Antivirals and Antiprotozoal Agents

Chapter 69


Antivirals and Antiprotozoal Agents






INDICATIONS




This chapter discusses the use of antiviral drugs and common antiprotozoal medications in primary care. This chapter does not discuss the use of antiviral drugs in the treatment of patients with HIV. The antiherpetic drugs acyclovir, famciclovir, and valacyclovir are closely related. They are used in the treatment of initial and recurrent (i.e., more than six outbreaks per year) mucosal and cutaneous herpes simplex types 1 and 2, and for the treatment of acute herpes simplex virus (HSV) infection. Acyclovir has the greatest antiviral activity in vitro against herpes simplex virus type 1, followed in decreasing order of potency by HSV type 2 (HSV-2), varicella-zoster virus, Epstein-Barr virus, and cytomegalovirus. Penciclovir is structurally similar but is used only topically (see Chapter 13).


Amantadine, rimantadine, zanamivir, and oseltamivir are used for the prevention and treatment of influenza virus infection although the effectiveness of oseltamivir has been called into question with new data. Amantadine is also used in Parkinson’s disease (see Chapter 46). Amantadine and rimantadine are similar, as are oseltamivir and zanamivir. Oseltamivir currently is being stockpiled in preparation for an avian influenza pandemic and is not generally available.


Metronidazole has several uses in addition to the treatment of protozoa, including treatment of bacterial and amebic infections. Chloroquine is used for malaria; however, many strains of malaria are now resistant to chloroquine. Many antiparasitic and antiprotozoal medications are important in international travel but are only rarely encountered in primary care. These are not discussed here.



Therapeutic Overview of Viruses and Protozoa


Anatomy and Physiology


Virus


A virus is a single- or double-stranded DNA or RNA molecule enclosed within a protein coat. Some may also have a lipoprotein envelope. They may contain proteins that cause antigenic reactions or enzymes that initiate viral replication. The virus lacks metabolic functions and must rely on the host cell for the metabolism or synthesis of chemicals. According to the definition of life, viruses are not alive. They do not eat or produce waste. They do not reproduce independently.


DNA viruses include herpesviruses (e.g., chickenpox, shingles, herpes), adenoviruses (e.g., conjunctivitis, pharyngitis), hepadna viruses (e.g., hepatitis B), and papillomaviruses (e.g., warts). RNA viruses include rubella (e.g., German measles), rhabdoviruses (e.g., rabies), picornaviruses (e.g., poliomyelitis, meningitis, colds), arboviruses (e.g., yellow fever), orthomyxoviruses (e.g., influenza), and paramyxoviruses (e.g., measles and mumps). The retroviruses are a subgroup of RNA viruses that are discussed in the chapter on antiretroviral medications (see Chapter 68). Several other viruses are discussed in the chapter on immunization and immunity (see Chapter 70). Some of the less common viruses are not described in this text.




Viral Disease Process


Herpes Simplex


Herpes simplex virus type 1 (HSV-1) causes infections of the mouth and face (herpes labialis), and of the skin, esophagus, and brain. Vesicles form moist ulcers after several days and epithelialize over 2 to 3 weeks. In some geographic locations, HSV-1 infection is a common cause of first episodes of genital herpes. These may occur in stable, monogamous relationships and are less likely to recur than genital infections caused by HSV-2.


HSV-2 causes infection of the genitals, rectum, skin, hands, and meninges. Asymptomatic shedding of the virus is commonly the mechanism of transmission. Thus, the disease can be transmitted sexually. Recent serologic surveys, which employ type-specific antibody assays, show a rising prevalence of previous HSV-2 infection in postadolescent populations in developed countries; many of these infections were asymptomatic.


Herpes simplex can be a primary infection (which can be asymptomatic) or can result from activation of a latent infection. It is unknown what triggers activation. Type 2 is latent in the presacral ganglia. Both type 1 and type 2 can cause keratitis, encephalitis, recurrent meningitis, disseminated infection, and Bell’s palsy.


The varicella-zoster virus (VZV) is the human herpesvirus 3. This virus causes chickenpox in children, which is highly contagious and is spread by inhalation of infective droplets or contact with lesions. In older adults or immunocompromised patients, the virus can cause shingles. Shingles is caused by reactivation of the virus that is latent in the nerve ganglion. It causes a vesicular rash that appears on an erythematous base in a dermatome pattern, accompanied by pain and systemic symptoms.




