This document discusses various antimalarial agents used to treat malaria infections caused by Plasmodium parasites. It describes the mechanisms of action and side effects of different drug classes, including aminoquinolines like chloroquine; quinoline-methanols like mefloquine; artemisinin derivatives like artesunate; antifolates like pyrimethamine; and antibiotics used in combination therapy like doxycycline. The document also covers parasite life cycles, drug resistance mechanisms, and how various drugs target different parasite stages to achieve treatment and prevention of malaria.
2. Introduction
Malaria is a protozoal disease, caused by
Plasmodium vivax
Plasmodium malariae
Plasmodium ovale
Plasmodium falciparum
ï Most of the serious complications and
death occur due to Plasmodium
falciparum.
ï
2
4. Types of malaria
Benign
tertian
âą P vivax and P ovale
âą with a fever every 2nd day
Benign
quartan
âą P malariae
âą with a fever every 3rd day
Malignant
tertian
âą P falciparum
âą This type of malaria is more dangerous
because of the complications
4
5. symptoms of malaria
Fever
ï Shivering
ï pain in the joints
ï Repeated vomiting
ï Generalized convulsion
ï
5
10. Antimalarial therapy and the
parasite life cycle
Drugs used to
treat acute
attack
âą Blood schizonticidal agents
âą Quinine,mefloquine,atovaquone,Pyrimethamine,art
emether,artesunate
Drugs that effect
a radical cure
Drugs used for
chemoprophylaxis
âą Tissue schinzonticidal
âą Primaquine and tafenoquine
âą Kill the sporozoites
âą Chloroquine,mefloquine,proquanil,pyrimethamine
10
12. Inhibition of haem polymerase
Haemoglobin
convert into
haem
Haem is free
and toxic
Haem
Polymerase
Haemozoin
Parasite
Inhibition of
haem
polymerase
cause
toxicity and
death of the
parasite
12
13. Chloroquine
4-Aminoquinoline derivatives
ï Uncharged at neutral pH
ï Diffuse freely into lysosome of parasite
ï At acid pH of lysosome, it converted to a
protonated, membrane impermeable form
and is âtrappedâ inside the parasite.
ï At high conc. It inhibits protein RNA and
DNA synthesis.
ï
13
14. Choroquine
Drug
Mechanism of
Action
Uses
Chloroquine
phosphate
(ARALEN)
concentrating in
parasite food vacuoles
Acute malarial Pruritus,Diarrhea,
attack
Loss of appetite,
Nausea,
Suppressive
Stomach cramps,
prophylaxis
Vomiting
,Retinopathy
Tablet250mg,
500mg
preventing the
polymerization of the
hemoglobin
breakdown product
heme, into hemozoin,
Adverse Effect
Half-life- 3-5
days
parasite toxicity due
Metabolise via to the buildup of free
CYPs
heme
Other
formulation
hydroxychloroquine sulfate (Rx) - Plaquenil
Use for treatment purpose
14
15. Resistance
ï¶Plsmodium
falciparum is now resistant to
chloroquine in most of the part.
ï¶Resistance
appears to result from
enhanced efflux of the drug from parasitic
vesicles as result from enhanced efflux of
the drug from parasitic vesicles as a
mutation in plsmodium transporter genes.
(pfcrt gene)
15
16. Contraindications & Cautions
Chloroquine is contraindicated in patients with
psoriasis or porphyria, in whom it may precipitate
acute attacks of these diseases.
ï It should generally not be used in those with retinal
or visual field abnormalities or myopathy.
ï Chloroquine should be used with caution in patients
with a history of liver disease or neurologic or
hematologic disorders. The antidiarrheal agent kaolin
and calcium- and magnesium-containing antacids
interfere with the absorption of chloroquine and
should not be coadministered with the drug.
