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Antimalarial Drugs
Malaria
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Malaria is an acute infectious disease
Causative agent : Plasmodium species
Protozoan parasite
4 species infecting humans
P. falciparum
P. vivax
P. malariae
P. ovale
• Transmitted by female Anopheles mosquito
• Is characterized by high fever with rigor, anaemia, profuse
sweating
Types of malaria
Plasmodium
falciparum
Plasmodium vivax
•most dangerous
•Causes a milder
species
form of the disease
•causes an acute,
rapidly fulminating
disease i.e.
characterized by
persistent high fever,
orthostatic
hypotension, and
massive
erythrocytosis
•capillary obstruction
and death if
treatment is delayed
Plasmodium
malariae
Plasmodium ovale
•Common to many
tropical regions
•rarely encountered
Life cycle of Malaria
1. Hepatic (Pre erythrocytic) stages
-parasites localize in liver
-patient is asymptomatic
2. Erythrocytic stages
-parasite invade RBCs
-patient develops fever cycle
3. Development of sexual forms
-occurs in Anopheles mosquitos
Life cycle of Malaria
Antimalarial Drugs
CLASSES
DRUGS
1. 4-Aminoquinolines
Chloroquine (CQ)
Amodiaquine (AQ)
Piperaquine
2. Quinoline-methanol
Mefloquine
3. Cinchona alkaloid
Quinine, Quinidine
4. Biguanide
Proguanil (Chloroguanide)
5. Diaminopyrimidine
Pyrimethamine
6. 8-Aminoquinoline
Primaquine
Tafenoquine
Antimalarial Drugs
CLASSES
DRUGS
7. Sulfonamides and sulfone
Sulfadoxine
Sulfamethopyrazine
Dapsone
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Antibiotics
Tetracycline
Doxycycline
Clindamycin
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Sesquiterpine lactones
Artesunate
Artemether
Arteether
Arterolane
10. Amino alcholos
Halofantrine
Lumefantrine
11. Naphthyridine
Pyronaridine
12. Naphthoquinone
Atovaquone
Drugs used in malaria
• Tissue schizontocides- drugs eliminating developing or
dormant liver forms
• Blood schizontocides- drugs acting on erythrocytic parasites
• Gametocides- drugs that kill sexual stages and prevent
transmission to mosquitoes
Forms of Antimalarial Drugs
• Clinically malarial infections can be controlled by the drugs
used in following ways:
1. Causal prophylaxis
2. Suppressive prophylaxis
3. Clinical cure
4. Radical cure
5. Gametocidal
1. Causal prophylaxis
• Drugs prevent the maturation of or destroy the sporozoites
within the infected hepatic cell- thus prevent erythrocytic
invasion
• Primaquine – for all species of malaria but not used due to its
toxic potential
• Proguanil- primarily for P. falciparum and not effective against
P. vivax (weak activity), rapid development of resistance
2. Suppressive prophylaxis
• Schizontocides inhibit erythrocyte phase and prevent the
rupture of the infected erythrocytes, lead to freedom from
rigors and pyrexia
• Includes quinine, chloroquine, proguanil, pyrimethamine,
artemicinin and tetracycline
3. Clinical cure
• Erythrocytic schizontocides are used to terminate episodes of
malarial fever
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Fast acting high efficacy drugs:
Chloroquine, quinine, mefloquine, halofantrine, artemicinin
Used singly to treat malaria fever
Faster acting, preferably used in falciparum malaria where
delayed treatment may lead to death even if parasites are
clear from blood
• Slow acting low efficacy drugs:
o Proguanil, pyrimethamine, sulfonamides, tetracyclines
o Used only in combination
4. Radical cure
• Drug attack exoerythrocytic stage (hypnozoites) given with
clinical curative for the total eradication of the parasite from
the patient’s body
• Radical cure of the P. falciparum malaria can be achieved by
suppressives only
• For radical cure of P.vivax infection, primaquine and
proguanil are effective
5. Gametocial
• Removal of male and female gametes of Plasmodia formed in
the patient’s blood
• It has no benefit for treated patient
• Primaquine and artemisinins are highly effective against
gametocytes of all species
Antimalarial drugs
CHLOROQUINE (CQ)
• Rapidly acting erythrocytic schizontocide against all species of
Plasmodia
• Drug of choice for treating acute attacks caused by sensitive
strains of P. vivax or P. falciparum
• Controls most clinical attack in 1-2days with disappearance of
parasite from peripheral blood in 1-3days
• No effect on exo- erythrocytic phase
• Neither prevent primary infection nor relapse in P. vivax and
P.ovale
• Drug of choice for use in pregnancy, prophylaxis
Chloroquine
Mechanism of action
Chloroquine
Mechanism of action
i.
