Transcript Stage-Specific Treatment of Malaria

PARASITIC INFECTIONS
 Parasitic
diseases are prevalent under
conditions of crowding, poverty and poor
sanitation and constitute one of the major
health problems of man.
PARASITIC INFECTIONS
 Found throughout
the world. With
increasing travel, immigration and the
use of immunosuppressive drugs and the
spread of AIDS, health care workers
anywhere may see infections caused by
previously unfamiliar parasites.
PARASITIC INFECTIONS
 They
are often chronic in nature . They
generally don’t produce sudden, severe
life-threatening infections.
PARASITIC INFECTIONS
 Successful
control is dependent on a
variety of public health measures
including vector control, improvement of
sanitation, health education and drug
administration.
MALARIA
 A world-wide
common cause of mortality
and morbidity.
 The
decrease in spraying and the increase
in resistance have resulted in a
resurgence of this disease.
MALARIA
 An
estimated 500 million people are
infected with malaria annually and at
least 2.5 million die mostly in Africa.
 In
endemic areas young children are at
greatest risk because their natural
immunity to the disease is weakest.
MALARIA CONTROL
MALARIA
 In
the near future the major mechanism
for combating the disease will be a
combination of vector control and drugs.
TREATMENT OF MALARIA
 Differs
greatly from one region to
another depending upon the type of
Plasmodium species and the degree of
drug resistance.
MALARIA
 Characterized clinically
by spasms of
severe chills, fever and profuse sweating.
 These
episodes sometimes occur at
reasonably well-defined intervals
determined by the life cycle of the
invading Plasmodium.
MALARIA

Other frequent symptoms of a malarial attack
include malaise, headache, delirium, aching
muscles, abdominal discomfort, vomiting and
diarrhea.

In some cases the disease can become chronic
with repeated relapses.

It results from infection with protozoa of the
genus Plasmodium.
MALARIA
 Usually
transmitted by mosquito bite but
also by transfusion of infected blood and
by sharing needles.
PLASMODIA SPP.
AFFECTING MAN
 More
than 100 species, those infecting
man include:
 P. vivax
 P.falciparum
 P.malaria
 P.ovale
MALARIA

P.Falciparum malaria causes a majority (80 %)
of the cases of malaria and nearly all the
deaths. (Malaria caused by other species is
rarely fatal but is more difficult to cure
completely).

