Antiviral Agents. Understanding Viruses Viral Replication A virus cannot replicate on its own. A...

Antiviral AgentsAntiviral Agents

Understanding VirusesUnderstanding Viruses

Viral ReplicationViral Replication A virus cannot replicate on its own.A virus cannot replicate on its own. It must attach to and enter a host cell.It must attach to and enter a host cell. It then uses the host cell’s energy to It then uses the host cell’s energy to

synthesize protein, DNA, and RNA.synthesize protein, DNA, and RNA.

Understanding VirusesUnderstanding Viruses

Viruses are difficult to kill because they Viruses are difficult to kill because they liveliveinside our cells.inside our cells.

Any drug that kills a virus may also kill our Any drug that kills a virus may also kill our cells.cells.

Viral InfectionsViral InfectionsCompetent immune system:Competent immune system: Best response to viral infectionsBest response to viral infections A well-functioning immune system will eliminate A well-functioning immune system will eliminate

or effectively destroy virus replicationor effectively destroy virus replication

Immunocompromised patients have frequent Immunocompromised patients have frequent viral infectionsviral infections

Cancer patients, especially leukemia or lymphomaCancer patients, especially leukemia or lymphoma Transplant patients, due to pharmacological Transplant patients, due to pharmacological

therapytherapy AIDS patients, disease attacks immune systemAIDS patients, disease attacks immune system

AntiviralsAntivirals

Key characteristics of antiviral drugs:Key characteristics of antiviral drugs: Able to enter the cells infected with virus.Able to enter the cells infected with virus.

Interfere with viral nucleic acid synthesis Interfere with viral nucleic acid synthesis and/or regulation.and/or regulation.

Some agents interfere with ability of virus Some agents interfere with ability of virus to bind to cells.to bind to cells.

Some agents stimulate the body’s immune Some agents stimulate the body’s immune system.system.

AntiviralsAntivirals

Viruses killed by current antiviral Viruses killed by current antiviral therapy:therapy:

cytomegalovirus (CMV)cytomegalovirus (CMV) herpes simplex virus (HSV)herpes simplex virus (HSV) human immunodeficiency virus (HIV)human immunodeficiency virus (HIV) influenza A (the “flu”)influenza A (the “flu”) respiratory syncytial virus (RSV)respiratory syncytial virus (RSV)

Antivirals: Mechanism of Antivirals: Mechanism of ActionAction

Inhibit viral replicationInhibit viral replication Inhibit viral attachmentInhibit viral attachment Prevent genetic copying of virusPrevent genetic copying of virus Prevent viral protein productionPrevent viral protein production

Sites of Drug ActionSites of Drug Action

Antiviral AgentsAntiviral Agents Block viral entry into the cell or must Block viral entry into the cell or must

work inside the cellwork inside the cell Most agents are pyrimidine or purine Most agents are pyrimidine or purine

nucleoside analogsnucleoside analogs

Antivirals Antivirals Synthetic Purine Nucleoside Synthetic Purine Nucleoside

AnaloguesAnaloguesTwo types of nucleosides:Two types of nucleosides:Purine nucleosidesPurine nucleosides guanineguanine adenosineadenosine

Pyrimidine nucleosidesPyrimidine nucleosides thyminethymine cytosinecytosine

Antivirals: Purine Antivirals: Purine NucleosidesNucleosides

AgentAgent Antiviral ActivityAntiviral Activity

guaninesguanines

acycloviracyclovir HSV 1 & 2, VZVHSV 1 & 2, VZV

ganciclovir (DHPG)ganciclovir (DHPG) CMV retinitis and CMV retinitis and systemicsystemic CMV infectionCMV infection

ribavirin (RTCD)ribavirin (RTCD) Influenza types A and Influenza types A and B,B, RSV, LV, HVRSV, LV, HV

adenosinesadenosines

didanosine (ddl)didanosine (ddl) HIVHIV

vidarabine (Ara-A)vidarabine (Ara-A) HSV, herpes zosterHSV, herpes zoster

Antivirals: Pyrimidine Antivirals: Pyrimidine NucleosidesNucleosides

AgentAgent Antiviral ActivityAntiviral Activitycytosinescytosines

lamivudine (3TC)lamivudine (3TC) HIVHIVzalcitabine (ddC)zalcitabine (ddC) HIVHIV

thyminethymineidoxuridine (IDU)idoxuridine (IDU) HSVHSVstavudine (d4T)stavudine (d4T) HIVHIVtrifluridinetrifluridine HSVHSVzidovudine (AZT)zidovudine (AZT) HIVHIV

Other AntiviralsOther Antivirals

amantadine amantadine (Symmetrel) and rimantadine (Symmetrel) and rimantadine (Flumadine)(Flumadine)

influenza Ainfluenza A

foscarnet (Foscavir)foscarnet (Foscavir) CMV (retinitis and systemic)CMV (retinitis and systemic)

Neuraminidase Inhibitors: oseltamivir (Tamiflu) Neuraminidase Inhibitors: oseltamivir (Tamiflu) and zanamivir (Relenza)and zanamivir (Relenza)

influenza types A and Binfluenza types A and B

Antivirals: Side EffectsAntivirals: Side Effects

acycloviracyclovir Burning when topically applied, nausea, Burning when topically applied, nausea,

vomiting, diarrhea, headachevomiting, diarrhea, headache

amantadine and rimantadineamantadine and rimantadine Anticholinergic effects, insomnia, Anticholinergic effects, insomnia,

lightheadedness, anorexia, nausealightheadedness, anorexia, nausea

didanosine (ddl)didanosine (ddl) Pancreatitis, peripheral neuropathies, seizuresPancreatitis, peripheral neuropathies, seizures

Antivirals: Side EffectsAntivirals: Side Effects

zidovudine (AZT)zidovudine (AZT) Bone marrow suppression, nausea, headacheBone marrow suppression, nausea, headache

foscarnet (Foscavir)foscarnet (Foscavir) Headache, seizures, acute renal failure, nausea, Headache, seizures, acute renal failure, nausea,

vomiting, diarrheavomiting, diarrhea

ganciclovir (Cytovene)ganciclovir (Cytovene) Bone marrow toxicity, nausea, anorexia, vomitingBone marrow toxicity, nausea, anorexia, vomiting

