Welcome to pharmacology by Lecturio. I'm Dr. Pravin
Shukle. We're going to be covering antiparasitic agents.
If you've been doing the lectures in order you
will know that this is the last of the series.
Congratulations on making it this far. In todays
lecture we're going to be covering the agents
that are used against the parasites commonly
affecting patients. We're going to be talking about
antimalarial agents and amebicides. We're going to
be talking about those agents that works against
nematodes and trematodes and cestodes. Let's start
off with antimalarial agents. The most well known
of the antimalarial agents is chloroquine. It was
one of the first ones developed and it's still used
in many countries today. Now chloroquine prevents
the polymerization of heme. Remember that intracellular
heme is toxic to the parasite. So any presence of
heme can actually kill the organism. We do have
resistance developing in many malarial strains
today. Malaria organisms develop membrane
transporters that actually will eject the intracellular
heme. Plasmodium falciparum or P.falciparum
can also develop a transporter for the chloroquine
itself, which is actually quite shocking when you
think about a organism actually being able to
eject a drug specifically because it's toxic.
Now the agent that is responsible or the gene that
is responsible for the ejection protein for chloroquine
is called the pfcrt gene.
Side effects associated with chloroquine are usually
GI disturbances. And you're going to notice that
will be a general theme throughout the entire
antimalarial agent lecture. Nausea, cramping,
and diarrhea. You may also see some skin rashes and
headaches as well. Although these are a little bit
less common. At very high doses of chloroquine,
we'll see severe skin reactions and we may also see
peripheral neuropathies. Some patients may also
develop a toxic psychosis and may also develop
retinal and auditory damage. At very high doses of
chloroquine we actually can see myocardial depression.
And this is usually in cases of overdose.
We may also precipitate porphyria attacks
because remember heme is an integral part of
the porphyria metabolism system. And by
altering the levels of heme in the blood you
can cause porphyria attack through chloroquine.
Another agent or another set of agents that we
talk about with respect to antimalarial treatment
are those agents that are derived from artemisinin.
Now, who is Artemis? Artemis was the Greek goddess
of the hunt and you can see her portrayed here.
She was fabled to always favor this one particular
plant, and whenever she would lay down, she would
lay down in this particular bed of plants,
because it was particularly soft. That interesting
little side note just gives us an idea of where
the name comes from. And you can see that all of
the names of the drugs are derived from her name.
Now the mechanism of action of these drugs is
that they accumulate in the food vacuoles of the
parasites themselves. They form toxic free radicals.
They will work against multidrug resistant strains
of malaria. And so we often see them used in
combination with other agents. There are rare
adverse side effects of nausea, vomiting and diarrhea
with these agents. Much less than, say chloroquine.
There is no increase in congenital abnormalities
or stillbirths in women taking these medications.
So we feel that they may be quite safe in pregnancy.
Another agent that has commonly been used to treat
malaria is quinine. In fact it's the oldest of the agents.
It combines with double stranded DNA and prevents
the strand separation from occuring. That's how
they work in the blood schizont. They block
replication and transcription of DNA. And it's used in
chloroquine resistant Plasmodium falciparum infections
as well. We're often combining this particular
agent with doxycycline or clindamycin in order to
shorten the duration of therapy and also limit the
toxicity of all of the agents. The toxicity of
quinine, it seems rather obvious and we touched on it
to some extent in our cardiology lecture. You'll
sometimes get cinchonism or gastrointestinal distress,
headache, vertigo, blurred vision and tinnitus.
Hemolysis is quite common in patients who have
glucose-6-phosphatase deficiency. So it's a very
important consideration and something you have to be
very aware of, that you don't want to be using
quinine in these patients. This is a particular
problem in your East Indian patient population
cause a lot of East Indians are deficient in
glucose-6-phosphatase deficiency. And when they
will travel from the United States back to India
to visit relatives, you have to be very aware that
you may not want to give these patients quinine.
Blackwater fever is a special kind of a fever that
involves intravascular hemolysis. It's something
that we have to be particularly aware
of in patients who are on quinine.
Mefloquine is probably the most used antimalarial
agent in patients from North America who are
travelling abroad. It's chemically related to
quinine and it's often considered our first line agent.
Generally speaking, for prophylaxis we give
the patient four weeks of therapy prior to,
and one week after with one pill once a week during
the treatment. So for example, if you're travelling
to say, an endemic area that's susceptible to
mefloquine for three weeks, you would take it for
four weeks before; once a week. During the three
weeks while you're travelling; once a week.
And then for one week after. Now how this particular
agent work is that it creates more toxic heme
particles in the food vacoules of the malaria strain.
