Obligate intracellular parasites that consist of double or single stranded DNA or RNA enclosed in a capsid
Have lipid envelope that may contain antigenic glycoproteins
Hijack host metabolic machinery
Single stranded RNA only
target virus specific steps in viral replication processes
Specifically inhibit virus-directed nucleic acid or protein synthesis
Non-specific toxicity
Selective toxicity
Amantadine
Oseltamivir
Adefovir
Rimantadine
Zanamivir
Adefovir
Cidofovir
Entecavir
Interferon
Lamivudine
Telbivudine
Acyclovir
Cidofovir
Famciclovir
Fomivirsen
Zanamivir
Foscarnet
Ganciclovir
Penciclovir
Interferon
Valacyclovir
Valganciclovir
Vadarabine
Mouth
Face
Skin
Esophagus
Hands
Brain
Genitals
Rectum
Hands
Menenges
Brain
Cause chicken pox
Cause shingles
Cause retinitis
Cause helminths
True
False
True
False
Inhibits viral RNA synthesis
Guanosine analog that is converted to monophosphate form via viral thymidine kinase
Acyclovir converted to the di- and tri-phosphate forms by the host cell
Acyclovir tri-phosphate competes with dGTP as a substrate for viral DNA polymerase and incorporated into viral DNA --> premature DNA chain termination
Acyclovir tri-phosphate irreversibly binds to the DNA polymerase, thereby inactivating the enzyme
Absence or partial production of viral thymidine kinase
Altered thymidine kinase substrate specificity
Altered viral DNA polymerase
True
False
True
False
Acyclic guanosine nucleoside derivatives
Famciclovir is orally active
Penciclovir only administered topically
Famiclovir is metabolized to penciclovir
Penciclovir is monophosphorylated by viral thymidine kinase
Cellular enzymes convert to triphosphate form
Inhibits HSV RNA polymerase
Use against CMV
Convert to triphosphate form by viral and host enzymes (uses protein kinase phosphotransferase)
Inhibits viral DNA polymerase
Incorporated into DNA and decrease rate of chain elongation
Resistance increases with duration of Rx
True
False
Treatment of CMV retinitis in AIDS patients
Nucleotide analog of guanosine
Phosphorylation not dependent upon viral enzymes
IV, intravitreal and topical formulations
Significant risk of liver toxicity
Antisense oligonucleotide (21 bp) directed against CMV mRNA
Complementary to the mRNA sequence for major immediate-early transcriptional region of CMV → inhibits CMV replication
Active against CMV strains resistant to ganciclovir, cidofovir & foscarnet
2-4 week washout following cidofovir therapy is recommended to ↓ toxicity
Inhibitors of viral un-coating
Inhibitors of neuraminidase
Inhibitors of RNA capping and function
True
False
Tricyclic amines
Use for Influenza A only
70-90% effective in preventing infection if Rx is begun at time of, or prior to, exposure of the virus
Decrease duration & severity of symptoms if started within 1st 48 hours after exposure to the virus
Especially useful for high-risk patients who have not been vaccinated during epidemics
Inhibits uncoating of the viral RNA within infected host cells → prevents replication
Block M2
Block M1
Inhibits neuraminidase
Sialic acid analogs
Antiviral spectrum: Influenza A and B viruses
Resistance is associated with mutations in hemagglutinin and/or neuraminidase genes
Most effective when administered within 24-28 hours after infection
True
False
Neuraminidase inhibitors
Competitively and reversibly interact with the active neuraminidase enzyme site to inhibit it’s activity
Virons aggregation at the internal surface of infected cells (they cannot be released)
Inhibits viral un-coating
Inhibits guanosine triphosphate formation
Prevents mRNA capping
Blocks RNA-dependent RNA polymerase
Inhibits cytosine triphosphate formation
Synthetic guanosine analog
Anti-viral spectrum: broad spectrum of DNA and RNA viruses
Oral administration for hepatitis E virus
