Transcript malaria

Species of
plasmodium.
Clinical features and
complications.
Life-cycle of
plasmodium.
Classification of
antimalarial drugs.
Individual drugs.
Each year, it
causes disease in
approximately 650
million people and
kills between one
and three million.
Plasmodium
falciparum.
P.vivax P.vivax &
P.ovale.
P.ovale is mainly
confined to Africa.
Acute falicparum
malaria is potentially
fatal.
Symptoms of malaria.
Complications:-.
Chronic repeated
infection.
Quiz?
• One cycle of liver
invasion and
multiplication:
• A) P vivax
B) P falciparum
C) P. malariae
D) P ovale
Tissue
schizontocides:
-.
Blood
schizontocides:-.
Gametocides:destroy the sexual
forms of the
parasite.
Hypnozoitocides:
-kill the dormant
hypnozoites of
P.vivax & P.ovale
in the liver.
Sprontocides:interupt
development
of sporogonic
phase in
mosquitoes .
Prophylactic:-to
prevent clinical attack
1. Suppressive
prophylaxis:-use of
blood schizontocides to
prevent acute attack
2. Causal prophylaxis:-use
of tissue schizontocides
to prevent the parasite
from establishing in the
liver
Curative:-suppressive treatment of
the acute attack usually with blood
schizontocides.
Prevention of transmission:Erradication of infection in
mosquitoes using gametocytocides
or sprontocides.
Chloroquine and amodiaquine
potent blood schizontocide.
At the acid pH of the lysosome
it is converted into protonated
form, trapped in the parasite.
Inhibits digestion of
haemoglobin by the parasite
AA supply necessary for
parasite viability.
It also haem polymerase.
Resistance results from enhanced efflux of the
expression of the human multi drug resistance
transpoter P-glycoprotein.
It is a disease modifying antirheumatoid
drug.
Rapidly & completely absorbed from the
GIT, has high volume of distribution(1001000l/kg).
Concentrated into parasitised RBCs.
Released slowly from tissues & metabolized
in the liver, excreted in the urine 70%
unchanged. Elimination is slow.
Initial t½ =2-3days & terminal t ½=12months.
ADR:-Nausea, vomiting, dizziness, blurring
of vision, headache,urticarial symptoms.
Large doses retinopathy.
Bolus injection hypotension &
dysrrhythmias
Safe for pregnant women.
Quiz?
• Plasmodial resistance to
chloroquine is due to
(A) Change in receptor structure
(B) Increased expression of Pglycoprotein
(C) Increase in the activity of DNA
repair mechanisms
(D) Induction of inactivating
enzymes
(E) Inhibition of dihydrofolate
reductase
Quiz?
• Of the following which is
not a clinical use of
chloroquine are:• A) amebiasis
B) malaria prophylaxis
C) acute malarial attacks
D) guardiasis
• E) rheumatoid arthritis
Blood schizontocide
effective against the
erythrocytic form of all
species of malaria.
Acts by parasite’s
haem polymerase.
Depresses the
myocardium,
Mild oxytoxic effect on pregnant
uterus,
Slight neuromuscular blocking
action,
weak antipyretic action.
Given orally in a7 day course or
by slow IV for severe P.
falciparum infection,
Metabolized in the liver,t½=10h.
ADR:-bitter taste
→poor compliance,
NV, concentrations
>30-60mol/l
cinchonism [nausea,
dizziness, headache,
tinnitus, blurring of
vision].
Higher doses can
cause hypotension ,
cardiac arrhythmias,
,delirium, coma.
Hypoglycaemia, blood
dyscrasias,
hypersensitivity
reactions
Blackwater fever, a
fatal condition in which
acute haemolytic
anaemia is associated
with renal failure.
Resistance →↑
expression of Pglycoprotein.
CONTRAINDICATIONS
Prolonged QT Interval
Glucose-6-Phosphate Dehydrogenase
Deficiency
Myasthenia Gravis
Hypersensitivity
Optic Neuritis, auditory problems
Dose should be reduced in renal
insufficiency
Drug Interactions:Antacids: Antacids containing aluminum
and/or magnesium may delay or decrease
absorption of quinine.
Erythromycin (CYP3A4 inhibitor):
Cimetidine
Mefloquine.
Quinine can raise plasma levels of
warfarin and digoxin.
Quiz?
• Which is false about
quinine :
A) rapid onset
B) poorly effective blood
schizonticide against P
vivax
C) gametocidal for P
ovale
D) causes cinchonism
E) causes hypoglycemia
Atovaquone parasite’s
electron transport chain
by mimicking the
natural substrate
ubiquinone
Has synergestic effect
with proguanil.
Pregnant & breast feeding women
should not use atavaquone.
Resistance to atavaquone is rapid ,
results from a single point mutation in the
gene for cytochrome b.
