Antiprotozoal drugs

Pharmacology PPT

1. CHEMOTHERAPY OF
PROTOZOAL INFECTIONS
1

2. PROTOZOAL INFECTIONS
MALARIA
AMEBIASIS
GIARDIASIS
TRICHOMONIASIS
TRYPANOSOMIASIS
LEISHMANIASIS
TOXOPLASMOSIS
BABESIOSIS
BALANTIDIASIS
OTHERPROTOZOALINFECTIONS
2

3. AMEBIASIS
3

4. DEFINITION:AMEBIASISisinfectionwiththeparasitic
intestinalprotozoanENTAMOEBA HISTOLYTICA(the
“tissue-lysingamoeba)
4

5. AMEBIASIS-A MAJOR HEALTH
PROBLEM
10%WorldPopulation
50millionpeoplewithInvasivedisease
Deathin1,00,000oftheseannually
Thirdmostcommoncauseofdeathfromparasitic
diseaseafterMalariaandSchistosomiasis
Morecommonlyseenwherepoorsanitationand
crowdingcompromisesbarrierstocontaminationof
drinkingwaterandfoodwithfeces
5

6. MODES OF TRANSMISSION
Fecalcontaminationof
drinkingwaterand
foods,butalsoby
directcontactwithdirty
handsorobjectsas
wellasbysexual
contact.
Additionally,geophagy
isacommonrouteof
infectionincertain
cultures.
6

7. SEVERAL FACTORS CONTRIBUTE TO
INFECTION
HOSTFACTORS
Stress
Malnutrition
Alcoholism
Corticosteroidtherapy
Immunodeficiency
Alterationofbacterialflora
RISKFACTORS
People indeveloping
countriesthathavepoor
sanitaryconditions
Immigrantsfromdeveloping
countries
Travellerstodeveloping
countries
HIV-positivepatients
Menwhohavesexwithmen
7

8. LIFE CYCLE
Infective form
Can survive outside
the human body
Transform to
trophozoites
Noninfective(invasive)
Canreproduce
feedonintestinalbacteria
orinvadeandulcerate
walloflargeintestine,&
maymigratetoliveror
othertissues
Transformtocystswhich
areexcretedinfeces
8
CYST TROPHOZOITE

9. LIFE CYCLE
9

10. CLASSIFICATION OF ANTIAMOEBIC
DRUGS
TISSUE AMOEBICIDES
INTESTINAL AND EXTRA
INTESTINALAMOEBICIDES
NITROIMIDAZOLES
METRONIDAZOLE ,
TINIDAZOLE, ORNIDAZOLE,
SECNIDAZOLE,
SATRANIDAZOLE
ALKALOIDS
EMETINE,DIHYDROEMETINE
EXTRA-INTESTINAL
AMOEBICIDES
CHLOROQUINE
LUMINAL AMOEBICIDE
AMIDES
DILOXANIDE FUROATE,
NITAZOXAMIDE
8-HYDROXYQUINOLINE
QUINODOCHLOR
(IODOCHLOROHYDROXYQU
IN,CLIOQUINOL),
DIIODOHYDROXYQUIN
(IODOQUINOL)
ANTIBIOTICS
TETRACYCLINES,
PAROMOMYCIN
10

11. METRONIDAZOLE -PROTOTYPE
OriginallydiscoveredandusedforTrichomoniasisin1959
1-(β-Hydroxyethyl)-2-Methyl-5-Nitroimidazole
Nitro group
on C5
essential for
its activity
11

12. ANTIMICROBIAL SPECTRUM
BroadspectrumcidalactivityagainstAnaerobicProtozoa
E.histolytica
T.vaginalis
G.lamblia
Anaerobicbacteria–B.fragilis,Cl.perfringes,H.pylori,Cl.
Difficile,Fusobacterium,Camplyobacter,Peptococci,
Spirochetes&AnaerobicStreptococci
Extractionofadultguineaworm(Drancunculiamedinensis)
Resistance–NosignificantresistanceforE.histolyticatill
now,butdevelopedforT.vaginalis
12

13. MECHANISM OF ACTION
SelectivetoxicitytoAnaerobic&Microaerophilic
microorganisms
Asystemuniquetoanaerobics-Pyruvate:ferredoxin
oxidoreductasepathway(PFOR)normallygenerates
ATPviaoxidativedecarboxylationofpyruvate
13