Aerosolized formulation administered via nebulizer to children and infants with severe RSV bronchiolitis or pneumonia
True
False
5% of world’s population are carriers for HBV
3% of world’s population is infected with HCV
HBV & HCV transmssion → blood-borne
Current therapies for Hepatitis B & C are suppressive rather than curative
Host cytokines that exert complex antiviral, immunomodulatory and antiproliferative effects
Synthesized by host cells in response to various inducer stimuli
Cause biochemical changes that result in reduced ability of viruses to infect cells
Injectable pegylated formulations (s.c, i.m) of IFNα (IFN α-2a and α-2b) are approved for treatment of HBV and HCV infections
Bind to specific IFN receptors and signal via JAK/STAT signaling pathways
Nuclear translocation of cellular protein complex
Bind to genes containing IFN-specific response element
Synthesis > 24 proteins which contribute to viral resistance
Inhibit viral penetration
Inhibit viral gene transcription
Inhibit viral protein translation
Inhibit viral protein processing
Inhibit virus maturation
Treatment of HBV
Adefovir dipivoxil enters cells and is de-esterified to adefovir
Converted to tri-phosphate form which is a competitive inhibitor of viral DNA polymerase and reverse transcriptase (vs. dATP) and serves as chain terminator to viral DNA synthesis
Q.d. dosing possible as di-phosphate form has long intracellular t1/2
Resistance: point mutation in HBV polymerase
Competitive inhibitor of HBV DNA polymerase
Inhibits HIV reverse transcriptase
Enhanced antiviral activity w/combo RX (adefovir or penciclovir) against hepatic adenoviruses
Potently and rapidly induces viral suppression
Chronic Rx associated w/lamivudine resistant strains
True
False
True
False
True
False
True
False
True
False
True
False
Human immunodeficiency viruses are lentiviruses
Replication is constant following infection
Current treatment strategies assume that all aspects of disease derive from direct toxic effects of HIV on host cells →CD4+ T-lymphocytes
Humans are only known hosts
True
False
Goals of modern Rx: suppress replication of HIV and restore the number of CD4+ cells and immunocompentency to the patient
Multi-drug regimen: “highly active antiretroviral therapy” or HAART
Antiviral agents
Nucleoside & nucleotide reverse transcriptase inhibitors (NTRIs)
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Protease inhibitors
Entry inhibitors
Integrase inhibitors
Competitive inhibition of HIV-1 reverse transcriptase
NRTIs prevent infection of susceptible cells but have no effect on infected cells
Require phosphorylation to triphosphate analog
Block viral replication by competitively inhibiting incorporation of native nucleotides
Block viral replication by terminating elongation of nascent proviral DNA as they lack a 3’-hydroxyl group
Typical resistance mutations include M184V, L74V, D67N and M41L
True
False
Highly selective competitive inhibitors of HIV-1 and HIV-2 reverse transcriptase
Bind directly to HIV-1 reverse transcriptase at a site adjacent to the active site
Inducing a conformational change resulting in allosteric enzyme inhibition
NNRTIs neither compete with nucleoside triphosphates nor require phosphorylation to be active
True
False
Zidovudine/AZT
Abacavir
Didanosine
Tenofovir
Lamivudine
Delavirdine
Etravirine
Efavirenz
Saquinavir
K103N and Y181C mutations confer resistance across the entire class of NNRTIs except for etravirine
L100I and Y188C mutations may confer cross-resistance across the entire drug class
No cross-reactivity w/NRTIs
Noncompetitively inhibit protease inhibitors
Prevent the post-translational cleavage of Gag and Pol polyproteins
Prevent the processing of viral proteins into functional form
Production of immature, non-infectious viral particles.