ï
16
17. Quinoline-Methanols derivatives
Drug
Mechanism of
action
Quinine sulfate
Same as
Qaulaquine(oral) Chloroquine
8-14 hr
IV
Inhibition of
haem
Metabolise via
polymerase
CYP3A4
Contra
indication
Uses
Adverse Effects
Treatment of severe
falciparum malaria
Cinchonism, sinus
arrhythmia,
atrioventricular
block, prolonged
QT interval,
ventricular
tachycardia,
hypoglycemia
Combine with
tetracycline,
doxycycline, or
clindamycin
Digoxin therapy, warfarin therapy, patients with tinnitus or
optic neuritis.
Resistance- pfmdr1 point mutations can contribute to quinine resistance,
in particular the N1042D mutation. The mechanism is same as chloroquine.
17
18. Quinidine
Drug
Mechanism of
action
Uses
Adverse Effects
Quinidine
gluconate
(IV)
Same as
Chloroquine
Severe malaria,
Patient unable to
take oral medication
Combine with
tetracycline,
doxycycline, or
clindamycin
Cinchonism,
tachycardia,
prolongation of
QT intervals,
Ventricular
arrhythmias,
hypotension,
hypoglycemia
Inhibition of
haem
polymerase
18
19. Mefloquine
Drug
Mechanism of
action
Uses
Adverse Effects
Mefloquine
(LARIAM)
Same as
Chloroquine
Chemoprophylaxis and
treatment
Half life â 30
days
Inhibition of
haem
polymerase
Contraindication-
nausea, vomiting,
dizziness, sleep
and behavioral
disturbances,
epigastric pain,
diarrohea,
abdominal pain,
headache, rash,
and dizziness,
seizures and
psychosis
CYP3A4
patients with a history
of seizures, depression,
bipolar disorder and
other severe
neuropsychiatric
conditions,
19
20. Inhibit electron transfer chain
8-aminoquinoline
ï More active against liver hynozoites
(Tafenoquine , Etaquine and Primaquine)
ï Use to Prevent the transmission of
disease.
ï Active against P.vivax and P.ovale
ï
20
21. Mechanism of action
ï
Primaquine may be converted to
electrophilic intermediates that act as
oxidation-reduction mediators. Such
activity could contribute to antimalarial
effects by generating reactive oxygen
species or by interfering with
mitochondrial electron transport in the
parasite
21
22. Primaquine
Drug
Mechanism of
action
Uses
Adverse Effects
Primaquine
ïŒInhibits electron
transport chain in
Plasmodium
ïŒactive against
hepatic stages of
all human malaria
parasites.
ïŒactive against
the hypnozoite
stages of P vivax
and P ovale.
For presumptive antirelapse therapy
GI disturbances,
methemoglobine
mia, hemolysis in
persons
with G6PD
deficiency
Halflife- 7 hr
metabolized by
CYP1A2
Prophylaxis for shortduration travel to
areas with principally
Radical cure of P.
vivax and P. ovale (to
eliminate
hypnozoites)
Bind with acute-phase reactant protein α1-glycoprotein in liver
22
23. G6pd defficiency
X chromosome linked genetic metabolic
condition-glucose 6-phosphate
dehydrogenase- in red cell
ï Red cell canât regenerate the NADPH
ï Primaquine
oxidative metabolites
derivative of primaquine
decrease the
concentration of NADPH
metabolic
function of red cell impaired and
heamolysis occurâŠ
ï
23
24. Hydroxynaphthaoquinone Drugs
Inhibit electron transfer chain
ï Atavaquone is used for treatment of
malaria and can prevent its development
ï Resistance to atavaquone is rapid and
result from a single point mutation in the
gene of cytochrome b.
ï
24
26. Atovaquone-proguanil
Drug
Mechanism of action Uses
Adverse Effects
Atovaquoneproguanil
MALARONE
(oral)
tablet
250mg/100mg
Atovaquone: Selective
Treatment of
inhibitor of parasite
acute attack of
mitochondrial electron malaria
transport
Proguanil: Primary effect
through metabolite
cycloguanil, a
dihydrofolate reductase
inhibitor in malaria
parasite, which leads to
disruption of
deoxythymidylate
synthesis
Abdominal pain
Transaminase
increases
Headache
Vomiting
Nausea
Half-life:
Atovaquone, 2-3
days; proguanil,
12-21 hr
26
27. Inhibit DNA replication transcription
ï
The quinghaousu based compound are
derivative from the herb quin hao.
