ANTIPROTOZOANS

(a)Specific antimalarial agents

• Malarial parasite undergoes a primary developmental stage in liver(pre-
erythrocytic stage;responsible for the cause of malaria and then it enters
the RBCs (erythrocytic stage;responsible for symptoms).
• Plasmodium may give rise to gametes in the blood which can be taken up
by the female anopheles(responsible for transmission of malaria.
• Some schizonts remain dormant in the liver and this dormant hepatic
stage is responsible for relapses of malaria(exo-erythrocytic).Exo-
erythrocytic stage is absent in P.falciparum ,so relapses do not occur
DRUG CLASSIFICATION

i. Primary tissue schizonticides.They are drugs that kill schizonts in the

liver(Pre-erythrocytic stage).They include:proguanil,primaquine and
pyrimethamine.Used for causal prophylaxis
ii. Erythrocytic schizonticides.These drugs kill schizonts in the blood and
can be used for treatment of acute attacks as well as suppressive
prophylaxis of malaria. They
include :chloroquine,mepacrine,atovaquone,mefloquine, artemisinin
derivatives,proguanil,pyrimethamine,sulfonamides and tetracyclines.
iii. Exoerythrocytic schizonts.Used for radical cure eg primaquine
iv . Sporonticides or gametocides .These drugs kill the gametes and thus
prevent transmission of malaria.Chloroquine,mepacrine and quinine kill the
gametes of P.vivax only .
Pyrimethamine,proguanil,primaquine and artemisinin kill gametes of
P.vivax as well as P.falciparum
Primaquine

 It is an 8 aminoquinolone.
 It is an oral antimalarial drug
MOA
Metabolites of primaquine are believed to act as oxidants that are
responsible for the schizonticidal action as well as for the hemolysis and
methemoglobenemia encountered as toxicities.
CLINICAL USES
(i)Radical cure of acute vivax and ovale malaria
(ii)Terminal prophylaxis of vivax and ovale malaria
(iii)Chemoprophylaxis of malaria
(iv)Gametocidal action
(v)Pneumocytis jirovecii infection.The combination of clindamycin and
primaquine is an alternative regimen of pneumocytosis.
Adverse effects
(a) Associated with drug induced hemolytic anemia in pts with glucose 6
phosphate dehydrogenase deficiency
(b) Large doses of the drug may cause abdominal discomfort and
occasional methemoglobinemia
CHLOROQUINE

 It is a 4 aminoquinoline
MOA
The drug acts by concentrating in parasite food vacuoles,preventing the
biocyrstallization of the hemoglobin breakdown product,heme,into
hemozoin and thus eliciting parasite toxicity due to the buildup of free
heme.
CLINICAL USES
(i)Treatment of uncomplicated and sensitive falciparum malaria.It has been
replaced by other drugs,principally artemisinin -based combination.
ii)Chemoprophylaxis .It is the preferred chemoprophylactic agent in
malarious region without resistant falciparum malaria
(iii)Amebic liver abscess.It reaches high liver concentration and may be
used for amebic abscess that fail initial therapy.
Adverse effects
(i)Pruritus
(ii)Blurred vision
(iii)Discoloration of the nail beds and mucous membranes may be seen on
chronic administration
(iv)Headache
NB
Patients with psoriasis or porphyria should not be treated with chloroquine
Chloroquine should be used cautiously in patients with hepatic
dysfunction,severe gastrointestinal problems or neurological disorders.
Chloroquine can prolong QT interval and use of drugs that also cause QT
prolongation should be avoided.
Atovaquone-proguanil

 It is effective for chloroquine resistant strains of P.falciparum.

 It is also used in the prevention and treatment of malaria.
MOA
Atovaquone inhibits mitochondrial processes such as electron transport,as
well as ATP and pyrimidine biosynthesis.
Cycloguanil,the active metabolite of proguanil inhibits plasmodial
dihydrofolate reductase,thereby preventing DNA synthesis
Adverse effects
Nausea,vomiting,headache,abdominal pain,anorexia and dizziness.
Mefloquine

 Synthetic 4 quinoline methanol that is chemically related to quinine.

 It is effective therapy for many chloroquine resistant strains of
P.falciparum and against other species.
MOA
Its exact mechanism of action remains undetermined.
Adverse effects
At high doses it causes nausea,vomiting and dizziness to
disorientation ,hallucinations and depression.
 Because of the potential for neuropsychiatric reactions,mefloquine iss
usually reserved for treatment of malaria when other agents cannot be
used
 ECG abnormalities and cardiac arrest are possible if mefloquine is taken
concurrently with quinine or quinidine.
Quinine

 Isolated from Cinchona tree.

