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Protozoa are eukaryotes and unicellular organisms.Most of the protozoal infections are due to unhygienicconditions.Less easily treated than bacterial infections andantiprotozoal drugs are more toxic.Protozoal infections may be one or more infectionresults from the following:Amoebiasis, trypanosomiasis, giardiasis, leishmaniasis,trichomoniasis, Malaria, toxoplasmosis.
PROTOZOAL INFECTIONS
Plasmodium species which infecthumans
Plasmodium vivax (tertian):
Plasmodium ovale (tertian)
Plasmodium falciparum (M.tertian)
Plasmodium malariae (quartan)
Sporogeny(sexual)
Schizogony(asexual)
Man : IntermediatehostMosquito :Definitive host
True causal prophylactics
CAUSALPROPHYLACTICS
SUPRESSIVES
GAMETOCIDAL
SPORONTICIDE
4 Aminoquinolines:CHLOROQUINE, HYDROXYCHLOROQUINE,AMODIAQUINE, PIPERAQUINE
8 Aminoquinolines:PRIMAQUINE, TAFENOQUINE, BULAQUINE
Cinchona alkaloids:QUININE, QUINIDINE
Quinoline methanol: MEFLOQUINEBiguanides: PROGUANIL, CHLORPROGUANIL
Diaminopyrimidines: PYRIMETHAMINESulfonamides: SULFADOXINE, DAPSONEAntibiotics: TETRACYCLINE, DOXYCYCLINE,
CLINDAMYCINNaphthoquinone: ATOVAQUONESesquiterpene lactones: ARTESUNATE, ARTEMETHER,
ARTEETHER, ARTEROLANEAmino-alcohols: HALOFANTRINE, LUMIFANTRINENaphthyridine: PYRONARIDINE
Synthesized by Germans in 1934 ( resochin)d & l isomers, d isomer is less toxicCl at position 7 confers maximal antimalarial efficacyAntimalarial activity:High against erythrocytic forms of vivax, ovale,malariae & sensitive strains of falciparumGametocytes of vivax
Hemoglobin Globin utilized bymalarial parasite
Heme (highly toxic for malaria parasite)ChloroquineQuinine, (+) Heme PolymerasemefloquineLumifantrinepyronaridine (-)
Hemozoin (Not toxic to plasmodium)
Other parasitic infections:Giardiasis, taeniasis, extrainstestinal amoebiasis
Other actions:Depressant action on myocardium, direct relaxant effecton vascular smooth muscles, anti-inflammatory,antihistaminic , local anaestheticResistance develops due to efflux mechanism
Well absorbed, tmax 2-3 hrs , 60 % protein boundConcentrated in liver , spleen, kidney, lungs , leucocytesSelective accumulation in retina: ocular toxicityT1/2 = 3-10 days increases from few days to weeks
Chloroquine is administered in loadingdose in malaria
Chloroquine is well absorbed after oral administration.It is extensively tissue bound and sequestrated bytissues particularly liver, spleen, kidney it has got largeapparent volume of distributionSo it is given in loading dose to rapidly achieve theeffective plasma conc.600 mg of base stat300 mg base after 8 hours150 mg of base BD for 2 days200 mg oral tablet of chloroquine phosphate consistsof 150 mg base
Intolerance:Nausea, vomiting, anorexiaskin rashes, angioneurotic edema, photosensitivity,pigmentation, exfoliative dermatitis'sLong term therapy may cause bleaching of hairRarely thrombocytopenia, agranulocytosis,pancytopenia
Ocular toxicity: High dose prolonged therapyTemporary loss of accommodationLenticular opacities, sub capsular cataractRetinopathy: constriction of arteries, edema, blueblack pigmentation , constricted field of vision.
