Chapter 10 anti-tb, art...

AntimycobacterialAntimycobacterial
AgentsAgents
Chemotherapy 1Compiled by Birhanu Geta

Drugs For the RX ofDrugs For the RX of
Tuberculosis & LeprosyTuberculosis & Leprosy
Treating mycobacterial infection present problems:Treating mycobacterial infection present problems:
– They are slow growing microbes.They are slow growing microbes.
– Can also be dormant; resistant to many drugs.Can also be dormant; resistant to many drugs.
– Lipid rich cell wall is impermeable to manyLipid rich cell wall is impermeable to many
agents.agents.
– A substantial portion is intracellular;A substantial portion is intracellular;
Needs prolonged treatment.Needs prolonged treatment.
Drug toxicity & poor patient compliance.Drug toxicity & poor patient compliance.
High risk of emergency of resistantHigh risk of emergency of resistant
bacteria.bacteria.

 The objective of therapy isThe objective of therapy is: to eliminate: to eliminate
symptoms & prevent relapse.symptoms & prevent relapse.
 To accomplish this goal tXt must kill activelyTo accomplish this goal tXt must kill actively
dividing & resting mycobacteria.dividing & resting mycobacteria.
 Since the response of mycobacterial infections toSince the response of mycobacterial infections to
chemotherapy is slow, tXt is prolonged.chemotherapy is slow, tXt is prolonged.
 Combination of drugs are required to prevent theCombination of drugs are required to prevent the
emergence of resistance.emergence of resistance.
TB resistance can be:TB resistance can be:
 Mono drug resistanceMono drug resistance
 Multi drug resistance (MDR-TB)Multi drug resistance (MDR-TB)
 Extensively drug resistance (XDR-TB)Extensively drug resistance (XDR-TB)
 Total drug resistance (TDR-TB India, Iran, Italy)Total drug resistance (TDR-TB India, Iran, Italy)

Individual Antituberculous AgentsIndividual Antituberculous Agents
First-line agentsFirst-line agents (in order of preference):(in order of preference):
 Superior efficacy & acceptable toxicity.Superior efficacy & acceptable toxicity.
 Isoniazid: 300 mg/dayIsoniazid: 300 mg/day
 Rifampin: 600 mg/dRifampin: 600 mg/d
 Pyrazinamide: 25 mg/kg/dPyrazinamide: 25 mg/kg/d
 Ethambutol: 15–25 mg/kg/dEthambutol: 15–25 mg/kg/d
 Streptomycin: 15 mg/kg/dStreptomycin: 15 mg/kg/d
Dosage: adult dose in normal renal functionDosage: adult dose in normal renal function

5
XDR= extensively drug-resistant TB
Definition
Resistance to at least rifampicin and isoniazid,
in addition to any fluoroquinolone, and to at
least one of the three following injectable
drugs used in anti-TB treatment:
capreomycin, kanamycin and amikacin.

6
1st
-line
oral
•INH
•RIF
•PZA
•EMB
•(Rfb)
Injectables
•SM
•KM
•AMK
•CM
Fluoroquinolones
•Cipro
•Oflox
•Levo
•Moxi
•(Gati)
Oral bacteriostatic 2nd line
Unclear efficacy•ETA/PTA
•PASA
•CYS
Not routinely recommended,
efficacy unknown, e.g.,
amoxacillin/clavulanic acid,
clarithromycin, clofazamine,
linezolid, inmipenem/cilastatin,
high dose isonizid
XDR= HR + 1 FQ + 1 Injectable (KM or AMK or CM)

Second-line agents:Second-line agents: adult dose in normal renal functionadult dose in normal renal function
Amikacin: 15 mg/kg/dAmikacin: 15 mg/kg/d
Aminosalicylic acid (PAS): 8–12 g/dAminosalicylic acid (PAS): 8–12 g/d
Capreomycin: 15 mg/kg/dCapreomycin: 15 mg/kg/d
Ciprofloxacin: 1500 mg/d, dividedCiprofloxacin: 1500 mg/d, divided
Clofazimine: 200 mg/dClofazimine: 200 mg/d
Cycloserine: 500–1000 mg/d, dividedCycloserine: 500–1000 mg/d, divided
Ethionamide: 500–750 mg/dEthionamide: 500–750 mg/d
Kanamycin:Kanamycin:
Levofloxacin: 500 mg/dLevofloxacin: 500 mg/d
Rifabutin: 300 mg/d ORRifabutin: 300 mg/d OR
 150 mg/d if used concurrently with a protease inhibitor
Rifapentine: 600 mg once or twice weeklyRifapentine: 600 mg once or twice weekly
Chemotherapy Compiled by Birhanu Geta 7

ISONIAZIDISONIAZID (INH/Isonicotinic hydrazide)-(INH/Isonicotinic hydrazide)-HH
MOAMOA::
 HH inhibits synthesis of mycolic acid, which is aninhibits synthesis of mycolic acid, which is an
essential component of mycobacterial cell wall.essential component of mycobacterial cell wall.
 HH is a prodrug that is activated byis a prodrug that is activated by KatGKatG, the, the
mycobacterial catalase-peroxidase.mycobacterial catalase-peroxidase.
 The activated form ofThe activated form of HH forms a covalentforms a covalent
complex with an acyl carrier protein (complex with an acyl carrier protein (AcpMAcpM) &) &
KasAKasA, a beta-ketoacyl carrier protein, a beta-ketoacyl carrier protein
synthetase, which blocks mycolic acid synthesissynthetase, which blocks mycolic acid synthesis
& kills the cell& kills the cell  cidalcidal

PharmacokineticsPharmacokinetics
 Well absorbed PO or IM.Well absorbed PO or IM.
 Distributed widely: CSFDistributed widely: CSF ≈≈ 20% of plasma conc.20% of plasma conc.
Increased in meningeal inflammation.Increased in meningeal inflammation.
 Metabolized by acetylation;Metabolized by acetylation;
– Fast acetylation: hepatotoxicityFast acetylation: hepatotoxicity
– Slow acetylation: peripheral neuropathySlow acetylation: peripheral neuropathy
 Acetylation status does not generally affect theAcetylation status does not generally affect the
outcome with daily therapy.outcome with daily therapy.
Therapeutic UsesTherapeutic Uses
1.1. Component of all TB chemotherapeutic regimens.Component of all TB chemotherapeutic regimens.
2.2. Alone is used to prevent TB.Alone is used to prevent TB.

Adverse effectsAdverse effects
 Allergic reactions (fever, skin rashes)Allergic reactions (fever, skin rashes)
 Direct toxicitiesDirect toxicities
1.1. Drug induced hepatitis:Drug induced hepatitis: high risk age, rifampin, alcohol.high risk age, rifampin, alcohol.
2.2. Peripheral neuropathy;Peripheral neuropathy;
– Due to relative pyridoxine deficiencyDue to relative pyridoxine deficiency
 Promotes excretion of pyridoxinePromotes excretion of pyridoxine
– Likely to occur in slow acetylators & pts withLikely to occur in slow acetylators & pts with
predisposing factor [malnutrition, alcoholism, diabetes,predisposing factor [malnutrition, alcoholism, diabetes,
AIDS & Uremia].AIDS & Uremia].
 Reversed by administration of vitamin B6.Reversed by administration of vitamin B6.
1.1. Other adverse effectOther adverse effect  reversed by vitamin B6.reversed by vitamin B6.
– Convulsion, optic neuritis, psychosis.Convulsion, optic neuritis, psychosis.
Drug interactionDrug interaction
– Reduces metabolism of phenytoin.Reduces metabolism of phenytoin.
– Absorption of INH is impaired by Al(OH)3.Absorption of INH is impaired by Al(OH)3.

RIFAMPICIN(R)RIFAMPICIN(R)
MOAMOA:: binds to thebinds to the ββ-subunit of bacterial DNA-subunit of bacterial DNA
dependent RNA polymerasedependent RNA polymerase ⇒⇒ inhibits RNAinhibits RNA
synthesis (synthesis (transcriptiontranscription))  cidalcidal
– Well absorbed; distributed throughout theWell absorbed; distributed throughout the
body.body.
– Excreted mainly through liver into bile.Excreted mainly through liver into bile.

Therapeutic usesTherapeutic uses
 Mycobacterial infection;Mycobacterial infection;
TB: cidal for intra & extracellular bacteria.TB: cidal for intra & extracellular bacteria.
In TB prevention as an alternative toIn TB prevention as an alternative to HH..
LeprosyLeprosy
Atypical mycobacteria.Atypical mycobacteria.
 Prophylaxis in contacts of children withProphylaxis in contacts of children with
H.influenzae type b disease(meningitis).H.influenzae type b disease(meningitis).
 In combination with other agents;In combination with other agents;
– To eradicate staphylococcal carriage.To eradicate staphylococcal carriage.
– For Rx of serious staphylococcal infections;For Rx of serious staphylococcal infections;
OsteomyelitisOsteomyelitis
Prosthetic valve endocarditis.Prosthetic valve endocarditis.

– HepatitisHepatitis
– Hypersensitivity reactionsHypersensitivity reactions
FeverFever
FlushingFlushing
PruritusPruritus
ThrombocytopeniaThrombocytopenia
Interstitial nephritisInterstitial nephritis
– Miscellaneous adverse reactionMiscellaneous adverse reaction
Harmless orange color appearing in urine,Harmless orange color appearing in urine,
saliva, tears, sweat & soft contact lenses.saliva, tears, sweat & soft contact lenses.
GI upsetGI upset

ETHAMBUTOL(E)ETHAMBUTOL(E)
MOAMOA::
 Inhibits mycobacterial arabinosyl transferases,Inhibits mycobacterial arabinosyl transferases,
which are encoded by thewhich are encoded by the embCABembCAB operon.operon.
 Arabinosyl transferases are involved in theArabinosyl transferases are involved in the
polymerization reaction of arabinoglycan, anpolymerization reaction of arabinoglycan, an
essential component of the mycobacterial cell wallessential component of the mycobacterial cell wall
 ⇒⇒ bacteriobacteriostaticstatic..

Therapeutic use:Therapeutic use: TB.TB.
– Retrobulbar neuritis (optic neuritis)Retrobulbar neuritis (optic neuritis)
Loss of visual acuity & red-green colorLoss of visual acuity & red-green color
blindness.blindness.
– GI intolerance.GI intolerance.
– Hyperuricemia due to deceased uric acidHyperuricemia due to deceased uric acid
excretion.excretion.

PYRAZINAMIDE(Z)PYRAZINAMIDE(Z)
 Synthetic pyrazine analogue of nicotinamide.Synthetic pyrazine analogue of nicotinamide.
 Converted toConverted to pyrazinoicpyrazinoic acidacid, active form of drug., active form of drug.
 Largely Bacteriostatic, but can be cidal onLargely Bacteriostatic, but can be cidal on
actively replicating mycobacteria.actively replicating mycobacteria.
MOAMOA:: the specific drug target is unknownthe specific drug target is unknown
 DisruptsDisrupts cell membrane metabolism & transport
functions  static
 Inhibit fatty acid synthase(FAS) I, which isInhibit fatty acid synthase(FAS) I, which is
required to synthesise fatty acids.required to synthesise fatty acids.
 In acidic media pyrazinoic acid accumulated ->In acidic media pyrazinoic acid accumulated ->
disrupts membrane potential & interferes withdisrupts membrane potential & interferes with
energy production necessary for survival ofenergy production necessary for survival of
M.tuberculosis at acidic site of infection.M.tuberculosis at acidic site of infection.Chemotherapy 16Compiled by Birhanu Geta

Therapeutic use:Therapeutic use: forfor RXRX ofof TB only.TB only.
 Sterilizing agent in IP of therapy
 Allows total duration of therapy to be shortened
to 6 months
 M.bovis & M.leprae are innately resistant toM.bovis & M.leprae are innately resistant to
Pyrazinamide.Pyrazinamide.
 GI intolerance,GI intolerance,
 Joint pains (arthralgia),Joint pains (arthralgia),
 The mostThe most hepatotoxichepatotoxic agentagent
 Hyperuricemia.Hyperuricemia.