Antiherpes AgentsAntiherpes Agents

Acyclovir- Acyclovir- prototypeprototype ValacyclovirValacyclovir FamciclovirFamciclovir PenciclovirPenciclovir TrifluridineTrifluridine VidarabineVidarabine

Mechanism of Action Mechanism of Action AcyclovirAcyclovir

an acyclic guanosine derivativean acyclic guanosine derivative Phosphorylated by Phosphorylated by viral thymidine viral thymidine

kinasekinase Di-and tri-phosphorylated by host Di-and tri-phosphorylated by host

cellular enzymescellular enzymes Inhibits viral DNA synthesis by:Inhibits viral DNA synthesis by:

1) competing with dGTP for viral DNA 1) competing with dGTP for viral DNA polymerasepolymerase

2) chain termination2) chain termination

Clinical Uses Clinical Uses AcyclovirAcyclovir

Oral, IV, and Topical formulationsOral, IV, and Topical formulations Cleared by glomerular filtration and Cleared by glomerular filtration and

tubular secretiontubular secretion UsesUses::

Herpes Simplex Virus 1 and 2 (HSV)Herpes Simplex Virus 1 and 2 (HSV) Varicella-zoster virus (VZV)Varicella-zoster virus (VZV)

Side EffectsSide Effects: : nausea, diarrhea, nausea, diarrhea, headache, tremors, and deliriumheadache, tremors, and delirium

ValacyclovirValacyclovir L-valyl ester of acyclovirL-valyl ester of acyclovir Converted to acyclovir when ingestedConverted to acyclovir when ingested M.O.A.M.O.A.:: same as acyclovir same as acyclovir UsesUses: :

1) recurrent genital herpes1) recurrent genital herpes 2) herpes zoster infections2) herpes zoster infections

Side EffectsSide Effects:: nausea, diarrhea, and nausea, diarrhea, and headacheheadache

FamciclovirFamciclovir Prodrug of Prodrug of penciclovirpenciclovir (a guanosine (a guanosine

analog)analog) M.O.A.:M.O.A.: same as acyclovir same as acyclovir does does not not cause chain terminationcause chain termination Uses: Uses: HSV-1, HSV-2, VZV, EBV, and HSV-1, HSV-2, VZV, EBV, and

hepatitis Bhepatitis B Side EffectsSide Effects:: nausea, diarrhea, and nausea, diarrhea, and

headacheheadache

TrifluridineTrifluridine

TrifluridineTrifluridine- fluorinated pyrimidine - fluorinated pyrimidine inhibits viral DNA synthesis same as inhibits viral DNA synthesis same as

acycloviracyclovir incorporates into viral and cellular DNAincorporates into viral and cellular DNA UsesUses: HSV-1 and HSV-2 (topically): HSV-1 and HSV-2 (topically)

VidarabineVidarabine An adenosine analogAn adenosine analog inhibits viral DNA polymeraseinhibits viral DNA polymerase incorporated into viral and cellular incorporated into viral and cellular

DNADNA metabolized to hypoxanthine metabolized to hypoxanthine

arabinosidearabinoside Side EffectsSide Effects: GI intolerance and : GI intolerance and

myelosuppressionmyelosuppression

Anti-Cytomegalovirus Anti-Cytomegalovirus AgentsAgents

GancyclovirGancyclovir ValgancyclovirValgancyclovir CidofovirCidofovir FoscarnetFoscarnet FomivirsenFomivirsen

GanciclovirGanciclovir An acyclic guanosine analogAn acyclic guanosine analog requires triphosphorylation for activationrequires triphosphorylation for activation monophosphorylation is catalyzed by a monophosphorylation is catalyzed by a

phosphotransferase in CMV and by phosphotransferase in CMV and by thymidine kinase in HSV cellsthymidine kinase in HSV cells

M.O.A.: M.O.A.: same as acyclovirsame as acyclovir UsesUses: CMV*, HSV, VZV,and EBV: CMV*, HSV, VZV,and EBV Side EffectSide Effect: myelosuppression: myelosuppression

HIVHIV

ValgancyclovirValgancyclovir Monovalyl ester prodrug of gancyclovirMonovalyl ester prodrug of gancyclovir Metabolized by intestinal and hepatic Metabolized by intestinal and hepatic

esterases when administered orallyesterases when administered orally

M.O.A.: M.O.A.: same as gancyclovirsame as gancyclovir UsesUses: CMV*: CMV* Side EffectSide Effect: myelosuppression: myelosuppression

FoscarnetFoscarnet An inorganic pyrophosphateAn inorganic pyrophosphate inhibits viral DNA polymerase, RNA inhibits viral DNA polymerase, RNA

polymerase, and HIV reverse polymerase, and HIV reverse transcriptasetranscriptase

does not have to be phosphorylateddoes not have to be phosphorylated Uses: Uses: HSV, VZV, CMV, EBV, HHV-6, HSV, VZV, CMV, EBV, HHV-6,

HBV, and HIVHBV, and HIV Resistance due to mutations in DNA Resistance due to mutations in DNA

polymerase genepolymerase gene Side Effects:Side Effects: hypo- or hypercalcemia hypo- or hypercalcemia

and phosphotemiaand phosphotemia

HIVHIV

AIDS- treatmentAIDS- treatment

Antiretroviral AgentsAntiretroviral Agents

1) Nucleoside Reverse Transcriptase 1) Nucleoside Reverse Transcriptase Inhibitors (NRTIs)Inhibitors (NRTIs)

2) Nonnucleoside Reverse 2) Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)Transcriptase Inhibitors (NNRTIs)

3)Protease inhibitors3)Protease inhibitors

Reverse Transcriptase Reverse Transcriptase InhibitorsInhibitors

Zidovudine (AZT)Zidovudine (AZT) Didanosine- Didanosine- causes pancreatitis*causes pancreatitis* Lamivudine- Lamivudine- causes pancreatitiscauses pancreatitis Zalcitabine- Zalcitabine- causes peripheral causes peripheral

neuropathyneuropathy**

Stavudine- Stavudine- causes peripheral neuropathy*causes peripheral neuropathy* AbacavirAbacavir

Mechanism of Action Mechanism of Action Zidovudine (AZT)Zidovudine (AZT)

