anti-protozoal drugs

Chloroquine - pharmacokinetics

rapidly and almost completely absorbed from GI tract
rapidly distributed to the tissues
large apparent volume of distribution and is slowly released from tissues and metabolized
principally excreted in the urine

Chloroquine - MOA

acts during the erythrocytic stage of the parasite
acts by concentrating in parasite food vacuoles, preventing the polymerization heme into hemozoin and thus eliciting parasite toxicity due to buildup of free heme
resistance is common among strains of P. falciparum and P. vivax

Chloroquine - clincal uses

drug of choice in treatment of nonfalciparum and sensitive falciparum malaria
rapidly terminates fever and clears parasitemia caused by sensitive parasites
does not eliminate dormant liver forms of P. vivax and P. ovale and for that reason primaquine must be added for the radical cure of these species
preferred chemoprophylactic agent in malarious regions w/o resistant falciparum malaria

chloroquine - amebic liver abcess

chloroquine reaches high liver concentrations and may be used for amebic abscesses that fail initial therapy w/ metronidazole

Chloroquine - adverse effects

usually very well tolerated even w/ prolonged use
pruritus is common primarily in africans
uncommon side effects are nausea, vomiting, abdominal pain, headache, anorexia, and blurring of vision

Chloroquine - contraindications

patients w/ psoriasis or porphyria in whome it may precipitate acute attacks of these diseases
antidiarrheal agent kaolin and calcium and magnesium containing antacids interfere w/ absorption of chloroquine
considered safe in pregnancy and for young children

Quinine and Quinidine - pharmacokinetics

alkaloid quinine was purified from bark in 1820
IV quinidine is used in treatment of severe falciparum malaria
oral administration, quinine is rapidly absorbed reaches peak plasma level in 1-3 hours and widely distributed in body tissues
primarily metabolized in the liver and excreted in the urine

quinine - antimalarial action/resistance

rapidly acting highly effective blood schizonticide (erythrocytic stage) against the four species of malaria parasites
gametocidal against P.vivax and P. ovale but not P. falciparum
not active against liver stage parasites

quinine - clinical uses

parenteral preparations of quinine are not available in the USA
Quinidine is standard therapy in the USA for parenteral tx of sever falciparum malaria
IV quinidine should be administered w/ cardiac monitoring
oral quinine sulfate is appropriate first line therapy for uncomplicated falciparum malari if documented resistance to chloroquin is present
quinine is commonly used w/ a second drug to shorten quinine's duration of use and to limit toxicity

quinine/ quinidine - adverse effects

tinnitus, headache, nausea, dizziness, flushing, and visual disturbances ( cinchonism)
hypersensitivity reactions include skin rashes, urticaria, angioedema and bronchospasm
hypoglycemia
severe hypotension can follow too rapid intravenous infusions of quinine or quinidien
QT prolongation

quinine/ quinidine - contraindications

should be discontinued if signs of severe cinchoism, hemolysis or hypersensitivity occur
must be used w/ caution in those w/ cardiac abnomalities
quinine should not be given w/ mefloquine and should be used w/ caution in a patient who has had previous chemoprophylaxis w/ mefloquine
absorption may be blocked by aluminum - contained antacids
quinine can raise levels of warfarin and digoxin

Mefloquine - general

effective therapy for many chloroquine- resistant strains of P. falciparum and against other species
toxicity is a concern
one of the recommended chemoprophylactic drugs for use in most malaria endemic regions w/ chloroquine resistant strains

mefloquine - pharmacokinetics

can only be given orally b/c sever local irritation occurs w/ parenteral use
well absorbed
highly protein bound, extensively distributed in tissues and eliminated slowly allowing a single dose treatment
slowly excreted mainly in feces

mefloquine - anti malarial action and resistance

strong blood schizonticidal activity (erythrocytic stage) against P. falciparum and P. vivax but it is not active against hepatic stages or gametocytes
resistance appears uncommon

mefloquine - clinical uses

effective in prophylaxis against most strains of P. falciparum and all other species
effective in treating most falciparum malaria
not appropriate for treating individuals w/ severe or complicated malaria

mefloquine - adverse effects

weekly dosing for chemoprophylaxis may cause nausea, vomiting, dizziness, sleep and behavioral disturbances, epigastric pain, diarrhea, abdominal pain, headache, rash and dizziness
more common w/ higher doses required for treatment

mefloquine - contraindications

contraindicated if history of epilepsy, psychiatric disorders, arrhythmia, cardiac conduction defects or sensitivity to related drugs
should not be coadministered w/ quinine and quinidine

Primaquine - general

drug of choice for eradication of dormant liver forms of P. vivax, and P. ovale

Primaquine - pharmacokinetics

well absorbed orally
reaching peak plasma levels in 1-2 hours
widely distributed to tissues
rapidly metabolized and excreted in urine

Primaquine - antimalaria action/ resistance

active against hepatic stages of all human malaria parasites
only available agent against dormant hyponozoite stages of P. vivax and P.ovale
gametocidal against all four

primaquine - clinical uses

radical cure of acute vivax and ovale malaria
standard therapy for infections includes chloroquine to eradicate erythrocytic forms and primaquine to eradicate liver hyponzoites and prevent subsequent relapse
14 day course
should be used after completion of travel to an endemic area b/c standard chemoprophylaxis does not prevent a relapse of vivax or ovale malaria

primaquine - adverse effects

recommended doses is generally well tolerated
infrequently causes nausea, epigastric pain, abdominal cramps, and headache
more common w/ higher doses and when taken on an empty stomach

primaquine - contraindications

patients w/ history of granulocytopenia or methemoglobinemia
those receiving potentially myelosuppresive drugs
never given parenterally b/c may induce marked hypotension
patients deficient in G6PD

atovaquone

combination w/ proguanil recommended for prophylaxis
administered orally
low bioavailabilty and erratic but absorption is increased by fatty food
drug is heavily protein bound
appears to disrupt mitochondrial electron transport in plasmodia
adverse effects: fever, rash, nausea, vomiting, diarrhea, headache and insomnia