ANTI-TB DRUGSANTI-TB DRUGS
 Drugs available in FDC in Ethiopia:Drugs available in FDC in Ethiopia:
ERHZERHZ – 275/150/75/400 mg– 275/150/75/400 mg
RHZRHZ – 150/75/400 mg– 150/75/400 mg
RHRH – 150/75 mg– 150/75 mg
EHEH – 400/150 mg– 400/150 mg
 TB medicines available as loose form are:TB medicines available as loose form are:
– Ethambutol 400mg,Ethambutol 400mg,
– Isoniazid 300mg,Isoniazid 300mg,
– Streptomycin sulphate vials 1gm.Streptomycin sulphate vials 1gm.

PHASES OF CHEMOTHERAPYPHASES OF CHEMOTHERAPY
 There are two phases:There are two phases:
1. Intensive (initial) phase(IP)1. Intensive (initial) phase(IP)
 Consists of 4 or more drugs.Consists of 4 or more drugs.
 Duration;Duration;
8 wks for new cases, and8 wks for new cases, and
12 wks for re-treatment cases.12 wks for re-treatment cases.
 The drugs must be swallowed daily under DOT.The drugs must be swallowed daily under DOT.
 Rapid killing of actively growing & semi dormantRapid killing of actively growing & semi dormant
bacilli.bacilli.
 It renders the patient non infectious (It renders the patient non infectious (≈≈ 2wks).2wks).
 Protects against the development of resistance.Protects against the development of resistance.

2. Continuation phase2. Continuation phase
Immediately follows the intensive phase.Immediately follows the intensive phase.
Consists of 2 or 3 drugs.Consists of 2 or 3 drugs.
Duration is 4 – 6 months.Duration is 4 – 6 months.
Except for re-treatment cases drugs must beExcept for re-treatment cases drugs must be
collected every month.collected every month.
Eliminates bacilli that are still multiplying.Eliminates bacilli that are still multiplying.
Reduces failures and relapses.Reduces failures and relapses.

1.1. New PatientsNew Patients
 New patients presumed or known to have drug-New patients presumed or known to have drug-
susceptible TB,susceptible TB, pulmonary TB:pulmonary TB: 2HRZE/4HR2HRZE/4HR..
Alternatives:Alternatives:
1.1. 2HRZE/4(HR)2HRZE/4(HR)33 (a daily intensive phase followed by(a daily intensive phase followed by
three times weekly continuation phase, provided thatthree times weekly continuation phase, provided that
each dose is directly observed).each dose is directly observed). OROR
2.2. 2(HRZE)2(HRZE)33/4(HR)/4(HR)33 (Three times weekly dosing(Three times weekly dosing
throughout therapy, provided that every dose isthroughout therapy, provided that every dose is
directly observed and the patient is NOT living withdirectly observed and the patient is NOT living with
HIV or living in an HIV-prevalent setting).HIV or living in an HIV-prevalent setting).
 Settings with high levels of INH resistance inSettings with high levels of INH resistance in
new patients:new patients: 2HRZE/4HRE2HRZE/4HRE..

2. Previously Treated Patients2. Previously Treated Patients
 Specimens for culture and drug susceptibilitySpecimens for culture and drug susceptibility
testing (DST) should be obtained from alltesting (DST) should be obtained from all
previously treated TB patients at or before thepreviously treated TB patients at or before the
start of treatment.start of treatment.
 DST should be performed for at least IsoniazidDST should be performed for at least Isoniazid
and Rifampicin.and Rifampicin.
 Recommendation:Recommendation: 2HRZE(S)/1HRZE/5HRE2HRZE(S)/1HRZE/5HRE..

22ndnd
line agentsline agents
EthionamideEthionamide
Chemically related to H & similarly blocks theChemically related to H & similarly blocks the
synthesis of mycolic acid.synthesis of mycolic acid.
Poorly water soluble & available only in oral form.Poorly water soluble & available only in oral form.
Metabolized by the liver.Metabolized by the liver.
CapreomycinCapreomycin
Is a peptide protein synthesis inhibitor antibioticIs a peptide protein synthesis inhibitor antibiotic
obtained fromobtained from Streptomyces capreolus.Streptomyces capreolus.
Aminosalicylic Acid (PAS)Aminosalicylic Acid (PAS)
A folate synthesis antagonist that is active almostA folate synthesis antagonist that is active almost
exclusively againstexclusively against M tuberculosisM tuberculosis ..
It is structurally similar to PABA & sulfonamidesIt is structurally similar to PABA & sulfonamidesChemotherapy Compiled by Birhanu Geta 23

Drugs active against atypical MycobacteriumDrugs active against atypical Mycobacterium
 M.avium:M.avium: cause disseminated TB in late stagescause disseminated TB in late stages
of AIDS.of AIDS.
 AzithromycinAzithromycin oror ClarithromycinClarithromycin plusplus
EthambutolEthambutol: well tolerated regimen.: well tolerated regimen.
 Rifabutin and Clarithromycin: prevent M.aviumRifabutin and Clarithromycin: prevent M.avium
complex bacterimia in AIDS patients.complex bacterimia in AIDS patients.

ANTILEPROTIC DRUGSANTILEPROTIC DRUGS
 Leprosy(Hansen’s disease) caused by M.leprae.Leprosy(Hansen’s disease) caused by M.leprae.
There are two types of leprosy;There are two types of leprosy;
1. Lepromatous Leprosy1. Lepromatous Leprosy
– SevereSevere
– Rapidly progressRapidly progress
– Marked ulcerationMarked ulceration
– Tissue destruction & nerve damageTissue destruction & nerve damage
– TXt lasts at least 2yrs withTXt lasts at least 2yrs with Dapsone + Rifampicin+Dapsone + Rifampicin+
ClofazimineClofazimine..
2. Tuberculoid Leprosy2. Tuberculoid Leprosy
- Mild infection.- Mild infection.
- Slow in progress & loss of sensation.- Slow in progress & loss of sensation.
- TXt lasts- TXt lasts 6months(Dapsone + Rifampicin).6months(Dapsone + Rifampicin).Chemotherapy 25Compiled by Birhanu Geta

DAPSONE/SULFONESDAPSONE/SULFONES
 The primary drug (effective, low in toxicity &The primary drug (effective, low in toxicity &
inexpensive).inexpensive).
MOAMOA:: inhibition of folate synthesis.inhibition of folate synthesis.
 Pharmacokinetics:Pharmacokinetics: given orally, well absorbed.given orally, well absorbed.
– Widely distributed.Widely distributed.
– Enterohepatic recycling.Enterohepatic recycling.
– Excreted as metabolites renally.Excreted as metabolites renally.
 Adverse effectsAdverse effects
– RashesRashes
– GI disturbanceGI disturbance
– Show erythema nodusom (Show erythema nodusom (↑↑ Inflammatory rxInflammatory rxnn).).

CLOFAZIMINECLOFAZIMINE
 Weakly bactericidal.Weakly bactericidal.
MOAMOA:: not known, may involve DNA bindingnot known, may involve DNA binding
 Has anti-inflammatory action.Has anti-inflammatory action.
 Used together with or as an alternative toUsed together with or as an alternative to
Dapsone inDapsone in sulfone-resistant leprosy or whensulfone-resistant leprosy or when
patients are intolerant to sulfones.patients are intolerant to sulfones.
 A common dosage is 100 mg/d orally.A common dosage is 100 mg/d orally.
– Red brown to nearly black discoloration of theRed brown to nearly black discoloration of the
skin & conjunctiva.skin & conjunctiva.
– GI intolerance (occasionally)GI intolerance (occasionally)

ANTIFUNGALANTIFUNGAL
AGENTSAGENTS

ANTIFUNGAL AGENTSANTIFUNGAL AGENTS
 Fungal infection termed as mycosis.Fungal infection termed as mycosis.
– Superficial infection (affecting skin, nails, scalp orSuperficial infection (affecting skin, nails, scalp or
mucous membranes).mucous membranes).
– Systemic infection (affecting deeper tissue & organ).Systemic infection (affecting deeper tissue & organ).
 Superficial fungal:Superficial fungal: dermatomycosis & candidiasis.dermatomycosis & candidiasis.
– Dermatomycosis:Dermatomycosis: skin, hair, & nail caused byskin, hair, & nail caused by
Trichophyton, Microsporum & EpidermophytonTrichophyton, Microsporum & Epidermophyton
spp.,these causes various types of ring worms &spp.,these causes various types of ring worms &
tinea.tinea.
Tinea capitis: scalp; Tinea pedis: footTinea capitis: scalp; Tinea pedis: foot
Tinea cruris: groin, thigh; Tinea barbae: beardTinea cruris: groin, thigh; Tinea barbae: beard
Tinea corporis: body.Tinea corporis: body.
– Superficial candidiasis:Superficial candidiasis: mucous membrane ofmucous membrane of
mouth (thrush), vagina or skin.mouth (thrush), vagina or skin.Chemotherapy 29Compiled by Birhanu Geta

Systemic fungal disease:Systemic fungal disease:
– Systemic candidiasis;Systemic candidiasis; other more seriousother more serious
cryptococcal meningitis or endocarditis,cryptococcal meningitis or endocarditis,
pulmonary aspergillosis,& rhino cerebralpulmonary aspergillosis,& rhino cerebral
mucormycosis.mucormycosis.

AMPHOTERICINAMPHOTERICIN
 Amphotericin A & B are antifungal antibioticsAmphotericin A & B are antifungal antibiotics
produced by Streptomyces nodosus.produced by Streptomyces nodosus.
 Amphotericin A is not in clinical use.Amphotericin A is not in clinical use.
Amphotericin-BAmphotericin-B
MOAMOA:: binds to sterols in the fungal cell membranebinds to sterols in the fungal cell membrane 
alters the permeability by forming amphotericin B-alters the permeability by forming amphotericin B-
associated poresassociated pores  Loss of intracellular K+.Loss of intracellular K+.
– Greater avidly to ergosterol.Greater avidly to ergosterol.
– Enhances antifungal effect of flucytosine.Enhances antifungal effect of flucytosine.

Amphotericin B is an amphoteric polyene macrolideAmphotericin B is an amphoteric polyene macrolide
(polyene =containing many double bonds; macrolide =(polyene =containing many double bonds; macrolide =
containing a large lactone ring of 12 or more atoms).containing a large lactone ring of 12 or more atoms).
It is nearly insoluble in water & is therefore preparedIt is nearly insoluble in water & is therefore prepared
as a colloidal suspension of amphotericinB & sodiumas a colloidal suspension of amphotericinB & sodium
desoxycholate for intravenous injection.desoxycholate for intravenous injection.
Absorption from GIT is negligible: effective on fungalAbsorption from GIT is negligible: effective on fungal
in lumen.in lumen.
Antifungal activity;Antifungal activity;
– Systemic fungal infections.Systemic fungal infections.
– Aspergillus, Candida, Cryptococcus.Aspergillus, Candida, Cryptococcus.
– Against protozoa Leishmania braziliensis.Against protozoa Leishmania braziliensis.

 Intrathecal infusion in meningitis caused byIntrathecal infusion in meningitis caused by
coccidioides.coccidioides.
 IV administration of amphotericin B treatmentIV administration of amphotericin B treatment
choice for mucormycosis, aspergillosis,choice for mucormycosis, aspergillosis,
extracutaneous sporotrichosis, cryptococcosis,extracutaneous sporotrichosis, cryptococcosis,
trichosporonosis & penicilliosis morneffei.trichosporonosis & penicilliosis morneffei.
 Bladder irrigation: in candida cystitis.Bladder irrigation: in candida cystitis.
 Topical amphotericin B in cutaneous candidiasis.Topical amphotericin B in cutaneous candidiasis.
 Oral tablet to decrease colonization of intestineOral tablet to decrease colonization of intestine
by candida.by candida.