Protozoal Disease Process


Giardiasis (Giardia)


This is the most common cause of waterborne diarrheal disease in the United States. It is transmitted by fecal-oral spread of cysts via contaminated food or water. It is resistant to chlorination levels found in water supplies and can survive freezing for several days. Symptoms include diarrhea, fatigue, malaise, abdominal cramps, and weight loss. A diagnostic test is available to detect antigens in the stool.



Malaria


Malaria is the most significant protozoal disease in the world, causing 1.5 to 2.7 million deaths annually. Symptoms of malaria include periodic attacks of chills, fever and sweating, headache, myalgia, splenomegaly, anemia, and leukopenia. Increasing drug resistance has caused treatment of malaria to be problematic. An additional complication is the fact that plasmodia go through distinct stages that affect their susceptibility to different agents. For example, chloroquine is active against asexual blood stages but not against sexual blood stages or asexual liver stages. Prophylaxis of malaria in travelers depends on risk factors, including the area to be visited and the type of malaria that is active in that area. Chloroquine and primaquine are used in non–chloroquine-resistant areas.



Mechanism of Action


Antivirals


If it is to be effective, an antiviral drug must enter infected cells and act at the site of infection. Effective agents have a narrow spectrum of activity, inhibiting replication but not killing the virus. They target a specific viral protein, usually an enzyme that is involved in viral nucleic acid synthesis. Resistance may develop quickly, but the time frame is influenced by many factors. The difference between in-vitro sensitivity testing and in-vivo effectiveness is not clear. The human patient must have a good immune system to recover from infection.


Acyclovir is a synthetic purine nucleoside analog. Valacyclovir is a prodrug of acyclovir, and famciclovir is a prodrug of penciclovir. (See Chapter 3 for a discussion of prodrugs.) Both have similar mechanisms of action as acyclovir. They work by inhibiting viral DNA synthesis. These drugs are activated by the enzyme thymidine kinase, which is found only in cells that are infected by the virus. Consequently, they are relatively nontoxic to cells that are not infected by the virus. In chemical terms, activation of the antiviral first occurs in the infected cells and is followed by phosphorylation by the enzyme thymidine kinase. Finally, acyclovir triphosphate (i.e., the active derivative obtained from monophosphate by host cell enzymes) inhibits viral DNA polymerase, thereby blocking viral replication.


Amantadine and rimantadine are structurally similar tricyclic amines. They both inhibit an early step in viral replication, and they have an effect on the viral assembly. The locus of action is the influenza A virus M2 protein, which is an integral membrane protein.


Zanamivir and oseltamivir are thought to inhibit the virus neuraminidase; this alters virus particle aggregation and release.




Treatment Principles


Standardized Guidelines


See World Health Organization at www.worldhealthwho/int for specific diseases treatment guidelines.




Cardinal Points of Treatment




• Herpes simplex and zoster



• Antiinfluenza



• Antiprotozoals




Pharmacologic Treatment


Herpes Simplex Treatment


Acyclovir, famciclovir, and valacyclovir all are useful in the treatment of herpesviruses. They are used as treatment for acute infection and for chronic suppression and recurrences. Systemic therapy for initial episodes does not prevent the establishment of latency or the development of future recurrences, even when given in high or prolonged dosage. Oral acyclovir is the most useful and effective form of the drug for the treatment of herpes simplex virus and varicella infection. In patients with frequent recurrences, oral acyclovir has prevented or reduced the frequency or severity of recurrences in more than 95% of patients. Topical acyclovir is significantly less effective but will shorten healing time and the duration of viral shedding and pain in patients with an initial outbreak of herpes. No clinical benefit was found when the topical form was given in recurrent episodes of genital herpes. Topical acyclovir is effective against herpes labialis; it reduces the duration of the condition by about half a day.


When prescribing these drugs, the practitioner should understand two important principles. First, the peak of viral activity and reproduction occurs prior to the appearance of any symptoms. Therefore, therapy is prescribed late in the disease process. Second, viral agents work by inhibiting reproduction without eradicating latent viruses. Elimination of the virus is not complete, but these agents can assist in reducing and suppressing symptoms. The effectiveness of the drug depends on how early treatment is initiated.


Almost all persons with initially symptomatic HSV-2 infection have symptomatic recurrences. More than 35% of such patients have frequent recurrences. Recurrence rates are especially high in persons with an extended first episode of infection, regardless of whether or not they receive antiviral chemotherapy with acyclovir. Men with genital HSV-2 infection have about 20% more recurrences than do women—a factor that may contribute to the higher rate of HSV-2 transmission from men to women than from women to men and to the continuing epidemic of genital herpes in the United States.