A deoxythymidine analogA deoxythymidine analog enters the cell via passive diffusionenters the cell via passive diffusion must be converted to the must be converted to the

triphosphate form by mammalian triphosphate form by mammalian thymidine kinasethymidine kinase

competitively inhibits competitively inhibits deoxythymidine triphosphate for the deoxythymidine triphosphate for the reverse transcriptase enzymereverse transcriptase enzyme

causes chain terminationcauses chain termination

Mechanism of Resistance Mechanism of Resistance ZidovudineZidovudine

Due to mutations in the reverse Due to mutations in the reverse transcriptase genetranscriptase gene

more frequent after prolong therapy more frequent after prolong therapy and in persons with HIVand in persons with HIV

Clinical Uses Clinical Uses ZidovudineZidovudine

Available in IV and oral formulationsAvailable in IV and oral formulations activity against HIV-1, HIV-2, and activity against HIV-1, HIV-2, and

human T cell lymphotropic viruseshuman T cell lymphotropic viruses mainly used for treatment of HIV, mainly used for treatment of HIV,

decreases rate of progression and decreases rate of progression and prolongs survivalprolongs survival

prevents mother to newborn prevents mother to newborn transmission of HIVtransmission of HIV

Side Effects Side Effects ZidovudineZidovudine

Myelosuppression, including anemia Myelosuppression, including anemia and neutropeniaand neutropenia

GI intolerance, headaches, and GI intolerance, headaches, and insomniainsomnia

Other NRTIsOther NRTIs

Didanosine- Didanosine- synthetic synthetic deoxy-deoxy-adenosineadenosine analog; causes pancreatitis* analog; causes pancreatitis*

Lamivudine- Lamivudine- cytosinecytosine analog analog Zalcitabine- Zalcitabine- cytosinecytosine analog; causes analog; causes

peripheral neuropathy*peripheral neuropathy* Stavudine- Stavudine- thymidinethymidine analog;causes analog;causes

peripheral neuropathy*peripheral neuropathy* Abacavir- Abacavir- guanosine analog; more guanosine analog; more

effective than the other agents; fatal effective than the other agents; fatal hypersensitivity reactions can occur hypersensitivity reactions can occur

Nucleotide InhibitorsNucleotide Inhibitors TenofovirTenofovir AdefovirAdefovir

TenofovirTenofovir An acyclic nucleoside phosphonate An acyclic nucleoside phosphonate

analog of adenosineanalog of adenosine M.O.AM.O.A.- competively inhibits HIV .- competively inhibits HIV

reverse transcriptase and causes reverse transcriptase and causes chain termination after incorporation chain termination after incorporation into DNAinto DNA

UsesUses – in combination with other – in combination with other antiretrovirals for HIV-1 suppressionantiretrovirals for HIV-1 suppression

AdefovirAdefovir An analog of adenosine monophosphateAn analog of adenosine monophosphate Phosphorylated by cellular kinases Phosphorylated by cellular kinases M.O.A.M.O.A. - Competitively inhibits HBV - Competitively inhibits HBV

DNA polymerase and results in chain DNA polymerase and results in chain termination after incorporation into viral termination after incorporation into viral DNADNA

UsesUses - Hepatitis B - Hepatitis B Side effectsSide effects - nephrotoxicity - nephrotoxicity

Nonnucleoside Reverse Nonnucleoside Reverse Transcriptase Inhibitors Transcriptase Inhibitors

(NNRTIs)(NNRTIs)

NevirapineNevirapine DelavirdineDelavirdine EfavirenzEfavirenz

Mechanism of ActionMechanism of ActionNNRTIsNNRTIs

Bind to site on viral reverse transcriptase, Bind to site on viral reverse transcriptase, different from NRTIsdifferent from NRTIs

results in blockade of RNA and DNA results in blockade of RNA and DNA dependent DNA polymerase activitydependent DNA polymerase activity

do do notnot compete with nucleoside compete with nucleoside triphosphatestriphosphates

do do notnot require phosphorylation require phosphorylation these drugs can these drugs can notnot be given alone be given alone substrates and inhibitors of CYP3A4substrates and inhibitors of CYP3A4

Nonnucleoside Reverse Nonnucleoside Reverse Transcriptase Inhibitors Transcriptase Inhibitors

(NNRTIs)(NNRTIs)

Nevirapine- Nevirapine- prevents transmission prevents transmission of HIV from mother to newborn when of HIV from mother to newborn when given at onset of labor and to the given at onset of labor and to the neonate at deliveryneonate at delivery

Delavirdine- Delavirdine- teratogenic, therefore teratogenic, therefore can not be given during pregnancycan not be given during pregnancy

Efavirenz- Efavirenz- teratogenic, therefore teratogenic, therefore can not be given during pregnancycan not be given during pregnancy

Protease InhibitorsProtease Inhibitors IndinavirIndinavir RitonavirRitonavir SaquinavirSaquinavir NelfinavirNelfinavir AmprenavirAmprenavir

Protease InhibitorsProtease Inhibitors The protease enzyme cleaves The protease enzyme cleaves

precursor molecules to produce precursor molecules to produce mature, infectious virionsmature, infectious virions

these agents inhibit protease and these agents inhibit protease and prevent the spread of infectionprevent the spread of infection

These agents cause a syndrome of These agents cause a syndrome of altered body fat distribution, insulin altered body fat distribution, insulin resistance, and hyperlipidemiaresistance, and hyperlipidemia

Indinavir Indinavir andand Ritonavir Ritonavir M.O.A.M.O.A.: Specific inhibitors of the HIV-1 : Specific inhibitors of the HIV-1

protease enzymeprotease enzyme M.O.R.M.O.R.: mediated by expression of : mediated by expression of

multiple and variable protease amino acid multiple and variable protease amino acid substitutionssubstitutions

Side EffectsSide Effects:: hyperbilirubinemiahyperbilirubinemia ContraindicationsContraindications:inhibitor/substrate for :inhibitor/substrate for

CPY3A4, do CPY3A4, do not not give with antifungal azolesgive with antifungal azoles

SaquinavirSaquinavir A synthetic peptide-like substrate A synthetic peptide-like substrate

analoganalog

inhibits HIV-1 proteaseinhibits HIV-1 protease

prevents cleavage of viral prevents cleavage of viral polyproteinspolyproteins

Nelfinavir Nelfinavir andand AmprenavirAmprenavir

M.O.A.M.O.A.: Specific inhibitors of the HIV-: Specific inhibitors of the HIV-1 protease enzyme1 protease enzyme