Low bioavailability, slow, erratic
absorption, ↑by food, highly proteinbound, t½ =2-3d, eliminated unchanged
in faeces.
ADR:- fever, rash, NVD, insomnia
Blood schizontocide
active against Pvivax &
P.falciparum, but no
effect on hepatic form
of the parasite.
Inhibits haem
polymerase.
Resistance has
occurred in southeast
Asia.
Given orally ,well absorbed, slow onset
of action, t½=30d enterohepatic
recycling or tissue storage.
ADR:-GIT disturbances, transient CNS
toxicity, confusion, Gidiness, dysphoria,
insomnia.
May provoke neuropsychiatric disorder.
Contra-indicated in pregnant women.
Quiz?
• Mefloquine :
• A) active against P
falciparum gametocytes
B) indicated to pregnant
women
C) active against hepatic
stages of P vivax
D) contraindicated in
cardiac conduction
anomalies
Blood schizontocide,
active against strains
resistant to chloroquine ,
pyrimethamine, quinine.
Cross resistance in
falicparum infection
occurred .
Absorbed orally slowly ,
t½=11-12d.,
Absorption by a fatty
meal, elimination in
faeces.
ADR:-abdominal pain, headache, transient
in hepatic enzymes, cough, pruritus,
lengthening of Q-T interval.
May cause haemolytic anaemia &
convulsions.
Reserved for infection caused by resistant
organisms.
Contraindicated with mefloquine.
Patients with cardiac conduction defects.
In pregnancy → embriotoxic in animals
Type 1 antifolates
sulphonamides &
sulphones ,
competes with
PABA.
Type 2
,pyrimethamine &
proguanil
dihydrofolate
reductase.
Have slow action
against the
erythrocytic forms
of the parasite.
Pyrimethamine is
used in
combination with
either dapsone or
sulfadoxine.
Sulfonamides & sulfones
are active against the
erythrocytic forms of
P.falciparum.
Pyrimethamine -sulfodoxine
is used for chloroquine –
resistant malaria.
Pyrimethamine & proguanil
are absorbed orally slowly.
t½ of pyrimethamine =4d,
proguanil=16h.
Proguanil is metabolized to
an active metabolite
,cycloguanil which is
excreted in urine.
ADR:- large doses of
pyrimethamine -dapsone
combination causes
haemolytic anaemia,
agranulocytosis.
In high doses pyrimethamine
mammalian dihydrofolate
reductase megaloblastic
anaemia.
Resistance → a single
mutation in the genes
encoding parasite
dihydrofolate reductase.
Quiz?
• Antimalarials
dihydrofolate reductase
inhibitors:• A) chloroquine
• B) chloroguanide
C) pyrimethamine
• D) trimethoprim
E) primaquine
Quiz?
•
Concerning sulfonamides &
sulfones and antimalarial
activity: a) Blood schizonticidal activity
against P falciparum
b) useful in acute sever attack
of P falciparum
c) Active against liver stages
of P falciparum or P vivax
d) rapid onset of action
e) minimal side effects
Active against liver
hypnozoites, produces radical
cure for parasites which have
dormant stage in the liver
[P.ovale &P.vivax].
Has gametocytcide action ,
most effective for preventing
transmission of the disease.
Combined with chloroquine,
mechanism unknown,
resistance rare.
Given orally, rapidly
metabolized to etaquine &
tafenoquine which are
more active & slowly
metabolized, t½=3-6h
For radical cure of acute
vivax and oval malaria”:chloroquine is given to
eradicate erythrocytic
forms and then
primaquine(30mg daily for
14 days) to eradicate liver
hypnozoites
ADR:- GIT
disturbances, in
large doses 
methaemoglobinae
mia with cyanosis
Causes haemolysis
in G-6-P –
dehdrogenase
deficiency,
metabolites have
greater haemolytic
activity
Quiz?
• This is the antimalarial agent
most commonly associated with
causing an acute hemolytic
reaction in patients with glucose6-phosphate dehydrogenase
deficiency.
• (A) Chloroquine
• (B) Clindamycin
• (C) Mefloqui
• (D) Primaquine
• (E) Quinine
Derived from the herb
qing haosu [Artemisia].
Artemisinin is poorly
soluble in water & fast
acting blood
schizontocide.
Effective in treating acute
attack , including
chloroquine –resistant &
cerebral malaria.
Artemesia annua
Artesunate[a water- soluble derivative],
artemether & artether[synthetic
analogues] have higher activity & are
better absorbed.
It damages the parasite membrane by
carbon- centered free radicals.
Rapidly absorbed , widely distributed,
Converted in the liver to
the active metabolite
dihydroartemisinin.
t½ of artemisinin
4h,artesunate=45min,
artemether 4-11h.
ADR:- transient heart
block, neutrophil count,
brief episodes of fever.
Neurotoxic in animal , no
reported resistance
Quiz?
