PROTOZOAL INFECTIONS

Protozoa are eukaryotes and unicellular organisms. Most of the

protozoal infections are due to unhygienic conditions. Less
easily treated than bacterial infections and antiprotozoal drugs
are more toxic. Protozoal infections may be one or more
infection results from the following: Amoebiasis,
trypanosomiasis, giardiasis, leishmaniasis, trichomoniasis,
Malaria, toxoplasmosis.
Plasmodium species which infect humans Plasmodium
vivax (tertian): Plasmodium ovale (tertian)
Plasmodium falciparum (M.tertian) Plasmodium
malariae (quartan)
4 Aminoquinolines:
CHLOROQUINE, HYDROXYCHLOROQUINE, AMODIAQUINE,
PIPERAQUINE
8 Aminoquinolines:
PRIMAQUINE, TAFENOQUINE, BULAQUINE
Cinchona alkaloids:
QUININE, QUINIDINE Quinoline methanol: MEFLOQUINE
Biguanides: PROGUANIL, CHLORPROGUANIL
Diaminopyrimidines: PYRIMETHAMINE Sulfonamides:
SULFADOXINE, DAPSONE Antibiotics: TETRACYCLINE,
DOXYCYCLINE,
 CLINDAMYCIN Naphthoquinone: ATOVAQUONE
Sesquiterpene lactones: ARTESUNATE, ARTEMETHER,
ARTEETHER, ARTEROLANE Amino-
alcohols: HALOFANTRINE, LUMIFANTRINE Naphthyridine:
PYRONARIDINE
Synthesized by Germans in 1934 ( resochin) d & l isomers, d
isomer is less toxic Cl at position 7 confers maximal antimalarial
efficacy Antimalarial activity: High against erythrocytic forms of
vivax, ovale,
malariae & sensitive strains of falciparum
Gametocytes of vivax
Hemoglobin

Globin utilized by malarial parasite

Heme (highly toxic for malaria parasite)

Chloroquine Quinine, (+) Heme Polymerase mefloquine
Lumifantrine

Hemozoin (Not toxic to plasmodium)

Other parasitic infections: Giardiasis, taeniasis, extrainstestinal
amoebiasis Other actions: Depressant action on myocardium,
direct relaxant effect
on vascular smooth muscles, anti-inflammatory,
antihistaminic , local anaesthetic Resistance develops due to
efflux mechanism
Well absorbed, tmax 2-3 hrs , 60 % protein bound
Concentrated in liver , spleen, kidney, lungs , leucocytes
Selective accumulation in retina: ocular toxicity T1/2 = 3-10
days increases from few days to weeks Chloroquine is well
absorbed after oral administration. It is extensively tissue
bound and sequestrated by tissues particularly liver, spleen,
kidney it has got large apparent volume of distribution
So it is given in loading dose to rapidly achieve the
effective plasma conc.
600 mg of base stat
300 mg base after 8 hours
150 mg of base BD for 2 days
200 mg oral tablet of chloroquine phosphate consists
of 150 mg base Intolerance:
Nausea, vomiting, anorexia
skin rashes, angioneurotic edema, photosensitivity,
pigmentation, exfoliative dermatitis's
Long term therapy may cause bleaching of hair
Rarely thrombocytopenia, agranulocytosis,
pancytopenia
Ocular toxicity: High dose prolonged therapy Temporary loss of
accommodation Lenticular opacities, sub capsular cataract
Retinopathy: constriction of arteries, edema, blue
black 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: Giardiasis Clonorchis sinensis
Rheumatoid arthritis Discoid Lupus Erythematosus Control
manifestation of lepra reaction Infectious mononucleosis
4 AMINOQUINOLINES:

HYDROXY CHLOROQUINE:
Less toxic, properties &uses similar
AMODIAQUINE:
As effective as chloroquine Pharmacological actions similar
May be effective in Chloroquine resistant strains
Adverse events: GIT, headache , photosensitivity,
rarely agranulocytosis Not recommended for
prophylaxis Pyronaridine: effective in resistant
cases
1820 Pelletier & caventou isolated quinine from cinchona bark.
Mechanism of action: Similar to chloroquine General
protoplasmic poison Pharmacokinetics-Administered orally is
completely absorbed Tmax = 1-3 hrs , crosses placental barrier
Metabolized in liver degradation products excreted in urine t
= 10 hrs
Antimalarial action:
Erythrocytic forms of all malarial parasites including
resistant falciparum strains . Gametocidal for vivax &
malariae
Local irritant effect: Local pain sterile abscess.
3. Cardiovascular: depresses myocardium, excitability,
conduc vity, refractory period, profound hypotension IV.
4. Miscellaneous actions: Mild analgesic, antipyretic activity ,
stimulation of uterine smooth muscle, curare mimetic effect
Malaria: uncomplicated resistant falciparum malaria Cerebral
malarial
Myotonia congenita: 300 to 600 mg BD/ TDS
Nocturnal muscle cramps: 200 300 mg before sleeping
Spermicidal in vaginal creams Varicose veins: along with
urethane causes thrombosis & fibrosis of varicose vein mass
 Cinchonism: (resembles salicylism) Tinnitus, nausea &
vomiting Headache mental confusion, vertigo, difficulty in
hearing & visual disturbances Diarrhoea , flushing & marked
perspiration Still higher doses , exaggerated symptoms with
delirium, fever, tachypnoea, respiratory depression , cyanosis.
Idiosyncrasy : similar to Cinchonism but occurs in therapeutic
doses-pruritis, urticaria, hemolytic anemia and agranulocytosis
Cardiovascular toxicity: cardiac arrest, hypotension fatal
arrhythmias Hypoglycemia

Black water fever-intravascular hemolysis,

hemoglobinuria, fever and acute renal failure
Primaquine-Converted to electrophiles Generates
reactive oxygen species Liver Hypnozoites Weak
action against erythrocytic stage of vivax, so used
with suppressive in radical cure No action against
erythrocytic stage of falciparum Has gametocidal
action and is most effective antimalarial to prevent
transmission disease against all 4 species Readily
absorbed,
t1/2 = 3-6 hrs Oxidized in liver excreted in urine Uses-Primary
use is radical cure of relapsing malaria 15 mg daily for 14 days
with dose of chloroquine Falciparum malaria 45 mg of single
dose with chloroquine curative dose to kill gametes & cut
down transmission of malaria.
Gastrointestinal: epigastric distress, abdominal
cramps , Hemopoetic: mild anemia,
methaemoglobinemia, cyanosis, hemolytic
anemia in G6PD deficiency Avoided during
pregnancy, G6PD deficient
Tafenoquine and Bulaquine