M.O.R.M.O.R.: mediated by expression of : mediated by expression of multiple and variable protease amino multiple and variable protease amino acid substitutionsacid substitutions

Less cross-resistance with Less cross-resistance with AmprenavirAmprenavir Side EffectsSide Effects: diarrhea and flatulence: diarrhea and flatulence AmprenavirAmprenavir can cause Stevens- can cause Stevens-

Johnson syndromeJohnson syndrome ContraindicationsContraindications:inhibitor/:inhibitor/

substrate for CPY3A4substrate for CPY3A4

Fusion InhibitorsFusion Inhibitors EnfuvirtideEnfuvirtide (T-20)- binds to the gp41 (T-20)- binds to the gp41

subunit of the viral envelope glycoprotein, subunit of the viral envelope glycoprotein, preventing the conformational changes preventing the conformational changes required for fusion of the viral and cellular required for fusion of the viral and cellular membranesmembranes

By blocking fusion (entry into cell), By blocking fusion (entry into cell), FUZEON prevents HIV from infecting CD4 FUZEON prevents HIV from infecting CD4 cellscells

Anti-Hepatitis AgentsAnti-Hepatitis Agents LamivudineLamivudine - -Nucleoside Reverse Nucleoside Reverse

Transcriptase Inhibitor (NRTI)Transcriptase Inhibitor (NRTI) Adefovir Adefovir --Nucleotide InhibitorNucleotide Inhibitor InterferonInterferon AlfaAlfa Pegylated Interferon AlfaPegylated Interferon Alfa RibavirinRibavirin

InterferonsInterferons Interferon AlfaInterferon Alfa

Endogenous proteins Endogenous proteins

induce host cell enzymes that inhibit viral induce host cell enzymes that inhibit viral RNA translation and cause degradation of RNA translation and cause degradation of viral mRNA and tRNAviral mRNA and tRNA

Bind to membrane receptors on cell Bind to membrane receptors on cell surfacesurface

May also inhibit viral penetration, May also inhibit viral penetration, uncoating, mRNA synthesis, and uncoating, mRNA synthesis, and translation, and virion assembly and translation, and virion assembly and releaserelease

InterferonsInterferons Pegylated interferon AlfaPegylated interferon Alfa A linear or branced polyethylene A linear or branced polyethylene

gylcol (PEG) moiety is attached to gylcol (PEG) moiety is attached to covalently to interferoncovalently to interferon

Increased half-life and steady drug Increased half-life and steady drug concentrationsconcentrations

Less frequent dosingLess frequent dosing Tx chronic hepatitis C in combination Tx chronic hepatitis C in combination

with ribavirinwith ribavirin

RibavirinRibavirin A guanosine analogA guanosine analog phosphorylated intracellularly by host phosphorylated intracellularly by host

enzymesenzymes inhibits capping of viral messenger RNAinhibits capping of viral messenger RNA inhibits the viral RNA-dependent RNA inhibits the viral RNA-dependent RNA

polymerasepolymerase inhibits replication of DNA and RNA inhibits replication of DNA and RNA

virusesviruses

Anti-Influenza AgentsAnti-Influenza Agents

AmantadineAmantadine RimantadineRimantadine ZanamivirZanamivir

AmantadineAmantadine and and RimantadineRimantadine

cyclic aminescyclic amines inhibit the uncoating of viral RNA inhibit the uncoating of viral RNA

therefore inhibiting replicationtherefore inhibiting replication resistance due to mutations in the resistance due to mutations in the

RNA sequence coding for the RNA sequence coding for the structural M2 proteinstructural M2 protein

used in the prevention and used in the prevention and treatment of Influenza Atreatment of Influenza A

Zanamivir Zanamivir andand OseltamivirOseltamivir

Inhibits the enzyme neuraminidaseInhibits the enzyme neuraminidase inhibit the replication of influenza A inhibit the replication of influenza A

and Influenza Band Influenza B treats uncomplicated influenza treats uncomplicated influenza

infectionsinfections administered intranasallyadministered intranasally

Antivirals: Nursing Antivirals: Nursing ImplicationsImplications

Before beginning therapy, thoroughly Before beginning therapy, thoroughly assess underlying disease and medical assess underlying disease and medical history, including allergies.history, including allergies.

Assess baseline VS and nutritional status.Assess baseline VS and nutritional status. Assess for contraindications, conditions Assess for contraindications, conditions

that may indicate cautious use, and that may indicate cautious use, and potential drug interactions.potential drug interactions.


Be sure to teach proper application Be sure to teach proper application technique for ointments, aerosol technique for ointments, aerosol powders, etc.powders, etc.

Emphasize hand washing before and after Emphasize hand washing before and after administration of medications to prevent administration of medications to prevent site contamination and spread of infection.site contamination and spread of infection.

Patients should wear a glove or finger cot Patients should wear a glove or finger cot when applying ointments or solutions to when applying ointments or solutions to affected areas.affected areas.


Instruct patients to consult their Instruct patients to consult their physician before taking any other physician before taking any other medication, including OTC medications.medication, including OTC medications.

Emphasize the importance of good Emphasize the importance of good hygiene.hygiene.

Inform patients that antiviral agents Inform patients that antiviral agents are not cures, but do help to manage are not cures, but do help to manage symptoms.symptoms.


Instruct patients on the importance of taking Instruct patients on the importance of taking these medications exactly as prescribed and these medications exactly as prescribed and for the full course of treatment.for the full course of treatment.

With zidovudine:With zidovudine: Inform patients that hair loss MAY occur so Inform patients that hair loss MAY occur so

that they are prepared for this rare adverse that they are prepared for this rare adverse reaction.reaction.

This medication should be taken on an This medication should be taken on an empty stomach.empty stomach.


Monitor for side effects:Monitor for side effects: effects are varied and specific to each effects are varied and specific to each

agentagent


Monitor for therapeutic effects:Monitor for therapeutic effects: effects will vary depending on the type of effects will vary depending on the type of

viral infectionviral infection Effects range from delayed progression of Effects range from delayed progression of

AIDS AIDS and ARC to decrease in flu-like symptoms, and ARC to decrease in flu-like symptoms, decreased frequency of herpes-like flare-decreased frequency of herpes-like flare-ups, ups, or crusting over of herpetic lesions.or crusting over of herpetic lesions.

