Download Antimalarial Drugs

Antimalarial Drugs
Drug Classifications
1.
Class 1 Drugs – Acts primarily on asexual erythrocytic phase
a. 4-Aminoquinoline
i. Chloroquine
b. Quinoline Methanol
i. Quinine
ii. Quinidine
c. Folate Antagonist Combination
i. Fansidar
1. Sulfadoxine
2. Pyrimethamine
d. Tetracycline
i. Tetracycline
ii. Doxycycline
e. Sesquiterprene Lactone Endoperoxide
i. Artemisnins Compounds
1. Artesunate
2. Artemether
3. Dihyroartemisnin
2. Class 2 Drugs – Acts on primary hepatic stage and erythrocytic phase
a. Biguanide Derivative
i. Proguanil
b. Hydroxynapthoquinone
i. Atovaquone
3. Class 3 Drugs – Acts primarily on hepatic stage
a. 8-Aminoquinoline
i. Primaquine
Treatment Regimes
Infections with
1.
2.
3.
4.
Plasmodium vivax
Plasmodium malariae
Plasmodium ovale
Chloroquine – sensitive Plasmodium falciparum
Regiments


Chloroquine
o
Loading dose
o
Followed by repeated dose for 3 days
Primaquine
o
Followed during the 4th days until 14th days for

Plasmodium vivax

Plasmodium ovale
Infections with
1.
Chloroquine-resistant Plasmodium falciparum
Regiments


Artemisnin-based Combination Therapy (ACT)
Quinine + Tetracyline/Doxycycline/Clindamycin
Infections with
1.
Severe Plasmodium falciparum
Regiments


Parenteral
o
Quinine
o
ACT
Followed by oral ACT
Prophylaxis Regimes
1.
Suppressive
a. Regiments
i. Chloroquine
ii. Doxycycline
b. Continue until 4th weeks after travelling to ensure complete parasite eradication
2. Causal
a. Regiments
i. Proquanil + ACT
ii. Primaquine
b. Continue until the 1st week after travelling is sufficient to ensure complete parasite
eradication
Class 1 Antimalarial Drugs
4-Aminoquinoline
Drugs
Chloroquine
1. Highly effective
blood schizonticide
2. Moderately effective
against gametocytes
a. P. vivax
b. P.malariae
c. P.ovale
d. NOT P.falciparum
3. CANNOT against
hepatic stage
parasite
Drug Resistance
 Distribution
o Very common in
P.falciparum
o Uncommon but
increasing in case
for P.vivax
 Mechanism
o P.falciparum
develops a
putative tansporter
of PfCRT
o In which this
transporter actively
eliminate
Chloroquine from
the parasite
Pharmacokinetics
Absorption
 Rapid and complete
upon oral admin
Distribution
 Reaches max plasma
concentration within
3 hours
 Widely distributed in
the tissue
 Extensive plasma
protein binding
Metabolism
 Hepatic metabolism
Excretion
 Long plasma half life
(due to high Vd level)
o 3-5 days
o 1-2 months (some
record)
 Advisable to start
with loading dose to
reach to
maintainance dose
immediately
 Excreted primarily
through urine
Mechanism of Action
1. Actively being
transported into RBCs
2. Tends to be
accumulated into
the food vacoules of
schizonts during
eating process of
heamoglobin
3. Chloroquine will be
ionized in the acidic
environment of food
vacoule making it
virtually impossible to
leave the vacoule
4. Chloroquine will
inhibit the
biocrytallization of
heme into hemozoine
leading to build up of
heme in the vacoule
5. Heme is toxic to
parasite therefore
suicidal to the
parasite
Indications
1. Infection of
a. P.falciparum
i. Clinical cure
ii. Radical cure
b. P.vivax and
P.ovalae
i. Clinical cure
2. Prophylaxis against
Chloroquine-sensitive
P.falciparum
3. Rheumatoid arthritis
4. Amoebic liver
abscess
Contraindication
1. G6PD defficiency
a. Severe hemolytic
anemia may occur
Adverse Effects
1. Oral admin
a. GIT disturbances
2. Parenteral admin
a. CNS effects
i. Convulsion
ii. Coma
b. CVS effects
i. Hypotension
ii. Cardiac
arrhythmias
3. Prolonged therapy (in
RA)
a. Visual disturbances
b. Retinopathy
Quinoline Methanol
Drugs
Quinine
1. Derived from the
bark of cinchona
tree which native
in the South
America
2. CANNOT against
hepatic stage
parasite
Pharmacokinetics
Absorption
 Rapid and
complete upon oral
admin
Distribution
 Reaches max
plasma
concentration
within 1- 3 hours
 Widely distributed in
the tissue
 Extensive plasma
protein binding
Metabolism
 Hepatic
metabolism
Excretion
 Long plasma half
life (due to high Vd
level)
o 18 hours
 Advisable to start
with loading dose
to reach to
maintainance dose
immediately
 Excreted primarily
through urine
Mechanism of Action
1. Highly active blood
schizontycide
2. Gametocidal to
a. P.vivax
b. P.ovalae
c. NOT
P.falciparum
MOA of Quinine is
remain uncertain
Indications
1.
line therapy for
a. Cerebral malaria
b. Chloroquine-resistant
infection
c. Severe P.falciparum
infection
2. Highly active against
infections of
a. P.vivax
b. P.falciparum
c. P.ovalae
d. P.malariae
3. Human babesiosis
a. Against Babesia microti
1st
Contraindication
1. G6PD defficiency
a. Black water fever
i. Marked hemolysis
ii. Hemoglobinaemia
iii. Hemoglobinuria
Adverse Effects
1. Quinine TRIADS
a. Cinchonism
i. Tinnitus
ii. Visual disturbance
b. Hypoglyceamia
c. Hypotension
2. Hypersensitivity
reaction
3. Cardiotoxicity
Sesquiterprene Lactone Endoperoxide
Drugs
Pharmacokinetics
Mechanism of Action
Absorption
1. Production of free
Artemisnin Compounds
 Rapidly and
radical in the food
(semisynthetic derivatives)
completely
absorp
vacoules
1. Artesunate – water soluble
upon admin
a. After the irona. Oral
Distribution
catalyzed
b. IV