Infusion related toxicity (immediate reactions)Infusion related toxicity (immediate reactions)
 Nearly universal & consist of fever, chills, muscleNearly universal & consist of fever, chills, muscle
spasms, vomiting, headache, and hypotension.spasms, vomiting, headache, and hypotension.
 They can be ameliorated by slowing the infusion rate orThey can be ameliorated by slowing the infusion rate or
decreasing the daily dose.decreasing the daily dose.
 Premedication with antipyretics, antihistamines,Premedication with antipyretics, antihistamines,
meperidine, or corticosteroids can be helpful.meperidine, or corticosteroids can be helpful.
Cumulative ToxicityCumulative Toxicity
 Renal damageRenal damage
 Anemia due to reduced erythropoietin production byAnemia due to reduced erythropoietin production by
damaged renal tubular cells.damaged renal tubular cells.
 Seizures & chemical arachnoiditis after intrathecalSeizures & chemical arachnoiditis after intrathecal
therapytherapy
 Abnormalities of liver function tests (occasionally)Abnormalities of liver function tests (occasionally)

FLUCYTOSINEFLUCYTOSINE
MOAMOA::
Is taken up by fungal cells via the enzyme cytosineIs taken up by fungal cells via the enzyme cytosine
permease.permease.
It is converted intracellularly first to 5-FU & thenIt is converted intracellularly first to 5-FU & then
to 5-FdUMP & FUTP, which inhibit DNA and RNAto 5-FdUMP & FUTP, which inhibit DNA and RNA
synthesis, respectively. (synthesis, respectively. (inhibit thymidylateinhibit thymidylate
synthetase)synthetase)
Human cells are unable to convert the parent drugHuman cells are unable to convert the parent drug
to its active metabolites, resulting in selectiveto its active metabolites, resulting in selective
toxicitytoxicity

 Given by IV infusion, also be given orally.Given by IV infusion, also be given orally.
 90% excreted renally unchanged.90% excreted renally unchanged.
 Combined with amphotericin for severeCombined with amphotericin for severe
infections such as cryptococcal meningitis.infections such as cryptococcal meningitis.
 Side effects are infrequent: anaemia,Side effects are infrequent: anaemia,
neutropenia, thrombocytopenia & alopecia;neutropenia, thrombocytopenia & alopecia;
reversed when therapy ceases.reversed when therapy ceases.

AZOLESAZOLES
According to the number of nitrogen atoms in the five-According to the number of nitrogen atoms in the five-
membered azole ring they can be;membered azole ring they can be;
TriazoleTriazole(3-N)(3-N) ImidazoleImidazole(2-N)(2-N)
– FluconazoleFluconazole -- ClotrimazoleClotrimazole
– ItraconazoleItraconazole -- MiconazoleMiconazole
– Terconazole -Terconazole - ketoconazoleketoconazole
– VoriconazoleVoriconazole -- OxiconazolOxiconazol
– PosaconazolePosaconazole - Sulconazole- Sulconazole
- Econazole- Econazole

AZOLES…AZOLES…
MOAMOA:: reduction of ergosterol synthesis by inhibitionreduction of ergosterol synthesis by inhibition
of fungal cytocrome P450 enzymes.of fungal cytocrome P450 enzymes.
 Greater affinity for fungal than for human CYP450Greater affinity for fungal than for human CYP450
enzymes.enzymes.
 Imidazoles exhibit a lesser degree of selectivity thanImidazoles exhibit a lesser degree of selectivity than
the triazoles, accounting for their higher incidence ofthe triazoles, accounting for their higher incidence of
drug interactions and adverse effects.drug interactions and adverse effects.
– Systemic fungal infections;Systemic fungal infections;
• Cryptococcal meningitis (fluconazole).Cryptococcal meningitis (fluconazole).
– Vaginal candidiasis.Vaginal candidiasis.
– Severe recalcitrant cutaneous dermatophyteSevere recalcitrant cutaneous dermatophyte
infectionsinfections..

KETOCONAZOLEKETOCONAZOLE
 Drug interactionsDrug interactions
– Inhibit CYP450: inhibit metabolism of proteaseInhibit CYP450: inhibit metabolism of protease
inhibitors, TCAs, benzodiazepines, warfarin.inhibitors, TCAs, benzodiazepines, warfarin.
 Adverse effectsAdverse effects
– Primarily GI effects, hepatotoxicity.Primarily GI effects, hepatotoxicity.

ITRACONAZOLE (PO)ITRACONAZOLE (PO)
PharmacodynamicsPharmacodynamics
 Absorption reduces in fasting, reduced gastricAbsorption reduces in fasting, reduced gastric
acidity,acidity,
 Itraconazole concentration are decreased byItraconazole concentration are decreased by
concomitant therapy with rifampin, phenytoin &concomitant therapy with rifampin, phenytoin &
carbamazepine, as well as by drugs that reducecarbamazepine, as well as by drugs that reduce
gastric acidity- H2 antagonist & proton pumpgastric acidity- H2 antagonist & proton pump
inhibitor.inhibitor.
Therapeutic use:Therapeutic use:
 Preferred over ketoconazole for txt of nonmeningealPreferred over ketoconazole for txt of nonmeningeal
hystoplasmosis.hystoplasmosis.
 Cryptococcus may respond better with amphotericinB orCryptococcus may respond better with amphotericinB or
fluconazole.fluconazole.
Untoward effect:Untoward effect: occasionally, hepatotoxicity & rash.occasionally, hepatotoxicity & rash.

FLUCONAZOLEFLUCONAZOLE
 Completely absorbed, not affected by food,Completely absorbed, not affected by food,
gastric acidity.gastric acidity.
 Diffuses readily into body fluids.Diffuses readily into body fluids.
Drug interaction:Drug interaction:
 Increase plasma levels of phenytoin, zidovudine,Increase plasma levels of phenytoin, zidovudine,
Rifabutin, cyclosporine, sulfonylureas & warfarin.Rifabutin, cyclosporine, sulfonylureas & warfarin.

Therapeutic useTherapeutic use
 Candidiasis:Candidiasis: oropharyngeal, esophageal, vaginaloropharyngeal, esophageal, vaginal
candidiasis, deep candidiasis.candidiasis, deep candidiasis.
 Cryptococcosis:Cryptococcosis: to prevent relapse cryptococcalto prevent relapse cryptococcal
meningitis in AIDS patient whose infection hasmeningitis in AIDS patient whose infection has
been controlled by amphotericin B.been controlled by amphotericin B.
 Treatment choice for coccidioidal meningitisTreatment choice for coccidioidal meningitis
because of much lesser morbidity than withbecause of much lesser morbidity than with
amphotericin B.amphotericin B.
Untoward effect:Untoward effect:
 Nausea & Vomiting: antiemetic drug may be used.Nausea & Vomiting: antiemetic drug may be used.

GRISEOFULVINGRISEOFULVIN
 Active against the dermatophytes: Microsporum,Active against the dermatophytes: Microsporum,
Epidermophyton & Trichophyton.Epidermophyton & Trichophyton.
MOAMOA:: Fungistatic by interacting withFungistatic by interacting with
microtubule & interfering with mitosis.microtubule & interfering with mitosis.
 To treat dermatophyte infections of skin & nail.To treat dermatophyte infections of skin & nail.
 Treatment need very prolonged.Treatment need very prolonged.
 Given orally.Given orally.
 Deposited in keratin precursor cells.Deposited in keratin precursor cells.

 Mycotic disease of skin, hair & nails.Mycotic disease of skin, hair & nails.
 Infection of hair (tinea capitis).Infection of hair (tinea capitis).
 Ringworm of the glabrous skin.Ringworm of the glabrous skin.
 Tinea cruris & tinea corporis.Tinea cruris & tinea corporis.
 Tinea of hand & bread.Tinea of hand & bread.
 Athlete’s foot.Athlete’s foot.
Not effective in subcutaneous or deep mycosis.Not effective in subcutaneous or deep mycosis.

RRXX of Superficial Fungalof Superficial Fungal
InfectionsInfections
 Diseases include;Diseases include;
Dermatophytosis(ring worm),Dermatophytosis(ring worm),
Candidiasis,Candidiasis,
Tinea versicolor,Tinea versicolor,
Tinea nigra &Tinea nigra &
Fungal keratitis.Fungal keratitis.

A. ClotrimazoleA. Clotrimazole
 Available as:Available as: 1% cream (body, vaginal), lotion &1% cream (body, vaginal), lotion &
solution, 10mg troches.solution, 10mg troches.
 Skin apply BID.Skin apply BID.
 Vagina: -Vagina: - 100mg/day at bed time for 7days.100mg/day at bed time for 7days.
» 500mg tab only once.500mg tab only once.
» Troches five times a day for 14days.Troches five times a day for 14days.
B. MiconazoleB. Miconazole
 Therapeutic use: 2% vaginal cream, 100mgTherapeutic use: 2% vaginal cream, 100mg
suppository at bed time for 7days (vulvovaginalsuppository at bed time for 7days (vulvovaginal
candidiasis).candidiasis).
 In txt of tinea pedis, tinea cruris & tineaIn txt of tinea pedis, tinea cruris & tinea
versicolor.versicolor.
 ADRADR: vaginal application: vaginal application →→ burning, itchingburning, itching
or irritation.or irritation.

C. NystatinC. Nystatin
MOAMOA:: binds to fungal sterols.binds to fungal sterols.
– Candidiasis of intestine, mouth, skin, etc.Candidiasis of intestine, mouth, skin, etc.
– NauseaNausea
– Bitter tasteBitter taste

D. Undecylenic Acid (UDA)D. Undecylenic Acid (UDA)
 11 carbon, unsaturated compound.11 carbon, unsaturated compound.
MOAMOA::
 Possibly, inhibition of enzymes involved in lipidPossibly, inhibition of enzymes involved in lipid
metabolismmetabolism  interfere with the alkalinizationinterfere with the alkalinization
of the cytoplasm which accompanies germ tubeof the cytoplasm which accompanies germ tube
formationformation  inhibits morphogenesis in candidainhibits morphogenesis in candida
 Useful in txt of various dermatomycosis,Useful in txt of various dermatomycosis,
especially tinea pedis.especially tinea pedis.
 The formulation is not irritant (Zn)The formulation is not irritant (Zn)
 FungiFungistaticstatic
 Cure rate is 50% lower than Imidazole.Cure rate is 50% lower than Imidazole.

E. Benzoic Acid & Salicylic AcidE. Benzoic Acid & Salicylic Acid
(Whitfield’s Ointment)(Whitfield’s Ointment)
 Fungistatic benzoic acid(6%) & keratolyticFungistatic benzoic acid(6%) & keratolytic
salicylic acid(3%).salicylic acid(3%).
 Used in the txt of tinea pedis.Used in the txt of tinea pedis.
 Txt ends for several weeks to months.Txt ends for several weeks to months.
 Mild irritation at site of application.Mild irritation at site of application.

AntiviralAntiviral
AgentsAgents

INTRODUCTION TO VIRUSESINTRODUCTION TO VIRUSES
Viruses;Viruses;
Are obligate intracellular parasitesAre obligate intracellular parasites
Lack both cell wall & cell membraneLack both cell wall & cell membrane
Do not carry out metabolic processesDo not carry out metabolic processes
Use much of the host’s metabolic machineryUse much of the host’s metabolic machinery

Introduction…Introduction…
Few drugs are selective enough to prevent viralFew drugs are selective enough to prevent viral
replication without injury to the infected hostreplication without injury to the infected host
cells.cells.
Therapy for viral diseases is furtherTherapy for viral diseases is further
complicated by the fact that the clinicalcomplicated by the fact that the clinical
symptoms appear late in the course of thesymptoms appear late in the course of the
disease, at a time when most of the virusdisease, at a time when most of the virus
particles have replicated.particles have replicated.
At this stage of viral infection, administrationAt this stage of viral infection, administration
of drugs that block viral replication has limitedof drugs that block viral replication has limited
effectiveness. However, some antiviral agentseffectiveness. However, some antiviral agents
are useful as prophylactic agentsare useful as prophylactic agents

Classification of VirusesClassification of Viruses
DNADNA VirusesViruses
Adenoviruses (URTIs)
Herpes simplex (genital herpes)
Cytomegalovirus(CMV)
Hepatitis-B(HBV)
Varicella(chikenpox) & Varicella-zoster (shingles)
Smallpox
RNARNA VirusesViruses:: influenza A & B.
RNARNA retrovirusesretroviruses::
Human Immunodeficiency Virus (HIV)

