Chapter 5

Therapy for Fungi and Viruses

BY : SANJAY RAJPUROHIT

Chapter 5 Topics

• Fungi and Antifungals

• Viruses and Antivirals

• Antiretrovirals

Learning Objectives

• Understand the differences between fungi and viruses and why the drugs to treat them must have very different mechanisms of action.

• Differentiate antifungals, antivirals, and antiretrovirals by their indications, therapeutic effects, side effects, dosages, and administration.

• Use antifungal, antiviral, and antiretroviral terminology correctly in written and oral communication.

• Define differences in mechanisms of action of antibiotics, antifungals, antivirals, and antiretrovirals.

Fungi and Their Characteristics

Fungus – Single-cell

organism– Lack of chlorophyll– Rigid cell wall and

nucleus– Reproduction by

spores

Discussion

In what ways are fungal cells similar to human cells? How are they different?

Discussion

In what ways are fungal cells similar to human cells? How are they different?

Answer: Human cell membranes contain cholesterol, and cell membranes of fungi contain ergosterol.

Fungi and Their Characteristics

Organism Disease

Aspergillus Aspergillosis

Blastomyces Blastomycosis

Candida (yeast) Candidiasis

Coccidioides Coccidioidomycosis

Cryptococcus Cryptococcosis

Histoplasma Histoplasmosis

Antifungals

How They Work– Prevent synthesis of ergosterol– Because human cells use cholesterol,

human cells are affected minimally

Antifungals

Dispensed in Two Forms– Topical Agents– Systemic Agents

Antifungals

• amphotericin B (Abelcet, AmBisome, Amphocin, Amphotec, Fungizone)

• butenafine (Mentax)• caspofungin (Cancidas)• ciclopirox (Loprox, Penlac)• clotrimazole (Gyne-Lotrimin, Mycelex-7)• clotrimazole-betamethasone (Lotrisone)• fluconazole (Diflucan)• flucytosine (Ancobon)• griseofulvin (Fulvicin P/G, Gris-PEG)

Drug List

Antifungals

• itraconazole (Sporanox)• ketoconazole (Nizoral)• miconazole (Lotrimin AF, Monistat Derm, Monistat 3)• nystatin (Mycostatin)• sertaconazole (Ertaczo)• terbinafine (Lamisil)• terconazole (Terazol)• voriconazole (VFEND)

Drug List

Antifungal Side Effects

• Serious side effects have been reported, even for topical agents.

• Pay close attention to dosing regimen to avoid overdosing.

amphotericin B (Fungizone)

• Used for blood-born, life-threatening fungal infections

• Infused slowly, not piggybacked, and not mixed with normal saline

• Blood levels of drug monitored and vitals monitored during infusion

• During treatment, monitor electrolytes, BUN, serum creatinine, temperature, CBC, fluid input and output

• Side effects: renal toxicity, anemia, fever, chills, shaking, headache

voriconazole (VFEND)

• Alternative to amphotericin B

• Can be started IV and switched to oral

• Can cause liver toxicity and blurred vision

fluconazole (Diflucan)

• Oral form used for vaginal or oral candidiasis

• IV used for patients who cannot tolerate oral

• Commonly prescribed medication

• Side effects: headache, rash, GI upset

itraconazole (Sporanox)

• Fungal infections of nails• Capsule taken twice a day with a fatty meal

and taken with a cola to increase stomach acidity and increase absorption

• Not in conjunction with antacids or H2 blockers

• Can cause liver toxicity• Capsules not substituted for oral solution due

to absorption issues

terbinafine (Lamisil)

• Kills fungus instead of just inhibiting growth• Oral form taken once daily

– Six weeks for fingernails – Twelve weeks for toenails

• Pulse dosing works well• Topical form for athlete’s foot, jock itch, and

ringworm– Do not use vaginally– Do not exceed four weeks

Antifungal Dispensing Issues

Lamisil, Lomotil, and Lamictal look alike.Use dose and dosage form to help keep these drugs from being dispensed incorrectly.