Primethamine - pharmacokinetics

inhibitor of enzymes involved in folate metabolism
related to trimethoprim
slowly but adequately absorbed from GI tract
pyrimethamine can be given for prophylaxis once a week
extensively metabolized before excretion

Proguanil -pharmacokinetics

inhibitor of enzymes involved in folate metabolism
biguaninde derivative
must be administered daily for prophylaxis
prodrug only cycloguanil (metabolite) is active

Pyrimethamine and Proguanil antimalarial action and resistance

both act slowly against erythrocytic forms of susceptible strains of all 4 malaria species
proguanil also has some acitvity against hepatic forms
neither drug has gameocidal effects or is effective against persistant liver stages of P. vivax and P.ovale

Pyrimathamine and Proguanil MOA

selectively inhibit plasmodial dihydrofolate reductase
provides synergistic activity w/ sulfonamids and sulfones which inhibit dihydropteroate synthase in the pathway

Pyrimathamine and Proguanil resistance

common for P. falciparum
less common for P. vivax
due primarily to enzyme mutations

Pyrimathamine and Proguanil
clinical uses

chloroquine and proguanil used as alternative to mefloquine
fansidar (comb. of sulfadoxine and pyrimethamine) used as presumptive treatment for travelers who develop fever while in malaria-endemic regions but not prophylaxis
Pyrimethamine w/ sulfadiazine is first-line therapy in treatment of toxoplasmosis

Pyrimathamine and Proguanil adverse effects

most tolerate both well
mouth ulcers and alopecia w/ proguanil
proguanil is considered safe in pregnancy but use w/ folate supplements

Coartem

Arthemether and Lumefantrin

Artemisinin - MOA

have an endoperoxide group that when it comes in contact w/ iron releases reactive radicals in the parasite food vacuole that damages the macromolecules in the parasite
important role in tx of multi-drug resistant P. falciparum
cannot be used as prophylactic agents
requires 2x daily dosing

Artemisinin - adverse effects

well tolerated
nausea, vomiting, diarrhea
avoided in pregnancy

antibiotics

not to be used as single agents of Tx
tetracycline and doxycyline - active against erythrocytic schizonts of all human parasites
clindamycin - slowly active against erythrocytic schizones and can be used in conjunction w/ quinine or quinidine

amebiasis

infection w/ entamoeba histolytica
can cause asymptomatic intestinal infection, mild to moderate colities, dysentery, ameboma, liver abscess

Metronidazole
Tinidazole

Metronidazole is drug of choice in treatment of extraluminal amebiasis
kills trophozoites but not cysts of E. histolytica
effectively eradicates intestinal and extraintestinal tissue infections
Tinidazole has similar activity and better toxicity profile

Pharmacokinetics of Metronidazole and tinidazole

readily absorbed and permeate all tissues by simple difussion
protein binding is low
excreted mainly in urine
plasma clearance is decreased in patients w/ impaired liver function

MOA of metronidazole and tinidazole

nitro group is reduced in anaerobic bacteria and sensitive to protozoans
reactive reduction appears responsible for antimicrobial activity

Clinical uses of metrondazole and tinidazole

amebiasis: drug of choice for all tissue infections of E. histolytica, not reliably effective against luminal parasites so must be used w/ luminal amebicide
giardiasis: metronidazole is treatment of choice, dosage is much lower and better tolerated than for amebiasis, efficacy after single treatment is 90%
trichomoniasis: metronidazole is Tx of choice, single dose is effective

Adverse effects of metronidazole and tinidazole

nausea, headache, dry mouth, metallic taste
taking w/ meal lessens GI irritation
if alcohol is ingested nausea and vomiting may occur
dosage adjusted in pts w/ sever liver or renal disease

iodoquinol

effective luminal amebicide commonly used w/ metronidazole to treat amebic infections
90% retained in intestine and excreted in feces remainder excreted in urine as glucuronides
MOA is unknown
adverse effects are infrequent and include diarrhea, anorexia, nausea, vomiting, abdominal pain, headache, rash and pruritus
should be taken w/ meals to limit GI toxicity
contraindicated in pts w/ intolerance to iodine

Paromomycin sulfate

aminoglycoside antibiotic not significantly absorbed from GI tract
used only as luminal amebicide w/ no effect against extraintestinal amebic infections
adverse effects include occasional abdominal distress, and diarrhea
should be avoided in pts w/ significant renal diesease and used w/ caution in those w/ GI ulcerations

Sodium stibogluconate

first line agent for cutaneous and visceral leishmaniasis
rapidly absorbed after IV or IM administration
Tx given once daily for 20 days in cutaneous leishmaniasis and 28 days in visceral and musculocutaneous disease
MOA is unknown
cure rates are good but resistance is increasing
toxicity increases over course of therapy
GI symptoms, fever, headache, myalgia, arthralgia, and rash
IM injections can be painful and lead to sterile abscesses
ECG - QT prolongation and T wave changes