VIRAL REPLICATION STEPSVIRAL REPLICATION STEPS
 AttachmentAttachment of the virus to receptors on theof the virus to receptors on the
host cell surfacehost cell surface
 EntryEntry of the virus through the host cellof the virus through the host cell
membranemembrane
 UncoatingUncoating of viral nucleic acidof viral nucleic acid
 SynthesisSynthesis ofof early regulatory proteinsearly regulatory proteins, eg,, eg,
nucleic acid polymerasesnucleic acid polymerases
 Synthesis ofSynthesis of new viral RNA or DNAnew viral RNA or DNA
 Synthesis ofSynthesis of late structural proteinslate structural proteins
 AssemblyAssembly (maturation) of viral particles(maturation) of viral particles
 ReleaseRelease from the cellfrom the cell

Mechanism ofMechanism of
actionaction
ofof
AntiviralAntiviral
agentsagentsChemotherapy Compiled by Birhanu Geta 55

Treatment of InfluenzaTreatment of Influenza
A.A. Amantadine (Symmetrel)Amantadine (Symmetrel)
MOAMOA:: block the M2 protein ion channel of theblock the M2 protein ion channel of the
virus particle and inhibit uncoating of the viralvirus particle and inhibit uncoating of the viral
RNA within infected host cells, thus preventingRNA within infected host cells, thus preventing
its replication.its replication.
Therapeutic use:Therapeutic use:
 Prophylaxis & treatment of Influenza A onlyProphylaxis & treatment of Influenza A only
due to resistancedue to resistance
Adverse Effects:Adverse Effects:
 GI upsetGI upset
 HeadacheHeadache
 NervousnessNervousnessChemotherapy 56Compiled by Birhanu Geta

B.B. Neuraminidase inhibitorsNeuraminidase inhibitors
Zanamivir (Relenza), Oseltamivir (Tamiflu)Zanamivir (Relenza), Oseltamivir (Tamiflu)
MOA:MOA: inhibit viral neuraminidase.inhibit viral neuraminidase.
Treatment of influenza A &B.Treatment of influenza A &B.
Prophylaxis: Oseltamivir.Prophylaxis: Oseltamivir.
Adverse EffectsAdverse Effects
Nausea, Vomiting, diarrhea, neutropenia.Nausea, Vomiting, diarrhea, neutropenia.
Bronchospasm & respiratory function.Bronchospasm & respiratory function.

AcyclovirAcyclovir
PenciclovirPenciclovir
GanciclovirGanciclovir
(‘Ovirs’) &(‘Ovirs’) &
NRTIsNRTIs
Virus-specified enzymesVirus-specified enzymes
(thymidine kinase, UL97)(thymidine kinase, UL97)
MonophosphateMonophosphate
Host kinasesHost kinasesTrifluridineTrifluridine
CidofovirCidofovir
DiphosphateDiphosphate
TriphosphateTriphosphate
Incorporation into viralIncorporation into viral
DNADNA
Chain terminationChain termination
Competitive inhibitionCompetitive inhibition
of viral DNA polymeraseof viral DNA polymerase
Inhibition of viralInhibition of viral
DNA synthesisDNA synthesis
Foscarnet, NNRTIsFoscarnet, NNRTIs

RRxx of Varicella Zoster & Herpesof Varicella Zoster & Herpes
SimplexSimplex
Acyclovir:Acyclovir: Nucleoside analog.Nucleoside analog.
MOAMOA:: inhibit viral DNA polymerase.inhibit viral DNA polymerase.
Therapeutic uses:Therapeutic uses:
 HSV(1&2)HSV(1&2)
 VZV since they have thymidine kinaseVZV since they have thymidine kinase
 Rash, headache, N/V, diarrhoea,Rash, headache, N/V, diarrhoea,
nephrotoxicity.nephrotoxicity.

Treatment of CMV infectionTreatment of CMV infection
A.A. Ganciclovir (Cytovene)Ganciclovir (Cytovene)
MOA:MOA: inhibits viral DNA polymerase.inhibits viral DNA polymerase.
Incorporation into viral DNA.Incorporation into viral DNA.
Therapeutic uses:Therapeutic uses: treatment oftreatment of
CMV retinitis in HIV infected patientsCMV retinitis in HIV infected patients
CMV infection in transplant patients.CMV infection in transplant patients.
Bone marrow suppressionBone marrow suppression
InfertilityInfertility
Teratogenic in animalsTeratogenic in animalsChemotherapy 61Compiled by Birhanu Geta

B.B. Foscarnet (Foscavir):Foscarnet (Foscavir): nonnon nucleosidenucleoside
MOAMOA:: inhibits viral DNA & RNA polymerase.inhibits viral DNA & RNA polymerase.
CMV retinitis.CMV retinitis.
Herpes Simplex infections.Herpes Simplex infections.
Acyclovir resistant (TK- strains)Acyclovir resistant (TK- strains)
Fever, nausea, diarrhea, headache.Fever, nausea, diarrhea, headache.
NephrotoxicityNephrotoxicity
Electrolyte & mineral imbalances.Electrolyte & mineral imbalances.

AntiretroviralAntiretroviral
DrugsDrugs

HIVHIV ReplicationReplication CycleCycle

STEPS IN HIV REPLICATIONSTEPS IN HIV REPLICATION
1.1. Binding of Gp120 to CD4 and co-receptor on theBinding of Gp120 to CD4 and co-receptor on the
cell surfacecell surface  AttachmentAttachment..
2.2. FusionFusion of the viral envelope with the cellof the viral envelope with the cell
membrane.membrane.
3.3. ReleaseRelease && disassemblydisassembly of the viral core in theof the viral core in the
cytoplasm.cytoplasm.
4.4. ReverseReverse transcriptiontranscription (Reverse transcriptase(Reverse transcriptase
enzyme translates HIV’s single stranded RNA intoenzyme translates HIV’s single stranded RNA into
a provirus made of double stranded DNA).a provirus made of double stranded DNA).
5. Viral DNA moves into cell nucleus.5. Viral DNA moves into cell nucleus.

STEPS IN HIV REPLICATION...STEPS IN HIV REPLICATION...
66. Viral DNA is. Viral DNA is integratedintegrated (by Integrase enzyme) into(by Integrase enzyme) into
host genome to form HIV provirus.host genome to form HIV provirus.
7.7. HIV provirus DNA isHIV provirus DNA is transcribedtranscribed back to both viralback to both viral
genomic RNA and viral mRNA, the latter which isgenomic RNA and viral mRNA, the latter which is
translatedtranslated to HIV polyproteins.to HIV polyproteins.
8.8. The RNA virus and polyproteins areThe RNA virus and polyproteins are assembledassembled
beneath the cell membrane.beneath the cell membrane.
9.9. The assembled package becomesThe assembled package becomes envelopedenveloped in the hostin the host
cell membrane as itcell membrane as it buds offbuds off to form an HIV virion.to form an HIV virion.
10.10. FurtherFurther assembly & maturationassembly & maturation occurs outside theoccurs outside the
cell by the protease enzyme, rendering the HIV virioncell by the protease enzyme, rendering the HIV virion
infectious.infectious.

AntiretroviralAntiretroviral
DrugsDrugs
AIDSAIDS
STOPSTOP
KEEP THE PROMISE!!!KEEP THE PROMISE!!!

The goals of therapy are to;The goals of therapy are to;
Maximally & durably suppress HIV RNA replication,Maximally & durably suppress HIV RNA replication,
Restore & preserve immunologic function,Restore & preserve immunologic function,
Reduce HIV-related morbidity & mortality,Reduce HIV-related morbidity & mortality,
Improve quality of life.Improve quality of life.
The preferred initial therapy is;The preferred initial therapy is;
2NRTIs + 1PI/NNRTI/integrase inhibitor.2NRTIs + 1PI/NNRTI/integrase inhibitor.
Selection of the appropriate combination is based on;Selection of the appropriate combination is based on;
1.1.Avoiding the use of 2agents of the same nucleosideAvoiding the use of 2agents of the same nucleoside
analoganalog
2.2.Avoiding overlapping toxicities & genotypic & phenotypicAvoiding overlapping toxicities & genotypic & phenotypic
characteristics of the viruscharacteristics of the virus
3.3.Patient factors (symptoms & concurrent illnesses)Patient factors (symptoms & concurrent illnesses)
4.4.Impact of drug interactionsImpact of drug interactions
5.5.Ease of adherence to the regimen.Ease of adherence to the regimen.Chemotherapy Compiled by Birhanu Geta 69

STEPS IN HIV REPLICATION...STEPS IN HIV REPLICATION...
6. Viral DNA is integrated (by Integrase enzyme) into host6. Viral DNA is integrated (by Integrase enzyme) into host
genome to form HIV provirusgenome to form HIV provirus
7. HIV provirus DNA is transcribed back to both viral7. HIV provirus DNA is transcribed back to both viral
genomic RNA and viral mRNA, the latter which isgenomic RNA and viral mRNA, the latter which is
translated to HIV polyproteins.translated to HIV polyproteins.
8. The RNA virus and polyproteins are assembled beneath8. The RNA virus and polyproteins are assembled beneath
the cell membranethe cell membrane
9. The assembled package becomes enveloped in the host9. The assembled package becomes enveloped in the host
cell membrane as it buds off to form an HIV virion.cell membrane as it buds off to form an HIV virion.
10. Further assembly and maturation occurs outside the cell10. Further assembly and maturation occurs outside the cell
by the protease enzyme, rendering the HIV virionby the protease enzyme, rendering the HIV virion
infectious.infectious.

Mechanism of ActionMechanism of Action
1. Inhibition of Binding of GP120 to CD4 receptor1. Inhibition of Binding of GP120 to CD4 receptor byby
“neutralizing antibodies” [?]“neutralizing antibodies” [?]
2. Fusion inhibition2. Fusion inhibition “Pentafuside T20”-Infuvertide“Pentafuside T20”-Infuvertide
(binds with gp41 & inhibits fusion of HIV-1 to CD4+(binds with gp41 & inhibits fusion of HIV-1 to CD4+
cells) & Maraviroc (CCR5 antagonist).cells) & Maraviroc (CCR5 antagonist).
3. Reverse Transcriptase Inhibition3. Reverse Transcriptase Inhibition
““NRTIs & NNRTIs”NRTIs & NNRTIs”
4. Integrase inhibition4. Integrase inhibition - integrase strand transfer- integrase strand transfer
inhibitors.inhibitors.
5. Protease Inhibition5. Protease Inhibition “Protease inhibitors”“Protease inhibitors”
 Currently therapy based mainly on 3 & 5 above.Currently therapy based mainly on 3 & 5 above.

Introduction to Antiretroviral DrugsIntroduction to Antiretroviral Drugs
Class Drugs Viral target Mode of action
Nucleoside
Reverse
Transcriptase
Inhibitor
(NRTI)
Zidovudine
Didanosine
Zalcitabine
Stavudine
Lamivudine
Abacavir
Tenofovir
Emtricitabine
Reverse
Transcriptase
Phosphorylated by
cellular enzymes
Competitively
inhibits viral DNA
synthesis or
causes chain
termination

Non
Nucleoside
Reverse
Transcriptase
Inhibitor
(NNRTI)
Nevirapine
Delavirdine
Efavirenz
Etravirine
Rilpivirine
Reverse
Transcriptase
Not
phosphorylated
non
Competitive
inhibition of viral
DNA synthesis.
Binds directly to
enzyme
Introduction to Antiretroviral Drugs…Introduction to Antiretroviral Drugs…

Protease
Inhibitor
Saquinavir
Indinavir
Ritonavir
Nelfinavir
Amprenavir
Lopinavir
Atazanavir
Tipranavir
Darunavir
Fosampreinavir
Protease Binds to
protease active
site, thereby
inhibiting
function
Introduction to Antiretroviral Drugs…Introduction to Antiretroviral Drugs…

The Adverse Effects of AntiretroviralThe Adverse Effects of Antiretroviral
DrugsDrugs
 HyperglycemiaHyperglycemia,, new onset of diabetes mellitus,
exacerbation of pre-existing diabetes, and
diabetic ketoacidosis have been reported in those
on ART. Disorder in lipid and CHO metabolism 
central adiposity, insulin resistance
 HyperlipidemiaHyperlipidemia has been most strongly, but not
exclusively, associated with protease inhibitor
therapy (Nelfinavir, Saquinavir, Ritonavir >
Indinavir, Amprenavir).
 Lipodystrophy:Lipodystrophy: Morphologic Changes Definitions.
–Protease inhibitor and/or Nucleoside RT inhibitor
effects on adipocytes.
–Nucleoside RT inhibitor-induced mitochondrial
toxicity.Chemotherapy 77Compiled by Birhanu Geta

ADRs of ART…ADRs of ART…
 Lactic acidosis:Lactic acidosis:
– Inhibition of mitochondrial DNA polymerase 
Mitochondrial drop out during cell division.
Zalcitabine(ddc) >Zalcitabine(ddc) >
Stavudine(d4T) >Stavudine(d4T) >
(AZT)Zidovudine(ZDV), Didanosine(ddI) >(AZT)Zidovudine(ZDV), Didanosine(ddI) >
Lamivudine(3TC), Abacavir(ABC)Lamivudine(3TC), Abacavir(ABC)
– Other effects on mitochondria
• Inhibition of Krebs cycle --> Lactic acid.