Warning!

grisefulvin (Fulvicin P/G, Gris-PEG)

• Fungal infections of the hair, skin, and nails

• Take with a fatty meal

• Avoid exposure to sunlight

• Dizziness and drowsiness are side effects, as well as passing headache

clotrimazole(Gyne-Lotrimin, Mycelex-7)

• Effective against oral candidiasis

• Supplied as a troche

• Available as OTC vaginal cream

• Topical form is the DOC for ringworm

clotrimazole-betamethasone (Lotrisone)

• Cream and lotion

• Commonly prescribed medication

miconazole(Lotrimin AF, Monistat Derm,

Monistat 3)

• Treatment of vulvovaginal candidiasis

• Available OTC

nystatin(Mycostatin)

• For patients with oral candidiasis

• Often used in liquid form, swish and swallow

ciclopirox (Loprox, Penlac)

• “Nail polish” treats nail tissue infections

• Do not take in combination with other oral antifungals

• Dispensed in amber-colored container

• Apply at bedtime to avoid exposure to light

Viruses and Their Characteristics

Virus – Does not have

components of a cell

– Unable to replicate outside of a living host cell

A virus infecting a bacterium.

Viruses and Their Characteristics

Most viruses are spread through the following routes:

– Direct contact– Ingestion of contaminated food and water– Inhalation of airborne particles– Exposure to contaminated body

fluids/equipment

Viruses and Their Characteristics

• Parts of a virus particle, virion– Nucleic acid consisting of either DNA or

RNA, not both– Capsid (protein shell) that surrounds and

protects the nucleic acid

• Naked virus– Virus without an envelope covering the

capsid

Stages of Viral Infection

1. Virus attaches to a cell receptor.

Stages of Viral Infection

1. Virus attaches to a cell receptor.

2. Cell membrane indents and closes around the virus, thus the virus penetrates the cell.

Stages of Viral Infection

1. Virus attaches to a cell receptor.

2. Cell membrane indents and closes around the virus, thus the virus penetrates the cell.

3. Virus escapes into cytoplasm.

Stages of Viral Infection

1. Virus attaches to a cell receptor.2. Cell membrane indents and closes

around the virus, thus the virus penetrates the cell.

3. Virus escapes into cytoplasm.4. Virus uncoats, shedding its

covering and releasing DNA or RNA into cell nucleus.

Stages of Viral Infection

1. Virus attaches to a cell receptor.2. Cell membrane indents and closes around

the virus, thus the virus penetrates the cell.3. Virus escapes into cytoplasm.4. Virus uncoats, shedding its covering and

releasing DNA or RNA into cell nucleus.5. Virus thus converts nuclear activity in

the cell to viral activity and reproduces new viral particles.

Discussion

Provide an example of a common viral infection and the symptoms of this condition.

Discussion

Provide an example of a common viral infection and the symptoms of this condition.

Answer: The flu (influenza). Symptoms include malaise, myalgia (muscle pain), headache, chills, fever.

Viral Classification

Two ways that viral infections are classified

– Duration and severity– Infection

Viral Classification

• Duration and severity– Acute: quickly resolves with no latent

infection such as common cold and flu– Chronic: protracted course with long

periods of remission interspersed with reappearance such as herpes virus infection

– Slow: progressive course, ultimately ending in death

Viral Classification

• Infection– Local: affects tissues of a single system,

such as the respiratory tract, the eye, or the skin

– Generalized: has spread or is spreading to other tissues by way of bloodstream or tissues of the CNS

Virus and Cell Interaction

A virus can damage a host cell in the following ways:

– Kill the host cell– Alter the cell– Incorporate into the genetic material of the

host cell– Divide when the host cell divides

Virus and Cell Interaction

Immunoglobulinantibody that may prevent an organism from attaching to a cell receptor and may destroy the organism

Virus and Cell Interaction

Interferona substance that exerts virus-nonspecific but host-specific antiviral activity by inducing gene coding for antiviral proteins that inhibit the synthesis of viral RNA

Virus and Cell Interaction

Vaccination– Exposes the patient to a component of a

virus or a similar strain that does not produce infection.

– When a vaccinated patient encounters the actual virus, the infection cannot develop.

Discussion

Who should receive an influenza vaccine?

Discussion

Who should receive an influenza vaccine?

Answer: High-risk patients such as healthcare workers, nursing home residents, public safety workers, individuals over 65 years old, immunocompromised patients.

Antivirals

Prevent virus cell replication without interfering with host cell’s normal function.