 It interferes with heme polymerization,resulting in death of erythrocytic
form of plasmodium parasite.
CLINICAL USES
(i)Parenteral treatment of severe falciparum malaria(intravenous
artesunate is now preferred)
(ii)Oral treatment of falciparum malaria.Quinine is usually administered
with doxycycline,or clindamycin to shorten duration of use and limit
toxicity.
Quinine is not generally used to treat non-falciparum malaria.
Adverse effects
(i) Cinchonism.A syndrome causing nausea,vomiting,tinnitus and vertigo.
(ii) Hemolytic anaemia.Therapeutic doses may cause hypoglycemia
through stimulation of insulin release.
(iii) Black water fever,is a rare severe illness that includes marked
hemolysis and hemoglobinura in the setting of quinine therapy for
malaria.It appears to be due to a hyperactivity reaction to the drug.
 Drug interactions include potentiation of NMJ blocking agents and
elevation of digoxin levels if taken concurrently.
Artemisinin

 A sesquiterpene lactone endoperoxidase.

MOA
The antimalarial activity of artemisinins appear to result from the
production of free radicals that follows the iron-catalyzed cleavage of the
artemisinin endoperoxide bridge.
 Artemisinins and its derivatives are recommended first line agents for
the treatment of multidrug resistant P. falciparum malaria.
 To prevent the development of resistance ,these agents should not be
used alone.For instance,artemether is coformulated with lumefantrine
and used for treatment o uncomplicated malaria.
 The short half lives precludes the use of these drugs for prophylaxis.
Adverse effects
Nause,vomiting,diarrhea,hypersensitivity reactions and rash can occur.
Prolongation of the QT interval
Pyrimethamine

MOA
It inhibits plasmodial dihydrofolate reductase required for synthesis of
tetrahydrofolate.
It acts as a blood schizonticide and a strong sporonticide when the
mosquito ingests it with the blood of the human host.
If megaloblastic anemia occurs with pyrimethamine treatment, it may be
reversed with leucovorin.
AMEBIASIS

 It is an infection with Entamoeba histolytica.

 This organism can cause asymptomatic intestinal infection,mild to
moderate colitis,severe intestinal infection(dysentery),ameboma,liver
abscess and other extraintestinal infection.
Treatment of specific forms of Amebiasis
i)Asymptomatic intestinal –luminal amebicide
Standard luminal amebicides are :diloxanide furoate,iodoquinol and
paromomycin
(ii)Amebic colitis-Metronidazole plus luminal amebicide
(iii)Extraintestinal –metronidazole plus a luminal amebicide is the treatment
of choice.
For unusual cases in which initial therapy with metronidazole has
failed,aspiration of the abscess and addition of chloroquine to a repeat
course of metronidazole should be considered.
Metronidazole

 Nitro-imidazole.
 Mixed amebicide of choice for treating amebic infections.
Clinical uses
I. Amebiasis
II. Giardisis
III. Trichomoniasis
IV. Treatment of pseudomembranous colitis caused by the anaerobic
gram positive bacillus clostridium difficile
MOA
The nitro group of metronidazole is able to serve as an electron
acceptor ,forming reduced cytotoxic compounds that bind to proteins and
DNA ,resulting in cell death of E.histolytica trophozoites.
Adverse effects
Abdominal cramps,an unpleasant metallic taste if taken with alcohol,a
disulfiram like reaction may occur,oral moniliasis(yeast infection of the
mouth) and neurotoxicity(dizziness,vertigo and numbness or paresthesia).
LUMINAL AMEBICIDES

Iodoquinol
 A halogenated and hydroxyquinolone amebicidal against E histolytica.
 Effective against the luminal trophozoites and cysts forms.
Adverse effects
Diarrhea,rash,dose related peripheral neuropathy including a rare optic
neuritis .
 Long term use of this drug should be avoided.
 The drug should be discontinued if it produces persistent diarrhea or
signs of iodine toxicity(dermatitis,urticarial,pruritus,fever).
Paromomycin

 An aminoglycoside.
 It is only effective against intestinal(luminal) forms of E.histolytica
because it is not significantly absorbed from the GI tract.
 Paromomycin is directly amebicidal and also exerts its antiamebic action
by reducing the population of intestinal flora.
Adverse effects
Gatrointestinal distress,diarrhea
Diloxanide furoate

 A dichloroacetamide derivative
 Effective luminal amebicide but is not active against trophozoite
Systemic amebicide