ADRs of ART…ADRs of ART…
 Peripheral NeuropathyPeripheral Neuropathy
– Usually due to Nucleoside RT Inhibitors:
Zalcitabine [ddc] (17-36%) > Stavudine [d4T] (5-
24%) > Didanosine [ddI] (5-24%).

Adverse Effects of Antiretroviral Drugs:Adverse Effects of Antiretroviral Drugs:
Particular to Individual DrugsParticular to Individual Drugs
1.1.Efavirenz (EFV):Efavirenz (EFV): CNS Effects [Dizziness,
impaired concentration, somnolence, abnormal
dreams, insomnia, ataxia, emotional lability].
2.2.Indinavir (IDV):Indinavir (IDV): Nephrolithiasis.
3.3.Nevirapine (NVP):Nevirapine (NVP): rash, SJS, or Toxic
Epidermal Necrolysis.
4.4.Abacavir (ABC):Abacavir (ABC): Hypersensitivity reaction.
5.5.Zidovudine (ZDV):Zidovudine (ZDV): Bone Marrow Suppression.
6.6.Tenofovir (TDF):Tenofovir (TDF): Renal toxicity (proximal
tubule), impairs lipid profile.

Characteristics of Antiretroviral AgentsCharacteristics of Antiretroviral Agents
 The CYP450 3A4 subset is the major enzymaticThe CYP450 3A4 subset is the major enzymatic
route of metabolism of the PIs & NNRTIs.route of metabolism of the PIs & NNRTIs.
 The following table shows characteristics of ARTThe following table shows characteristics of ART
drugs.drugs.

Antiretroviral agentAntiretroviral agent
MetabolismMetabolism Effect on CYP450Effect on CYP450
ZidovudineZidovudine Hepatic glucuronidation,
Renal excretion
--
Other NRTIs Renal excretion
--
Nevirapine Cytochrome P450 Modest Induction
Delavirdine Cytochrome P450 Modest Inhibition
Efavirenz Cytochrome P450 Modest Induction &
Inhibition
Ritonavir Cytochrome P450 Potent Inhibition
Amprenavir,
Indinavir,
Nelfinavir
Cytochrome P450 Modest Inhibition
Saquinavir Cytochrome P450 Weak Inhibition

3TC/FTC
EFV
NVP
Preferred:
1) TDF
2) AZT
Alternatives:
1) d4T
2) ABC
FIRST LINE REGIMEN: ETHIOPIAN
ART PROGRAM 2008
REGIMENS:
PREFERRED
1. TDF+FTC+EFV
2. ZDV+3TC+EFV
3. ZDV+3TC+NVP
ALTERNATIVES
1. D4T+3TC+NVP
2. TDF+3TC+NVP
3. D4T+3TC+EFV
4. ABC+3TC+NVP
5. ABC+3TC+EFV
6.ABC+3TC+ZDVChemotherapy 83Compiled by Birhanu Geta

Combining NRTIsCombining NRTIs
 Interactions between NRTIs occur due to competitionInteractions between NRTIs occur due to competition
for the same intracellularfor the same intracellular phosphorylating enzymesphosphorylating enzymes, or, or
due to overlapping toxicities.due to overlapping toxicities.
 Nucleoside analogues that are activated by the sameNucleoside analogues that are activated by the same
intracellular enzymes include ZDV & d4T, or ddc &intracellular enzymes include ZDV & d4T, or ddc &
3TC.3TC.
 Combinations of ddI + ddc, d4T + ddI & d4T+ ddc,Combinations of ddI + ddc, d4T + ddI & d4T+ ddc,
are not recommended due to overlapping potential forare not recommended due to overlapping potential for
the development of peripheral neuropathy.the development of peripheral neuropathy.
 Recommended ART regimen(2014):Recommended ART regimen(2014):
TDF + FTC + EFV PreferredTDF + FTC + EFV Preferred
TDF + 3TC + EFV/NVPTDF + 3TC + EFV/NVP
ZDV + 3TC + EFV/NVP alternativesZDV + 3TC + EFV/NVP alternatives
ABC + 3TC + EFV/NVPABC + 3TC + EFV/NVP
ABC + 3TC + ZDVABC + 3TC + ZDV

Second-line Regimens(2014)Second-line Regimens(2014)
1.1. A boosted protease inhibitor (bPI) + 2NRTIsA boosted protease inhibitor (bPI) + 2NRTIs
are recommended for 2are recommended for 2ndnd
line ART.line ART.
2.2. ATV/r and LPV/r are the preferred bPIs forATV/r and LPV/r are the preferred bPIs for
second-line ART.second-line ART.
 IfIf TDF + FTC/3TC + EFV/NVP isTDF + FTC/3TC + EFV/NVP is 11stst
lineline
therapytherapy
ZDV ± 3TC + LPV/r or ATV/r ORZDV ± 3TC + LPV/r or ATV/r OR
ZDV + ABC + LPV/r or ATV/rZDV + ABC + LPV/r or ATV/r
 IfIf ZDV + 3TC + EFV/NVP isZDV + 3TC + EFV/NVP is 11stst
line therapyline therapy
 TDF + 3TC ± ZDV + LPV/r or ATV/r ORTDF + 3TC ± ZDV + LPV/r or ATV/r OR
 ABC + ddI + LPV/r or ATV/rABC + ddI + LPV/r or ATV/r
 If ABC + 3TC + ZDV is 1If ABC + 3TC + ZDV is 1stst
line therapyline therapy
 EFV or NVP + LPV/r or ATV/rEFV or NVP + LPV/r or ATV/rChemotherapy 85Compiled by Birhanu Geta

Preferred & alternative 1Preferred & alternative 1stst
-line regimens-line regimens
for children according to the 2013 WHOfor children according to the 2013 WHO
consolidated guidelinesconsolidated guidelines
Age groupAge group Preferred first-linePreferred first-line
regimensregimens
Alternative first-lineAlternative first-line
regimensregimens
Children<3Children<3
yearsyears
ABC/AZT + 3TC + LPV/rABC/AZT + 3TC + LPV/r ABC/AZT + 3TC + NVPABC/AZT + 3TC + NVP
Children 3–9Children 3–9
years &years &
adolescentsadolescents
<35 kg<35 kg
ABC + 3TC + EFVABC + 3TC + EFV ABC/AZT/TDF + 3TC/FTCABC/AZT/TDF + 3TC/FTC
+ NVP/EFV+ NVP/EFV
AdolescentsAdolescents
(10–19 yrs)(10–19 yrs)
≥35 kg≥35 kg
TDF + 3TC/FTC + EFVTDF + 3TC/FTC + EFV ABC/AZT/TDF + 3TC/FTCABC/AZT/TDF + 3TC/FTC
+ NVP/EFV+ NVP/EFV

Interactions Between NRTIs & PIsInteractions Between NRTIs & PIs
No significant alterations.No significant alterations.
 One important interaction involves didanosineOne important interaction involves didanosine
and indinavir, or didanosine and nelfinavir.and indinavir, or didanosine and nelfinavir.
 The neutralising agents in the oral formulationsThe neutralising agents in the oral formulations
of didanosine result in increased gastric pH.of didanosine result in increased gastric pH.
 Optimal absorption of indinavir and nelfinavirOptimal absorption of indinavir and nelfinavir
requires an acidic pH.requires an acidic pH.
 It is recommended that these drugs are given atIt is recommended that these drugs are given at
least one hour apart from didanosine.least one hour apart from didanosine.

Saquinavir – RitonavirSaquinavir – Ritonavir
 The combination reduces the pill burden (fromThe combination reduces the pill burden (from
1200 mg tid to 400mg/400 mg bd). Hence, may1200 mg tid to 400mg/400 mg bd). Hence, may
also improve adherence and reduce costs ofalso improve adherence and reduce costs of
therapy.therapy.
 PI “Boosting” Using Ritonavir.PI “Boosting” Using Ritonavir.

Interactions Between PIs & NNRTIsInteractions Between PIs & NNRTIs
NNRTIs alter the kinetics of PIs:NNRTIs alter the kinetics of PIs:
 Nevirapine induces hepatic enzymes, reducingNevirapine induces hepatic enzymes, reducing
the plasma concentrations of some proteasethe plasma concentrations of some protease
inhibitors.inhibitors.
– The dose of indinavir or nelfinavir may beThe dose of indinavir or nelfinavir may be
increased to accommodate for decreasedincreased to accommodate for decreased
AUCs when administered with Niverapine.AUCs when administered with Niverapine.

Interactions Between Antiretroviral Agents &Interactions Between Antiretroviral Agents &
Other DrugsOther Drugs
Hepatic metabolism:Hepatic metabolism:
Macrolide antibiotics, azole antifungals and H-2Macrolide antibiotics, azole antifungals and H-2
blockers are P450 inhibitors and hence interactblockers are P450 inhibitors and hence interact
with PIs and NNRTIs.with PIs and NNRTIs.
Rifamycin derivatives, alcohol and anticonvulsantsRifamycin derivatives, alcohol and anticonvulsants
are P450 inducers and hence also interact withare P450 inducers and hence also interact with
PIs and NNRTIs.PIs and NNRTIs.
Simvastatin and lovastatin are potent inducers,Simvastatin and lovastatin are potent inducers,
and other agents such as atorvastatin andand other agents such as atorvastatin and
pravastatin are less likely to interact and arepravastatin are less likely to interact and are
recommended for use.recommended for use.

Anti-tuberculosis Agents & ARVsAnti-tuberculosis Agents & ARVs
RifampicinRifampicin
– is the most potent P450 inducer, and results inis the most potent P450 inducer, and results in
significant reductions in PI and NNRTI plasmasignificant reductions in PI and NNRTI plasma
concentrations.concentrations.
RifabutinRifabutin
– is a less potent inducer, and current guidelinesis a less potent inducer, and current guidelines
suggest that it may be used with agents suchsuggest that it may be used with agents such
as indinavir or nelfinavir with appropriateas indinavir or nelfinavir with appropriate
dosage adjustments.dosage adjustments.

