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

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

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

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)

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

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

Viral Infections Types of viral infections HIV infection Herpes Influenza Hepatitis

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

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

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

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

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

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

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

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

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

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

Protease Inhibitors This class includes saquinavir Nelfinavir ritonavir

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

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

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

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

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

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

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

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

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

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

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

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

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

Antihepatic Viral Agents Oral therapy includes lamivudine adefovir telbivudine

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

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

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

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.

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.