Active against HIV-1 & HIV-2
A syndrome of redistribution and accumulation of body fat →central obesity, “buffalo hump”, cushings-like symptoms
Most HIV protease inhibitors are substrates for the P-gp efflux pump (found in BBB) → limits brain penetration
DDI are significant problem →All PI drugs are extensively metabolized by CYP3A4; some are substrates as well as inhibitors
Binding of the viral envelope glycoprotein complex gp160 (gp 120 + gp 41) to it’s receptor, CD4
Binding induces conformational change in gp120→access to chemokine co-receptors, CCR5 or CXCR4
Co-receptor binding induces further conformational changes in gp120→allows exposure of gp41 → fusion of viral envelope w/host cell membrane → entry of viral core into the cellular cytoplasm
Binding of the viral envelope glycoprotein complex gp160 (gp 140 + gp 21) to it’s receptor, CD4
Saquinavir
Indinavir
Enfuvirtide
Maraviroc
Raltegravir specifically binds to, and inhibits integrase
Resistance: Occurs with mono-Rx. Requires only single point mutation at codons 148 or 155
Metabolized via UGT1A1-mediated glucuronidation; does not interact w/CYP P450 enzymes
Polyvalent cations (e.g. Mg2+, Ca2+ ) may bind integrase inhibitors and alter activity
DDI possible w/drugs that are strong inducers or inhibitors of UGT1A1
True
False
Infants
Individuals with cancer
Transplant recipients
Persons with HIV infections
Those receiving immunosuppressive drugs or extensive antibiotic therapy
Infections caused by Entamoeba dispar (90%) and Entamoeba histolytica
Humans only known hosts; fecal-oral route of infection
Ingested E. histolytica cysts from contaminated food or water survive acid gastric contents
Transform into trophozoites in the large intestine
True
False
Luminal
Systemic
Mixed
Cilliary
True
False
Nitroimidizone compound that is mixed amebicide of choice for treating amebic infections as it kills E. histolytica trophozoites
Taken up by the parasite and is non-enzymatically reduced by reacting with reduced ferredoxin
Reduction causes the production of reduced cytotoxic compounds that bind to protein and DNA→ cell death
Metronidazole
Tinidazole
Iodoquinol
Iodoquinol
Chloroquine
Paromomycin sulfate
True
False
Halongenated 8-hydroxy quinolone
Amebicidal against E. histolytica (luminal trophozoites and cyst forms)
Chelate ferrous ions required for metabolism
Aminoglycoside antibiotic effective only against luminal forms of E. histolytica (and tapeworm)
Not significantly absorbed from the GI tract
Blocks protein synthesis
Chloroquine + metronidazole + diloxanide furoate cocktail
Emetine and dehydroemetine
Metronidazole + Tinidazole
Treat and prevent amebic liver abscesses
Eliminates trophozoites in liver abscesse
Not useful in treating luminal amebiasis
Protein synthesis inhibitors that block chain elongation
Due to major toxicity, used only under unusual circumstances where severe amebiasis requires effective therapy and metronidazole cannot be use
Should be used for minimal treatment period (3-5 d) under supervision
Trypanosomiasis (African sleeping sickness)
Chagas’ disease (Central & South American)
Available therapies for are seriously deficient in efficacy, safety, or both
Caused by Trypanosoma brucei gambiense and Trypanosoma brucei rhodiense
Transmitted via bite of the tsetse fly
Live and grow in blood → CNS → inflammation of brain and spinal cord →lethargy → continuous sleep
Stage 1: fever, enlarged lymph nodes & spleen, myocarditis
Drug of choice to treat early hemolymphatic stage of West African sleeping sickness (T. brucei gambiense)
Inferior to suramin for treatment of early East African sleeping sickness (T. brucei rhodiense)
Should be used for Stage 2 disease w/CNS involvement
T. brucei concentrate pentamidine via energy-dependent, high affinity uptake system
MOA not well defined, but drug appears to bind to parasite DNA
Interferes w/DNA, RNA and protein synthesis
Used in the prophylaxis and early treatment of African sleeping sickness
Highly reactive; inhibits many enzymes involved in energy metabolism e.g. glycerol phosphate dehydrogenase
Requires close patient monitoring
Derivative of mersalyl oxide, a trivalent arsenical
Use limited to treatment of late Stage 1 sleeping sickness
MOA: reacts with sulfhydryl groups of enzymes (parasite and host)
Resistance due to ↓ permeability
Mammalian cells may be less permeable to drug vs. parasite
Parasite enzymes appear more sensitive to the drug
Suramin
Melarsoprol
Pentamidine isethionate
Caused by Trypanosoma cruzi (flagellate protozoan)
Primarily transmitted by feces of bugs e.g. “kissing bug”
No vaccine available; management via insecticides
Acute may be asymptomatic and is largely undiagnosed
Chronic disease (may take many years to develop)
Least commonly prescribed drug to treat Chagas’ (acute stage disease)
Efficacy for treatment of chronic stage is poor
MOA: oxidative stress → futile redox cycling
Suppressive, not curative, therapy
Recommended for prophylaxis in hematopoietic stem cell transplant recipients (donors may not be treated/cured)
MOA: may involve oxidative stress (inhibit specific reductase enzymes)
Nitroimidizone derivative that is alternative choice for treatment of acute and indeterminate phases of Chagas’ disease
Major syndromes : cutaneous, mucocutaneous, diffuse cutaneous, and visceral (kala azar) forms
The mucocutaneous, diffuse cutaneous, and visceral forms of the disease do not resolve without therapy
Cutaneous forms of leishmaniasis generally are self-limiting, with cures occurring 3-18 mo. post- infection
Visceral leishmaniasis caused by L. donovani is fatal unless treated
Nifurtimox
Benznidazole
Miltefosine
First line therapy for cutaneous and visceral leishmaniasis
MOA: not well established. Some evidence for inhibition of glycolysis via phosphofructokinase inhibition.