This is called malignant tertian malaria (fever
spikes occur irregularly).
MALARIA
 The
next most common type is the tertian
variety caused by P.vivax (fever spikes
occurring every other day).
 P.ovale
similar to vivax.
 Quartan
malaria is caused by P.malariae.
MALARIA
 The
lapse between invasion time and
onset of clinical symptoms varies with the
Plasmodium species as does the frequency
of the fever spikes.
Plasmodia in RBC’s
ANTIMALARIAL DRUGS
 Antimalarials can
be classified on the
basis of their action at different stages in
the life cycle of the parasite in the human.
 None
of the antimalarials are true
prophylactics.
Artemesinin, atovaquone
BLOOD SCHIZONTICIDES
 Drugs
in this class act rapidly on the
erythrocytic stage to relieve clinical
attacks (most sensitive to antimalarial
drugs).
BLOOD SCHIZONTICIDES
 Treatment
of the erythrocytic stage
makes the patient asymptomatic but
often does not completely get rid of the
parasite.
 When
therapy is stopped symptoms will
resume.
BLOOD SCHIZONTICIDES
 If
a person stays in the area, continual
reinvasion will occur and it is not
reasonable to attempt complete
eradication of the parasite.
TISSUE
SCHIZONTOCIDES
 Used
prophylactically to prevent the
erythrocytic stage of malaria.
 Prevent relapse
tissue forms.
 Primaquine.
as they act on primary
P.falciparum
 Upon
rupture of the hepatic schizont
there is no reinvasion of the liver.
 Resistance
occurs more readily with
P.falciparum.
Gametocytocides and
Sporontocides
CL
N
A 4-aminoquinoline
NH
CH (CH2)3N(C2H5)2
CH3
CHLOROQUINE
ANTIMALARIAL ACTIVITY
 Highly
effective vs. erythrocytic forms of
P.vivax, P.ovale, P.malariae and sensitive
forms of P.falciparum.
 No
activity vs. latent tissue forms of
P.vivax and P.ovale.
MECHANISM OF ACTION
 Multiple
effects.
MECHANISM OF ACTION
 Intercalation into
 Inactivation of
parasitic DNA.
hemoglobin proteases
vital to the organism by direct
binding or raising the intravacuolar
pH .
MECHANISM OF ACTION
 Interferes
with Hb digestion in the blood
stages of the parasite life cycle.
 The
parasite degrades Hb in an acidic
food vacuole producing free heme and
reactive oxygen spp. as toxic by-products.
MECHANISM OF ACTION
 Heme
is neutralized by polymerization
while the free radicals are also detoxified.
MECHANISM OF ACTION
 Chloroquine
accumulates several
thousand-fold in the food vacuole of the
parasite.
 Interferes
with heme polymerization
and/or detoxification of the free radicals
effectively killing the parasite with its
own metabolic waste.
Mechanism of action of Chloroquine
Food Vacuole
RBC
Hb
Chloroquine
Globin
digestion
Parasite
Heme
Polymerization
Inhibition of Free Radical Peroxidation
Heme-Fe(III)3+
Heme-Fe(II)2+
eO2
O 2-
SOD
2H+
Chloroquine
H2O2
X
Catalase
H2O +1/2 O2
Peroxidase
Rox + H2O
RESISTANCE
 Probably
involves multiple mechanisms
under complex multigenic control.
 Decreased
drug accumulation.
ADVICE FOR TRAVELERS
 Up
to date automated information for
travelers is available from the CDC at
888-232-3229 or on the internet at
www.cdc.gov.
 Malaria
7788.
branch of the CDC at 770-488-
PHARMACOKINETICS
 Rapid
and complete absorption after
oral administration (also IM and SC).
 Accumulates
in many tissues
especially RBC’s (especially infected
ones) and liver.
PHARMACOKINETICS
 Undergoes
 Excreted
appreciable metabolism.
in the urine.
CLINICAL USES
 Used
for acute malarial attacks as it is
rapidly acting- cures Plasmodium
falciparum malaria.
 Chemoprophylactic
agent (areas
without resistant falciparum malaria).
CLINICAL USES
 Rheumatoid arthritis
 Hepatic
amebiasis.
and lupus.
TOXICITY
 Adverse
effects are usually mild and
reversible especially when used for the
short-term treatment of malaria.
 Acute
toxicity occurs when therapeutic or
high doses are administered too rapidly
by parenteral routes (primarily
cardiovascular and CNS).
TOXICITY

Oral chloroquine-GI upset, headache, urticaria
, pruritis and visual disturbances.

High doses and prolonged treatment can
produce severe visual and cardiac reactions.

