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Classification
Blood schizonticides:
Chloroquine, mefloquine, quinine, proguanil,
pyrimethamine, artemisinin derivatives,
lumefantrine, atovaquone, Doxycycline,
pyronaridine etc.
Tissue schizonticides: (exoerythrocytic pahse)
- Primary exoerythrocytic phase:
primaquine, atovaquone, proguanil
- Secondary exoerythrocytic phase: Primaquine
Gametocidal: Primaquine, artemisinin
derivatives
Chloroquine
A 4-aminoquinoline compound- erythrocytic
schizontocide against all species
No effect on tissue phases of the parasite
Does not prevent relapses (vivax & ovale)
MOA:
Interfere with heme detoxification
A weak base - accumulates in organism’s
acidic food vacuole
Generates free radicals and iron bound
heme as highly reactive byproducts
Chloroquine specifically binds to heme and
prevents its polymerization to hemozoin
Oxidative damage to membrane, digestive
proteases or other biomolecules
A chloroquine transporter glycoprotein
encoded by the “pfcrt” gene appears to
play a role in chloroquine resistance of P.
falciparum – other mech. are also possible
This gene encodes a transporter in the
membrane of acidic vacuoles – efflux
chloroquine via an energy dependent
process
Well absorbed by oral, i.m or s.c. routes
Sequestrated in lung, spleen, liver, kidney,
melanin containing tissues etc.
Terminal t/2 is 1
1--2 months
A loading dose is required b’coz of extensive
tissue binding to get therapeutic conc.
Metabolized by hepatic CYPs to two active
metabolites
Renal excretion of parent & metabolites is
increased by acidification of urine
ADRs
Narrow safety margin drug
Nausea, vomiting, anorexia, headache etc.
Rapid i.v. inj-
inj- hypotension, arrhythmia,
cardiac arrest, confusion, seizure & coma
High daily doses may result in retinotoxicity,
ototoxicity, toxic myopathy, neuropathy
Avoid in epilepsy and M. gravis patients
Use cautiously in liver/renal dysfunction,
severe GI or neurological disorders
Can be used in pregnancy
Hemolysis in G6PD deficiency (rare)
It inhibits CYP2D6 – drug interactions
Should not be given with mefloquine - ↑
risk of seizure and no added benefit
Patient taking long
long--term, high dose
therapy should undergo eye and
neurological examination every 3- 3-6 mo
DOC for clinical cure and suppressive
prophylaxis of all types of malaria, except
that caused by resistant P. falciparum
DLE
Rheumatoid arthritis
Amoebiasis
Mefloquine
Highly effective blood schizonticide –
effective against chloroquine sensitive as
well as resistant plasmodia
Very long t/2 (13-
(13-24 d); can cause
significant neuropsychiatric s/s in 10%
Avoid in pregnancy or use if no alternative
Contraindicated if, h/o seizure, MDI,
depression, neuropsychiatric conditions or
severe ADRs to other quinolines
With halofantrine or quinine - ↑ QTc
Quinine
More toxic and less effective than
chloroquine
Erythrocytic schizontocide for all species of
plasmodia
Chloroquine and MDR strains of P.
falciparum respond
MOA – similar to chloroquine
Metabolized by CYP3A4 (20% excreted
unchanged in urine)
t/2 increases in malaria based on severity
(due to ↓ clearance mainly) to 18 hrs
Higher peak levels achieved in malaria with
lower toxicity (↑ α1 acid GP, less free drug)
Dose related toxicities are – hypoglycemia
hypoglycemia,,
hypotension;
hypotension; Cinchonism - tinnitus,
nausea, vomiting (gastric irritation and CTZ
stimulation), headache, vertigo, difficulty in
hearing and vision (direct neurotoxicity +
constriction of retinal and auditory vessels)
Diarrhoea, flushing and perspiration also
Reversible if the drug is stopped
Discontinue if evidence of hemolysis
appears
Appears to be safe in pregnancy
Used orally for uncomplicated and iv for
complicated/ cerebral malaria (chloroquine
sensitive or resistant)
Proguanil & pyrimethamine
Erythrocytic schizontocide; proguanil also
inhibits primary exoerythrocytic phase
Proguanil cyclizes in the body to a triazine
derivative (cycloguanil) which inhibits
plasmodial DHFRase
Pyrimethamine is a directly acting inhibitor
of plasmodial DHFRase
Primaquine
An 8- aminoquinoline compound- Inactive
against erythrocytic schizonts
Highly effective on primary as well as secondary
(hypnozoites) tissue (liver) phases
Gametocidal for all species
MOA: not clear; may be generation of reactive
oxygen species and/or interference with
mitochondrial electron transport
t/2 (avg. 7 hrs); not a cumulative drug
Induces CYP1A2 (may interact with warfarin)
ADRs:
Dose related haemolysis (mainly in G-6-PD
deficiency), methaemoglobinaemia (severe
in NADH MetHb reductase deficiency) - due
to the oxidant property of primaquine
Artemisinin derivatives (Artesunate,
Artemether, Arteether)
Active against sensitive & MDR P. falciparum strains
Potent and rapid blood schizonticide
More rapid parasite clearance & fever resolution
Action on a wide range of parasite blood stages -
broadest time window of antimalarial action
Artemether is oil & Artesunate is water soluble
MOA: free radicals within food vacuoles following
cleavage of the drug’s endoperoxide bridge by
heme Fe in parasitized RBCs
DOA is short and recrudescence rate is
high (if used alone in short courses)
Monotherapy needs to be extended
beyond the disappearance of the parasites
to prevent recrudescence
Can be totally prevented by combining 3
day artesunate/artemether with a long-
acting drug
Artesunate: administered oral, im or iv
Rapidly converted to the active metabolite
dihydroartemisinin (DHA)
The t/2 of DHA is 1-2 hours
After repeated dosing, causes autoinduction
of its own metabolism (3A4, 2B6)
Artemether: administered orally/im, not
iv
Substantial 1st pass metabolism to DHA
Arteether: for complicated/ cerebral
malaria (im); longer elimination t/2 (23
hours), effective in a 3 day schedule with a
recrudescence rate of 5%
Recent (2006) WHO Regional guidelines for
SE Asia recommend a 5 day course
ACTs should not be used in children <5 kg
and during 1st trimestar of pregnancy
Lumefantrine
Orally active, high efficacy, long-acting
erythrocytic schizontocide
Acts in food vacuole to inhibit heme
polymerization
Metabolized predominantly by CYP3A4
Inhibits isoenzyme CYP2D6
Terminal t/2 is 2-3 days, (prolonged to 4-6
days in malaria patients)
Used only in combination with artemether
Only ACT currently available as FDC tablets
Active in MDR including mefloquine resistance
Artemether quickly reduces parasite burden,
lumefantrine prevents recrudescence
Not given with drugs metabolized by CYP2D6, or
with drugs which prolong QTc interval
Contraindicated in first trimester of pregnancy and
during breastfeeding
Atovaquone
Highly lipophilic analog of ubiquinone
Active against P falciparum blood and liver stages
Act by disrupting mitochondrial electron transport
Proguanil is synergistic and prevents resistance
BA is low but increased by food – mostly eliminated
unchanged in feces; t/2 = 2-2-3 d
Also used in treatment of P jiroveci and T. gondii in
AIDS
Objectives of therapy
To prevent and treat clinical attack of
malaria
To completely eradicate the parasite from
the patient's body
To reduce the human reservoir of infection
- cut down transmission to mosquito
Forms of antimalarial therapy
Causal prophylaxis: drugs affecting
primary exoerythrocytic phase, the cause of
malaria is target for such drugs
- Proguanil: mainly for falciparum (given
daily) & not very effective against vivax
- Primaquine: prophylactic for all species
of malaria; used only for subjects
who cannot take other prophylactic drug
Suppressive prophylaxis
Drugs suppressing erythrocytic phase and thus attacks
of malarial fever
- Chloroquine base 300mg 5mg/kg/wk; Start 1-2
week before and continue till 4 wks after return
- Proguanil 200 mg daily with chloroquine 300 mg
weekly
- Mefloquine 250 mg weekly (1-2 wks before) and
till 4 weeks after return
- Doxycycline 100 mg daily starting 1-2 day before
travel and taken till 4 weeks after return
Clinical cure
The blood schizonticides are used to
terminate an episode of malarial fever
Fast-acting high-efficacy drugs:
Chloroquine, quinine, mefloquine, artemisinin
etc.
Slow-acting low-efficacy drugs:
Proguanil, pyrimethamine, tetracyclines etc.
Radical cure
Drugs which attack hypnozoites given
together with a clinical curative achieve total
eradication of the parasite
Needed in relapsing malaria (vivax & ovale)
Primaquine 15mg daily for 14 days
Gametocytocidal
Elimination of gametes in the patient's
blood
No benefit to the patient but reduce the
transmission to mosquito
Primaquine and artemisinins are
gametocidal to all species of Plasmodia
A single 45 mg (0.75 mg/kg) dose of
primaquine base in falciparum malaria to
kill the gametes
Not necessary when an artemisinin is used
for clinical cure
Treatment regimens
P. vivax malaria
Chloroquine base: 10mg/kg (600mg) on
day 1, 10mg/kg (600mg) on day 2 and
5mg/kg (300 mg) on day 3
+
Primaquine base: 0.25 mg/kg body weight
(15mg) daily for 14 days from day 1