PMTCTPMTCT
ART options recommended for HIV-infectedART options recommended for HIV-infected
pregnant women who are eligible for treatmentpregnant women who are eligible for treatment
Maternal ART + infant ARV prophylaxisMaternal ART + infant ARV prophylaxis
MotherMother: Maternal ante partum daily ART,: Maternal ante partum daily ART,
starting as soon as possible irrespective ofstarting as soon as possible irrespective of
gestational age, and continued duringgestational age, and continued during
pregnancy, delivery and thereafter.pregnancy, delivery and thereafter.
InfantInfant: Daily NVP or twice-daily AZT from: Daily NVP or twice-daily AZT from
birth until 4 to 6 weeks of age (irrespective ofbirth until 4 to 6 weeks of age (irrespective of
the mode of infant feeding).the mode of infant feeding).
92

Post-Exposure ProphylaxisPost-Exposure Prophylaxis
Use of therapeutic agent to preventUse of therapeutic agent to prevent
establishment of infection following exposure toestablishment of infection following exposure to
pathogenpathogen
HIV occupational exposure: An “occupationalHIV occupational exposure: An “occupational
exposure” to HIV when an individual is exposedexposure” to HIV when an individual is exposed
to blood or bodily fluids during the course of theto blood or bodily fluids during the course of the
individual’s duty of work.individual’s duty of work.
93

Risk factors for Occupational HIV TransmissionRisk factors for Occupational HIV Transmission
Type of contact or exposure:Type of contact or exposure: Percutaneous, muco-Percutaneous, muco-
cutaneous non intact skin and bites resulting in bloodcutaneous non intact skin and bites resulting in blood
exposureexposure
Type and amount of fluid/tissueType and amount of fluid/tissue
Disease status of source patient:Disease status of source patient:
Higher viral loads (terminally ill patients orHigher viral loads (terminally ill patients or
individuals with Acute HIV infection)individuals with Acute HIV infection)
 Host defenses:Host defenses:
The host immune response may prevent HIVThe host immune response may prevent HIV
infection after exposureinfection after exposure
 Community HIV status:Community HIV status:
Risk higher in areas with high HIVRisk higher in areas with high HIV
seroprevalence.seroprevalence.
94

HIV: non-occupational exposures & PEP
1. Survivors of sexual assault
2. Children (needle stick, community fights,
sexual abuse)
3. Unanticipated high risk Exposure(sexual or
non-sexual e.g. Needle stick injury )
4. Sharing of needles in IDUs
95

Factors that can affect risk of HIV transmissionFactors that can affect risk of HIV transmission
Type of sexual contactType of sexual contact
HIV status of the assailantHIV status of the assailant
Presence/absence of torn or damaged skinPresence/absence of torn or damaged skin
The number of attackers/assailantsThe number of attackers/assailants
HIV prevalence in the areaHIV prevalence in the area
96

Indications on Eligibility of PEPIndications on Eligibility of PEP
Knowing the Source status and exposure status isKnowing the Source status and exposure status is
used to decide on eligibility of an exposed personused to decide on eligibility of an exposed person
for PEPfor PEP
Source statusSource status
1=Assymptomiatic, or stage 1 and 21=Assymptomiatic, or stage 1 and 2
2=Stage 3 and 42=Stage 3 and 4
97

ExposureExposure codecode
1.1.Exposure on mucus membrane and non intact skinExposure on mucus membrane and non intact skin
few drops, short durationfew drops, short duration
2.2.Exposure on mucus membrane and non intact skinExposure on mucus membrane and non intact skin
several drops long duration or major splash orseveral drops long duration or major splash or
superficial solid bore needle stick injurysuperficial solid bore needle stick injury
3.3.Hollow bore needle and deep puncture injuryHollow bore needle and deep puncture injury
98

99
StatusStatus
codecode
Exposure code (mucous membrane & non-Exposure code (mucous membrane & non-
intact skin exposure)intact skin exposure)
EC 1EC 1 EC 2EC 2 EC 3EC 3
SC 1SC 1 2-drug PEP2-drug PEP 2-drug PEP2-drug PEP 3-drug3-drug
PEPPEP
SC 2SC 2 2-drug PEP2-drug PEP 3-drug PEP3-drug PEP 3-drug3-drug
PEPPEP
SCSC
unknownunknown
no PEPno PEP no PEP*no PEP* no PEP*no PEP*
HIV-HIV-
No PEPNo PEP
warrantedwarranted
No PEP warrantedNo PEP warranted No PEPNo PEP
warrantewarrante

ARV drugs for PEP use in EthiopiaARV drugs for PEP use in Ethiopia
100
2-Drug PEP2-Drug PEP 3-Drug PEP3-Drug PEP
ZDV/3TCZDV/3TC
d4T/3TCd4T/3TC
TDF/3TCTDF/3TC
ZDV/3TC + LPV/r or EFVZDV/3TC + LPV/r or EFV
d4T/3TC + LPV/r or EFVd4T/3TC + LPV/r or EFV
TDF/3TC + LPV/r or EFVTDF/3TC + LPV/r or EFV
 Should be given in the shortest time possibleShould be given in the shortest time possible
(within the first 1-4 hours of exposure).(within the first 1-4 hours of exposure).
 Do not consider PEP beyond 72 hours.Do not consider PEP beyond 72 hours.

NEW & INVESTIGATIONAL ANTIRETROVIRALNEW & INVESTIGATIONAL ANTIRETROVIRAL
AGENTSAGENTS
New therapies are continually being sought that exploitNew therapies are continually being sought that exploit
other HIV targets, have activity against resistant viralother HIV targets, have activity against resistant viral
strains, have a lower incidence of adverse effects, andstrains, have a lower incidence of adverse effects, and
offer convenient dosing.offer convenient dosing.
Newly approved agents and those currently in advancedNewly approved agents and those currently in advanced
stages of clinical development include the NRTI agentsstages of clinical development include the NRTI agents
elvucitabine, racivir,elvucitabine, racivir, && apricitabine;apricitabine; the NNRTI agentthe NNRTI agent
rilpivirine;rilpivirine; entry inhibitors such as the CCR5 receptorentry inhibitors such as the CCR5 receptor
antagonistsantagonists vicrivirocvicriviroc && PRO 140,PRO 140, the fusion inhibitorthe fusion inhibitor
TNX-355 (ibalizumabTNX-355 (ibalizumab); and integrase inhibitors such as); and integrase inhibitors such as
elvitegravir.elvitegravir. In addition, new drug classes such asIn addition, new drug classes such as
maturation inhibitorsmaturation inhibitors (bevirimat)(bevirimat) are under investigation.are under investigation.

STOPSTOP
AIDSAIDSKEEP THE PROMISE!!!KEEP THE PROMISE!!!

ANTIPROTOZOALANTIPROTOZOAL
AGENTSAGENTS

Introduction
Protozoal infections are;
Common among people in underdeveloped
tropical & subtropical countries, where;
Sanitary conditions,
Hygienic practices, &
Control of the vectors of transmission are
inadequate.
However, with increased world travel,
protozoal diseases are no longer confined to
specific geographic locales.

Introduction…Introduction…
Protozoas are unicellular eukaryotes
Have metabolic processes closer to those
of the human host than to prokaryotic
bacterial pathogens.
Less easily treated than bacterial
infections,
Serious toxic effects in the host,
particularly on cells showing high metabolic
activity.
Most antiprotozoal agents have not proven
to be safe for pregnant patients.Chemotherapy Compiled by Birhanu Geta 105

MALARIAMALARIA
 Caused by protozoa of the genus plasmodium.Caused by protozoa of the genus plasmodium.
 Affects > 5million people; killing > 2 million eachAffects > 5million people; killing > 2 million each
year.year.
 Life cycle of malaria parasite:Life cycle of malaria parasite: takes place intakes place in
two hosts.two hosts. HHyperlinkyperlink
In human (asexual reproduction) &In human (asexual reproduction) &
Female anopheles (sexual reproduction)Female anopheles (sexual reproduction)
Types of malariaTypes of malaria
 Caused by five different species of plasmodiumCaused by five different species of plasmodium
(P.Vivax, P.Falciparum, P.Ovale, P.Malariae, P.Knowlesi(P.Vivax, P.Falciparum, P.Ovale, P.Malariae, P.Knowlesi).).

Chemotherapy of MalariaChemotherapy of Malaria
Considered in relation to the biology of infection.Considered in relation to the biology of infection.
1.1. Drugs active against SporozoitesDrugs active against Sporozoites::
– True causal prophylaxis.True causal prophylaxis.
 No drug is yet available.No drug is yet available.
2.2. Drugs active against Pre or Primary Exo-Drugs active against Pre or Primary Exo-
erythrocytic Stage;erythrocytic Stage;
– Causal prophylaxis [primaryCausal prophylaxis [primary tissue schizonticidestissue schizonticides]]
 Proguanil & PyrimethamineProguanil & Pyrimethamine
 Kill the parasites before RBCs are invaded.Kill the parasites before RBCs are invaded.
 Primaquine has causal prophylaxis activity especiallyPrimaquine has causal prophylaxis activity especially
against Pagainst P.falciparum.falciparum but its use is unsafe.but its use is unsafe.

Chemotherapy of Malaria…Chemotherapy of Malaria…
3.3. Drugs active against the secondary exo-Drugs active against the secondary exo-
erythrocytic stageerythrocytic stage (persistent liver cycle,(persistent liver cycle,
hypnozoite).hypnozoite).
 Secondary tissue schizonticides.Secondary tissue schizonticides.
 Primaquine acts on hypnotic ofPrimaquine acts on hypnotic of P.Vivax.P.Vivax.
4.4. Drugs active against the erythrocytic stageDrugs active against the erythrocytic stage
(blood schizonticides)(blood schizonticides)
 Suppression or clinical prophylaxis.Suppression or clinical prophylaxis.
 Chloroquine, Proguanil, MefloquineChloroquine, Proguanil, Mefloquine..
 Used for temporary prevention of clinical symptoms.Used for temporary prevention of clinical symptoms.
 Kill blood schizonts, but the tissue schizonts are notKill blood schizonts, but the tissue schizonts are not
destroyed.destroyed.
 Falciparum promptly cured.Falciparum promptly cured.

Clinical cure:Clinical cure:
A.A.4-aminoquinolines:4-aminoquinolines: Chloroquine, AmodiaquineChloroquine, Amodiaquine
B.B.Quinoline methanol:Quinoline methanol: Quinine, Quinidine, MefloquineQuinine, Quinidine, Mefloquine
C.C. Arthmisinine compounds:Arthmisinine compounds:
Dihyddroartemisinin, Artemether, ArtesunateDihyddroartemisinin, Artemether, Artesunate
 Interrupt the erythrocytic cycle of the malariaInterrupt the erythrocytic cycle of the malaria
parasite.parasite.
5. Drugs active against the sexual stage5. Drugs active against the sexual stage
A.A. Gametocidal:Gametocidal: PrimaquinePrimaquine
B.B. Sporontocides:Sporontocides: Proguanil & PyrimethamineProguanil & Pyrimethamine
A.A. Gamates become incapable of forming sporozoite.Gamates become incapable of forming sporozoite.

Therapeutic ObjectiveTherapeutic Objective

CHLOROQUINECHLOROQUINE
MOAMOA::
 Acts by concentrating in parasite food vacuoles,Acts by concentrating in parasite food vacuoles,
preventing the bio-crystallization of thepreventing the bio-crystallization of the
haemoglobin breakdown product, heme, intohaemoglobin breakdown product, heme, into
hemozoin, and thus eliciting parasite toxicity duehemozoin, and thus eliciting parasite toxicity due
to the build up of free heme.to the build up of free heme.
 Inhibition of heme polymeraseInhibition of heme polymerase

 Malaria:Malaria:
 A highly effective blood schizonticide for all formsA highly effective blood schizonticide for all forms
 Moderately gametocidal for P vivax, P ovale, and PModerately gametocidal for P vivax, P ovale, and P
malariae but not against those of P falciparum.malariae but not against those of P falciparum.
 Chloroquine is not active against liver stage parasitesChloroquine is not active against liver stage parasites
(hypnozoites)(hypnozoites)
 ChemoprophylaxisChemoprophylaxis
 Amebic liver abscess:Amebic liver abscess: with metronidazole.with metronidazole.
 Rheumatoid arthritisRheumatoid arthritis..
 Discoid lupus erythromatous.Discoid lupus erythromatous.

 CVS (parenteral dose): vasodilation, hypotension,CVS (parenteral dose): vasodilation, hypotension,
decrease myocardial infarction, ECG changes.decrease myocardial infarction, ECG changes.
 Oral route can cause (high dose)Oral route can cause (high dose)
– Visual disturbanceVisual disturbance
– UrticariaUrticaria
– Head acheHead ache
– GI upsetGI upset
 Rare reaction include hemolysis in pts with GRare reaction include hemolysis in pts with G66PDPD
deficient.deficient.
 High daily doses of chloroquine: irreversibleHigh daily doses of chloroquine: irreversible
ototoxicity & retinopathy.ototoxicity & retinopathy.
Contraindication:Contraindication: psoriasis, porphyria cutaneapsoriasis, porphyria cutanea
tardatarda it may precipitate acute attacks of theseit may precipitate acute attacks of these
diseases.diseases.Chemotherapy 115Compiled by Birhanu Geta

QUININE & QUINIDINEQUININE & QUINIDINE
 Derived from the bark of cinchona.Derived from the bark of cinchona.
MOAMOA:: unknown;unknown;
Pharmacological effectsPharmacological effects
– Quinine acts primarily as blood schizonticidal.Quinine acts primarily as blood schizonticidal.
• Gametocidal for P.Vivax, P.Ovale, P.MalariaeGametocidal for P.Vivax, P.Ovale, P.Malariae
• Not effective liver stage parasite.Not effective liver stage parasite.
– Quinine is the drug of choice for severe illnessQuinine is the drug of choice for severe illness
due to chloroquine resistant & MDR strains ofdue to chloroquine resistant & MDR strains of
P.falciparum.P.falciparum.
– Potentiation of neuromuscular blocking drugs.Potentiation of neuromuscular blocking drugs.