The parasite digests the host cell’s hemoglobin to obtain
essential amino acids
ii. The process releases large amounts of heme, which is toxic
to the parasite
iii. To protect itself the parasite ordinarily polymerizes the
heme to nontoxic hemozoin, which is sequestered in the
parasite’s food vacuole
iv. Cholroquine prevents the polymerization to hemozoin
v. The accumulation of heme results in lysis of both the
parasite and the red blood cell
Chloroquine
Pharmacokinetics
• Rapidly and completely absorbed from GI tract
• Substantial amount is deposited in erythrocytes, liver, spleen,
kidney, lung, melanin containing tissues and leukocytes
• Slow release from these sites helps in maintaining the
therapeutic plasma levels – when used for prophylaxis, it is
administered just once a week
• Also crosses the blood- brain barrier and traverses the
placenta
• Excreted predominantly in the urine
Chloroquine
Adverse effects
• CNS- mild headache, confusion, psychosis,
convulsion, impaired hearing
• Eye (with high dose)- loss of vision due to retinal
damage, reversible corneal damage
• GIT- Nausea, vomiting, anorexia, epigastric pain,
diarrhea( can be minimized by taking with meal)
• Skin- uncontrolled itching, urticaria, exfoliative
dermatitis
• Parenteral administration- Hypotension, cardiac
arrhythmias, cardiac depression
Chloroquine
Uses
• Extraintestinal amoebiasis
• Rheumatoid arthritis
• Discoid lupus erythematosus
• Lepra reaction
• Photogenic reactions
• Infectious mononucleosis
Chloroquine
Contraindications
• Patient with psoriasis, porphyria
• In dermatitis, liver damage, alcoholism, neurological, retinal
and hematological diseases
MEFLOQUINE (MQ)
• Fast acting erythrocytic(blood) schizontocide but slower than
CQ or quinine
• Effective against CQ-sensitive as well as resistant Plasmodia
• Efficacious suppressive prophylactic for multi-resistant P.
falciparum
Mefloquine
Mechanism of action
• Like CQ, it accumulates in infected RBCs, binds to heme and
this complex damages the parasite’s membrane
• However recent evidence suggests that the site of action of
MQ is in the parasitic cytosol rather than in the acidic vacuole
Mefloquine
Pharmacokinetics
• Prolonged absorption after oral ingestion
• It is highly plasma protein bound and concentrated in the
liver, lung and intestines
• Extensive metabolism occurs in liver and is primarily secreted
in bile
• It has a long half life (17days) due to its concentration in
various tissues and its continuous circulation through the
enterohepatic and enterogastric systems
• Its major excretory route is feces
Mefloquine
Adverse effects
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MQ is bitter in taste
At high doses:
Nausea, vomiting, diarrhea, abdominal pain, bradycardia
Ataxia, hallucinations, depression
MQ is safe in pregnancy
Rare events of toxicity are seen
Contraindications
• In patients with anxiety, depression, psychosis, and in cardiac
conduction defects
Mefloquine
Drug interactions
• Cardiac arrests are possible if MQ is taken concurrently with
quinine or quinidine
Uses
• Effective for multidrug resistant P. falciparum
• However its use is restricted due to its toxicity, cost and long
half life
QUININE
• Quinine is a l-isomer of alkaloid obtained from cinchona bark
and quinidine (antiarrhythmic) is its d-isomer
• An effective erythrocytic schizontocide as suppressive and
used to prevent or terminate attacks of vivax, ovale, malariae,
sensitive falciparum
• Moderately effective against hepatic form (preexoerythrocyte and gametocytes)
Quinine
Mechanism of action
• Like CQ it is a weak base, and acts by inhibiting polymerization
of heme to hemozoin
• Free heme or heme-quinine complex damages parasite’s
membrane and kills it
Pharmacokinetics
• Well absorbed from GI tract, even in patients with diarrhea
• Metabolized in liver and excreted in urine
Quinine
Adverse effects
• Cinchonism:
o Higher dose symptoms include nausea, vomiting, tinnitus,
vertigo, headache, mental confusion, difficulty in hearing and
visual defects, diarrhea, flushing
• Rapid i.v. injection:
o Hypotension and cardiac arrhythmias
• Can cause profused hypoglycemia
Adverse effects
• Pregnancy:
o Causes abortion in early pregnancy by stimulating