Tafenoquine: More active slowly metabolized analog of

primaquine, has advantage that it can be given on weekly
basis. Tried for radical cure in 3 days
Bulaquine: Congener of primaquine developed in India
Comparable antirelapse activity when used for 5
days Partly metabolized to primaquine Better tolerated in
G6PD deficiency
Quinoline methanol derivative developed to deal with
chloroquine resistant malaria and MDR-Muti Drug resistant
species Rapidly acting erythrocytic schizonticide, slower than
chloroquine & quinine Mechanism of action similar to
chloroquine Neither gametocidal, nor kills Hypnozoites Good
but slow oral absorption High protein binding Concentrated in
liver, lung, intestine
Extensive metabolism in liver, primarily secreted in bile , under
goes enterohepatic circulation Long t1/2 = 2 3 weeks
Caution-minimum of 12hr interval after quinine administration
as both are cardiotoxic Effective drug for MDR falciparum
 T/t of uncomplicated falciparum in MDR malaria should 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 not be used as drug for
prophylaxis in residents of endemic area GIT: bitter in taste,
nausea, vomiting , abdominal pain , diarrhoea
 Neuropsychiatric disturbances: anxiety, hallucinations, sleep
disturbances, psychosis, errors in operating machinery,
convulsions CVS: Bradycardia, sinus arrhythmia, & QT
prolongation Teratogenicity: Avoided in first trimester
Miscellaneous: allergic skin reactions, hepatitis & blood
dyscrasias Quinoline methanol Used in chloroquine resistant
malaria since 1980 Erratic bioavailabilty, lethal cardiotoxicity &
cross resistance to mefloquine limited its use Now a days used
only when no other alternative available can act against
chloroquine, quinine and pyrimethamine resistant strains
Adverse events; Nausea, vomiting, QT prolongation , diarrhoea,
itching , rashes C/I: along with quinine, chloroquine,
antidepressants, antipsychotics.
Synthetic naphthoquinone Rapidly acting erythrocytic
schizonticide for plasmodium falciparum & other plasmodia
MOA: Collapses mitochondrial membrane & interferes ATP
production Proguanil potentiates action of atovaquone and
prevents development of resistance Also used in P. Jiroveci &
Toxoplasma gondi infections
Proguanil : Biguanide converted to cycloguanil active
compound Act slowly on erythrocytic stage of vivax &
falciparum Prevents development of gametes Adverse effects:
Stomatitis, mouth ulcers, larger doses cause depression of
myocardium, megaloblastic anemia Not a drug for acute attack
Causal prophylaxis: 100 200 mg daily
Pyrimethamine is diaminopyrimidine more potent than
proguanil & effective against erythrocytic forms of all species,
toxoplasmosis, polycythemia vera Inhibits dihydrofolate
reductase enzyme Tasteless so suitable for children Used in
uncomplicated chloroquine resistant malaria
Sulfadoxine(1500mg)+ Pyrimethamine(75mg)-single dose
Adverse events: sulfa related megaloblastic
anemia, thrombocytopenia, agranulocytosis.
Artemisinin is the active principle of the plant Artemisia annua
Sesquiterpene lactone derivative Most potent and rapid acting
blood schizonticides Short duration of action Poorly soluble in
water & oil
Artesunate Artemether Arteether Arterolane
These compounds have presence of endoperoxide bridge
Endoperoxide bridge interacts with heme in parasite Heme iron
cleaves this endoperoxide bridge There is generation of highly
reactive free radicals which damage parasite membrane by
covalently binding to membrane proteins
 Conventional
Treatment

MOA-Artemisinin 2) Artemisinin free radicals specifically inhibit a

plasmodial sarcoplasmic-endoplasmic calcium ATPase
Water soluble ester of dihydroartemisinin Dose: can be given
oral, IM,IV, rectal t1/2-1-2hrs Oral -100 mg BD onday 1, 50 mg
BD day 2 to day 5 Parenteral-120 mg on day 1 (2.4 mg/kg BD )
60 mg OD ( 2.4 mg/kg) for 7 days
Methyl ether of dihydroartemisinin Converted to DHA-
dihydroartemisinin, not given IV, t1/2-3-10hrs Dose: Oral & IM-80
mg BD on day 1 (3.2 mg/kg)
80 mg OD (1.6 mg/kg) for 7 days
ARTEETHER
Ethyl ether of dihydroartemisinin Therapeutically equivalent to
quinine in cerebral malaria A longer t1/2 & more lipophilic than
artemether favoring
accumulation in brain
Given IM only T1/2-23hrs
Dose:3.2 mg/kg on day1 followed by 1.6 mg/kg daily for next 4 days
ARTEROLANE-available for oral use only in combination
Leucopenia Hypersensitivity: Drug fever, itching GIT: nausea,
vomiting, abdominal pain (common) ECG changes: ST-T
changes, QT prolongation Abnormal bleeding, dark urine
Reticulocytopenia D/I-concurrent administration with
astemizole, antiarrhythmics, tricyclic antidepressants and
phenothiazines increase the risk of cardiac conduction defects
Artemisinin compounds are shorter acting drugs Monotherapy
needs to be extended beyond disappearance of parasite to
prevent recrudescence This can be prevented by combining 3-5
day regimen of Artemisinin compounds with one long acting
drug like mefloquine 15 mg/kg single dose Indicated by WHO
in acute uncomplicated resistant falciparum malaria Rapid
clinical & parasitological cure High cure rates and low relapse
rates
 Combinations which have been evaluated:
mefloquine Artemisinin +

