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Medical University of Sofia, Faculty of Medicine
Department of Pharmacology and Toxicology
Antiprotozoal drugs
(Abstract)
Assoc. Prof. Ivan Lambev
e-mail: [email protected]
1. Malaria
Malaria is the most important of
the transmissible parasitic diseases.
Over 90 million cases occur each year.
DRUG-RESISTANT MALARIA
Plasmodium falciparum is now resistant to chloroquine
in many parts of the world. Areas of high risk for
resistant parasites include Sub-Saharan Africa, Latin
America, Oceania, and some parts of South-East Asia.
Chloroquine-resistant Plasmodium vivax is also
reported.
The incubation period of malaria is 10–35 days.
Female anopheles mosquitoes
require a blood meal for egg production and in the
process of feeding they inject salivary fluid containing
sporozoites into humans. Since no drugs are effective
against sporozoites, infection with the malaria
parasite cannot be prevented.
Hepatic cycle
Sporozoites enter liver cells where they develop into tissue
(liver) schizonts which form large numbers of merozoites
which, usually after 5–16 days but sometimes after months or
years, are released into the circulation. Plasmodium
falciparum differs in that it has no persistent hepatic cycle.
Primaquine, proguanil, and tetracyclines (tissue
schizonticides) act at this site and are used for:
• Radical cure, i.e. an attack on persisting hepatic
forms. This is most effectively accomplished
with primaquine.
• Preventing the initial hepatic cycle. This is also
called causal prophylaxis. Primaquine may be
used safely; proguanil is weakly effective;
doxycycline may be used short-term.
Erythrocyte cycle
Merozoites enter red cells where they develop into
blood schizonts which form more merozoites which are
released when the cells burst giving rise to the
features of the clinical attack. The merozoites
reenter red cells and the cycle is repeated.
Chloroquine, quinine, mefloquine, halofantrine,
proguanil, pyrimethamine, and tetracyclines (blood
schizontocides) kill these asexual forms. Drugs which
act at this stage in the cycle may be used for:
• Treatment of acute attacks of malaria.
• Prevention of attacks by early destruction of the
erythrocytic forms. This is called suppressive
prophylaxis as it does not cure the hepatic cycle.
Sexual forms
Some merozoites differentiate into male and female
gametocytes in the erythrocytes and can develop further only if they are ingested by a mosquito where they
form sporozoites and complete the transmission cycle.
Quinine, mefloquine, chloroquine, artesunate,
artemether and primaquine (gametocytocides) act on
sexual forms and prevent transmission of the infection
because the patient becomes noninfective and the
parasite fails to develop into mosquito.
In summary, drugs may be selected for:
• treatment of clinical attacks
• prevention of clinical attacks
• radical cure.
Life cycle
of malaria
parasites
•Pl. falciparum
•Pl. malariae
•Pl. ovale
•Pl. vivax
Quinine as cinchona bark was introduced into
Europe from South America in 1633. It was
used for all fevers, amongst them malaria.
Further advance in the chemotherapy
of malaria was delayed until 1880, when
Charles Louis Alphonse Laveran, Prof. of Military
Medicine in Paris (Nobel prize winner 1907) finally
identified the parasites in the blood.
Quinine (Chinine) is an alkaloid, obtained
from the bark of the South American Cinchona tree.
It binds to plasmodial DNA to prevent protein
synthesis. It is used to treat Plasmodium falciparum
malaria in areas of multiple-drug resistance. Apart
from its antiplasmodial effect, quinine is used for
myotonia and muscle cramps because it prolongs
the muscle refractory period. Quinine is included in
dilute concentration in tonics and aperitifs for its
desired bitter taste. Adverse effects include tinnitus,
diminished auditory acuity, headache, blurred vision,
nausea, and diarrhoea. Idiosyncratic reactions include
pruritus, urticaria, and rashes. Hypoglycemia may be
significant when quinine is given by i.v. infusion.
Amodiaquine is closely related to chloroquine, and
it probably shares its mechanisms of action and resistance. Amodiaquine has been widely used to treat
malaria because of its low cost, limited toxicity, and,
in some areas, effectiveness against chloroquineresistant strains of P. falciparum. Important toxicities
of amodiaquine, including agranulocytosis, aplastic
anemia, and hepatotoxicity, have limited use, but
serious toxicity is rare.
Chloroquine is concentrated within parasitised
red cells and forms complexes with plasmodial
DNA. It is active against the blood forms and also the
gametocytes (formed in the mosquito) of Plasmodium
vivax, Plasmodium ovale, and Plasmodium malariae.
It is ineffective against many strains of Plasmodium
falciparum and also its immature gametocytes.
Chloroquine is readily absorbed from the GIT
and is concentrated several-fold in various tissues,
e.g. erythrocytes, liver, spleen, heart,
kidney, cornea, and retina. The long
t1/2 (50 d) reflects slow release from these sites.
Chloroquine is partly inactivated by metabolism
and the remainder is excreted unchanged in the urine.
