine monophosphate
Clinical use is limited to HBV infections
Oral adefovir dipivoxil shows dose-dependent inhibition of hepadnavirus replication in animal models
Adefovir: Mechanism of Actions
Converted by cellular enzymes to the diphosphate, which acts as a competitive inhibitor of viral DNA polymerases and reverse transcriptases and also serves as a chain terminator of viral DNA synthesis

34. Adefovir: Pharmacokinetics
The parent compound has low oral bioavailability, whereas the dipivoxil prodrug is absorbed rapidly and hydrolyzed by esterases in the intestine and blood to adefovir with liberation of pivalic acid
Adefovir bioavailability is approximately 30% to 60%
Food does not affect bioavailability
Adefovir is eliminated unchanged by renal excretion through a combination of glomerular filtration and tubular secretion

35. Adefovir: Adverse Effects
Adefovir dipivoxil causes dose-related nephrotoxicity and tubular dysfunction, glycosuria, and proteinuria
The lower dose (10 mg/day) used in chronic HBV infection patients has been associated with few adverse events, e.g., headache, abdominal discomfort, diarrhea

36. Study Question 1. A 30-year-old male patient with an HIV infection is being treated with a HAART regimen. Four weeks after initiating therapy, he comes to the emergency department complaining of fever, rash, and grastointestinal upset. Which one of the following drugs is most likely the cause of his symptoms?
A. Zidovudine.
B. Nelfinavir.
C. Abacavir.
D. Efavirenz.
E. Darunavir.

37. Study Question 2. A 25-year-old man is diagnosed with HIV, and therapy is initiated. After the first week of therapy, the patient complains of headaches, irritability, and nightmares. Which one of the following antiretroviral drugs is most likely to be causing these symptoms?
A. Efavirenz.
B. Indinavir.
C. Lamivudine.
D. Nevirapine.
E. Stavudine.