Artimisinin generate
carbon centered free
radical by breaking
down ferrrous
porphyrin IX
This radical cause
alkylation of protein
or damage the cell
membrane
27
28. Artesunate
Drug
Mechanism of
action
Artesunate (IV)
60mg/vial
may inhibit DNA Treatment of acute
replication &
attack of malaria
transcription
Cerebral malaria
Half-Life: 40-50
min
Uses
Adverse Effects
Cardiotoxicity
(high doses)
Neurotoxicity
observed in
animal studies
Drug induced
fever
Skin rash
28
34. Antibiotics
Doxycline and tetracycline used in acute
attack of malaria and chemopropylaxis
purpose.
ï Sometimes given in combination with
other drug.
ï Clindamycin is also used.
ï
34
35. Tetracycline
Drug
Mechanism of Uses
action
Adverse
Effects
Doxycycline
Doryx
(oral or
IV)
Tetracycline
Inhibit the
protein
synthesis by
compettition
with tRNA for
A site
Nausea, vomiting,
diarrhea,
abdominal pain,
dizziness,
photosensitivity,
headache,staining
of teeth
Tetracycline
(oral or
IV)
Oral quinine and
Doxycycline for acute
attacks
Oral chloroquine and
Doxycycline for
chemoprophylaxis
35
37. 4-Aminoquinolone derivatives
ï
Pyronaridine, a chloroquine relative, is being used in
combination with artesunate as a promising new
artemisinin- based combination therapy.
ï
Pyronaridine-artesunate has been studied in Phase II and
Phase III clinical trials, and has been shown to be effective
against uncomplicated P. falciparum and blood stage P.
vivax.
ï
Pyronaridine-artesunate is available as PyramaxÂź tablets
and pediatric granule formulations,and manufacture of this
compound is being undertaken by Shin Poong
Pharmaceuticals.
37
38. 8-Aminoquinolone derivatives
ï Tafenoquine
is a lead candidate drug
aimed at a radical cure of P. vivax, and is
being studied in a Phase II/III.
ïA
fixed dose artemisinin combination
therapy,
artesunate-amodiaquine
(Coarsucam) has been approved by WHO
and developed by Sanofi- Aventis.
38
39. Artemisinin derivatives
ï The
endoperoxide feature of artemisinins,
which confers antimalarial activity, is shared by
ozonide OZ439, a synthetic endoperoxide.
ï OZ439
carries the hope of providing a single
dose oral cure in humans when used in
combination.
ï OZ439
is a rapidly acting agent against asexual
stage parasites.This drug is currently
undergoing Phase IIa trials.
39
40. Newer target
ï
ï
TE3, a prodrug of a bis-ammonium
compound that acts on phospholipid
metabolism through the inhibition of de
novo
phosphatidylcholine
synthesis,
combined with a putative activity on heme
detoxification.
This new class of compounds has shown
potent in vivo antimalarial activity in the
primatemodel Aotus and is not cross
resistance in vitro with known antimalarials.
40
41. osmidomycin
osmidomycin, which inhibits the 1desoxy-D-xylulose-5-phosphate
reductoisomerase in the mevalonateindependent pathway of isoprenoid
synthesis in the apicoplast.
ï The apicoplast, a specialized parasite
organelle of algal origin, appears to be
important for lipid and heme biosynthesis.
ï
41
42. References
1)
Rang H P. Dale M M. How drugs act:
molecular aspects, Pharmacology, Fifth
edition. Elsevier publishers. P.703-709
2)
Katzung B., Masters S., Trevor A., Basic and
clinical pharmacology, New york: Mc Graw
Hill Medical Publisher;2009;p.699-705
3)
Seth S., Seth V., Textbook of pharmacology
,New Delhi: Elsevier, publisher;2009;p.VIII.63
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