Reaches
max
cleavage of
c. IM
plasma
artemisnin
d. Rectal
concentration
endoperoxide
2. Artemether – lipid soluble
within
12
hours
bridge
a. Oral
Metabolism
2. Inhibition of
b. IM
 Rapidly metabolize
Ca2+ATPase pump
c. Rectal
in the liver into
of the parasite
3. Dihyroartemisnin – water
o Dihyroartemisnin
soluble
(for artesunate
a. Oral
and artemether)
Excretion
Infos
 Derived from Chinese herbs  Half life of 1-3 hours
after oral admin
o Artemisia annua
 Excreted primarily
 Used as antipyretic in the
through urine
ancient China
 Rapidly acting blood
schizonticide
 Higher sensitivity to
Chloroquine-resistant
parasite
 10-100 times more potent
compared to other
antimalarial
 Never given alone to avoid
relapse
Indications
Never be given alone
due to
1. Might produce
resistance
2. Less efficacious
Indications
1. Severe P.falciparum
infection
2. Multi-drug resistant
malaria
Adverse Effects
Very well tolerated
Safety usage in
pregnancy and very
young children is yet to
be established
Folate Antagonist Combination
Drugs
Fansidar
1. Pyrimethamine
2. Sulfadoxine
Infos



It is under the group of
Sulfonamide
Never be given as
prophylaxis as it develops
resistance very quickly
Slo acting blood
schizonticide
*Proguanil