CNS: Insomnia, transient depression seizures,rarely neuromyopathy & ototoxicity
CVS: ST & T wave abnormalities, abrupt fall in BP &cardiac arrest in children reported
Hepatic Amoebiasis:GiardiasisClonorchis sinensisRheumatoid arthritisDiscoid Lupus ErythematosusControl manifestation of lepra reactionInfectious mononucleosis
HYDROXY CHLOROQUINE:Less toxic, properties &uses similar
AMODIAQUINE:As effective as chloroquinePharmacological actions similarChloroquine resistant strains may be effectiveAdverse events: GIT, headache , photosensitivity,rarely agranulocytosisNot recommended for prophylaxis
Pyronaridine: effective in resistant cases
4 AMINOQUINOLINES:
1820 Pelletier & caventou isolated quinine fromcinchona bark.Mechanism of action:Similar to chloroquinePharmacokinetics-Administered orally is completelyabsorbedTmax = 1-3 hrs , crosses placental barrierMetabolized in liver degradation products excreted inurine t ½ = 10 hrs
Antimalarial action:Erythrocytic forms of all malarial parasites includingresistant falciparum strains .Gametocidal for vivax & malariae
Local irritant effect: Local pain sterile abscess.3. Cardiovascular: depresses myocardium, ↓ excitability,↓ conduc vity, ↑ refractory period, profoundhypotension IV.4. Miscellaneous actions: Mild analgesic, antipyreticactivity , stimulation of uterine smooth muscle, curaremimetic effect
Malaria:uncomplicated resistant falciparum malariaCerebral malarial
Myotonia congenita: 300 to 600 mg BD/ TDSNocturnal muscle cramps: 200 – 300 mg before
sleepingSpermicidal in vaginal creamsVaricose veins: along with urethane causes thrombosis& fibrosis of varicose vein mass
Cinchonism:Tinnitus, nausea & vomitingHeadache mental confusion, vertigo, difficulty inhearing & visual disturbancesDiarrhoea , flushing & marked perspirationStill higher doses , exaggerated symptoms withdelirium, fever, tachypnoea, respiratory depression ,cyanosis.
Idiosyncrasy : similar to Cinchonism but occurs intherapeutic dosesCardiovascular toxicity: cardiac arrest, hypotensionfatal arrhythmiasBlack water feverHypoglycemia
Primaquine-Converted to electrophiles Generatesreactive oxygen speciesLiver HypnozoitesWeak action against erythrocytic stage of vivax, soused with suppressive in radical cureNo action against erythrocytic stage of falciparumHas gametocidal action and is most effectiveantimalarial to prevent transmission disease against all4 species
Readily absorbed,t1/2 = 3-6 hrs
Oxidized in liverexcreted in urineUses-Primary use is radical cure of relapsing malaria 15mg daily for 14 days with dose of chloroquineFalciparum malaria 45 mg of single dose withchloroquine curative dose to kill gametes & cut downtransmission of malaria.
Gastrointestinal:epigastric distress, abdominalcramps ,
Hemopoetic:mild anemia,methaemoglobinemia,cyanosis, hemolytic anemia inG6PD deficiency
Avoided during pregnancy, G6PDdeficient
Tafenoquine:More active slowly metabolized analog ofprimaquine, has advantage that it can be given onweekly basis.
Bulaquine:Congener of primaquine developed in IndiaComparable antirelapse activity when used for 5daysPartly metabolized to primaquineBetter tolerated in G6PD deficiency
Tafenoquine and Bulaquine
Quinoline methanol derivative developed to deal withchloroquine resistant malariaRapidly acting erythrocytic schizonticide , slower thanchloroquine & quinineEffective against chloroquine sensitive & resistantplasmodiaMechanism of action similar to chloroquineNeither gametocidal, nor kills Hypnozoites
Good but slow oral absorptionHigh protein bindingConcentrated in liver, lung, intestineExtensive metabolism in liver, primarily secreted in
bile , under goes enterohepatic circulationLong t1/2 = 2 – 3 weeks
Effective drug for MDR falciparumT/t of uncomplicated falciparum in MDR malariashould be used along with Artesunate (ACT)Prophylaxis in MDR areas 250 mg per week started 2-3 weeks before to assess side effects
Due to fear of drug resistance mefloquine should notbe used as drug for prophylaxis in residents of endemicarea
GIT: bitter in taste, nausea, vomiting , abdominal pain ,diarrhoeaNeuropsychiatric disturbances: anxiety, hallucinations,
sleep disturbances, psychosis, errors in operatingmachinery, convulsionsCVS: Bradycardia, sinus arrhythmia, & QT prolongationTeratogenicity: Avoided in first trimesterMiscellaneous: allergic skin reactions, hepatitis & blooddyscrasias
Quinoline methanolUsed in chloroquine resistant malaria since 1980Erratic bioavailabilty, lethal cardiotoxicity & crossresistance to mefloquine limited its useNow a days used only when no other alternativeavailableAdverse events; Nausea, vomiting, QT prolongation ,diarrhoea, itching , rashesC/I: along with quinine, chloroquine, antidepressants,antipsychotics.
