Pharmacology Final Practice

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