Adverse effects are infrequent at doses normally
used for malaria prophylaxis and treatment, but are
more common with the higher or prolonged
doses given for resistant malaria or for
rheumatoid arthritis or lupus erythematosus.
Corneal deposits of chloroquine may cause
halos around lights or photophobia. These reverse when
the drug is stopped. Retinal toxicity may be irreversible.
In the early stage it takes the form of visual field
defects; late retinopathy classically gives the picture
of macular pigmentation surrounded by a ring of
pigment. The functional defect can take the form
of scotomas, photophobia, defective colour
vision resulting, in the extreme case, in blindness.
Other reactions include pruritus (which may be
intolerable), headaches, GI disturbance, precipitation
of acute intermittent porphyria in susceptible individuals, mental disturbances and interference with
cardiac rhythm; especially if the drug is given i.v.
in high dose (it has a quinidine-like action). Long-term
use is associated with reversible bleaching of the hair
and pigmentation of the hard palate.
Halofantrine (t1/2 2.5 d) is active against the
erythrocytic forms of all four Plasmodium species,
and at the schizont stage. It is used for the treatment
of uncomplicated chloroquine-resistant Plasmodium
falciparum and Plasmodium vivax malaria.
Halofantrine may cause GI adverse effects; pruritus (but
to a lesser extent than with chloroquine). It prolongs the
cardiac QT interval and may predispose to arrhythmia.
Mefloquine (t1/2 21 d) is similar in several respects
to quinine. It is used for malaria chemoprophylaxis,
to treat Pl. falciparum and chloroquine-resistant
Pl. vivax malaria. It should not be given to patients
with hepatic or renal impairment.
Adverse effects include nausea, dizziness, vomiting,
abdominal pain, diarrhoea, and loss of appetite.
More rarely, hallucinations, seizures, and psychoses
are observed.
Primaquine acts at several stages in the
development of the plasmodial parasite, possibly by
interfering with its mitochondrial function. Its unique
effect is to eliminate the hepatic forms of Plasmodium
vivax and Plasmodium ovale after standard chloroquine
therapy, but only when the risk of reinfection is absent.
Adverse effects: anorexia, nausea, abdominal cramps,
methaemoglobinaemia and haemolytic anaemia,
especially in patients with genetic deficiency of
erythrocyte glucose-6-phosphate dehydrogenase
(G6PD). Subjects should be tested for G6PD and, in
those that are deficient, the risk of haemolytic
anaemia is greatly reduced by giving primaquine in
reduced dose.
Proguanil (t1/2 17 h) inhibits dihydrofolate reductase
which converts folic to folinic acid, deficiency of
which inhibits plasmodial cell division. Plasmodia,
like most bacteria and unlike humans, cannot make
use of preformed folic acid. Pyrimethamine and
trimethoprim, which share this mode of action, are
collectively known as the “antifols”. Their plasmodicidal action is markedly enhanced by combination
with sulphonamides or sulphones because there is
inhibition of sequential steps in folate synthesis.
Poguanil must be used daily when given for
prophylaxis, its main use, particularly in pregnant
women (with folic acid 5 mg/d).
Antifols
Pyrimethamine (t1/2 4 d) inhibits plasmodial dihydrofolate reductase, for which it has a high affinity. It is
well absorbed from the GIT and is extensively
metabolized. Pregnant women should receive
supplementary folic acid when taking pyrimethamine.
Adverse effects reported include anorexia,
abdominal cramps, vomiting, ataxia, tremor, seizures,
and megaloblastic anaemia.
Pyrimethamine acts synergistically with Sulfadoxine
(as Fansidar®) to inhibit folic acid metabolism;
sulfadoxine is excreted in the urine. The combination
is chiefly used with quinine to treat acute attacks of
malaria caused by susceptible strains of Pl. falciparum.
Artesunate and artemether are soluble derivatives of artemisinin which is isolated from the leaves
of the Chinese herb Artemisia annua.
They act against the blood, including sexual forms of
plasmodia and may also reduce transmissibility.
Artesunate (i.v.) and artemether (i.m.) are rapidly
effective in severe and multidrug-resistant malaria.
They are well tolerated but should be used with
caution in patients with chronic cardiac disorders
as they prolong the PR and QT interval in some
experimental animals.
Doxycycline is commonly used in the treatment of falciparum malaria in conjunction with quinidine or quinine,
allowing a shorter and better-tolerated course of quinine.
Riamet® tablets contain artemether and lumefantrine. These
are both antimalarial medicines. It is used for treatment of
uncomplicated Pl. falciparum malaria in adults, children
and infants weighing 5 kg and above.
2. Amoebiasis
Infection occurs when mature cysts of E. histolytica
are ingested and pass into the colon where they
divide into trophozoites. Amoebiasis occurs in two
forms, both of which need treatment.