Antivirals

Systemic Agents• acyclovir (Zovirax)• amantadine (Symmetrel)• cidofovir (Vistide)• famciclovir (Famvir)• foscarnet (Foscavir)• ganciclovir (Cytovene)

Drug List

Antivirals

Systemic Agents• oseltamivir (Tamiflu)• ribavirin (Copegus, Rebetol, Virazole)• rimantadine (Flumadine)• valacyclovir (Valtrex)• valganciclovir (Valcyte)• zanamivir (Relenza)

Drug List

Antivirals

Ocular Agent

• ganciclovir (Vitrasert)

Drug List

Therapeutic Uses of Antivirals

• Cytomegalovirus (CMV) retinitis

• Herpes simplex

• Herpes simplex keratitis

• Herpes zoster (shingles)

• Influenza prophylaxis

• Varicella (chicken pox)

Antiviral Side Effects

Range from mild to severe.– Mild: headache– Severe: renal disorders

Antiviral Dispensing Issues

Amatadine, rimantadine, and ranitidine can be easily confused.

Dosing and indications will help keep them straight.

Warning!

acyclovir (Zovirax)

• Treatment of– Genital herpes– Herpes zoster (shingles)– Varicella (chicken pox) – Herpes encephalitis (in IV form)

• Range of short- and long-term side effects reported

famciclovir (Famvir)

• Treatment of – Acute herpes zoster– Herpes simplex in immunocompromised

patients– Genital herpes

• Dosed less frequently than acyclovir

• Prodrug

valacyclovir (Valtrex)

• Treats herpes zoster in immunocompetent adults and genital herpes

• Take with water and within forty-eight hours of the onset of zoster rash

• Shortens duration of postherpetic neuralgia• Commonly prescribed medication• Side effects: nausea, vomiting, diarrhea,

constipation

zanamivir (Relenza)

• Treatment of influenza A and B• Therapy initiated within 48 hr of symptom

onset• 2 inhalations daily, at 12 hr intervals, for 5

days• If using brochodilator, use it immediately

prior to admin of zanamivir• Sometimes Rx as prophylactic

oseltamivir (Tamiflu)

• Prevents influenza A and B

• Initiated within forty-eight hours of symptom onset

• Food improves tolerance

ganciclovir (Cytovene)

• Treating cytomegalovirus (CMV) infections in immunocompromised patients

• Follow chemotherapy preparations and dispensing guidelines when mixing, labeling, and packaging

• IV form not used for rapid or bolus injection

Antiviral Dispensing Issues

• Cytovene and Cytosar might be confused. – Cytovene: 250 mg, 500 mg– Cytosar: Chemotherapy agent, 10 mg

Warning!

foscarnet (Foscavir)

• Treatment of CMV infections in immunocompromised patients

• IV infusion, not rapid or bolus injection

• Patient must be hydrated, and Rx for hydration should be included with order for drug

Antiviral Dispensing Issues

• Patients who are given ganciclovir (Cytovene) or foscarnet (Foscavir) IV must be well hydrated.

• Typically there are “standing orders” for hydration when these drugs are prescribed.

Warning!

ribavirin (Virazole)

• Treating viral infections and pediatric patients with RSV

• Absorbed systemically from the respiratory tract following nasal and oral inhalation

• Side effects: fatigue, headache, insomnia, nausea, anorexia

Antiretrovirals

• Developed to limit the progression of the retrovirus HIV, the cause of AIDS

Antiretrovirals

• Developed to limit the progression of the retrovirus HIV, the cause of AIDS

• Five classes of antiretroviral drugs

Antiretrovirals

• Developed to limit the progression of the retrovirus HIV, the cause of AIDS

• Five classes of antiretroviral drugs– NRTIs– NNRTIs– NtRTIs– PIs– Fusion inhibitors

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

• Inhibit the action of reverse transcriptase to prevent the formation of viral RNA from proviral DNA

• Cause a decrease in the amount of virus in the body and subsequent spread to other healthy cells

NRTI Side Effects

• Lactic acidosis

• Degeneration of the liver

NRTI Dispensing Issues

• Taken with or without food

• Generally do not interfere with other drugs

• Administered in two or three doses per day

NRTIs

• abacavir (Ziagen)• didanosine (Videx)• emtricitabine (Emtriva)• lamivudine (Epivir)• stavudine (Zerit)• zalcitabine (Hivid)• zidovudine, AZT (Retrovir)• zidovudine-lamivudine (Combivir)• zidovudine-lamivudine-abacavir (Trizivir)

Drug List

zidovudine (Retrovir)