Little or no toxicity when used prophylactically.
PRECAUTIONS AND
CONTRAINDICATIONS
 Liver disease,
GI, neurological or blood
disorders.
 Glucose-6-phosphate dehydrogenase
deficient patients.
 Considered
safe in pregnancy and in
young children.
DRUG INTERACTIONS
 Mefloquine
 Anticonvulsants
 Inhibits
CYP2D6
QUININE AND QUINIDINE
 Natural
alkaloids isolated from the
cinchona tree bark.
 Quinidine
 Quinidine
is an optical isomer of quinine.
is more potent and more toxic
than quinine.
MECHANISM OF ACTION
 Blood
schizonticide.
 Similar to
 Not
chloroquine.
as extensively concentrated in the
food vacuole as chloroquine and may
have some alternative targets in the
parasite.
RESISTANCE
 May
result from increased efflux.
PHARMACOKINETICS
 Readily
absorbed when given orally or
IM(also given IV).
 Rapidly
acting with a short t1/2.
 Extensively
metabolized (CYP3A4).
THERAPEUTIC USES
 Drug
of choice for chloroquine-resistant
and MDR falciparum malaria (with a
sulfonamide, clindamycin or
doxycycline).
 For severe
malaria it is used parenterally
(quinidine in the U.S.).
ADVERSE EFFECTS
 Bitter taste.
 Quinine
is an irritant to the GI
mucosa and often causes nausea,
vomiting or pain.
QUININE- TRIAD OF DOSERELATED TOXICITIES
 Cinchonism
(tinnitis, headache and
disturbed vision, may progress to C.V.
and dermal). GI symptoms are
prominent in Cinchonism.
ADVERSE EFFECTS
 Hyperinsulinemia and
severe
hypoglycemia.
 Severe
hypotension when given too
rapidly IV.
ADVERSE EFFECTS
 EKG
abnormalities with IV quinidine.
 Hypersensitivity reactions
 Severe
.
toxicity is rare but may include
fever, skin eruptions, GI effects, deafness,
visual abnormalities and CNS effects.
PRECAUTIONS AND
CONTRAINDICATIONS

Pregnancy (teratogenic).

Hemolysis in patients with G-6-P DH
deficiency.

Patients with a history of episodes of
hemolysis, hypersensitivity and cardiac
arrhythmias, tinnitus and optic neuritis.
DRUG INTERACTIONS
 Mefloquine
FANSIDAR
 Sulfadoxine plus
pyrimethamine
CH3CH2
NH2
N
N
NH2
CL
PYRIMETHAMINE
PHARMACOKINETICS

Pyrimethamine-slow but complete absorption
when given orally.

Binds to plasma proteins and accumulates in
certain organs.

Pyrimethamine-t1/2 80-95h

Sulfadoxine-t½ 7-9 days
CLINICAL USES
 Chloroquine-resistant falciparum
malaria in a one dose presumptive selftreatment when medical care is not
immediately available (within 24h) for a
presumed malaria illness.
CLINICAL USES
 Prophylaxis and
treatment of MDR
falciparum malaria (with mefloquine).
TOXICITY

Pyrimethamine alone- little toxicity except
occasional skin rashes and decreased
hematopoiesis.

High doses - folic acid deficiency (megaloblastic
anemia).

Combination- severe and even fatal cutaneous
reactions.
P.falciparum,
P.vivax, P.ovale
MECHANISM OF ACTION
 Converted in
the liver to active quinone
metabolites (active electrophiles). These
may generate active oxygen species or
Primaquine
PHARMACOKINETICS
 Completely
and promptly absorbed when
given orally.
 Rapidly
and extensively metabolized.
 Excreted
as metabolites.
CLINICAL USES
 To
prevent relapses (radical cure) of
P.vivax and P.ovale infections (used with
a blood schizonticide,usually
chloroquine).
 Terminal
prophylaxis after completion of
travel to an endemic area to diminish
likelihood of a relapse.
ADVERSE EFFECTS
 Large
doses may cause abdominal
distress, nausea and headache.
 Hemolytic anemia,
cyanosis
(methemoglobinemia) and leukocytosis less common.
ADVERSE EFFECTS
 Produces
hemolytic anemia in people
with glucose-6-phosphate dehydrogenase
deficiency.
PRECAUTIONS AND
CONTRAINDICATIONS

Glucose-6-phosphate DHase deficiency.

Patients with a tendency towards
granulocytopenia or methemoglobinemia.

Other potentially hemolytic or bone marrow
depressing drugs.

Pregnancy.
MECHANISM OF ACTION
 4-aminoquinoline
methanol.
 It
is a blood schizonticide similar to
chloroquine and quinine in many aspects.
 May
inhibit heme polymerization and
may form toxic complexes with free heme
that damages membranes.
RESISTANCE
 Sporadic
resistance in many areas has
been reported.
PHARMACOKINETICS
 Given
orally (parenterally it can cause
severe local reactions).
 Slowly
eliminated (t½ around 20 days)
CLINICAL USES
 Used
for the treatment and prophylaxis
of chloroquine-resistant and multidrug resistant P.falciparum malaria.
 It
is the drug of choice for
chemoprophylaxis for most travelers.
ADVERSE EFFECTS
 GI
upset (common).
 CNS
toxicity is seen in about half of the
people who take the drug (dizziness,
ataxia, headache etc).
 Severe
rare).
neuropsychiatric disturbances (
CONTRAINDICATIONS

Pregnancy.