14. Entry into the microorganism by
diffusion
Nitro group is reduced by redox
proteins to highly reactive nitro
radical
Nitro radicals act as an electron sink
Competes with Biological acceptor
sites of anaerobic organisms for the
electrons generated by PFOR
pathway of pyruvate reduction
14

15. METRONIDAZOLE InAddition,
3
CAUSE
RADIOSENSITIZATION
2
1
INHIBITS CELL
MEDIATED IMMUNITY
INDUCE
MUTAGENESIS
15

16. PHARMACOKINETICS
ABSORPTION
Vd~ total
body
water
<20%
bound to
plasma
protein
t1/2-8 hrs
Completely
absorbed from
small intestine,
little amount
reaches colon
16

17. THERAPEUTIC USES
1.AMEBIASIS
Firstlinedrugamongallformsofamoebicinfection
Currentrecommendations
•800mg TDS for 7-10 days
INVASIVE DYSENTRY & LIVER ABSCESS
•500mg iv infusion 6-8hrly for 7-10days or till oral therapy
can be started
SEVERE CASES OF AMEBIC DYSENTRY &
LIVER ABSCESS
•400 mg TDS for 5-7 days
MILD INTESTINAL DISEASE
17

18. 2.GIARDIASIS
Highlyeffectiveinadose400mgTDSfor7days
Shortercourseof3dayswith2g/day-equallyeffective
3.TRICHOMONAS VAGINALIS
DrugofChoice:2gSingledosepreferred
18

19. 4.ANAEROBICBACTERIALINFCETIONS
OccursmostlyafterColorectalorpelvicsurgery,
appendicectomy
Brainabscess&endocarditismaybecausedbyanaerobic
organisms
MetronidazoleinCombinationwithGentamycinor
Cephalosporins-Effective
SevereCasesi.v.administrationrecommended
ProhylacticUseinhighrisksituations(Colorectal/BiliarySx)
Other drugs used in
anaerobic infections-
Clindamycin &
Chloramphenicol
19

20. 5.PSEUDOMEMBRANOUS ENTEROCOLITIS
400-800mgBD-TDSfor10-14daysmoreeffective,more
convenient,lesstoxic&preferredoverVancomycin
6.HELICOBACTER PYLORIGASTRITIS/PEPTICULCER
Metronidazole
400mg TDS or
Tinidazole500
mg BD
Amoxicillin/
Clarithromycin
Proton pump
inhibitor
Triple drug for 2 week regimens
20

21. 7.ACUTENECROTIZINGULCERATIVEGINGIVITIS(ANUG)
Alsok/aTRENCH MOUTH causedbyanaerobeslike
fusobacteria,spirochetes&bacteroides
Metronidazole/TinidazoleDrugofChoice
21

22. 8.GUINEAWORMINFESTATION
Niridazole-Drugofchoice,butunavailableinIndia
DOSE:200-400mgTDSfor7days
Local reaction suppressed
Anti-inflammatory action
Extraction facilitated
Metronidazole
22

23. ADVERSE DRUG REACTIONS
Mostcommon-Anorexia,Nausea,Vomiting,abdominal
crampsandmetallictaste
Lessfrequent–headache,glositis,rashes,drynessofmouth,
dizziness&loosestools
Urticaria,flushing,itching,rashes&fixeddrugeruption
occursinallergicsubjects,warrantsdiscontinuation&
precludesfurtheruse
Prolongedadministration–Peripheralneuropathyand
CNSeffect
Seizuresathighdoses
Leucopenia,likelywithrepeatedcourses
Thrombophlebitisofinjectedvein,ifsolutionisnotwelldiluted
23

24. CONTRA-INDICATIONS
Firsttrimesterofpregnancyduetoitsmutagenic
potential
NeurologicaldiseasesandBlooddyscrasias
Chronicalcoholism
Disulfiram-likeintolerancetoalcoholoccursinsome
patientstakingMetronidazole
Symptoms:flushing,burningsensation,throbbing
headache,perspiration,dizziness,vomiting,visual
disturbance,mentalconfusion,faintingandcirculatory
collapse
24

