Dr. RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSORDEPT. OF PHARMACOLOGYSSIMS & RC.

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

5

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

THANK YOUDownload slides from

Authorstream-raghuprasadaSlideshare-raghuprasada

Youtube-raghuprasada