(i)Dehydroemetin
It inhibits protein synthesis by blocking chain elongation
Intramuscular injection is the preferred route,since it is an irritant when
taken orally.
Adverse effects
Pain at the injection site,nausea,cardiotoxicity(arrhythmias and congestive
heart failure),neuromuscular weakness,dizziness and rash.
CHEMOTHERAPY FOR
TRYPANASOMIASIS
 African trypanosomiasis(sleeping sickness),is caused by the flagellated
protozoan T.brucei.It exist in two morphological forms:
 T.brucei rhodesiense(East African) is transmitted by infected
tsetseflies(Glossina morsitans)
 T.brusei gambiense is transmitted by infected tsetseflies(Glossina
palpalis)
 American trypanosomiasis(Chagas disease) is caused bt T.cruzi.
Pentamidine

 It has activity against trypanosomatid protozoans and against P.jirovecii.

MOA
The drug interferes with parasite synthesis of RNA,DNA,phospholipids and
proteins.
Clinical uses
(i)Pneumocystosis
(ii)African trypanosomiasis.The drug of choice to treat early hemolymphatic
stage of disease caused by Trypanosoma brucei gambiense
(iii)Leishmaniasis.It is an alternative drug to sodium stibogluconate for
treatment of visceral leishmaniasis
Adverse effects
Serious renal dysfunction may occur
Pancreatic toxicity
Hypoglycemia
Hyperglycemia
Suramin

 It is used primarily in the first stage(without CNS involvement) of African

trypanosomiasis due to T.brucei rhodensiense.
 It is very reactive and inhibits many enzymes especially those involved
in energy metabolism,which appears to be mechanism coorelated with
trpanocidal activity.
Adverse effects
Nausea,vomiting,shock,blepharitis,neuropathies,acute urticaria
Melasoprol

 A trivalent arsenical compound used for treatment of African

trypanosomal infections in the second stage(CNS involvement).
 It is the only drug available for second stage trypanosomiasis due to T.
brucei rhodesiense.
 It is extremely toxic.
Immediate adverse effects
Fever,vomiting,abdominal pain and arthralgias.
The most important toxicity is a reactive encephalopathy that generally
appears within the first week of therapy and is probably due to disruption
of trypanosomes in the CNS.
 Coadministration with corticosreoids may decrease the likelihood of
encephalopathy.
 Consequences of encephalopathy are:cerebral edema,seizures,coma
and death.
 Other serious toxicities include renal and cardiac arrest &
hypersensitivity reactions.
Eflornithine

 Irreversible inhibitor of ornithine decarboxylase.

 The IV formulation of eflornithine is a first line treatment for second
stage African trypanosomiasis caused by T brucei gambiense.
 Less toxic than melarsoprol.
Adverse effects
Anemia,thrombocytopenia,leukopenia,seizures and temporary hear loss.
Nifurtimox

 Nitrofuran
 Standard drug for Chagas disease.
 Nifurtimox is also used in the treatment of African trypanosomiasis in
combination with eflornithine.
Adverse effects
Nausea,vomiting,headache,hypersensitivity reactions,peripheral
neuropathy and dizziness.
Benznidazole

 Nitroimidazole.
 It tends to be better tolerated than nifurtimox and is an alternative for
treatment of Chagas disease.
Adverse effects
Peripheral neuropathy.
Insomnia
Anorexia
CHEMOTHERAPY FOR LEISHMANIASIS

 There are three types of leishmaniasis:cutaneous,mucocutaneous and

visceral(liver and spleen)
 Transmitted from animals to humans (and between humans) by the bite
of infected sandflies.
 For visceral leishmaniasis parenteral treatments may
include:amphotericin B and pentavalent antimony such as sodium
stibogluconate with pentamidine and paromomycin.
 Miltefosin is an orally active agent against visceral leishmaniasis.
CHEMOTHERAPY FOR
TOXOPLASMOSIS
 T.gondii(causative agent)
 Treatment of choice is sulfadiazine and pyrimethamine.
 Leucovorin is commonly administered to protect against folate
deficiency.
 At first appearance of a rash,pyrimethamine should be discontinued
because hypersensitivity to this can be severe.
 Trimethroprim sulfamethoxazole are alternative agents.
 Trimetroprim sulfamethoxazole is used for prophylaxis against
toxoplasmosis(as well as P.jorovecii in immunocompromised patients).
CHEMOTHERAPY FOR GIARDIASIS

 Treatment of choice is metronidazole or tinidazole.

 Nitazoxanide is also approved for treatment of giardiasis(3 day course of
oral therapy)
 Paromomycin is sometimes used for treatment of giardiasis in pregnant
patients.
 Albendazole may also be efficacious for giardiasis