25. TINIDAZOLE
Suited for Single dose or Once daily therapy
Metabolism slower, t1/2-12 hr, longer duration of
action
Higher cure rates
Better tolerated
Lower incidence of side effects: Nausea(1%),
Rash 0.2(%), Metallic taste (2%)
25

26. THERAPEUTIC USE
INTESTINAL AMEBIASIS
AMEBIC LIVER ABSCESS
TRICHOMONIASIS & GIARDIASIS
H.pylori
ANAEROBIC INFECTIONS
26

27. SECNIDAZOLE
•Congener of
Metronidazole with
similar spectrum of
activity & potency
•Rapid & complete
oral absorption
•Slower metabolism
•t1/2: 17-29 hrs
•Single 2 g dose
high cure rate
•Side effect similar
to Metronidazole
with incidence of
2-10%
ORNIDAZOLE
•Similar activity to
Tinidazole
•Slower metabolism
•Longer t1/2:12-14
hrs
•Dose & duration of
regimen similar to
Tinidazole
•Side effects similar
to Tinidazole
SATRANIDAZOLE
•Longer t1/2: 14 hrs
•Better tolerated
•No nausea,
vomiting or
metallic taste
•Absence of
Neurological &
Disulfiram-like
reactions
•Doesn’t produce
acetabolite
metabolite, which
is weak
carcinogen
27

28. ALKALOIDS
EMETINE
DEHYDROEMETNE
CHLOROQUINE
28

29. EMETINE AND DEHYDROEMETNE
CHEMISTRY
Emetine hydrochloride, plant alkaloid
derived from Cephaelisipecacuanha
Dehydroemetine, Synthetic Analogue
29

30. MECHANISM OF ACTION
Inhibits
elongation of peptide chain
Inhibits Protein synthesis
Inhibits intraribosomal translocation of
tRNA-amino acid complex1
3
2
Effective
against
trophozoites
only
Potent,
rapid
action
but not
curative
30

31. USES
Amebic liver abscess
Intestinal wall infections
Severe forms of amebiasis, Acute Amebic Dysentery
dehydroemetine is preferable as its less toxic to heart & less
cummulative
Seldom used now onlyfor patients not responding to
metronidazole
Luminalamoebicidemustbefollowedtoeradicatecyst
formingtrophozoites
31

32. ADVERSE DRUG REACTIONS
Localirritant:pain,tenderness&evenabscessformation
atsiteofinjectionismostcommon
Gastrointestinaltractdiscomfort:
Nausea,Vomiting,DiarrhoeaduetoCTZstimulation&
gastricirritation-Mostfrequent
abdominalcramps
Neuromuscularblockade:muscleweakness&muscle
stiffness
Cardiactoxicity:Arrhythmias,Hypotension,Tachycardia,
Myocarditis&ECGChanges
Notbeusedinpatientswithcardiacorrenaldisease,in
children,orinpregnancy
32

33. CHLOROQUINE
Kills trophozoitesof E.histolytica
Highly concentrated in liver –used in Hepatic Amoebiasis
Completely absorbed from upper intestine –not effective in
invasive dysentery or luminal cycle
Efficacy in amoebic liver abscess is equal to emetine, but
has longer duration of treatment & frequent relapse
Used after a course of Metronidazole –but a luminal
amoebicide must be added
33

34. DILOXANIDE FUROATE
Highlyeffectiveluminalamoebicide
Killstrophozoitesresponsibleforproductionofcysts–
howevernoantibacterialaction
Diloxanide
Furoate
Diloxanide Furoicacid
80-90% of free diloxanide
absorbed
No systemic effects
10-20% not absorbed,
real antiamoebic
substance
Hydrolysed
34

35. MetabolisedbyGlucurinadtion&Excretedinurine
USES
Singlecourseproducehighcurerate(90%):Mildintestinal
amoebiasis/Asymptomaticcystpassers
Tissueamoebiasis&LiverabscesswithMetronidazole
ChroniccystpassersrequirerepeatcourseforEradication
Dose:500mgTDSfor5-10days
ADRs:Welltolerated,flatulence,nausea,itching&rarely
urticaria 35