And it's quite effective in killing the malaria schizont.
We classify it as a blood schizonticide because it
kills that schizont form in the red blood cells.
Toxicity includes GI distress, skin rash, headache,
and dizziness. Nightmares is actually surprisingly
common. And in children who are on mefloquine, it's
exceedingly common. I myself saw it happen in my son
who developed nightmares and parasitosis; the fear
of being eaten up by parasites while he was taking
mefloquine on a recent trip to Peru. So it's a very
real problem and it's something that sometimes
limits our ability to use this medication. These
agents may also cause cardiac conduction defects,
and seizures at very high doses.
Primaquine is another tissue schizonticide and it's
also a gametocide. So it actually kills the gamete
form of malaria. It eliminates liver stages of P.vivax
and P.ovale as well. It's used in conjunction with
a blood schizont agent so that we can really do
a good kill job with respect to malaria.
Now how it works is that it forms quinoline and
quinone metabolites that acts as oxidants
for these agents, for the schizont. So that it
actually becomes toxic and makes a toxic environment
for both the schizont and the gamete.
In terms of toxicity of primaquine, most of the
patients who complain of symptoms will complain
of GI distress. Most often abdominal cramping and a
sense of fullness. Some patients may also develop
headaches while they're on this medication. Something
you have to be very aware of is you can cause
methemoglobinemia. And also in patients who have
glucose-6-phosphatase deficiency, you have to be
aware that you can precipitate a hemolysis in
this patients. With primaquine, it is contraindicated
We have a whole group of antifolate drugs that we
use. We use them predominantly as schizonticides.
Proguanil, pyrimethamine, sulfadoxine, dapsone.
These are all agents that are combined in various
ways to give a synergistic effect through sequential
blockade and causing an antimetabolic effect
which will block the folic acid synthesis within the
malaria organism. Toxicity causes, it causes skin rash,
and can cause gastrointestinal distress. And once
again, any antimetabolite drug will be contraindicated
Doxycycline is also used. It's used for chemoprophylaxis
for travellers through an unknown mechanism.
And despite the fact that it seems like a fairly
prosaic drug it's actually shockingly effective.
So it's something that you should consider in your
patients who can't take one of the other agents.
Amodiaquine is also another agent that we use for
the treatment of malaria. It's a relatively cheap drug.
We use it extensively in the third world settings.
It's used in fixing dosing with artesunate,
which is one of those artemesinin drugs that we had
talked about earlier. Toxicity includes hematological
problems including agranulocytosis and aplastic
anemia. So be aware that these agents can cause
problems with your white count and the
development of white blood cells lines.
Atovaquone is another agent that we use for the
prevention and treatment of malaria. We consider this
an erythrocide agent. Now Malarone is atovaquone
plus proguanil. It's a very very commonly sold
pill in the United States. It's used as
treatment and as once daily prophylaxis
It is an alternative treatment for patients
who have Pneumocystis jiroveci infection.
Mechanism of action, we know that it acts on the
mitochondrial electron transport system to somehow
cause death inside the cell of the malaria organism.
We're not sure much more beyond that. There are lots of
interesting articles that are coming out now in the
literature, taking a look at how this particular agent works.
In terms of toxicity, abdominal pains and GI side
effects are very common with this particular agent.
Halofantrine is another erythrocide agent that are
active against all erythrocytic forms of all 4
malaria strains. It is not at this point used as a
chemoprophylactic agent because it has a high
potential for cardiotoxicity and a prolonged QT
interval. It is also contraindicated in pregnancy
because it is toxic to the embryo.
In terms of prevention of malaria, you should always
consult local guidelines because the malaria guidelines
will vary from country to country. And in fact some
seasons there may be strains of say, mefloquine
resistant malaria in South East Asia, whereas other
seasons there may not be. So keep up to date,
take a look at the guidelines. You're not going to
be expected to know the exact guidelines from
year to year for your exam, but you will be expected
to be able to look them up when you're in clinical practice.
In terms of the principles of prevention behind malaria
prophylaxis, chloroquine generally remains the
first line choice in areas without resistant Plasmodium
falciparum. And mefloquine remains the first line
choice in areas with chloroquine resistant Plasmodium
falciparum. And in terms of travel from the
United States to other countries, mefloquine is
actually used more commonly than chloroquine
simply because the travellers seem to be travelling
more to those areas with chloroquine resistant
P. falciparum areas. In areas with multidrug-resistant
malaria; so think in South east Asia, in certain areas
of South east Asia, we will use doxycycline or the
Malarone that I had spoken to you about before.
Primaquine is also used in terminal
prophylaxis of P. vivax and P. ovale as well.