 Rx malariaRx malaria
– Cure of chloroquine resistant & MDRCure of chloroquine resistant & MDR
– Rx nocturnal leg cramps.Rx nocturnal leg cramps.
Toxicities & side effectsToxicities & side effects
– Commonly causes:Commonly causes:
TinnitusTinnitus
NauseaNausea
Head acheHead ache CinchonismCinchonism
DizzinessDizziness
FlushingFlushing

Toxicities & side effects…Toxicities & side effects…
 Hyperinsulinema- severe hypoglycemia.Hyperinsulinema- severe hypoglycemia.
 Stimulate uterine contraction.Stimulate uterine contraction.
 Black water fever:Black water fever:
Marked hemolysis & hemoglobinuria.Marked hemolysis & hemoglobinuria.
Due to hypersensitivity reaction to the drug.Due to hypersensitivity reaction to the drug.
ContraindicationsContraindications
 Hypersensitivity reaction to quinine.Hypersensitivity reaction to quinine.
 Severe Cinchonism.Severe Cinchonism.
Drug interactionsDrug interactions
 Absorption blocked by aluminum containingAbsorption blocked by aluminum containing
antacids.antacids.
 Should not be given concurrently with MefloquineShould not be given concurrently with Mefloquine
(cardiac arrest).(cardiac arrest).

MEFLOQUINEMEFLOQUINE
MOAMOA::
– Effective blood schizonticidal.Effective blood schizonticidal.
 Chemoprophylaxis:Chemoprophylaxis: nonimmune travelersnonimmune travelers
 Treatment:Treatment: for malaria caused by chloroquinefor malaria caused by chloroquine
resistant & MDR P.falciparum.resistant & MDR P.falciparum.
For severe or complicated malaria: Quinine orFor severe or complicated malaria: Quinine or
Quinidine are selected.Quinidine are selected.

– NVD; Abdominal pain, dizziness, dysphoriaNVD; Abdominal pain, dizziness, dysphoria
– Higher doses causeHigher doses cause
• Neuropsychiatric toxicity [disorientation,Neuropsychiatric toxicity [disorientation,
seizure, encephalopathy].seizure, encephalopathy].
• Alter cardiac conduction, arrhythmias &Alter cardiac conduction, arrhythmias &
bradycardia.bradycardia.
ContraindicationsContraindications
– History of seizure & neuropsychiatry.History of seizure & neuropsychiatry.
– Combination with quinine & QuinidineCombination with quinine & Quinidine ⇒⇒
Arrhythmia.Arrhythmia.

PRIMAQUINEPRIMAQUINE
Chemistry:Chemistry: synthetic 8-aminoquinoline.synthetic 8-aminoquinoline.
MOA:MOA: not completely understood
 Metabolites of primaquine are believed to actMetabolites of primaquine are believed to act
as oxidants that are responsible for theas oxidants that are responsible for the
schizonticidal action as well as for theschizonticidal action as well as for the
hemolysis & methemoglobinemia encountered ashemolysis & methemoglobinemia encountered as
toxicities.toxicities.
 Active against hepatic stages of all humanActive against hepatic stages of all human
malarial parasite.malarial parasite.
 Gametocidal.Gametocidal.

Reserved primarily for radical cure of vivaxReserved primarily for radical cure of vivax
& ovale malarias.& ovale malarias.
Occasionally to interrupt malarialOccasionally to interrupt malarial
transmission by rendering plasmodialtransmission by rendering plasmodial
gametocytes noninfectious to mosquitoes.gametocytes noninfectious to mosquitoes.
Primaquine +Clindamycin: an alternativePrimaquine +Clindamycin: an alternative
regimen for PCP.regimen for PCP.

PRIMAQUINE…PRIMAQUINE…
Adverse effectsAdverse effects:: generally toleratedgenerally tolerated
 Infrequently causes: nausea, epigastric pain,Infrequently causes: nausea, epigastric pain,
abdominal cramp, head ache.abdominal cramp, head ache.
 Hemolysis & methehemoglobinemia especially inHemolysis & methehemoglobinemia especially in
persons with G6PD deficiency.persons with G6PD deficiency.
ContraindicationContraindication
 Granulocytopenia.Granulocytopenia.
 Methemoglobinemia.Methemoglobinemia.
 Pregnancy as the fetus is deficient in G6PD.Pregnancy as the fetus is deficient in G6PD.

ARTEMISININ & ITS DERIVATIVESARTEMISININ & ITS DERIVATIVES
 Artemisinin orArtemisinin or Qinghaosu was isolated in 1972 fromwas isolated in 1972 from
Artemisia annua L.Artemisia annua L.
 Has been used in traditional Chinese medicine.Has been used in traditional Chinese medicine.
 Derivatives:Derivatives: Artemether, Arteether, Artesunate,Artemether, Arteether, Artesunate,
Artlinic acid.Artlinic acid.
MOAMOA::
 Production of free radicals that follows the iron-Production of free radicals that follows the iron-
catalyzed cleavage of the artemisinin endoperoxidecatalyzed cleavage of the artemisinin endoperoxide
bridge in the parasite food vacuole or from inhibitionbridge in the parasite food vacuole or from inhibition
of a parasite calcium ATPase.of a parasite calcium ATPase.
In contrast to other antimalarials:In contrast to other antimalarials:
 Artemisinins have very fast action.Artemisinins have very fast action.
 Parasite clearance times are short.Parasite clearance times are short.
 Unlike most of the antimalarials work at the lateUnlike most of the antimalarials work at the late
trophozoite & schizont stage; Artemisinin & itstrophozoite & schizont stage; Artemisinin & its
derivatives also acts at the early trophozoite.derivatives also acts at the early trophozoite.

 Active against all plasmodium species.Active against all plasmodium species.
 Should be administered in combination in orderShould be administered in combination in order
to:to:
– Reduce recrudescence.Reduce recrudescence.
– Prevent or slow development of resistance.Prevent or slow development of resistance.
 Uncomplicated malaria.Uncomplicated malaria.
 Due to short t1/2, they are not useful forDue to short t1/2, they are not useful for
chemoprophylaxis.chemoprophylaxis.
Adverse effect:Adverse effect: safe & well tolerated.safe & well tolerated.
 NVD.NVD.
 Avoided in pregnancy if possible.Avoided in pregnancy if possible.

INHIBITORS OF FOLATE SYNTHESISINHIBITORS OF FOLATE SYNTHESIS
PYRIMETHAMINE, PROGUANILPYRIMETHAMINE, PROGUANIL
MOAMOA:: Inhibit dihydrofolate reductase of plasmodia.Inhibit dihydrofolate reductase of plasmodia.
 With sulphonamide.With sulphonamide.
 Not 1Not 1stst
line because it is slow to act.line because it is slow to act.
 Suppressive Rx of chloroquine resistantSuppressive Rx of chloroquine resistant
 Given concurrently with sulfadiazine for Rx ofGiven concurrently with sulfadiazine for Rx of
toxoplasmosis.toxoplasmosis.
Adverse effectAdverse effect
 Erythema multiformErythema multiform
 Steven’s Johnson syndromeSteven’s Johnson syndrome
 Toxic epidermal necrosisToxic epidermal necrosis

PROGUANILPROGUANIL
 Prodrug metabolized to an active metabolite,Prodrug metabolized to an active metabolite,
cycloguanil.cycloguanil.
MOAMOA:: inhibits DHFRinhibits DHFR
– Inhibition of DNA synthesis.Inhibition of DNA synthesis.
– Depletion of folate co-factors.Depletion of folate co-factors.
 Slow antimalarial action.Slow antimalarial action.
– With chloroquine used as alternative toWith chloroquine used as alternative to
Mefloquine for prophylaxis.Mefloquine for prophylaxis.
– Not suitable for acute attack.Not suitable for acute attack.
– Considered safe for use during pregnancy.Considered safe for use during pregnancy.

HALOFANTRINE & LUMEFANTRINEHALOFANTRINE & LUMEFANTRINE
HALOFANTRINEHALOFANTRINE::
 Effective againstEffective against erythrocytic stageserythrocytic stages of all forof all for
human malaria species.human malaria species.
 Oral absorption is variable & is enhanced withOral absorption is variable & is enhanced with
food.food.
 Plasma t 1/2Plasma t 1/2 ≈≈ 4 days.4 days.
ADRsADRs::
 Generally well tolerated.Generally well tolerated.
 Abdominal pain, Diarrhea, Vomiting, Cough, rashAbdominal pain, Diarrhea, Vomiting, Cough, rash
& head ache, Altered cardiac conduction.& head ache, Altered cardiac conduction.

LUMEFANTRINE:LUMEFANTRINE:
 Available in fixed dose combination withAvailable in fixed dose combination with
artemether as Coartem.artemether as Coartem.
 T 1/2T 1/2 ≈≈ 4.5 hrs4.5 hrs
COARTEM®:COARTEM®: very effective for Rx ofvery effective for Rx of

AmebiasisAmebiasis:: infestation with E.hystolyticainfestation with E.hystolytica..
 Usually asymptomatic, when symptoms areUsually asymptomatic, when symptoms are
present the most characteristics are:present the most characteristics are:
– Diarrhea & abdominal pain.Diarrhea & abdominal pain.
Drugs forDrugs for
AmebiasisAmebiasis

A. Asymptomatic Intestinal Infection(Cyst)A. Asymptomatic Intestinal Infection(Cyst)
 In nonendemic areas they are treated by luminalIn nonendemic areas they are treated by luminal
amebicide.amebicide.
Diloxanide furoate, Iodoquinol, Paramomycin.Diloxanide furoate, Iodoquinol, Paramomycin.
 Therapy with a luminal amebicide is also required inTherapy with a luminal amebicide is also required in
the Rx of all other forms of amebiasis.the Rx of all other forms of amebiasis.
B. Amebic colitisB. Amebic colitis
 MetronidazoleMetronidazole PLUSPLUS luminal amebicide is the Rx ofluminal amebicide is the Rx of
choice for colitis & dysentery.choice for colitis & dysentery.
 TTC & erythromycin are alternative for moderateTTC & erythromycin are alternative for moderate
colitis.colitis.
 Dehydroemetine or emetine can also be used(toxic).Dehydroemetine or emetine can also be used(toxic).
C. Extra-intestinal infectionsC. Extra-intestinal infections
 Rx of choice are metronidazole + a luminal amebicide.Rx of choice are metronidazole + a luminal amebicide.

Classification of Antiamebic agentsClassification of Antiamebic agents
Luminal AmebicidesLuminal Amebicides
– DiloxanideDiloxanide
– IdoquinolIdoquinol
– TTCsTTCs
– Paramomycin(an aminoglycoside)Paramomycin(an aminoglycoside)
Tissue AmebicidesTissue Amebicides
– Both intestinal & extraintestinalBoth intestinal & extraintestinal
MetronidazoleMetronidazole
TinidazoleTinidazole
Emetine & DihydroemetineEmetine & Dihydroemetine
– For extraintestinal onlyFor extraintestinal only
ChloroquineChloroquine

METRONIDAZOLEMETRONIDAZOLE
MOAMOA::
 Amebas possess ferredoxin-like, low-redox-Amebas possess ferredoxin-like, low-redox-
potential, electron transport proteins thatpotential, electron transport proteins that
participate in metabolic electron removalparticipate in metabolic electron removal
reactions.reactions.
 The nitro group of metronidazole is able to serveThe nitro group of metronidazole is able to serve
as an electron acceptor, forming reducedas an electron acceptor, forming reduced
cytotoxic compounds that bind to proteins andcytotoxic compounds that bind to proteins and
DNADNA  death of the E. histolytica trophozoites.death of the E. histolytica trophozoites.

