Anti-Protozoals
Malaria
Malaria represents an infection of Plasmodium spp. The
protozoa is introduced by mosquitoes in its sporozoite form. An initial
infection presents these sporozoites to the liver, a form of the protozoa
referred to as tissue schizonts. Two species of Plasmodium
(P. falciparum and P. malariæ) undergo only one cycle
in the liver. The other two spp. (P. ovale and P. vivax)
may become dormant in the liver as hypnozoites, to become active and cause
a relapse of malaria. In the liver, the protozoa transforms to the
merozoite form which re-enters the circulation and enters the red blood
cells (blood schizonts). In the RBCs, the protozoa then begins to
multiply, producing gametocytes. Damage to the erythrocyte will ultimately
cause the cell to lyse, releasing merozoites and gametocytes into the plasma.
These gametocytes may then be taken back up into mosquitoes, where they
mature and form additional sporozoites. Drugs may be effective against
the tissue schizonts (primaquine) or blood schizonts (quinine, chloroquine,
mefloquine, pyrimethamine). Additionally, some drugs exhibit gametocidal
activity in plasma (primaquine against P. falciparum and chloroquine
against P. malariæ, vivax, and ovale) and mosquitoes (pyrimethamine).
NOTE on clinical approach to treatment of malaria -- Treatment with
agents effective against blood schizonts will be effective in acute malarial
attacks. However, they are not effective against the tissue schizonts.
Additionally, for the dormant forms of malaria, chloroquine (as an example)
would treat the acute form but have no effect on the hypnozoite, permitting
a future relapse (primaquine would be an effective cure). Pyrimethamine
has been used as a treatment/prophylaxis in many third world countries.
It may be introduced into the water or food, resulting in blood levels
of the drug that may then be transferred to mosquitoes, where it is gametocidal,
theoretically reducing the further spread of malaria by that vector.
Drugs Used in the Treatment of Malaria
Quinine -- a naturally occurring alkaloid derived from the bark of
Cinchona
spp.
Mechanism of Action -- Quinine is effective against all four spp. of
Plasmodium.
Its exact mechanism is unknown. It does decrease DNA strand separation
and transcription, thereby inhibiting protozoal protein synthesis.
This is presumed to be the effective mechanism of action. Resistance
may develop to the effects of quinine.
Adverse Effects -- GI disturbances (may be severe), hæmolysis,
cardiac effects (quinidine-like effects, but less pronounced), hypoglycæmia
(directly causes insulin release).
Toxicity -- Cinchonism -- Headache, nausea, visual disturbances, dizziness,
tinnitus
Contraindications -- Pre-existing hæmolysis, hypersensitivity,
pregnancy (quinine may also directly stimulate uterine contractions), arrhythmias.
Quinidine -- a stereoisomer of quinine, this agent is used primarily as
an intravenous version of quinine (parenteral quinine is not available
in the U.S.A.). The mechanisms and side effects have been discussed
previously (above and in the anti-arrhythmic section).
Chloroquine and Hydroxychloroquine
Mechanism of Action -- These agents are probably acting in a manner
similar to quinine. They may also increase the pH of the erythrocyte
and decrease phospholipid metabolism of the protozoa, both of which could
contribute to their efficacy. Resistance may develop to chloroquine
and hydroxychloroquine.
Adverse Effects -- Typically, less severe than quinine -- Headache,
GI, pruritus.
Uses -- Chloroquine may be used for acute treatment or prophylaxis of
malaria, amebiasis (see below), and auto-immune diseases (see previous
section on arthritis).
Mefloquine
Mechanism -- Presumably the same as the above drugs.
Adverse Effects -- Generally similar to quinine. May also see
CNS effects including psychosis.
Uses -- Chloroquine-resistant malaria, although resistance may also
develop to mefloquine.
Contraindications -- The same as for quinine.
Primaquine
Mechanism of Action -- The exact mechanism is unknown. It may
be due to an oxidant effect of the drug, since electron-carrying redox
intermediates are formed. Resistance does develop to the efficacy
of primaquine.
Adverse Effects -- Generally mild GI effects. May also see hæmolysis
and methæmoglobinæmia, especially in persons deficient in glucose-6-phosphate
dehydrogenase (results in an increase in the reactive intermediary which
may directly damage and lyse the RBC).
Uses -- Prophylaxis and treatment of malaria.
Contraindications -- Same as previous drugs.
Pyrimethamine
Mechanism of Action -- Pyrimethamine is a sulphonamide-type antibiotic
that works by inhibiting bacterial and protozoal dihydrofolate reductase,
thereby decreasing protozoal protein synthesis. Resistance may develop
to its efficacy.
Adverse Effects -- At high doses, macrocytic anæmia may develop.
Uses -- Prophylaxis and treatment of malaria and protozoal toxoplasmosis.
Other Drugs Used in the Treatment of Malaria
Doxycycline -- A tetracycline antibiotic that is effective against
Plasmodium. It is used for multi-drug resistant cases of malaria.
The pharmacology of doxycycline will be covered in the anti-biotic section.
Quinacrine -- An older preparation that has been replaced by newer agents
with fewer side effects. Quinacrine is primarily in the treatment
of giardiasis, covered below.
