Download P vivax

Antimalarial Agents
1
Introduction
Malaria is a protozoal disease, caused by
Plasmodium vivax
Plasmodium malariae
Plasmodium ovale
Plasmodium falciparum
 Most of the serious complications and
death occur due to Plasmodium
falciparum.

2
Structure of plasmodium
3
Types of malaria
Benign
tertian
• P vivax and P ovale
• with a fever every 2nd day
Benign
quartan
• P malariae
• with a fever every 3rd day
Malignant
tertian
• P falciparum
• This type of malaria is more dangerous
because of the complications
4
symptoms of malaria
Fever
 Shivering
 pain in the joints
 Repeated vomiting
 Generalized convulsion

5
Life cycle of the malarial parasite
6
Classification




4-Aminoquinolines:
Chloroquine, Amodiaquine, Piperaquine
Quinoline-methanol:
Mefloquine
Cinchona alkaloid:
Quinine, Quinidine
Biguanides:
Proguanil, Cholrproguanil
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



Diaminopyrimidines:
Pyrimethamine
8-Aminoquinoline:
Primaquine, Bulaquine
Sulfonamides and sulfone:
Sulfadoxine, Sulfamethopyrazine,
Dapsone
Tetracyclines :
Tetracycline, Doxycycline
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Sesquiterpine
lactones:
Artesunate, Artemether, Arteether
Amino alcohols:
Halofantrine, Lumefantrine
Mannich base:
Pyronaridine
Naphthoquinone :
Atovaquone
9
Antimalarial therapy and the
parasite life cycle
Drugs used to
treat acute
attack
• Blood schizonticidal agents
• Quinine,mefloquine,atovaquone,Pyrimethamine,art
emether,artesunate
Drugs that effect
a radical cure
Drugs used for
chemoprophylaxis
• Tissue schinzonticidal
• Primaquine and tafenoquine
• Kill the sporozoites
• Chloroquine,mefloquine,proquanil,pyrimethamine
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Malarial Parasite Developmental Stages
Targeted by Antimalarial Drugs
11
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
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Chloroquine
4-Aminoquinoline derivatives
 Uncharged at neutral pH
 Diffuse freely into lysosome of parasite
 At acid pH of lysosome, it converted to a
protonated, membrane impermeable form
and is ‘trapped’ inside the parasite.
 At high conc. It inhibits protein RNA and
DNA synthesis.

13
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
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Resistance
Plsmodium
falciparum is now resistant to
chloroquine in most of the part.
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
Contraindications & Cautions
Chloroquine is contraindicated in patients with
psoriasis or porphyria, in whom it may precipitate
acute attacks of these diseases.
 It should generally not be used in those with retinal
or visual field abnormalities or myopathy.
 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.

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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.
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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
Mefloquine
Drug
Mechanism of
action
Uses
Adverse Effects
Mefloquine
(LARIAM)
Same as
Chloroquine
Chemoprophylaxis and
treatment
Half life – 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
Inhibit electron transfer chain
8-aminoquinoline
 More active against liver hynozoites
(Tafenoquine , Etaquine and Primaquine)
 Use to Prevent the transmission of
disease.
 Active against P.vivax and P.ovale

20
Mechanism of action

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
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Primaquine
Drug
Mechanism of
action
Uses
Adverse Effects
Primaquine
Inhibits electron
transport chain in
Plasmodium
active against
hepatic stages of
all human malaria
parasites.
active 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
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G6pd defficiency
X chromosome linked genetic metabolic
condition-glucose 6-phosphate
dehydrogenase- in red cell
 Red cell can’t regenerate the NADPH
 Primaquine
oxidative metabolites
derivative of primaquine
decrease the
concentration of NADPH
metabolic
function of red cell impaired and
heamolysis occur…

23
Hydroxynaphthaoquinone Drugs
Inhibit electron transfer chain
 Atavaquone is used for treatment of
malaria and can prevent its development
 Resistance to atavaquone is rapid and
result from a single point mutation in the
gene of cytochrome b.