AbsorptionAbsorption: complete & rapid after PO: complete & rapid after PO
DistributionDistribution: well throughout the body.: well throughout the body.
 Therapeutic levels can be found in vaginal andTherapeutic levels can be found in vaginal and
seminal fluids, saliva, breast milk & CSF.seminal fluids, saliva, breast milk & CSF.
MetabolismMetabolism: depends on hepatic oxidation of its: depends on hepatic oxidation of its sideside
chain bychain by mixed-function oxidase, followed bymixed-function oxidase, followed by
glucuronidation. Therefore, concomitant treatment withglucuronidation. Therefore, concomitant treatment with
inducers of the cytochrome P450 enhances the rate ofinducers of the cytochrome P450 enhances the rate of
metabolism & inhibitors prolong the plasma half-life ofmetabolism & inhibitors prolong the plasma half-life of
metronidazolemetronidazole..
 The drug accumulates in patients with severe hepaticThe drug accumulates in patients with severe hepatic
disease.disease.
ExcretionExcretion: via urine (parent drug & its metabolites): via urine (parent drug & its metabolites)

1. Amebiasis1. Amebiasis
 For all symptomatic tissue infections: used withFor all symptomatic tissue infections: used with
luminal amebicide.luminal amebicide. Combination provides cureCombination provides cure
rates of > 90%rates of > 90%
2. Gardiasis:2. Gardiasis: hhighly effective, lower dosage than forighly effective, lower dosage than for
amebiasisamebiasis
3. Trichomoniasis:3. Trichomoniasis: hhighly effective, can be givenighly effective, can be given
topicallytopically
4. Anaerobic(G-/+ve) bacterial infection;4. Anaerobic(G-/+ve) bacterial infection;
– Bacteriodes, Clostridium (pseudomembranousBacteriodes, Clostridium (pseudomembranous
colitis), Fusobacterium.colitis), Fusobacterium.
5.5. H. pylori (PUD):H. pylori (PUD): with other ABXwith other ABX
66.. To facilitate extraction ofTo facilitate extraction of guinea worm inguinea worm in
drancunculiasis.drancunculiasis.

 Common:Common: head ache, nausea, dryness of mouth,head ache, nausea, dryness of mouth,
metallic taste, dizziness.metallic taste, dizziness.
 Has a disulfiram like effect copious vomiting, flushing,Has a disulfiram like effect copious vomiting, flushing,
palpitation, head ache.palpitation, head ache.
 Used with caution in pts with active disease of CNS.Used with caution in pts with active disease of CNS.
 Its use during 1st trimester is not recommended.Its use during 1st trimester is not recommended.
Drug InteractionDrug Interaction
 With alcohol: disulfiram like effect.With alcohol: disulfiram like effect.
 Inhibits inactivation of oral anticoagulant.Inhibits inactivation of oral anticoagulant.
 Phenobarbitone: enhaced metabolism of metronidazole.Phenobarbitone: enhaced metabolism of metronidazole.
 Cimetidine: reduces metabolism of metronidazoleCimetidine: reduces metabolism of metronidazole..

TINIDAZOLETINIDAZOLE
 22ndnd
generation nitroimidazole.generation nitroimidazole.
 Similar to Metronidazole.Similar to Metronidazole.
 Differ in: better toxicity profile & higher t½.Differ in: better toxicity profile & higher t½.

DILOXANIDE FUROATEDILOXANIDE FUROATE
Useful in the Rx of:Useful in the Rx of:
 Asymptomatic passers of cyst.Asymptomatic passers of cyst.
 In conjugation with metronidazole in the Rx ofIn conjugation with metronidazole in the Rx of
intestinal & systemic amebiasis.intestinal & systemic amebiasis.
 90% absorbed & the nonabsorbed is effective.90% absorbed & the nonabsorbed is effective.
Adverse effectAdverse effect
– FlatulenceFlatulence
– Dryness of mouthDryness of mouth
– PruritusPruritus

EMETINE & DEHYDROEMETINEEMETINE & DEHYDROEMETINE
MOAMOA: inhibits protein synthesis by blocking chain: inhibits protein synthesis by blocking chain
elongation.elongation.
 IM is the preferred route, since it is an irritantIM is the preferred route, since it is an irritant
when taken orally.when taken orally.
 Due to its toxicity, it has largely been replacedDue to its toxicity, it has largely been replaced
by metronidazole.by metronidazole.
UseUse: as alternative agent: as alternative agent
– Pain at the site of injectionPain at the site of injection
– Transient nausea & vomitingTransient nausea & vomiting
– Cardio toxicity [arrhythmia, CHF]Cardio toxicity [arrhythmia, CHF]
– Neuromuscular weaknessNeuromuscular weakness
– Dizziness & rash.Dizziness & rash.

Drugs ForDrugs For PPneumoneumoccystis Jiroveciystis Jiroveci PPneumonianeumonia
((PCPPCP))
– CotrimoxazoleCotrimoxazole
– PentamidinePentamidine
– Trimethoprim + DapsoneTrimethoprim + Dapsone
– Primaquine + ClindamycinPrimaquine + Clindamycin
DRUGS FOR TRICHOMONIASISDRUGS FOR TRICHOMONIASIS
– MetronidazoleMetronidazole
– TinidazoleTinidazole
DRUGS FOR TOXOPLASMOSISDRUGS FOR TOXOPLASMOSIS
– Pyrimethamine + Sulfadoxine = (FANSIDAR®)Pyrimethamine + Sulfadoxine = (FANSIDAR®)
– Pyrimethamine + SulfadiazinePyrimethamine + Sulfadiazine

DRUGS FOR LEISHMANIASISDRUGS FOR LEISHMANIASIS
 Has three different forms:Has three different forms:
Cutaneous leishmaniasisCutaneous leishmaniasis
Mucocutaneous leishmaniasisMucocutaneous leishmaniasis
Visceral leishmaniasis [kalazar]Visceral leishmaniasis [kalazar]
 DrugsDrugs include:include:
– PentavalentPentavalent antimony(Sb)antimony(Sb)
• SodiumSodium StiboStibogluconate (SSG)gluconate (SSG): 1: 1stst
line agentline agent
• Meglumine antimonite(MA)Meglumine antimonite(MA)
– AllopurinolAllopurinol ++ SSGSSG
– Miltefosine: visceralMiltefosine: visceral
– Amphotericin-BAmphotericin-B
– KetoconazoleKetoconazole

DRUGS FOR TRYPANOSOMIASISDRUGS FOR TRYPANOSOMIASIS
(AFRICAN SLEEPING SICKNESS)(AFRICAN SLEEPING SICKNESS)
Caused by:Caused by:
A. Trypanosomia brucei gambienseA. Trypanosomia brucei gambiense
- Slow to enter CNS- Slow to enter CNS
- Causes sleeping sickness- Causes sleeping sickness
Suramine & PentamidineSuramine & Pentamidine are used in early stage ofare used in early stage of
the disease [hemolymphatic stage]the disease [hemolymphatic stage]
 Pentamidine interferes with parasite synthesisPentamidine interferes with parasite synthesis
of RNA, DNA, phospholipids & proteins.of RNA, DNA, phospholipids & proteins.
Enflornithine:Enflornithine: used in early stage or CNSused in early stage or CNS
involvement.involvement.

B. Trypanosomia brucei rhodesienseB. Trypanosomia brucei rhodesiense
- Early invasion of the CNS- Early invasion of the CNS
- Usually fatal if not treated- Usually fatal if not treated
Melarsoprol:Melarsoprol:
 A trivalent arsenical compoundA trivalent arsenical compound
MOAMOA: reacts with sulfhydryl groups of various: reacts with sulfhydryl groups of various
substances, including enzymes in both thesubstances, including enzymes in both the
organism and hostorganism and host
UseUse: involvement of CNS in both ‘a’ & ‘b’: involvement of CNS in both ‘a’ & ‘b’

CHAGA’S DISEASE [AMERICAN TRYPANOSOMIAS]CHAGA’S DISEASE [AMERICAN TRYPANOSOMIAS]
-- Caused by Trypanosoma cruzi.Caused by Trypanosoma cruzi.
-- Parasites invade cardiac cells & neurons ofParasites invade cardiac cells & neurons of
myenteric cause cardiomyopathy & mega colonmyenteric cause cardiomyopathy & mega colon
⇒⇒ death.death.
Rx optionsRx options::
- Nifurtimox &- Nifurtimox &
- Benznidazole22- Benznidazole22::

Benznidazole22Benznidazole22
Nitroimidazole derivativeNitroimidazole derivative
MOAMOA: similar to nifurtimox.: similar to nifurtimox.
Better tolerated than nifurtimoxBetter tolerated than nifurtimox
An alternative for the treatment of ChagasAn alternative for the treatment of Chagas
diseasedisease

HelminthicHelminthic
InfestationInfestation
&&
Drugs of ChoiceDrugs of Choice

ANTHELMINTICSANTHELMINTICS
 Helminthes: Parasitic worms.Helminthes: Parasitic worms.
 Classification of parasitic worms;Classification of parasitic worms;

NEMATODE INFESTATION [INTESTINAL]NEMATODE INFESTATION [INTESTINAL]
1. ASCARIASIS (Giant round worm infestation)1. ASCARIASIS (Giant round worm infestation)
 Most prevalent helminthic infestation.Most prevalent helminthic infestation.
 Adult worm inhabit the intestineAdult worm inhabit the intestine
heavy infestationheavy infestation ⇒⇒ intestinal blockade.intestinal blockade.
Drug of choice:Drug of choice: AlbendazoleAlbendazole
MebendazoleMebendazole
Pyrantel pamoatePyrantel pamoate
Alternative drug:Alternative drug: Piperazine citrate 4g statPiperazine citrate 4g stat
Levamisole??Levamisole??

ALBENDAZOLEALBENDAZOLE
MOAMOA:: produce many biochemical changes.produce many biochemical changes.
 Inhibition of mitochondrial fumarate reductase.Inhibition of mitochondrial fumarate reductase.
 Uncoupling of oxidative phosphorylation.Uncoupling of oxidative phosphorylation.
 Inhibits microtubule polymerizationInhibits microtubule polymerization ⇒⇒
irreversibly impairing glucose uptakeirreversibly impairing glucose uptake ⇒⇒
immobilized & slowly die.immobilized & slowly die.
Pharmacokinetics:Pharmacokinetics:
– Erratically absorbed PO.Erratically absorbed PO.
– Rapidly undergoes 1st pass metabolism in liverRapidly undergoes 1st pass metabolism in liver
to albendazole sulfoxide.to albendazole sulfoxide.
– ↑↑ absorption when taken with fatty meal.absorption when taken with fatty meal.

Therapeutic uses of albendazole:Therapeutic uses of albendazole:
– Broad antiparasitic spectrum.Broad antiparasitic spectrum.
1. Effective as single dose for the Rx of;1. Effective as single dose for the Rx of;
 A.lumricoidesA.lumricoides
 Hookworm: Ankylostoma.duodenalis(A.duodenalis) & N.Hookworm: Ankylostoma.duodenalis(A.duodenalis) & N.
americanusamericanus
 Trichuris.trichuria(T.trichuria)Trichuris.trichuria(T.trichuria)
2. Also effective against:2. Also effective against:
– E.vermicularisE.vermicularis
– T.spiralisT.spiralis
– S.sterocoralis [invermectin is superior]S.sterocoralis [invermectin is superior]
3. High dose in Rx of hydatid disease.3. High dose in Rx of hydatid disease.
4. Useful for Rx of neurocycticercosis4. Useful for Rx of neurocycticercosis [Superior[Superior
to praziquantel].to praziquantel].
Corticosteroids: used to control inflammatoryCorticosteroids: used to control inflammatory
response.response.

Albendazole…Albendazole…
– Fewer ADR when used for short term therapyFewer ADR when used for short term therapy
abdominal painabdominal pain
DiarrheaDiarrhea
Nausea & dizzinessNausea & dizziness
Head acheHead ache
– With protracted therapyWith protracted therapy
GI painGI pain
Severe head acheSevere head ache
FeverFever
FatigueFatigue
Loss of hairLoss of hair
↑↑ in serum transaminasein serum transaminase
Leucopenia & thrombocytopeniaLeucopenia & thrombocytopeniaChemotherapy 153Compiled by Birhanu Geta

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