Children less than 2 years old.

Patients with a history of seizures or
neuropsychiatric disturbances.

Patients who have had adverse reactions to
quinoline antimalarials.
ATOVAQUONE/
PROGUANIL
 A fixed
dose combination of atovaquone
and proguanil hydrochloride.
 Prevents
rapid development of resistance
to atovaquone.
ATOVAQUONE
ANTIMALARIAL ACTIVITY
 Both
drugs are active vs the erythrocytic
forms of P.falciparum including strains
resistant to chloroquine, mefloquine and
pyrimethamine/sulfadoxine (not active vs
hepatic stages).
ATOVAQUONE
Proguanil
Cycloguanil
PHARMACOKINETICS
 Atovaquone
is poorly absorbed from the
GI tract .
 Proguanil is
rapidly absorbed.
CLINICAL USES
 Prevention and
treatment of chloroquineresistant P.falciparum malaria.
ADVERSE EFFECTS

Abdominal pain, nausea, vomiting, diarrhea,
headache and rash have occurred and are more
common with high doses.

Dose-related maculopapular rashes.

Mild elevations in liver aminotransferase
activity.
ARTEMISININ

Extract from a Chinese herb.

Artemisinin is insoluble and can only be used
orally.

Analogs have been synthesized to improve
solubility and improve antimalarial efficacy
(artesunate and artemether) .
ANTIMALARIAL ACTIVITY
 Active
against all malarial species
(especially useful for P.falciparum
resistance).
 Rapidly
acting blood schizonticide.
MECHANISM OF ACTION
 Free
radical production that follows the
iron-catalyzed cleavage of the artemisinin
endoperoxide bridge.
 These
covalently modify and damage
specific malarial proteins.
PHARMACOKINETICS
 Active
form is dihydroartemesinin.
 Short t½ (45
use.
mins)-precludes prophylactic
CLINICAL USES
 Treatment
of multidrug-resistant
P.falciparum ( in conjunction with
another agent such as fansidar or
doxycycline).
ADVERSE EFFECTS
 Nausea,
vomiting and diarrhea.
 Irreversible
neurotoxicity has been seen
with very high doses or long term
therapy in animal studies.
 Prolongation of
the QT interval.
PRECAUTIONS AND
CONTRAINDICATIONS.
 Avoid
in pregnancy.
DOXYCYCLINE
 Used
for treatment and prophylaxis in
regions where multi-drug resistance is
common.
 Used
alone for short term prophylaxis.
 For treatment they
are used in
combination with other antimalarials
(work slowly).
ANTIMALARIAL
CHEMOTHERAPY
 For acute
attacks chloroquine is the
treatment of choice.
 For resistant
strains use quinine plus
fansidar or plus doxycycline or
mefloquine (or atovaquone/proguanil).
ANTIMALARIAL
CHEMOTHERAPY
 For a
radical cure of P.vivax or P.ovale
use primaquine after departure from the
endemic area.
 For severe
attacks use quinine or
quinidine parenterally.
CHEMOPROPHYLAXIS OF
MALARIA

Chloroquine for sensitive strains.

If symptoms of malaria occur while taking chloroquine
a therapeutic dose of fansidar should be administered
and medical care sought immediately.

Mefloquine and atovaquone/proguanil for chloroquineresistant strains.

Doxycycline for multi-drug resistance.
AMEBIASIS

Asymptomatic cyst passers- organisms found in
the intestinal lumen but patients show no
symptoms.

Mild to moderate intestinal amebiasis.

Severe intestinal infection (dysentery).