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Atovaquone
Drug
Mechanism of Uses
action
Adverse
Effects
Atovaquone
Mepron tablet
250mg
oral suspension
750mg/5mL
Inhibits
electron
transport chain
in Plasmodium
Abdominal pain
Cough
Depression
Diarrhea
Dyspnea
Fever
Headache
Infection
Insomnia
Treatment of acute
attack of malaria
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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
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Inhibit DNA replication transcription

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
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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
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Artemether-lumefantrine
Drug
Artemetherlumefantrine
(COARTEM)
Mechanism of
action
Both
artemether and
lumentantrine
inhibit nucleic
tablet
acid and protein
20mg/120mg
synthesis
Metabolism via
Half-Life:
lumefantrine:
artemether 2 hr; CYP2D6
lumefantrine 3-6 artemether:
days
CYP3A4
Uses
Adverse Effects
Treatment of acute
attack of malaria
Abdominal pain
Anorexia
Arthralgia
Chills
Dizziness
Fatigue
Headache
Myalgia
Cerebral malaria
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Drugs affecting synthesis and
utilization of folate
PABA
Dihydropteroate
synthetase
Folate
Dihydrofolate
reductase
Tetrahydrofalate
Synthesis of
thymidylate
DNA
synthesis
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Proguanil
Drug
Mechanism of
action
Uses
Adverse Effects
Proguanil
Paludrine
tablet
26.3mg
inhibit
plasmodial
dihydrofolate
reductase
Treatment of acute
attack of malaria
Abdominal pain
Hemolytic anemia
in G6PD
deficiency
Nausea
Vomiting
Half-life,
Elimination: 3.79.6 hr
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Pyrimethamine
Drug
Mechanism
of action
Uses
Adverse Effects
Pyrimethamine
Daraprim
Folic acid
antagonist
Treatment of
acute attack of
malaria
Abdominal cramps
Abnormal skin
pigmentation
Anaphylaxis
Anorexia
Arrhythmias (large
doses)
Atrophic glossitis
Depression
Fever
Insomnia
Lightheadedness
Malaise
Seizures
tablet
25mg
Half life: 96 hr
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Pyrimethamine/sulfadoxine
Drug
Mechanism of
action
Uses
Adverse Effects
pyrimethamine/s
ulfadoxine (Rx)
– Fansidar
Folic acid
antagonists
Treatment of acute
attack of malaria
Agranulocytosis
Anemias
Insomnia
Lightheadedness
Malaise
Seizures
Abnormal skin
pigmentation
Dermatitis
tablet
25mg/500mg
Pyrimethamine:
96 hr
Sulfadoxine:
~200 hr
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Antibiotics
Doxycline and tetracycline used in acute
attack of malaria and chemopropylaxis
purpose.
 Sometimes given in combination with
other drug.
 Clindamycin is also used.

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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
Clindamycin
Drug
Mechanism of Uses
amalctosobion
Adverse Effects
Clindamycin
(oral or
IV)
Inhibit the
ribosomal
translocation
Diarrhea, nausea,
rash
Treatment of malaria
Always use in
combination
with quinine-quinidine
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4-Aminoquinolone derivatives

Pyronaridine, a chloroquine relative, is being used in
combination with artesunate as a promising new
artemisinin- based combination therapy.

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.

Pyronaridine-artesunate is available as Pyramax® tablets
and pediatric granule formulations,and manufacture of this
compound is being undertaken by Shin Poong
Pharmaceuticals.
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8-Aminoquinolone derivatives
 Tafenoquine
is a lead candidate drug
aimed at a radical cure of P. vivax, and is
being studied in a Phase II/III.
A
fixed dose artemisinin combination
therapy,
artesunate-amodiaquine
(Coarsucam) has been approved by WHO
and developed by Sanofi- Aventis.
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Artemisinin derivatives
 The
endoperoxide feature of artemisinins,
which confers antimalarial activity, is shared by
ozonide OZ439, a synthetic endoperoxide.
 OZ439
carries the hope of providing a single
dose oral cure in humans when used in
combination.
 OZ439
is a rapidly acting agent against asexual
stage parasites.This drug is currently
undergoing Phase IIa trials.
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Newer target


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.
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osmidomycin
osmidomycin, which inhibits the 1desoxy-D-xylulose-5-phosphate
reductoisomerase in the mevalonateindependent pathway of isoprenoid
synthesis in the apicoplast.
 The apicoplast, a specialized parasite
organelle of algal origin, appears to be
important for lipid and heme biosynthesis.

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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
42
4) Hobbs C., Duffy P., Drugs for malaria:
something
old,
something
new,
something borrowed, F1000 Biology
Reports 2011, 3(24),1-9
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