• Bowel lumen amoebiasis is asymptomatic
and trophozoites (noninfective) and cysts
(infective) are passed into the faeces. Treatment
is directed at eradicating cysts with a luminal
amoebicide; diloxanide furoate is the drug of choice;
iodoquinol or paromomycin is sometimes used.
Paromomycin is an aminoglycoside antibiotic
that is not significantly absorbed from the GIT. It is
used only as a luminal amebicide and has no effect
against extraintestinal amebic infections. The small
amount absorbed is slowly excreted unchanged.
However, the drug may accumulate with renal
insufficiency and contribute to renal toxicity.
Paromomycin is an effective luminal amebicide
that appears to have similar efficacy and probably
less toxicity than other agents.
• Tissue-invading amoebiasis gives rise to
dysentery, hepatic amoebiasis, and liver abscess.
A systemically active drug (tissue amoebicide)
effective against trophozoites must be used, e.g.
dehydroemetine, metronidazole, tinidazole.
In severe cases of amoebic dysentery,
tetracycline lessens the risk of
opportunistic infection, perforation, and
peritonitis when it is given in addition to the
systemic amoebicide.
Dehydroemetine (from Ipecacuanha), less toxic than the parent
emetine, is claimed to be the most effective tissue amoebicide.
Dehydroemetine inhibits protein synthesis. It is reserved for
dangerously ill patients, but these are more likely to be vulnerable
to its cardiotoxic effects. When dehydroemetine is used to treat
amoebic liver abscess, chloroquine should also be given.
Metronidazole, a nitroimidazole, is the drug of choice in the
treatment of extraluminal amebiasis. It kills trophozoites but not
cysts of E. histolytica and effectively eradicates intestinal and
extraintestinal tissue infections. It has anaerobic
antibacterial activity and antihelicobacater activity too.
It is an enzyme inhibitor.
Tinidazole appears to have similar activity and a better toxicity
profile than metronidazole, and it offers simpler dosing regimens.
3. African trypanosomiasis (sleeping disease)
It is caused by the hemoflagellates Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense.
The organisms are transmitted by bites of tsetse flies
(genus Glossina), which inhabit shaded areas along
streams and rivers. The largest number of cases is
in the Congo. Annual incidence estimates are about
100 000 cases and 48 000 deaths.
American Trypanosomiasis (Chagas’ Disease)
is caused by Trypanosoma cruzi.
African trypanosomiasis – treatment:
Suramin or pentamidine is effective during
the early stages but not for the later
neurological manifestations for which
melarsoprol should be used. Eflornithine
is effective for both early and late stages.
American Trypanosomiasis – treatment:
Prolonged (1–3 months) treatment with
benznidazole or nifurtimox may be effective.
4. Leishmaniasis is a zoonosis.
•Visceral leishmaniasis (kala azar) is caused mainly
by Leishmania donovani in the Indian subcontinent
and East Africa. Treatment:
Sodium stibogluconate or meglumine antimoniate;
resistant cases may benefit from combining
antimonials with allopurinol, pentamidine,
paromomycin, or amphotericin B.
•(Muco-) Cutaneous leishmaniasis is caused
mainly by Leishmania tropica, L. major, and
L. donovani. Treatment:
Mild lesions heal spontaneously,
antimonials may be injected intralesionally.
5. Toxoplasmosis
T. gondii, an obligate intracellular protozoan, is found
worldwide in humans and in many species of animals
and birds. The definitive hosts are cats. Humans are
infected after ingestion of cysts in raw or undercooked meat, ingestion of oocysts in food or water
contaminated by cats, transplacental transmission
of trophozoites or, rarely, direct inoculation of
trophozoites via blood transfusion or organ
transplantation.
Life cycle of Toxoplasma gondii
Most infections are self-limited in the
immunologically normal patient.
Pyrimethamine with sulfadiazine is used for treattement of chorioretinitis, and active toxoplasmosis
in immunodeficient patients; folinic acid is
used to counteract the fatal megaloblastic anaemia.
Alternatives include pyrimethamine with
clindamycin or clarithromycin or azithromycin.
Spiramycin is for treeatment of primary
toxoplasmosis in pregnant women.
Expert advice is essential.
6. Human Trichomoniasis
(Metronidazole or tinidazole
is effective)
Human trichomoniasis caused by Tr. vaginalis,
seen in both females and males. It is usually transmitted by coitus and is sometimes asymptomatic.
The symptomatic condition in females may take the
form of a severe vaginitis associated with discharge,
burning, and pruritus.
In males it may produce urethritis, enlargement of
the prostate, and epididymitis.
7. Giardiasis
It is a common infection of
the human small intestine with
the protozoan Giardia lamblia, spread via
contaminated food or water, or by direct
person-to-person contact.
Treatment:
Metronidazole, mepacrine, or tinidazole
8. Pneumocystis
Pneumocystis carinii, the causative agent
of interstitial plasma cell pneumonia,
which can also cause extrapulmonary
disease in immunocompromised
patients (AIDS, etc) .
Treatment:
Co-trioxazole: i.v./p.o. in high daily doses