piperaquine mefloquine
Artesunate +

artemether +

lumefantrine

mefloquine dihydroartemisinin +
piperaquine naphthoquine
chloroquine amodiaquine sulfadoxine

pyrimaethaminine mefloquine proguanil-dapsone chlorproguanil-dapsone atovaquone-proguanil

clindamycin tetracycline doxycycline
There are now more trials involving Artemisinin and its derivatives than other
antimalarial drugs, so although there are still gaps in our knowledge, there is a
reasonable evidence base on safety and efficacy from which to base
recommendations.
Indication: Duration :1-2 weeks before to 4 weeks after
returning from endemic area Drug regimens:
Chloroquine sensitive malaria: 300 mg / week
Chloroquine resistant malaria: Mefloquine 250 mg once a
week , Doxycycline 100 mg daily , Atovaquone + Proguanil
daily
Quinine , Artemisinin compounds Pyrimethamine sulfadoxine
Amodiaquine

Drugs used in chloroquine resistant malaria

Mefloquine Quinine Sulfadoxine pyrimethamine Artemisinin
compounds Lumefantrine is highly effective, long acting oral
erythrocytic schizonticide related to mefloquine MOA-similar
to chloroquine -also affects nucleic acid and protein synthesis
of parasite Fatty food increases absorption Highly lipophilic
onset delayed , peak 6 hrs Available as fixed dose combination
80 mg artemether bd with 480 mg lumefantrine bd for 3 days
Tetracyclines and doxycycline
Slow but potent action on erythrocytic stage of all MP & Pre-
erythrocytic stage of falciparum Always used in combination
with quinine or S-P for treatment of chloroquine resistant
malaria
CLINDAMYCIN
Bacteriostatic antibiotic, erythrocytic schizontocide
Potentiates the action of quinine and artemisinin
Tab. Chloroquine phosphate 250 mg Contains 150 mg of base
Give 4 tablets stat , 2 tablets after 8 hours and , 1
tablet BD for 2 days Patients who cannot take orally
3.5 mg/kg IM every 6 hrs for 3 days Tab primaquine 15 mg
OD for 14 days in Plasmodium vivax, ovale Primaquine 45 mg
single dose for falciparum after chloroquine (gametocidal) Pts
who can take orally:
3 tablets of (Pyrimethamine + sulfadoxine) single dose
followed by quinine 600 mg TDS for 2 days or Tab Quinine
600 mg TDS X 3 days with Cap
doxycycline 100 mg BD for 7 days or Quinine 3 days with
mefloquine or (Atovaquone 250 mg + Proguanil 100 mg) 4
tab(Single
dose ) for 3 days or Artesunate 100 mg BD x 3 days with
Sulfadoxine-Pyrimethamine or mefloquine
Chloroquine resistant malaria
Pts who cannot take orally
Inj Quinine Hcl 20 mg/kg in 500 ml dextrose saline over 4
hrs then 10 mg/kg in dextrose saline over 2 hrs every 8
hrly
till patient is able to swallow Then quinine 600 mg TDS for 7
days & tetracycline/ doxycycline Or Artemether / Arteether
injection
Artesunate 2.4 mg/kg IV/IM, BD on day1 then 2.4 mg/kg daily
for 7 days OR Artemether 3.2 mg/kg IM on day 1 then 1.6
mg/kg daily for 7 days OR Arteether 3.2 mg/kg IM on day1,
followed by 1.6 mg/kg daily for next 4 days Switchover to 3 Day
oral ACT in between whenever patient can take oral
medication
Quinine: 20 mg quinine salt/kg on admission
(i.v. infusion in 5% dextrose/dextrose saline over a period of 4
hours) followed by maintenance dose of 10 mg/kg body weight
8 hourly.
When ever patient can swallow orally switch over to oral
quinine 10 mg/kg 8 hrly and complete 7 days course
 Malaria in children

Quinine parenteral high toxicity / oral well tolerated

Primaquine avoided in neonates Mefloquine not used in
children below 15 kg weight

Acute malaria in pregnant women

Chloroquine in usual doses Mefloquine
C/I in first trimester Primaquine/
tetracycline avoided Anemia: folic acid &
iron
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