Amebic liver abscesses.
PAROMOMYCIN (Humatin)
 Direct
amebicide with antibacterial
activity (an aminoglycoside) (luminal
amebicide).
 Insignificant absorption.
 May
be useful in other protozoal
infections and some worm infections.
ADVERSE EFFECTS
 Diarrhea
and abdominal pain are the
main side effects.
 Ototoxicity and
renal toxicity associated
with the systemic aminoglycosides are
not seen.
 GI
superinfections are possible.
IODOQUINOL (Yodoxin)
 Exact
mechanism of action is not known.
 Variable
but significant absorption.
 Luminal
amebicide for asymptomatic
cyst passers.
 Toxicity-myelooptic
neuropathy (rare).
METRONIDAZOLE
 Metronidazole is
amebicide.
the prototypical mixed
METRONIDAZOLE  Drug
of choice for all symptomatic cases
although a luminal amebicide must also
be given.
 Intestinal
amebiasis with or without liver
involvement.
OTHER DRUGS USED IN THE
TREATMENT OF AMEBIASIS
 Tinidazole
 Chloroquine
 Emetine
and dihydroemetine
Metronidazole
Metronidazole
HELMINTHIASIS
 Prevalence
is greatest in tropical regions.
 Simultaneous
infestation with more than
one type of worm is common.
 Due
to travel and immigration worms
can spread to locations that previously
had been free of a particular organism.
ANTHELMINTICS

Many of these parasites have complex life
cycles, parts of which occur in other animal
hosts besides man.

In man most worms have some stage of their
development within the GI tract and it is here
that they are easiest to attack.

The adult form of the worm is the form usually
attacked chemotherapeutically.
ANTHELMINTICS
 Common
target sites for anthelmintics
• Ion channels
• Microtubules
• Bioenergetics
BENZIMIDAZOLES
 Mebendazole, Thiabendazole
and
Albendazole.
 Versatile antihelminthic
agents.
MEBENDAZOLEPHARMACOKINETICS
 Given
orally but absorption is poor and
erratic.
 Undergoes
rapid 1st. pass metabolism.
THERAPEUTIC USES
 Broad
spectrum anthelminthic. Highly
effective against GI nematode infections
including roundworms, hookworm,
whipworm and pinworm.
 Particularly valuable
infections.
for mixed
ADVERSE EFFECTS
 Little
systemic toxicity due to poor
absorption.
 There
is some transient abdominal pain
such as cramping.
 Teratogenic
so it is contraindicated in
pregnant women.
THIABENDAZOLEPHARMACOKINETICS
 Rapidly
absorbed after oral
administration.
 Metabolized
and excreted in the urine as
the glucuronide and sulfate conjugates.
THERAPEUTIC USES
 Drug
of choice for treatment of
“cutaneous larval migrans” caused by the
larva of the dog hookworm.
THERAPEUTIC USES
 Alternative drug
for the treatment of
threadworm (Strongyloides stercoralis)
infections.
ADVERSE EFFECTS
 GI-
anorexia, nausea, vomiting and
diarrhea (frequent).
 CNS-
(less frequent)dizziness, weariness,
drowsiness, giddiness and headache.
ALBENDAZOLEPHARMACOKINETICS
 Variably and
erratically absorbed from
the gut.
 Undergoes 1st.pass
metabolism in the
liver.
 Well
distributed into various tissues.
THERAPEUTIC USES
 Broad
range of activity vs. many
nematodes and cestodes including mixed
infections of A. lumbricoides (intestinal
roundworm),hookworm (Necator
americanus) and whipworm (Trichuris)
THERAPEUTIC USES
 Cystic
hydatid disease (larval form of the
dog tapeworm)(Echinococosis).
 Cutaneous larval
migrans.
 Neurocysticercosis (larval
pork tapeworm).
form of the
NEUROCYSTICERCOSIS
 Develops
when humans or pigs ingest
food contaminated with taenia (Taenia
solium) eggs, which cross the digestive
tract, enter the circulation and lodge in
the tissues (usually brain or muscles).
 A frequent
cause of seizures often
resistant to anticonvulsant therapy.
NEUROCYSTICERCOSIS
 Adequate
therapy with 1 week course of
albendazole or a 1 day treatment with
praziquantel (albendazole has better and
more effective penetration into the brain
tissue).
 Corticosteroids
to prevent inflammation.
ADVERSE EFFECTS
 Transient
abdominal pain, diarrhea,
nausea and vomiting, headache, dizziness
and allergic reactions.
 At
higher doses and prolonged use the
most common effect is elevated serum
aminotransferase (ATase).
PRAZIQUANTEL
N
N
C
MECHANISM OF ACTION

