Antimalarial drug

1. Antimalarial Drugs
SAURAVYADAV
Submitted To:-
Amrita Ma'am
Assistant Professor
MCSCOP
Submitted By:-
Saurav Yadav
B.pharm 3rd year
MCSCOP
Antimalarial Drugs

2. Malaria
• Malaria is an acute infectious disease
• Causative agent: Plasmodium species
 Protozoan parasite
 4 species infecting humans
Transmitted by female Anopheles mosquito
Is characterized by high fever with rigor, anaemia, profuse sweating.
• P. falciparum:- cause anacute, rapidly fluminating disease i.e. characterized by peristant high
fever, orthostatic hypertension and massive.
• P. vivax:- Causes a mider form of the disease.
• P. malariae:- Common to many tropical regions.
• P. ovale:- rarely encountered.
Life cycle of Malaria
.
.
3. Development of sexual forms
-occurs in Anopheles mosquitos
2. Erythrocytic stages
• Parasite invade RBCs
• Patient develops fever cycle
1. Hepatic (Pre erythrocytic) stages
-parasites localize in liver
-patient is asymptomatic

4. Antimalarial Drugs
CLASSES DRUGS
4-Aminoquinolines Chloroquine
Amodiaquine (AD)
Piperaquine
Quinoline methanol Mefloquine
Cinchona alkaloid Quinine, Quinidine
Biguanide Proguanil (Chloroguanide)
Diaminopyrimidine Pyrimethamine
8 Aminoquinoline Primaquine
Tafenoquine

5. Continue.....
Sulfonamides and suffone Sulfadoxine
Sulfamethopyrazine
Daptone
Antibiotics Tetracycline
Doxycycline
Clindamycin
Amino aicholos Halofantrine
Lumefantrine
Naphthyridine Pyronaridine
Naphthoquinone Atovaquone
Sesquiterpine lactose Artesunate
Artemother Arteether
Arterolane

6. Antimalarial drugs
CHLOROQUINE (CQ)
.
• Rapidly acting erythrocytic schizontocide against all species of
• Plasmodio.
• 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
Mechanism of action
• The parasite digests the host cell's hemoglobin to obtain essential amino acids
• The process releases large amounts of heme, which is toxic to the parasite
• To protect itself the parasite ordinarily polymerizes the heme to nontoxic hemozoin, which is
sequestered in the parasite's food vacuole
• Cholroquine prevents the polymerization to hemozoin
• The accumulation of heme results in lysis of both the parasite and the red blood cell

7. Pharmacokinetics
• Rapidly and completely absorbed from Gl 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
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
Uses
Extraintestinal amoebiasis,Rheumatoid arthritis, Discoid lupus erythematosus, Lepra reaction,
Photogenic reactions, Infectious mononucleosis

8. 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
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
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

9. Adverse effects
• 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
Uses
• Effective for multidrug resistant P. falciparum
• However its use is restricted due to its toxicity, cost and long half life

10. 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 (pre experythrocyte and gametocytes)
Mechanism of action
• 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
Uses
Malarial attacks :-Uncomplicated resistant falciparum, Complicated and severe malaria
including cerebral malaria
Is not highly active, adjunctive therapy with doxycycline, tetracycline and clindamycin is
needed

11. Adverse effects
 Cinchonism:
• Higher dose symptoms include nausea, vomiting, tinnitus, vertigo, headache, mental
confusion, difficulty in hearing and visual defects, diarrhea, flushing
 Rapid i.v. injection:
• To Hypotension and cardiac arrhythmias
• Can cause profused hypoglycemia
 Pregnancy:
• Causes abortion in early pregnancy by stimulating myometrium and premature labor by
stimulating uterus
• a Hypoglycaemia
uses
• Malarial attacks
• Uncomplicated resistant falciparum o Complicated and severe malaria including cerebral
malaria
• Is not highly active, adjunctive therapy with doxycycline, Tetracycline and clindamycin is
needed.

12. 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
• 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

13. 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
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 (5/P) or dapsone for treatment of falciparum malaria

14. 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 fakciparum
• Treatment and prophylaxis of falciparum malaria
• resistant to chloroquine
Adverse effects
• Mild GIT upset
• Megaloblastic anemia, bone marrow depletion
• Rashes, urticaria, serum sickness, drug fever
• Exfoliative dermatitis, Stevens Johnson syndrome
• Nephrotoxicity

15. 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
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

16. Adverse effects
• Abdominal pain, gastrointestinal upset, weakness or uneasiness chest
• Leucopenia (high dose)
• Hemolysis
• Methaemoglobinaemia
• Tachypnoea
• Cyanosis
uses
• radical cure of relapsing malaria (Povale and P.vivax)
• single 45mg dose given with curative dose of chloroquine to kill gametes (P. falciparum)
Contraindications
• Should not be given during pregnancy because fetus is glucose-6-phosphate
dehydrogenase (G-6-PD) deficient

17. 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
• 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

18. ARTEMISININ AND ITS DERIVATIVES:
• Active principle of plant Artemisia annua
• Sesquiterpene lactone endoperoxide
It includes:
1. Artesunate
2. Artemether
3. Arteether
4. Arterolane
Mechanism of action
• These compounds have presence of endoperoxide bridge
• Endoperoxide bridge interacts with heme in parasite
• Heme iron cleaves this endoperoxide bridge
• There is generation of highly reactive free radicals which damage parasite membrane by
covalently binding to membrane proteins

19. 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 im.
• 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. a/ß ARTEETHER
• Available for l.m. administration only to adults for complicated malaria
• Due to its longer elimination (tu-23hrs), it is recommended in a three day schedule

20. 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

21. 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:
 Arteether with quinine
 Artemether with quinine
Thank You