myometrium and premature labor by stimulating uterus
o Hypoglycaemia
Clinical uses
• Malarial attacks
o Uncomplicated resistant falciparum
o Complicated and severe malaria including cerebral malaria
• Is not highly active, adjunctive therapy with doxycycline,
tetracycline and clindamycin is needed
PROGUANIL (CHLOROGUANIDE)
• Slow acting erythrocytic schizontocide
• Cyclized in body to a triazine derivative(cycloguanil)
• Cycloguanil inhibits plasmodial dihydrofolate reductase
(DHFRase)
• Resistance developed due to mutational changes in the
plasmodial DHFRase enzyme
Proguanil
• Slow but adequate absorption from the gut
• Partly metabolized and excreted in urine
• Half life 16-20 hour ; noncumulative
Adverse effects
• Mild abdominal upset, vomiting
• Occasional stomatitis
• Haematuria, rashes and transient loss of hair
• Note : Safe during pregnancy
PYRIMETHAMINE
• Slow acting erythrocytic schizontocide
• Direct inhibitor of plasmodial dihydrofolate reductase
(DHFRase)
• Conversion of dihydrofolic acid to tetrafolic acid is inhibited
• High doses inhibits Toxoplasma gondii
• Resistance develops by mutation in DHFRase enzyme
Pyrimethamine
Adverse effects
• Occasional nausea and rashes
• Folate deficiency rare
• Megaloblastic anaemia and granulocytopenia with higher
dose
• Can be treated with folinic acid
• Combined with a sulfonamide (S/P) or dapsone for treatment
of falciparum malaria
SULFONAMIDE-PYRIMETHAMINE(S/P)
• Sulphadoxine is a sulfonamide thus competes with para–
amino benzoic acid – inhibits the formation of dihydropteric
acid
• Pyrimethamine inhibits DHFRase enzyme as a result of which
conversion of dihydrofolic acid to tetrahydrofolic acid is
blocked – thus inhibits DNA synthesis
• Effective blood schizontocide against Plasmodium
falciparum
• Treatment and prophylaxis of falciparum malaria
resistant to chloroquine
Sulfonamide-Pyrimethamine(S/P)
Adverse effects
• Mild GIT upset
• Megaloblastic anemia, bone marrow depletion
• Rashes, urticaria, serum sickness, drug fever
• Exfoliative dermatitis, Stevens Johnson syndrome
• Nephrotoxicity
PRIMAQUINE
• Poor erythrocytic schizontocide
• Has marked effect on primary and secondary hepatic phases
of malarial parasite
• Highly active against gametocytes and hypnozoites
Mechanism of action
• Intermediate act as oxidant that are responsible for the
schizontocial action
Primaquine
Pharmacokinetics
• Readily absorbed after oral absorption
• Oxidized in liver with a plasma half life of 3-6 hours
• Excreted in urine within 24 hour
• Not a cumulative drug
Primaquine
Adverse effects
• Abdominal pain, gastrointestinal upset, weakness or
uneasiness chest
• Leucopenia (high dose)
• Hemolysis
• Methaemoglobinaemia
• Tachypnoea
• Cyanosis
Primaquine
Contraindications
• Should not be given during pregnancy because fetus is
glucose-6-phosphate dehydrogenase ( G-6-PD) deficient
Clinical uses
• radical cure of relapsing malaria (P.ovale and P.vivax)
• single 45mg dose given with curative dose of chloroquine
to kill gametes (P. falciparum)
TETRACYCLINE AND DOXYCYCLINE
( Antibiotics)
• Used against chloroquine resistant malaria
• Kills erythrocytic stage of the malarial parasite
• Tetracycline is used for acute attack only
• Doxycycline is used for prophylaxis and acute attack
• For treating acute attack they are used in combination with
quinine
• Should not be given to children and pregnant women
CLINDAMYCIN
( Antibiotics)
• Active against the erythrocytic stage of the malaria parasite
• Liver stage and gametocytes are not affected
• Drug used adjunct to quinine to treat malaria caused by
chloroquine resistant Plasmodium falciparum
• Can be used in children and pregnant women
ARTEMISININ AND ITS DERIVATIVES:
• Active principle of plant Artemisia annua
• Sesquiterpene lactone endoperoxide
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It includes:
Artesunate
Artemether
Arteether
Arterolane
Mechanism of action
1. ARTESUNATE
• Its sodium salt is water soluble and is administered by oral,
i.m. or i.v. route
• Rapidly converted to active metabolite dihydroartemisinin
(DHA)
• After repeated dosing, artesunate causes autoinduction of its
own metabolism by CYP2B6 and CYP3A4
2. ARTEMETHER
• Lipid soluble and is administered orally or i.m.