Antitubercular AgentsAntitubercular Agents


Tuberculosis, “TB”Tuberculosis, “TB” Caused by Mycobacterium Caused by Mycobacterium

tuberculosistuberculosis Antitubercular agents treat all forms Antitubercular agents treat all forms

of mycobacteriumof mycobacterium

Mycobacterium InfectionsMycobacterium Infections

Common Infection SitesCommon Infection Sites lung (primary site)lung (primary site) brainbrain bonebone liverliver kidneykidney


Aerobic bacillusAerobic bacillus Passed from infected:Passed from infected:

HumansHumans Cows (bovine)Cows (bovine) Birds (avian)Birds (avian)


Tubercle bacilli are conveyed by droplets.Tubercle bacilli are conveyed by droplets. Droplets are expelled by coughing or sneezing, Droplets are expelled by coughing or sneezing,

then gain entry into the body then gain entry into the body by inhalation.by inhalation.

Tubercle bacilli then spread to other body Tubercle bacilli then spread to other body organs organs via blood and lymphatic systems.via blood and lymphatic systems.

Tubercle bacilli may become dormant, or Tubercle bacilli may become dormant, or walled walled off by calcified or fibrous tissue.off by calcified or fibrous tissue.


Primary AgentsPrimary Agents Secondary AgentsSecondary Agentsisoniazid*isoniazid* capreomycincapreomycin

ethambutolethambutol cycloserinecycloserine

pyrazinamide (PZA)pyrazinamide (PZA) ethionamideethionamide

rifampinrifampin kanamycinkanamycin

streptomycinstreptomycin para-aminosalicyclic para-aminosalicyclic acidacid (PSA)(PSA)

*most frequently used*most frequently used

Antitubercular Agents: Antitubercular Agents: Mechanism of ActionMechanism of Action

Three GroupsThree Groups Protein wall synthesis inhibitors Protein wall synthesis inhibitors

streptomycin, kanamycin, capreomycin, streptomycin, kanamycin, capreomycin, rifampin, rifabutinrifampin, rifabutin

Cell wall synthesis inhibitors cycloserine, Cell wall synthesis inhibitors cycloserine, ethionamide, isoniazidethionamide, isoniazid

Other mechanisms of actionOther mechanisms of action

Antitubercular Agents:Antitubercular Agents:Mechanism of Action Mechanism of Action

isoniazid (INH)isoniazid (INH) Drug of choice for TBDrug of choice for TB Resistant strains of mycobacterium Resistant strains of mycobacterium

emergingemerging Metabolized in the liver through Metabolized in the liver through

acetylation—watch for “slow acetylation—watch for “slow acetylators”acetylators”

Used for the prophylaxisUsed for the prophylaxisor treatment of TBor treatment of TB

Antitubercular Antitubercular Agents:Agents:

Therapeutic UsesTherapeutic Uses

Antitubercular TherapyAntitubercular Therapy

Effectiveness depends upon:Effectiveness depends upon: Type of infectionType of infection Adequate dosingAdequate dosing Sufficient duration of treatmentSufficient duration of treatment Drug complianceDrug compliance Selection of an effective drug Selection of an effective drug

combinationcombination

Antitubercular Agents: Side Antitubercular Agents: Side EffectsEffects

INHINHperipheral neuritis, hepatotoxicityperipheral neuritis, hepatotoxicity

ethambutolethambutolretrobulbar neuritis, blindnessretrobulbar neuritis, blindness

rifampinrifampinhepatitis, discoloration of urine, hepatitis, discoloration of urine, stoolsstools

Antitubercular Agents: Antitubercular Agents: Nursing ImplicationsNursing Implications

Obtain a thorough medical history and Obtain a thorough medical history and assessment.assessment.

Perform liver function studies in patients Perform liver function studies in patients who are to receive isoniazid or rifampin who are to receive isoniazid or rifampin (especially in elderly patients or those who (especially in elderly patients or those who use alcohol daily).use alcohol daily).

Assess for contraindications to the various Assess for contraindications to the various agents, conditions for cautious use, and agents, conditions for cautious use, and potential drug interactions.potential drug interactions.


Patient education is CRITICAL:Patient education is CRITICAL: Therapy may last for up to 24 months.Therapy may last for up to 24 months. Take medications exactly as ordered, Take medications exactly as ordered,

at the same time every day.at the same time every day. Emphasize the importance of strict Emphasize the importance of strict

compliance compliance to regimen for improvement of condition to regimen for improvement of condition or cure.or cure.


Patient education is CRITICAL:Patient education is CRITICAL: Remind patients that they are contagious Remind patients that they are contagious

during during the initial period of their illness—instruct in the initial period of their illness—instruct in proper hygiene and prevention of the proper hygiene and prevention of the spread of infected droplets.spread of infected droplets.

Emphasize to patients to take care of Emphasize to patients to take care of themselves, including adequate nutrition themselves, including adequate nutrition and rest.and rest.


Patients should not consume alcohol while Patients should not consume alcohol while on these medications nor take other on these medications nor take other medications, including OTC, unless they medications, including OTC, unless they check with their physician.check with their physician.

Diabetic patients taking INH should monitor Diabetic patients taking INH should monitor their blood glucose levels because their blood glucose levels because hyperglycemia may occur.hyperglycemia may occur.

INH and rifampin cause oral contraceptives INH and rifampin cause oral contraceptives to become ineffective; another form of birth to become ineffective; another form of birth control control will be needed.will be needed.


Patients who are taking rifampin should be Patients who are taking rifampin should be told that their urine, stool, saliva, sputum, told that their urine, stool, saliva, sputum, sweat, or tears may become reddish-sweat, or tears may become reddish-orange; even contact lenses may be orange; even contact lenses may be stained.stained.

Vitamin BVitamin B66 may is needed to combat may is needed to combat peripheral neuritis associated with INH peripheral neuritis associated with INH therapy.therapy.

Antitubercular Agents:Antitubercular Agents:Nursing ImplicationsNursing Implications

Monitor for side effectsMonitor for side effects Instruct patients on the side effects that Instruct patients on the side effects that

should be reported to the physician should be reported to the physician immediately.immediately.