• Previously called AZT• One of first drugs developed specifically for

treatment of HIV• Can be combined with all NRTIs except

stavudine • Used in combination with lamivudine (with

or without PI) used for needlestick or sexual exposure treatment

lamivudine (Epivir)

• Treatment– HIV– Chronic hepatitis B

• Must be taken exactly as prescribed

• Fewest side effects of any of the NRTIs

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

• Inhibit the action of HIV reverse transcriptase but at a different site on the enzyme than the site targeted by NRTIs

• Block RNA-dependent DNA polymerase activities

NNRTIs

• delavirdine (Rescriptor)

• efavirenz (Sustiva)

• nevirapine (Viramune)

Drug List

efavirenz (Sustiva)

• Dosed once a day, preferably at bedtime

• Patients should avoid high-fat meals• Side effects

– Dizziness, headache– Vivid dreams, nightmares, hallucinations– Typically occur 1-3 hr after administration– Typically subside after 2-4 weeks on drug

nevirapine (Viramune)

• Lower dose first 2 weeks and then increased to appropriate therapeutic level to avoid rash

• The antibiotic rifampin interferes with this drug

• This drug decreases serum concentration of PIs

• Must monitor liver functions

Nucleotide Reverse Transcriptase Inhibitors (NtRTIs)

• Inhibit the activity of HIV-1 reverse transcriptase by competing with natural nucleic acid substrates

• Cause termination of chain formation after incorporating in viral nucleic acid

NtRTIs

• tenofovir (Viread)

Drug List

Protease Inhibitors (PIs)

• Inhibit the protease enzyme, which typically cleaves certain HIV protein precursors that are necessary for the replication of new infectious virons

• Results in production of immature, noninfectious virons

• Combined with other antiretroviral drugs

PI Side Effects

• Protease paunch

• Facial atrophy

• Breast enlargement

• Hyperglycemia

• Hyperlipidemia

• Increase in bleeding episodes in hemophiliacs

PIs

• amprenavir (Agenerase)• atazanavir (Reyataz)• fosamprenavir (Lexiva)• indinavir (Crixivan)• lopinavir-ritonavir (Kaletra)• nelfinavir (Viracept)• ritonavir (Norvir)• saquinavir (Fortovase, Invirase)

Drug List

indinavir (Crixivan)

• Do not take with– St. John’s wort– Grapefruit juice– With food, especially high-fat

• Do take with a lot of water (48 oz/day) to avoid kidney stones

• Package with a desiccant, and patient to store in original container

lopinavir-ritonavir (Kaletra)

• Combination inhibits metabolism of lopinavir, allowing increased plasma levels of lopinavir

• Side effects– Nausea and vomiting– Diarrhea– Pancreatitis

• Solution contains alcohol

nelfinavir (Viracept)

• Can cause diarrhea, but loperamide and calcium carbonate can help control

• Take with food

ritonavir (Norvir)

• Causes increase in serum concentrations and thus decreases dosage frequency of other PIs, thus decreasing side effects

• Given at a low dose• Take with food• Causes an altered sense of taste• Store in the refrigerator

Fusion Inhibitors

How do fusion inhibitors represent an advance in the treatment of HIV?

Fusion Inhibitors

How do fusion inhibitors represent an advance in the treatment of HIV?

Answer: Prevents AIDS virus from entering the immune cells.

Fusion Inhibitors

• enfuvirtide (Fuzeon)

Drug List

Responding to HIV Exposure

• Centers for Disease Control guidelines

• Post-exposure prophylaxis (PEP)

• Begin within two hours

• Can decrease risk of infection by 80%

Combining AntiretroviralsRegimen Type Recommendation

standard therapy NNRTI: efavirenz + lamivudine + (zidovudine or tenofovir or stavudine)

PI: lopinavir-ritonavir + lamivudine + (zidovudine or stavudine)

alternative therapy 3 × NRTI: abacavir + lamivudine + (zidovudine or stavudine)

post-exposure prophylaxis (PEP)

zidovudine + lamivudine + (indinavir or nelfinavir)

Antiretroviral Dispensing Issues

Avoid the following antiretroviral drug combinations:– didanosine with zalcitabine

– zidovudine with stavudine

– lamivudine with zalcitabine

– stavudine with zalcitabine

Warning!

Discussion

What is one of the biggest problems when treating HIV?

Discussion

What is one of the biggest problems when treating HIV?

Answer: Noncompliance with drug regimen due to problematic side effects and complex dosing.