• Absorption after oral or i.m. dosing is slower taking 2-6 hrs
• Undergoes substantial first pass metabolism and is converted
to DHA
• Extensive metabolism by CYP3A4 yields a variable half life of
3-4 hrs
3. α/β ARTEETHER
• Available for i.m. administration only to adults for complicated
malaria
• Due to its longer elimination (t1/2=23hrs), it is recommended
in a three day schedule
ARTEMISININ
Adverse effects
• First degree A-V block
• Q-T prolongation
• Transient reticulopenia and leucopenia (rare)
• Bleeding, dark urine
• Headache, tinnitus, dizziness
• Abdominal pain, itching, nausea, vomiting
Artemisinin
Drug interaction
• Concurrent administration of artemisinins with drugs
prolonging Q-T like astemizole, antiarrhythmics, tricyclic
antidepressants and phenothiazines may increase the risk of
cardiac conduction
ARTEMISININ BASED COMBINATION
THERAPY (ACT)
• One of artemisinin compound in combination with another
effective erythrocytic schizontocide is used.
• Consideration must be made about t1/2 of companion drug to
maintain its effective concentration in the blood for at least
3-4 asexual cycles of the parasite.
• Kills >95% of the plasmodia
Advantages of ACT
• Rapid clinical and parasitological cure
• High cure rates(>95%) and low recrudescence rate
• Absence of parasite resistance
• Good tolerability profile
• Dosing schedule is simpler
1. Artesunate-sulfadoxine +
pyrimethamine(AS-S/P)
• First line drug for uncomplicated falciparum malaria
• Not effective against multidrug-resitant strains which are non
responsive to S/P
• Fewer side effects than AS/MQ
2. Artesunate/mefloquine(AS/MQ)
• Highly effective and well tolerated in uncomplicated
falciparum malaria
3.Artemether-lumefantrine(AS/LF)
• Clinical efficacy: 95-99%
• Must be administered with fatty food or milk to allow
absorption and ensure adequate blood level of AS/LF
• Quickly reduces parasite biomass, resolve symptoms, prevent
recrudescence, check gametocyte population
AS/LF
Adverse drug reaction
• Headache, dizziness, abdominal pain, arthralgia, myalgia,
pruritus and rashes
Drug interaction
• Not to be given with drugs metabolized by CYP2D6( e.g.
metoprolol) as lumefantrine inhibits isoenzyme CYP2D6
Contraindication
• during first trimester of pregnancy and lactation period
4. Dihydroartemisinin(DHA)piperaquine
• Used in dose ratio of 8:1 for multidrug resistant Plasmodium
falciparum
• Good safety profile and even tolerated by children (>98%
response rate)
Adverse drug reaction
• Dizziness, rashes
• Vomiting and GI symptoms
5. Artesunate-amodiaquine(AS/AQ)
• First line therapy of uncomplicated falciparum malaria
• To be taken twice daily for three day treatment
• Other recently developed ACT are:
6. Arterolane-piperaquine
• Acts rapidly at all stages of asexual schizogony of malarial
parasite including multidrug resistant P. falciparum
7. Artesunate-pyronaridine
• Under clinical trial
CEREBRAL MALARIA
• Most severe neurological complication of infection
with Plasmodium falciparum
• Aggregation of infected and non infected red cells and
plugging in capillary endothelium of brain due to secreted
proteins on red cell surface by late stage schizonts
• Enhanced by the pro-inflammatory status of the host and
virulence characteristics of the infecting parasite variant
• Manifested by confusion, coma and death due to anoxia,
ischaemia and haemorrhage
Drugs used in Cerebral malaria
• Quinine by slow intravenous infusion
• Artemisinin derivatives that produce a very rapid therapeutic
response and are effective against multi-drug resistant P.
falciparum are preferred
• Some of the drugs used as a combination therapy for cerebral
malaria are:
o Arteether with quinine
o Artemether with quinine
REFERENCES
1. Tripathi KD, Essentials of MEDICAL PHARMACOLOGY, Jaypee
Brothers Medical Publishers (P) Ltd, 7th edition, 2013.
2. Finkel Richard et all, Pharmacology, Lippincott’s Illustrated
Reviews, 4th edition.
3. The treatment of complicated and severe malaria, BRITISH
MEDICAL BULLETIN.