These antiviral drugs are indicated for the treatment of genital herpes in the following circumstances: initial episode of genital herpes, frequently recurring episodes (more than six per year), immunocompromised patients (treatment or long-term suppression), and severe genital herpes. Antivirals should not be used in mildly affected patients because resistance to the medication can occur. Although resistance is rare, it is more likely to occur with prolonged or repeated therapy in severely immunocompromised patients. Use of acyclovir, valacyclovir, and famciclovir in the nonpregnant and the pregnant woman can significantly alter the disease and influence transmission rates, along with decreasing morbidity and mortality associated with HSV infection. The three oral antiherpes medications are equally effective; acyclovir is less expensive than the others.




Antiinfluenza Drugs


Many strains of influenza A have developed resistance to amantadine and rimantadine. These drugs are not recommended for prophylaxis of seasonal influenza.


Considerable concern has arisen about the possibility of an avian influenza pandemic. Preparation for a pandemic has produced many problems. Oseltamivir was viewed as the most effective drug and was stockpiled by the government, but production problems have been reported. It is made from the seed of star anise, which has limited availability, and is thus an expensive medication. New reports suggest that the drug may not be very effective in reducing influenza-related lower respiratory tract complications and has more adverse effects such as nausea than previously reported.


Because zanamivir is inhaled, concern has been expressed about its effectiveness against systemic influenza. However, one study showed 70% to 90% effectiveness for prophylaxis before or after exposure to influenza A or B. Neuraminidase inhibitors can decrease the severity and duration of symptoms in patients with influenza if treatment is started within 48 hours after the onset of illness; the earlier treatment is started, the better is the outcome. Resistance to oseltamivir has started to occur in Vietnam.


There have been reported neuropsychiatric symptoms following administration of these drugs. Symptoms of delirium and abnormal behavior have prompted new warnings regarding use.



Antiprotozoal Drugs


Metronidazole


Metronidazole has both antibiotic and antiprotozoal actions. It is useful for a wide variety of infections. Metronidazole has excellent activity against most gram-negative and gram-positive anaerobes and is indicated for use in many serious infections. Because metronidazole reaches high concentrations in most body tissues, it is very successful in the treatment of intraabdominal, intrapelvic, and cerebral infections, as well as endocarditis, bone and joint infections, and head and neck infections caused by susceptible anaerobes. Metronidazole also reaches high concentrations in abscesses (e.g., cerebral, hepatic, abdominal abscesses) and often is indicated in their treatment. Metronidazole does not cover gram-positive cocci or aerobic organisms; hence it usually is used in combination with another drug for the treatment of complicated infections.


In primary care settings, metronidazole is the drug of choice for the treatment of T. vaginalis. Because trichomoniasis is a sexually transmitted disease, both partners have to be treated for a cure to be achieved (i.e., to prevent reinfection of the other partner). The practitioner has the option of prescribing a 1- or 7-day course of treatment. A single oral dose (2 g) usually is as effective as the 7-day course. Although some evidence has shown that the 7-day treatment may have a slightly higher cure rate, the 1-day treatment may be justified if patient compliance is in question. Metronidazole also is indicated for the treatment of bacterial or nonspecific vaginitis.


Metronidazole is the current treatment of choice for symptomatic intestinal infection caused by G. lamblia and E. histolytica. Both parasites are found worldwide, and they usually are contracted by ingesting contaminated water or food. Sporadic outbreaks of Giardia occur throughout the United States and occasionally are seen in the primary care setting.


Metronidazole is the recommended first-line treatment of patients with C. difficile. Studies have shown that metronidazole is effective in most cases of C. difficile. However, vancomycin remains the drug of choice for severe cases.


Much attention has been focused on the use of metronidazole in the treatment of patients with Helicobacter pylori, an organism involved in the development of gastritis and peptic ulcer disease. Metronidazole, when given in conjunction with bismuth (and sometimes omeprazole or a histamine blocker) an antibiotic and a PPI, appears to be effective in treating H. pylori. The addition of tetracycline may increase the length of remission (see Chapter 27).




How to Monitor


Antivirals


Monitor closely for toxicity and adverse effects, especially in patients with renal impairment.

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Jul 22, 2016 | Posted by in PHARMACY | Comments Off on Antivirals and Antiprotozoal Agents

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