These include fatigue, nausea, vomiting, These include fatigue, nausea, vomiting, numbness and tingling of the extremities, numbness and tingling of the extremities, fever, loss of appetite, depression, fever, loss of appetite, depression, jaundice.jaundice.

Antitubercular Agents:Antitubercular Agents:Nursing ImplicationsNursing Implications

Monitor for therapeutic effects:Monitor for therapeutic effects: Decrease in symptoms of TB, such as Decrease in symptoms of TB, such as

cough cough and feverand fever

Lab studies (culture and sensitivity tests) Lab studies (culture and sensitivity tests) and CXR should confirm clinical findingsand CXR should confirm clinical findings

Watch for lack of clinical response to Watch for lack of clinical response to therapy, indicating possible drug therapy, indicating possible drug resistanceresistance

Antimalarial, Antimalarial, Antiprotozoal, and Antiprotozoal, and

Antihelmintic AgentsAntihelmintic Agents

Protozoal InfectionsProtozoal Infections

Parasitic protozoa: live in or on Parasitic protozoa: live in or on humanshumans

malariamalaria leishmaniasisleishmaniasis amebiasisamebiasis giardiasisgiardiasis trichomoniasistrichomoniasis

MalariaMalaria

Caused by the plasmodium protozoa.Caused by the plasmodium protozoa. Four different plasmodium species.Four different plasmodium species. Cause: the bite of an infected adult Cause: the bite of an infected adult

mosquito.mosquito. Can also be transmitted by infected Can also be transmitted by infected

individuals via blood transfusion, individuals via blood transfusion, congenitally, or via infected needles congenitally, or via infected needles by drug abusers.by drug abusers.

Malarial Parasite Malarial Parasite (plasmodium)(plasmodium)

Two Interdependent Life CyclesTwo Interdependent Life Cycles Sexual cycle: in the mosquitoSexual cycle: in the mosquito Asexual cycle: in the humanAsexual cycle: in the human

Knowledge of the life cycles is essential Knowledge of the life cycles is essential in understanding antimalarial drug in understanding antimalarial drug treatment.treatment.

Drugs are only effective during the Drugs are only effective during the asexual cycle.asexual cycle.

Plasmodium Life CyclePlasmodium Life Cycle

Asexual cycle: two phasesAsexual cycle: two phases Exoerythrocytic phase:Exoerythrocytic phase:occurs “outside” occurs “outside”

the erythrocytethe erythrocyte Erythrocytic phase:Erythrocytic phase: occurs “inside” occurs “inside”

the erythrocytethe erythrocyte

Erythrocytes = RBCsErythrocytes = RBCs

Antimalarial AgentsAntimalarial Agents

Attack the parasite during the asexual Attack the parasite during the asexual phase, when it is phase, when it is vulnerablevulnerable

Erythrocytic phase drugs: chloroquine, Erythrocytic phase drugs: chloroquine, hydroxychloroquine, quinine, mefloquinehydroxychloroquine, quinine, mefloquine

Exoerythrocytic phase drug: primaquineExoerythrocytic phase drug: primaquine

May be used together for synergistic or additive May be used together for synergistic or additive killing power.killing power.

Antimalarials: Antimalarials: Mechanism of ActionMechanism of Action

4-aminoquinoline derivatives chloroquine 4-aminoquinoline derivatives chloroquine and hydroxychloroquineand hydroxychloroquine

Bind to parasite nucleoproteins and interfere with Bind to parasite nucleoproteins and interfere with protein synthesis.protein synthesis.

Prevent vital parasite-sustaining substances from Prevent vital parasite-sustaining substances from being formed.being formed.

Alter pH within the parasite.Alter pH within the parasite.

Interfere with parasite’s ability to metabolize andInterfere with parasite’s ability to metabolize anduse erythrocyte hemoglobin.use erythrocyte hemoglobin.

Effective only during the erythrocytic phaseEffective only during the erythrocytic phase

Antimalarials: Mechanism of Antimalarials: Mechanism of ActionAction

4-aminoquinoline derivatives quinine 4-aminoquinoline derivatives quinine and mefloquineand mefloquine

Alter pH within the parasite.Alter pH within the parasite. Interfere with parasite’s ability to Interfere with parasite’s ability to

metabolize and use erythrocyte metabolize and use erythrocyte hemoglobin.hemoglobin.

Effective only during the erythrocytic Effective only during the erythrocytic phase.phase.

Antimalarials: Mechanism of Antimalarials: Mechanism of Action Action

diaminophyrimidines pyrimethamine and diaminophyrimidines pyrimethamine and trimethoprimtrimethoprim

Inhibit dihydrofolate reductase in the parasite.Inhibit dihydrofolate reductase in the parasite. This enzyme is needed by the parasite to make This enzyme is needed by the parasite to make

essential substances.essential substances. Also blocks the synthesis of tetrahydrofolate.Also blocks the synthesis of tetrahydrofolate.

These agents may be used with sulfadoxine or These agents may be used with sulfadoxine or dapsone dapsone for synergistic effects.for synergistic effects.

Antimalarials: Mechanism Antimalarials: Mechanism of Actionof Action

primaquineprimaquine Only exoerythrocytic drug.Only exoerythrocytic drug. Binds and alters DNA.Binds and alters DNA.

sulfonamides, tetracyclines, sulfonamides, tetracyclines, clindamycinclindamycin

Used in combination with antimalarials to Used in combination with antimalarials to increase protozoacidal effectsincrease protozoacidal effects

Antimalarials: Drug EffectsAntimalarials: Drug Effects

Kill parasitic organisms.Kill parasitic organisms. Chloroquine and hydroxychloroquine Chloroquine and hydroxychloroquine

also have antiinflammatory effects.also have antiinflammatory effects.

Antimalarials: Therapeutic Antimalarials: Therapeutic UsesUses

Used to kill plasmodium organisms, the Used to kill plasmodium organisms, the parasites that cause malaria.parasites that cause malaria.

The drugs have varying effectiveness on The drugs have varying effectiveness on the different malaria organisms.the different malaria organisms.

Some agents are used for prophylaxis Some agents are used for prophylaxis against malaria.against malaria.