Never be used alone as
resistance develops quickly
Acts by inhibiting the
Dihyrofolate Reductase
enzyme
Used with combination
atavaquone (primarily) for
o Multi-drug resistance
falciparum malaria
Very safe
CLASS 2 ANTIMALARIAL
DRUGS
Pharmacokinetics
Absorption
 Very well absorp
upon admin
Distribution
 Distributed in
almost every body
compartments
Metabolism
o Undergoes
hepatic
metabolism
Excretion
 Excreted primarily
through urine
Mechanism of Action
1. Sulfadoxine inhibits
Dihyropteroate
Synthase enzyme
a. Inhibits the
formation of
Dihyropteroic
Acid
2. Pyrimethamine
inhibits the
Dihydrofolate
Reductase enzyme
a. Inhibits the
formation of
Tetrahydrofolate
3. These substances is
weak to be used
alone as Malarial
parasite has the
capability to uptake
exogenous folate
a. But when they
are given
together, it
produces
synergistic effect
outbalancing the
capability of
parasite of taking
exogenous folate
Indications
1. Chloroquine-resistant
P.falciparum malaria
a. With combination
with
i. Quinine
ii. Artemisnin
2. Toxoplasmosis
Adverse Effects
1. Severe fatal
cutaneous
reaction
a. StevenJohnson
Syndrome
Drugs
1. Tetracycline
2. Doxycycline
Infos
 Slow acting blood
schizonticide in all
types of malarial
parasites
Tetracycline
Pharmacokinetics
Mechanism of Action
Absorption
1. Binds to 30S
1. Tetracycline – 60-80%
ribosomal subunit
2. Doxycycline – 95%
2. Blocks tRNA binding
3. Best absorbed in acidic
to A site
condition especially during
fasting
a. ↓ absorption when taken
with dairy products and
antacids
4. At stomach and upper
intestine
Distribution
1. Wide distribution in
numerous parts of body
a. Reticuloendothelial
system
b. Prostate
c. Bone
d. Dentine
e. Unerupted teeth
Excretion
1. Tetracycline
a. Renal excretion
b. 20-60% of total oral
absorption is excreted
within 24 hrs
2. Doxycycline
a. Undergoes hepatic
metabolism and
excreted via liver
b. Therefore best indicated
for renal failure p
Indications
1. Prophylaxis for
travelers
2. Drug resistant
malaria
a. With combination
with quinine
Contraindication
1. Pregnant ladies
2. Children
Due to permanent
discoloration of teeth
Should be replaced
with Clindamycin; a
group of Lincosamide
antibiotic
1.
2.
3.
4.
5.
6.
Adverse Effects
GIT upset
Photosensitivity
Hepatic toxicity
a. High dose
Permanent brown
discoloration of
teeth
Renal toxicity
Bone growth
inhibition
Class 2 Antimalarial Drugs
Hydroxynapthoquinone
Drugs
Atovaquone
Infos
 Given together with
Proguanil in
preparation named
Malarone
Pharmacokinetics
Absorption
 Increased absorption
with fatty food
Distribution
 Low bioavailibility
 Heavily protein
bound
Excretion
 Half life of 2-3 days
 Excreted unchanged
in feces
Mechanism of Action
1. Acts by interfering
with the parasitic
mitochondrial
function
Indications
1. Drug resistant malaria
It is not advisable to be
used in pregnant ladies
and children
Adverse Effects
 GIT disturbances
a. Nausea
b. Diarhea
c. Vomitting
Class 3 Antimalarial Drugs
8-Aminoquinoline
Drugs
Primaquine


The only antimalarial
can fight againt
hepatic latent and
primary stage
No activity against
erythrocytic stage
Pharmacokinetics
Absorption
 Well absorp orally
Distribution
 Distributed in almost
every body
compartments
 Peak plasma level at
1-2 hours
Metabolism
 Undergoes hepatic
metabolism
Excretion
 Half life 3-8 hours
 Excreted primarily
through urine
Mechanism of Action
1. Inhibition of parasitic
respiratory function
Yet remain unproven
Indications
1. Radical cure and
prophylaxis of
a. P.vivax
b. P.ovalae
Contraindication
1. G6PD defficiency
a. Severe hemolytic
anemia may occur
Adverse Effects
1. GIT disturbances
a. Nausea
b. Vomiting
c. Epigastric pain
d. Abdominal cramp
2. Dizziness