Increases cell membrane permeability to
calcium resulting in vacuolization, marked
contractions, paralysis, dislodgement and
death.

At low doses it causes increased muscular
activity, followed by contraction and spastic
paralysis (worms detach from host).
MECHANISM OF ACTION
 At
higher therapeutic concentrations it
causes damage to the worms integument.
This seems to activate host defense
mechanisms and results in destruction
and elimination of the worms.
PHARMACOKINETICS
 Rapid
absorption after oral
administration.
 Undergoes
 Rapidly
extensive metabolism.
excreted in the urine mainly as
metabolites.
Tapeworm life cycle
Taenia
infections
ADVERSE EFFECTS
 Abdominal
discomfort (pain and
nausea).
 Headache, dizziness
 Indirect
and drowsiness.
effects such as fever, pruritus,
urticaria, rashes, arthralgia and myalgia.
CONTRAINDICATIONS
 Pregnancy
PYRANTEL PAMOATE
(Antiminth)
MECHANISM OF ACTION

Effective vs susceptible worms in the intestinal
tract (not other forms).
 Depolarizing neuromuscular blocking agent.
 Opens nonselective cation channels and induces
marked persistent activation of nicotinic ACH
receptors ,which results in spastic paralysis of
worms.
 Inhibits cholinesterase.
PHARMACOKINETICS
 Poorly
absorbed from the GI tract.
THERAPEUTIC USES
 Broad
spectrum anthelmintic.
 Highly effective
for the treatment of
pinworm (Enterobius).
PINWORM

Most common helminthic infection in the
U.S.(more than 40 million schoolchildren
affected).

More prevalent in temperate than tropical
climates.

Rarely causes serious complications-pruritus in
the perianal and perineal areas.
PINWORM
 Easily
distributed throughout members
of a family, a school, or an institution.
THERAPEUTIC USES
 DOC-Roundworm
ADVERSE EFFECTS
 Nausea,
vomiting, diarrhea and
abdominal cramps.
 Dizziness,
drowsiness, headache,
insomnia, rash, fever and weakness.
PRECAUTIONS AND
CONTRAINDICATIONS
 Not
recommended in pregnancy and in
children under 2.
IVERMECTIN (Stromectol)
 Macrocyclic
lactone which belongs to a
class of natural compounds known as
avermectins.
MECHANISM OF ACTION
 Potentiation ,
direct activation or both of
glutamate gated chloride channels found
only in invertebrates.
 It
causes an influx of negatively charged
ions and this hyperpolarization of the
affected cells results in muscle paralysis.
PHARMACOKINETICS
 Well
absorbed when given orally.
 Extensively
metabolized.
THERAPEUTIC USES
 Onchocerciasis (river blindness).
 Lymphatic
filariasis.
THERAPEUTIC USES
 Intestinal
nematode infections:
Strongyloides (threadworm), cutaneous
larval migrans, ascariasis (roundworm).
TOXICITY
 Almost
all the reactions are as a result of
an immunological reaction to dead
microfilariae (Mazotti reaction) fever
,itching, dizziness, edema.
TOXICITY
 In
patients being treated for nematode
infections diarrhea, nausea, dizziness and
pruritus are common.
 Some
patients develop corneal opacities
and other eye lesions.
PRECAUTIONS AND
CONTRAINDICATIONS
 Children
under 5
 Pregnancy