Chloroquine is also used for rheumatoid Chloroquine is also used for rheumatoid arthritis and lupus.arthritis and lupus.

Antimalarials: Side EffectsAntimalarials: Side Effects

Many side effects for the various Many side effects for the various agentsagents

Primarily gastrointestinal: nausea, Primarily gastrointestinal: nausea, vomiting, diarrhea,vomiting, diarrhea, anorexia, and anorexia, and abdominal painabdominal pain

AntiprotozoalsAntiprotozoals

atovaquone (Mepron)atovaquone (Mepron) metronidazole (Flagyl)metronidazole (Flagyl) pentamidine (Pentam)pentamidine (Pentam) iodoquinol (Yodoxin, Di-Quinol)iodoquinol (Yodoxin, Di-Quinol) paromomycin (Humatin)paromomycin (Humatin)


amebiasisamebiasis giardiasisgiardiasis pneumocystosispneumocystosis toxoplasmosistoxoplasmosis trichomoniasistrichomoniasis


TransmissionTransmission Person-to-personPerson-to-person Ingestion of contaminated water or foodIngestion of contaminated water or food Direct contact with the parasiteDirect contact with the parasite Insect bite (mosquito or tick)Insect bite (mosquito or tick)

Antiprotozoals: Antiprotozoals: Mechanism of Action Mechanism of Action and Uses atovaquone and Uses atovaquone

(Mepron)(Mepron) Protozoal energy comes from the Protozoal energy comes from the mitochondriamitochondria

Atovaquone: selective inhibition of Atovaquone: selective inhibition of mitochondrial electron transportmitochondrial electron transport

Result: no energy, leading to cellular Result: no energy, leading to cellular deathdeath

Used to treat mild to moderate P. carinii Used to treat mild to moderate P. carinii

Antiprotozoals: Antiprotozoals: Mechanism of Action and Mechanism of Action and

Uses metronidazoleUses metronidazole Disruption of DNA synthesis as well as Disruption of DNA synthesis as well as

nucleic acid synthesisnucleic acid synthesis Bactericidal, amebicidal, Bactericidal, amebicidal,

trichomonacidaltrichomonacidal

Used for treatment of trichomoniasis, Used for treatment of trichomoniasis, amebiasis, giardiasis, anaerobic amebiasis, giardiasis, anaerobic infections, and antibiotic-associated infections, and antibiotic-associated pseudomembranous colitispseudomembranous colitis


Uses pentamidineUses pentamidine Inhibits DNA and RNAInhibits DNA and RNA

Binds to and aggregates ribosomesBinds to and aggregates ribosomes

Directly lethal to Pneumocystis cariniiDirectly lethal to Pneumocystis carinii

Inhibits glucose metabolism, protein and RNA Inhibits glucose metabolism, protein and RNA synthesis, and intracellular amino acid synthesis, and intracellular amino acid transporttransport

Mainly used to treat P. carinii pneumonia Mainly used to treat P. carinii pneumonia and other protozoal infectionsand other protozoal infections

Antiprotozoals: Mechanism Antiprotozoals: Mechanism of Action of Action

and Uses iodoquinol and Uses iodoquinol (Yodoxin, Di-Quinol)(Yodoxin, Di-Quinol) ““Luminal” or “contact” amebicideLuminal” or “contact” amebicide

Acts primarily in the intestinal lumen Acts primarily in the intestinal lumen of the infected hostof the infected host

Directly kills the protozoaDirectly kills the protozoa

Used to treat intestinal amebiasisUsed to treat intestinal amebiasis


Uses paromomycinUses paromomycin ““Luminal” or “contact” amebicideLuminal” or “contact” amebicide Kills by inhibiting protein synthesisKills by inhibiting protein synthesis

Used to treat amebiasis and intestinal Used to treat amebiasis and intestinal protozoal infections, and also adjunct protozoal infections, and also adjunct therapy in management of hepatic comatherapy in management of hepatic coma

Antiprotozoals: Side EffectsAntiprotozoals: Side Effects

atovaquoneatovaquone nausea, vomiting, diarrhea, anorexianausea, vomiting, diarrhea, anorexia

metronidazolemetronidazole metallic taste, nausea, vomiting, diarrhea, metallic taste, nausea, vomiting, diarrhea,

abdominal crampsabdominal cramps

iodoquinoliodoquinol nausea, vomiting, diarrhea, anorexia, nausea, vomiting, diarrhea, anorexia,

agranulocytosisagranulocytosis


pentamidinepentamidine bronchospasms, leukopenia, bronchospasms, leukopenia,

thrombocytopenia, acute pancreatitis, thrombocytopenia, acute pancreatitis, acute renal failure, increased liver function acute renal failure, increased liver function studiesstudies

paromomycinparomomycin nausea, vomiting, diarrhea, stomach nausea, vomiting, diarrhea, stomach

crampscramps

AntihelminticsAntihelmintics

diethylcarbamazine (Hetrazan)diethylcarbamazine (Hetrazan) mebendazole (Vermox)mebendazole (Vermox) niclosamide (Niclocide)niclosamide (Niclocide) oxamniquine (Vansil)oxamniquine (Vansil) piperazine (Vermizine)piperazine (Vermizine) praziquantel (Biltricide)praziquantel (Biltricide) pyrantel (Antiminth)pyrantel (Antiminth) thiabendazole (Mintezol)thiabendazole (Mintezol)


Drugs used to treat parasitic worm Drugs used to treat parasitic worm infections: helmintic infectionsinfections: helmintic infections

Unlike protozoa, helminths are large Unlike protozoa, helminths are large and have complex cellular structuresand have complex cellular structures

Drug treatment is very specificDrug treatment is very specific


It is VERY IMPORTANT to identify the It is VERY IMPORTANT to identify the causative wormcausative worm

Done by finding the parasite ova or Done by finding the parasite ova or larvae in feces, urine, blood, larvae in feces, urine, blood, sputum, or tissuesputum, or tissue cestodes (tapeworms)cestodes (tapeworms) nematodes (roundworms)nematodes (roundworms) trematodes (flukes)trematodes (flukes)

Antihelmintics: Mechanism Antihelmintics: Mechanism of Action and Usesof Action and Uses

diethylcarbamazine (Hetrazan)diethylcarbamazine (Hetrazan)