Artemisinin -- A naturally occurring product currently being investigated.
Its short half-life precludes its use as a prophylactic treatment.
It is effective only against blood schizonts. The mechanism of action
is not known. Side effects include minor GI irritation. It
may be teratogenic.
Amebiasis
Amebiasis is a protozoal infection of Entamœba histolytica/dispar.
It presents as varying stages of GI infection (from asymptomatic to severe
dysentery) and may specifically infect the intestinal lumen, the intestinal
wall, and the liver. Agents available in the U.S.A. that are effective
against luminal infection include iodoquinol and paromomycin. Tissue
infections (intestinal wall and liver) may be treated with metronidazole
(see below, under trichomonas) and emetine while liver infections also
respond to chloroquine (see above).
Drugs Available in the U.S.A. for amebiasis
Emetine -- a naturally occurring alkaloid that is the active constituent
of ipecac.
Mechanism of Action -- Emetine decreases ribosomal/RNA interaction
to decrease protozoal protein synthesis. It also blocks adrenergic
and cholinergic transmission in humans. The emetic effect of oral
emetine is primarily local (although some activation of the CTZ does occur).
Adverse Effects -- Serious toxicity may develop if therapy is continued
for more than 10 days, including central nausea and vomiting, diarrhœa,
tachycardia, arrhythmias, congestive heart failure, and muscle weakness.
Contraindications -- Pre-existing cardiac or renal disease.
Iodoquinol (Diiodohydroxyquin)
Mechanism of Action -- The mechanism of action of iodoquinol is unknown.
Adverse Effects -- Neurotoxicity (especially if more than 650 mg t.i.d.
for 21 days is used) including visual disturbances and peripheral neuropathies,
GI upset, headache, rash, goiter (decreases iodine uptake).
Paromomycin -- An aminoglycoside antibiotic, which will be covered in the
anti-biotic section.
Leishmaniasis
This protozoal infection may occur in a visceral, cutaneous, or mucocutaneous
form. It generally responds poorly to treatment (non-chemotherapeutic
approaches include cryotherapy, heat therapy, and surgery). Typically,
chemotherapeutic treatment involves extended durations of therapy, often
with toxic compounds. One drug that may be used is pentamidine, discussed
below and amphotericin an antifungal to be discussed in the next section.
Pneumocystis carnii Pneumonia and Trypanosomiasis
Pneumocystis carnii rarely causes infectious disease.
However, there has been an increasing incidence of pneumonia caused by
this protozoa in persons who are immunocompromised (i.e. patients
infected with HIV). Trypanosomiasis may be found in two forms, American
trypanosomiasis (Chagas Disease) and African trypanosomiasis (sleeping
sickness).
Drugs used in pneumocystis and trypanosomal infections
Pentamidine -- may be used to treat pneumocystis pneumonia and sleeping
sickness (the drug of choice for Chagas disease is nifurtimox, available
only from the CDC).
Mechanism of Action -- Pentamidine decreases DNA, RNA, protein, and
phospholipid synthesis. The exact mechanism of this inhibition is
not known.
Other Actions of Pentamidine include histamine release, which may cause
severe hypotension. It is also toxic to the beta cells of the islets
of Langerhans in the pancreas. This may manifest as an initial hypoglycæmia
(caused by initial insulin release) followed by hyperglycæmia and
the development of diabetes mellitus.
Adverse Effects -- Other than those discussed above, pentamidine may
cause blood dyscrasias and hepatotoxicity.
Atovaquone -- an analogue of ubiquinone used in the treatment of pneumocystis
pneumonia.
Mechanism of Action -- The exact mechanism is unknown. Atovaquone
may inhibit the mitochondrial electron transport chain that would inhibit
ATP synthesis (this is the most likely mechanism, given its similarity
to ubiquinone) or it may decrease nucleic acid synthesis.
Adverse Effects -- Rash, GI upset, headache
Eflornithine -- used primarily in the treatment of sleeping sickness
Mechanism of Action -- Eflornithine inhibits the enzyme ornithine decarboxylase,
thus inhibiting the synthesis of polyamines such as putrescine, spermine,
and spermidine. These compounds are thought to play a role in cell
proliferation and differentiation (which is depressed with eflornithine
therapy).
Adverse Effects -- Primarily myelosuppression with subsequent anæmia,
leukopænia, and thrombocytopænia, GI upset, alopecia, and possibly
seizures.
Trichomoniasis -- Most often involving vaginal infections of Trichomonas,
which may be transmitted to male partners.
Metronidazole (may also be used in the treatment of giardiasis)
Mechanism of Action -- A nitro (NO2) group on metronidazole
is reduced in vivo which may then interact with macromolecules on
the protozoa, resulting in protozoal death.
Adverse Effects -- Nausea, headache, dry mouth, metallic taste, all
of which are common. Metronidazole should be taken with meals to
reduce their incidence. It may also turn the urine a reddish-brown
colour. Less often, metronidazole may cause pancreatitis. It
may also produce a strong disulfiram type reaction.
Giardiasis -- Usually intestinal infections of the protozoa Giardia
lamblia.
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