Synthetic naphthoquinoneRapidly acting erythrocytic schizonticide forplasmodium falciparum & other plasmodiaMOA: Collapses mitochondrial membrane & interferesATP productionProguanil potentiates action of atovaquone andprevents development of resistanceAlso used in P. Jiroveci & Toxoplasma gondi infections
Proguanil :Biguanide converted to cycloguanil active compoundAct slowly on erythrocytic stage of vivax &falciparumPrevents development of gametes
Adverse effects:Stomatitis, mouth ulcers, larger doses causedepression of myocardium, megaloblastic anemia
Not a drug for acute attackCausal prophylaxis: 100 – 200 mg daily
Pyrimethamine is diaminopyrimidine more potent thanproguanil & effective against erythrocytic forms of allspeciesInhibits dihydrofolate reductase enzymeTasteless so suitable for childrenUsed in uncomplicated chloroquine resistant malariaSulfadoxine(1500mg)+ Pyrimethamine(75mg)-single doseAdverse events: sulfa related
megaloblastic anemia, thrombocytopenia,agranulocytosis.
Artemisinin is the active principle of the plantArtemisia annuaSesquiterpene lactone derivativeMost potent and rapid acting blood schizonticidesShort duration of actionPoorly soluble in water & oil
ArtesunateArtemetherArteetherArterolane
These compounds have presence of endoperoxidebridgeEndoperoxide bridge interacts with heme in parasiteHeme iron cleaves this endoperoxide bridgeThere is generation of highly reactive free radicalswhich damage parasite membrane by covalentlybinding to membrane proteins
MOA-2) Artemisinin free radicals specifically inhibit a plasmodialsarcoplasmic-endoplasmic calcium ATPase
Water soluble ester of dihydroartemisininDose: can be given oral, IM,IV, rectal t1/2- 1-2hrsOral -100 mg BD on day 1, 50 mg BD day 2 to day 5Parenteral-120 mg on day 1 (2.4 mg/kg BD )
60 mg OD ( 2.4 mg/kg) for 7 days
Artemisinin
Artemisinin
ConventionalTreatment
Methyl ether of dihydroartemisininConverted to DHA-dihydroartemisinin, not given IV, t1/2-3-10hrsDose: Oral & IM-80 mg BD on day 1 (3.2 mg/kg)
80 mg OD (1.6 mg/kg) for 7 daysARTEETHER –Ethyl ether of dihydroartemisininTherapeutically equivalent to quinine in cerebral malariaA longer t1/2 & more lipophilic than artemether favoringaccumulation in brainGiven IM only T1/2-23hrsDose:3.2 mg/kg on day1 followed by 1.6 mg/kg daily for next 4daysARTEROLANE-available for oral use only in combination
LeucopeniaHypersensitivity: Drug fever, itchingGIT: nausea, vomiting, abdominal pain (common)ECG changes: ST-T changes, QT prolongationAbnormal bleeding, dark urineReticulocytopeniaD/I-concurrent administration with astemizole,antiarrhythmics, tricyclic antidepressants andphenothiazines increase the risk of cardiac conductiondefects
Artemisinin compounds are shorter acting drugsMonotherapy needs to be extended beyonddisappearance of parasite to prevent recrudescenceThis can be prevented by combining 3-5 day regimen ofArtemisinin compounds with one long acting drug likemefloquine 15 mg/kg single doseIndicated by WHO in acute uncomplicated resistantfalciparum malariaRapid clinical & parasitological cureHigh cure rates and low relapse rates
There are now more trials involving Artemisinin and its derivatives thanother antimalarial drugs, so although there are still gaps in ourknowledge, there is a reasonable evidence base on safety and efficacyfrom which to base recommendations.