Requires parenteral administration
Potential targets include protein kinase C and lipid and phosphatidylcholine biosynthesis pathways
Resistance associated with a point mutation in the expression of a miltefosine transporter, specifically a P-type ATPase, leading to ↓ uptake of miltefosine
Used to treat Chaga's infections
True
False
Caused by the flagellated protozoan Trichomonas vaginalis
Trichomoniasis is a sexually transmitted disease
Only trophozoite forms of T. vaginalis have been identified in infected secretions
Metronidazole remains the drug of choice for the treatment of trichomoniasis
Caused by flagellated protozoan Giardia intestinalis
Most commonly reported intestinal protozoal infection in the US
Infection from ingestion of the cyst form of the parasite found in fecally contaminated water or food
Least commonly reported intestinal protozoal infection in the US
Metronidazole is the treatment of choice for giardiasis
A single dose of tinidazole probably is superior to metronidazole for the treatment of giardiasis due to single dose efficacy and better toleration
Tinidazole is not approved for children under 12 years of age
True
False
True
False
True
False
True
False
True
False
True
False
True
False
True
False
True
False
True
False
Falciparum
Vivax
Malariae
Knowlesi
True
False
Falciparum
Malariae
Vivax
Ovale
True
False
True
False
True
False
Method of treatment (prophylaxis or treatment) and general mechanism (stage of life cycle of parasite they affect)
Eliminate both hepatic and erythrocytic stages
Few available agents are causal prophylactic drugs → capable of preventing erythrocytic infection
Tissue schizonticides
Blood schizonticides
Gametocides
Tissue schizonticides
Blood schizonticides
Gametocides
Tissue schizonticides
Blood schizonticides
Gametocides
Tissue schizonticides
Blood schizonticides
Gametocides
True
False
Quinine
Quinidine
Chloriquine
Hemoglobin
Heme
Amino Acids
Hemozoin
Rapidly and completely absorbed
Crosses BBB and placenta
Accumulates in tissues (large VD) including erythrocytes, liver, spleen, kidney, lung, melanocytes and leukocytes
Parent drug and active metabolites primarily excreted in urine
CG1
CG2
CG3
True
False
Woodworm
Cocoa
Cinchona
Guava
True
False
Act primarily against asexual erythrocytic forms with little efficacy on hepatic forms of malarial parasites
Especially valuable for parenteral treatment of severe disease due to drug-resistant P. faliciparum
Not suitable for prophylaxis due to toxicity and short t1/2
MOA similar to Chloroquine
Used for prophylaxis and treatment of drug-resistant P. falciparum and P. vivax malaria
Racemic mixture of 4 optical isomers with similar anti-malarial potency
Potent blood schizonticide, no efficacy against early hepatic stages and mature gametocytes
MOA similar to chloroquine
Artemisinin
Mefloquine
Quinine
Potency in vivo is 10X-100X greater than other anti-malarials
Act against the asexual erythrocytic stage of P. vivax and P. falciparum
Gametocidal activity but do not affect either primary or latent liver stages
Cleavage of the compound’s endoperoxide bridge by heme iron from parasitized erythrocytes, resulting in free radical production
The free radicals (and direct binding of the drug itself) cause damage to proteins in the parasite
Anti-folate agent
Anti-chelating agent
Anti-inflammatory
Acts as a strong sporonticide in the mosquito’s gut when the mosquito ingests it from the human host
Effective solo Rx for P. falciparum and in combo with a sulfonamide for P. malariae
Potently inhibits plasmodial dihydrofolate reductase at much lower concentrations than needed to inhibit the mammalian enzyme
Resistance due primarily to mutations in dihydrofolate reductase and dihydropteroate synthase
True
False
Antibiotic
Antimalaria
Antiviral
1
2
3
4
Class 1
Class 2
Class 3
1
2
3