36. NITAZOXANIDE
SalicylamidecongenerofAntihelminthicNiclosamide
introducedfortreatmentofGiardiasis&Cryptosporidiosis
SPECTRUM
G.lamblia
Cryptosporidiumparvum
AlsoEffectiveagainstE.Histolytica,T.Vaginalis,H.Pylori,
Ascaris
P/Ks
ProdrugconvertedtoTizoxanideafterabsorption
Glucuronideconjugated&excretedinUrine&Bile 36

37. MOA
Tizoxanide,InhibitorofPFORenzyme(essentialforelectron
transportenergymetabolisminAnaerobicorganisms)
USES
Giardiasis,AmoebicDysenteryasluminalamoebicide
MosteffectiveforCryptosporidiuminfection(88%)causing
DiarrhoeainChildren&AIDSpatients
ADRs
Mild&infrequent-Abdominalpain,vomiting&headache
Dose:500mgBDfor3days
37

38. 8-HYDROXYQUINOLONES
SPECTRUM
ActiveagainstEntamoeba,Giardia,Trichomonas,some
fungi(Dermatophytes&Candida)&Bacteria
QUINODOCHLOR
(IODOCHLOROHYDROXY
QUIN, CLIOQUINOL),
DIIODOHYDROXYQUIN
(IODOQUINOL)
38

39. 8-HYDROXYQUINOLONES
USES
AlternativetoDFinintestinalamebiasis(cheap&goodacceptability)
Giardia,localtreatmentofMonilial&TrichomonasVaginitis,Fungaland
bacterialinfections
ADRsOnceapopulardrug–butlessnowbecauseofADRs
Welltolerated–onlyNausea,transientloose&greenstools&pruritusbut
ifusedimproperlyhastoxicpotential
Iodism(furunculosis&inflammationofmucousmembrane)Goitermay
develop
•Thosesensitive-Acutereactionwithfever,chills,angioedema&
cutaneoushaemorrhages
39

40. Withprolonged/repeateduseofrelativelyhighdosescaused
aNeuropathicsyndromek/aSubacutemyelo-optic
neuropathy(SMON)
inflammation of the optic nerve
completeorpartiallossofvision&peripheralneuropathy
InIndia,prohibitedforpediatricuse(useforchronic
diarrhoeascausedblindness)
Fixeddosecombinationexceptforexternalapplication
bannedinIndia
Cautionnoteisinsertedthatuseofhighdoseformorethan
14days,maycauseNeuritis&Opticdamage
40

41. ANTIBIOTICS-TETRACYCLINE
MOA:DirectinhibitoryactiononEntamoeba
41
Older tetracyclinesabsorbed
incompletely
Larger amount reaches Colon
Inhibits bacterial flora with which
Entamoebalives symbiotically
Indirectly reduces proliferation of
Entamoeba

42. USES
Chroniccaseinconjunctionwithmoreeffaciousluminal
amoebicide
ManagementofAmoebicdysentry:Addedasthirddrug
incombinationwithNitroimidazole&aluminal
Amoebicide
42

43. PAROMOMYCIN
AminoglycosideresemblesNeomycin
SPECTRUM
E.Histolytica,G.lamblia,Cryptosporidiumparvum,T.
Vaginalis,Leishmania&sometapeworm
AntibacterialSpectrumsimilartoNeomycin
43

44. MECHANISMOFACTION
Bindingto30SribosomeinterswithProteinsynthesis
Efficaciousluminalamoebicide
P/KS
Orallyadministered-actsingutlumenonly
Neitherabsorbednordegraded
Eliminatedunchangedinfaeces
44
FREE
FROM
SYTEMIC
TOXICITY

45. USE
Asymptomaticcystpasser&ChronicAmebiccolitis
AlongwithMetronidazoleinAcuteAmebicDysentryaswell
asinHepaticAmebiasistoeradicateluminalcycle
AlternativedrugforGiardiasisespeciallyduring1
st
trimester
ofpregnancywhenMetronidazole&otherdrugsare
contraindicated
Cryptosporidiosis,efficacyuncertain
TrichomonasVaginitis&DermaLeishmaniasis-usedtopically
SIDEEFFECTS:Nausea,Vomitting,Abdominalcramps,
Diarrhoea,rarelyRashes 45

46. 46