Inhibits rate of embryogenesisInhibits rate of embryogenesis

thiabendazole (Mintezol)thiabendazole (Mintezol) Inhibits the helminth-specific enzyme, fumarate Inhibits the helminth-specific enzyme, fumarate

reductasereductase

Both used for nematodes Both used for nematodes (tissue and some roundworms)(tissue and some roundworms)

Antihelmintics: Mechanism Antihelmintics: Mechanism of Actionof Action

piperazine (Vermizine) and pyrantel piperazine (Vermizine) and pyrantel (Antiminth)(Antiminth)

Blocks acetylcholine at the neuromuscular Blocks acetylcholine at the neuromuscular junction, resulting in paralysis of the junction, resulting in paralysis of the worms, which are then expelled through worms, which are then expelled through the GI tractthe GI tract

Used to treat nematodes (giant worm and Used to treat nematodes (giant worm and pinworm)pinworm)

Pin wormsPin worms

Pin wormsPin worms

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mebendazole (Vermox)mebendazole (Vermox) Inhibits uptake of glucose and other Inhibits uptake of glucose and other

nutrients, leading to autolysis and death of nutrients, leading to autolysis and death of the parasitic wormthe parasitic worm

Used to treat cestodes and nematodesUsed to treat cestodes and nematodes


niclosamide (Niclocide)niclosamide (Niclocide) Causes the worm to become dislodged Causes the worm to become dislodged

from the GI wallfrom the GI wall They are then digested in the intestines They are then digested in the intestines

and expelledand expelled

Used to treat cestodesUsed to treat cestodes


oxamniquine (Vansil) and praziquantel oxamniquine (Vansil) and praziquantel (Biltricide)(Biltricide)

Cause paralysis of worms’ musculature and Cause paralysis of worms’ musculature and immobilization of their suckersimmobilization of their suckers

Cause worms to dislodge from mesenteric Cause worms to dislodge from mesenteric veins veins to the liver, then killed by host tissue reactionsto the liver, then killed by host tissue reactions

Used to treat trematodes, cestodes Used to treat trematodes, cestodes (praziquantel only)(praziquantel only)

Antihelmintics: Side EffectsAntihelmintics: Side Effects

niclosamide, oxamniquine, niclosamide, oxamniquine, praziquantel, thiabendazole, praziquantel, thiabendazole, piperazine, pyrantelpiperazine, pyrantel

nausea, vomiting, diarrhea, dizziness, nausea, vomiting, diarrhea, dizziness, headacheheadache

mebendazolemebendazole diarrhea, abdominal pain, tissue necrosisdiarrhea, abdominal pain, tissue necrosis

Antimalarial, Antiprotozoal, Antimalarial, Antiprotozoal, Antihelmintic Agents: Antihelmintic Agents: Nursing ImplicationsNursing Implications

Before beginning therapy, perform a Before beginning therapy, perform a thorough health history and thorough health history and medication history, and assess for medication history, and assess for allergies.allergies.

Check baseline VS.Check baseline VS. Check for conditions that may Check for conditions that may

contraindicate use, and for potential contraindicate use, and for potential drug interactions.drug interactions.


Some agents may cause the urine to Some agents may cause the urine to have an asparagus-like odor, or cause an have an asparagus-like odor, or cause an unusual skin odor, or a metallic taste; be unusual skin odor, or a metallic taste; be sure to warn the patient ahead of time.sure to warn the patient ahead of time.

Administer ALL agents as ordered and for Administer ALL agents as ordered and for the prescribed length of time.the prescribed length of time.

Most agents should be taken with food to Most agents should be taken with food to reduce GI upset.reduce GI upset.

Antimalarial Agents: Antimalarial Agents: Nursing ImplicationsNursing Implications

Assess for presence of malarial Assess for presence of malarial symptoms.symptoms.

When used for prophylaxis, these When used for prophylaxis, these agents should be started 2 weeks agents should be started 2 weeks before potential exposure to malaria, before potential exposure to malaria, and for 8 weeks after leaving the area.and for 8 weeks after leaving the area.

Medications are taken weekly, with 8 Medications are taken weekly, with 8 ounces of water.ounces of water.


Instruct patient to notify physician Instruct patient to notify physician immediately if ringing in the ears, immediately if ringing in the ears, hearing decrease, visual difficulties, hearing decrease, visual difficulties, nausea, vomiting, profuse diarrhea, or nausea, vomiting, profuse diarrhea, or abdominal pain occur.abdominal pain occur.

Alert patients to the possible recurrence Alert patients to the possible recurrence of the symptoms of malaria so that they of the symptoms of malaria so that they will know to seek immediate treatment.will know to seek immediate treatment.


Monitor for side effects:Monitor for side effects: Ensure that patients know the side effects Ensure that patients know the side effects

that should be reported.that should be reported. Monitor for therapeutic effects and Monitor for therapeutic effects and

adverse effects with long-term therapy.adverse effects with long-term therapy.

Antimalarial, Antimalarial, Antiprotozoal, and Antiprotozoal, and

Antihelmintic AgentsAntihelmintic Agents


Parasitic protozoa: live in or on Parasitic protozoa: live in or on humanshumans

malariamalaria leishmaniasisleishmaniasis amebiasisamebiasis giardiasisgiardiasis trichomoniasistrichomoniasis

Malaria Endemic countriesMalaria Endemic countries

MalariaMalaria

Caused by the plasmodium protozoa.Caused by the plasmodium protozoa. Four different plasmodium species.Four different plasmodium species. Cause: the bite of an infected adult Cause: the bite of an infected adult

mosquito.mosquito. Can also be transmitted by infected Can also be transmitted by infected

individuals via blood transfusion, individuals via blood transfusion, congenitally, or via infected needles congenitally, or via infected needles by drug abusers.by drug abusers.

Malarial Parasite Malarial Parasite (plasmodium)(plasmodium)

Two Interdependent Life CyclesTwo Interdependent Life Cycles Sexual cycle: in the mosquitoSexual cycle: in the mosquito Asexual cycle: in the humanAsexual cycle: in the human

Knowledge of the life cycles is essential Knowledge of the life cycles is essential in understanding antimalarial drug in understanding antimalarial drug treatment.treatment.

Drugs are only effective during the Drugs are only effective during the asexual cycle.asexual cycle.

Malaria CycleMalaria Cycle