Combinations which have been evaluated:
piperaquineArtemisinin +mefloquine
Artesunate +
piperaquinedihydroartemisinin +mefloquine
lumefantrineartemether +mefloquine
naphthoquine
chloroquineamodiaquinesulfadoxine-pyrimaethamininemefloquineproguanil-dapsonechlorproguanil-dapsoneatovaquone-proguanilclindamycintetracyclinedoxycycline
Indication:Duration :1-2 weeks before to 4 weeks afterreturning from endemic areaDrug regimens:
Chloroquine sensitive malaria: 300 mg / weekChloroquine resistant malaria:
Mefloquine 250 mg once a week ,Doxycycline 100 mg daily ,Atovaquone + Proguanil daily
Quinine ,Artemisinin compoundsPyrimethamine sulfadoxineAmodiaquine
Drugs used in chloroquine resistant malariaMefloquineQuinineSulfadoxine pyrimethamineArtemisinin compounds
Lumefantrine is highly effective, long acting oralerythrocytic schizonticide related to mefloquineMOA- similar to chloroquine-also affects nucleic acid and protein synthesis of parasiteFatty food increases absorptionHighly lipophilic onset delayed ,peak 6 hrsAvailable as fixed dose combination80 mg artemether bd with 480 mg lumefantrine bd for 3days
Tetracyclines and doxycyclineSlow but potent action on erythrocytic stage of all MP& Pre-erythrocytic stage of falciparumAlways used in combination with quinine or S-P fortreatment of chloroquine resistant malariaCLINDAMYCINBacteriostatic antibiotic, erythrocytic schizontocidePotentiates the action of quinine and artemisinin
Tab. Chloroquine phosphate 250 mgContains 150 mg of baseGive 4 tablets stat , 2 tablets after 8 hours and , 1tablet BD for 2 days
Patients who cannot take orally3.5 mg/kg IM every 6 hrs for 3 days
Tab primaquine 15 mg OD for 14 days in Plasmodiumvivax, ovalePrimaquine 45 mg single dose for falciparum afterchloroquine (gametocidal)
Pts who can take orally:3 tablets of (Pyrimethamine + sulfadoxine) single dosefollowed by quinine 600 mg TDS for 2 days orTab Quinine 600 mg TDS X 3 days with Capdoxycycline 100 mg BD for 7 days orQuinine 3 days with mefloquine or(Atovaquone 250 mg + Proguanil 100 mg) 4 tab(Singledose ) for 3 days orArtesunate 100 mg BD x 3 days with Sulfadoxine-Pyrimethamine or mefloquine
Pts who cannot take orallyInj Quinine Hcl 20 mg/kg in 500 ml dextrose salineover 4 hrs then10 mg/kg in dextrose saline over 2 hrs every 8 hrlytill patient is able to swallowThen quinine 600 mg TDS for 7 days & tetracycline/doxycycline
OrArtemether / Arteether injection
Chloroquine resistant malaria
Artesunate 2.4 mg/kg IV/IM, BD on day1 then 2.4mg/kg daily for 7 days ORArtemether 3.2 mg/kg IM on day 1 then 1.6 mg/kgdaily for 7 days ORArteether 3.2 mg/kg IM on day1, followed by 1.6mg/kg daily for next 4 daysSwitchover to 3 Day oral ACT in between wheneverpatient can take oral medication
Quinine: 20 mg quinine salt/kg on admission(i.v. infusion in 5% dextrose/dextrose saline over aperiod of 4 hours) followed by maintenance dose of 10mg/kg body weight 8 hourly.
When ever patient can swallow orally switch over tooral quinine 10 mg/kg 8 hrly and complete 7 dayscourse
Quinine parenteral high toxicity / oral well toleratedPrimaquine avoided in neonatesMefloquine not used in children below 15 kg weight
Acute malaria in pregnant womenChloroquine in usual dosesMefloquine C/I in first trimesterPrimaquine/ tetracycline avoidedAnemia: folic acid & iron
Malaria in children