• An antimalarial drug effective
against multidrug resistant P.
falciparum, which rapidly
terminates an attack of malarial
fever, but has a short duration of
action, so that recrudescence is
common:• (A) Chloroquine
• (B) Artemisinine
• (C) Mefloquine
• (D) Primaquine
• (E) Quinine
Doxycycline is used as a suppressive
prophylactic in areas where mefloquine
resistance is common.
Clindamycin has proved effective in the
treatment of uncomplicated falicparum
malaria, may be used in combination with
quinine.
Use of prophylactic drugs is seldom
practical for full-time residents of malariaendemic areas, and their use is usually
restricted to short-term visitors and
travelers to malarial regions.
People temporarily visiting malariaendemic areas usually begin taking the
drugs one to two weeks before arriving
and must continue taking them for 4
weeks after leaving.
include mefloquine ,doxycycline and the
combination of atovaquone and proguanil
hydrochloride
A 35-year-old medical entomologist comes
to the hospital with chief complaints of
fever, headache, and photophobia. This
illness began about 6 days prior to
admission, when he returned from a 2month visit to the jungles of Central and
South America. He took a drug for
prophylaxis of malaria before starting the
trip. On his return flight, about 6 days prior
to admission, he described having fever
and shaking chills. He saw his physician 2
days prior to admission; the physician
made a diagnosis of influenza and
prescribed tetracycline.
On the day of admission, the patient had
shaking chills followed by temperature
elevation to 104°F (40°C). Physical
examination revealed a well-developed man
who appeared ill. There is some left upper
quadrant tenderness but no organomegaly;
blood pressure,126/90; pulse, 120; and
respirations, 22. Laboratory findings were
hemoglobin, 14.5 mg/dL (normal, 13.4–17.4
mg/dL); hematocrit, 45% (normal, 40–54%);
Giemsa-stained blood smear (thick and thin)
revealed Plasmodium vivax
Q1
• The drug she took for
prophylaxis was probably
(A) Chloroquine
(B) Mefloquine
(C) Primaquine
(D) Proguanil
(E) Pyrimethamine
Q2?
• Which of the following drugs
should be used for oral
treatment of the
entomologist's acute attack of
P vivax malaria?
• (A) Chloroquin
• (B) Mefloquine
• (C) Primaquin
• (D) Pyrimethamine-sulfadoxine
• (E) Quinine
Q3?
•
Which of the following drugs
should be given later in
order to eradicate schizonts
and latent hypnozoites in
the patient's liver?
(A) Chloroquine
(B) Mefloquine
(C) Primaquine
(D) Proguanil
(E) Quinine
About 90% of malaria deaths occur in sub
Saharan Africa.
The key factor contributing tomalarial morbidity
& mortality is resistance of P.falciparum to
chloroquine, sulfodoxin-pyrimethamin [SP] &
amodiaquine.
Artemisinin compounds produce a very rapid
therapeutic response ,active against multi-drug
resistant P.falciparum, well tolerated by the
patient,gametocyte carriage, no resistance is
detected.
Artemisinins cure falciparum malaria in 7d, if
combined with another drug in 3d.
1.
2.
3.
4.
5.
WHO recommends that all countries
experiencing resistance to conventional
monotherapies should use combination
therapy, preferably containing artemisinins
[ACTs -artemisinin-based combination
therapies].
WHO recommends the following therapeutic
options:Artemether/lumefantrine
Artesunate+amodiaquine
Artesunate+SP
Artesunate+ mefloquine [area with low to
moderate transmission.
Amodiaquine+SP
Quiz?
• Regarding drugs used for malaria, which
one of the following statements is false?
(A) Chloroquine is the drug of choice for
acute attacks of non falciparum malaria
(B) Cinchonism is associated with the use of
quinine
(C) Hemolysis has occurred with primaquine
in patients deficient in G6P
dehydrogenase
(D) Mefloquine is used for prophylaxis in
regions where chloroquine resistance
occurs
(E) Quinine is contraindicated in pregnancy
A57-year-old photographer developed
fever, diarrhea, headache, vomiting,
and dark urine about 10 days after
returning to the United States from a
month-long trip to East Africa. The
patient has been taking chloroquine
and proguanil chemoprophylaxis. On
physical examination the patient is
feverish, agitated, sweating, weak,
and in mild distress, with a blood
pressure 95/60 (normal, 120/80), a
pulse of 120 (normal, 60–100),
and temperature of 104°F (40°C)
(normal, 98.6°F, 37°C). Laboratory
findings are a hematocrit of 25% (normal
for male, 40–54%); platelet count 29,000
(normal, 150,000–400,000/mm3);
parasitemia 6% (P. falciparum); serum
creatinine 3.5 mg/dL (Normal for male,
0.8–1.5 mg/dL); and plasma glucose 39
mg/dL
(Normal fasting, 65–110 mg/dL).
Q1
• What is the best choice of
drug therapy?