The Lecture prepared for UG students

1. Pharmacology of Anti-
malarial drugs
Lecture by
Dr.T.S.Mohamed Saleem
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2. Malaria
• Important parasitic disease of humans and causes hundreds of millions of illnesses per
year.
• Four species of plasmodium typically cause human malaria:
• Plasmodium falciparum, P vivax, P malariae, and P ovale.
• A fifth species, P knowlesi, is primarily a pathogen of monkeys, but has recently been
recognized to cause illness, including severe disease, in humans in Asia.
• P falciparum is responsible for the majority of serious complications and deaths.
• Drug resistance is an important therapeutic problem, most notably with P falciparum.
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3. 3

4. Malaria transmission cycle
Parasite undergoes
sexual reproduction in
the mosquito
Some merozoites
differentiate into male or
female gametocyctes
Erythrocytic Cycle:
Merozoites infect red
blood cells to form
schizonts
Dormant liver stages
(hypnozoites) of P.
vivax and P. ovale
Exo-erythrocytic (hepatic) Cycle:
Sporozoites infect liver cells and
develop into schizonts, which release
merozoites into the blood
MOSQUITO HUMAN
Sporozoires injected
into human host during
blood meal
Parasites
mature in
mosquito
midgut and
migrate to
salivary
glands
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5. Signs and symptoms
• Initial manifestation of malaria are
non-specific and resembles to flu
like symptoms.
• The presentation includes
headache, fever, shivering,
arthralgia, myalgia.
• The paroxysm which includes
fever spikes, chills and rigors are
classical for malaria
The typical paroxysmal attack comprises of three distinct
stages:
a) Cold stage- The onset is with lassitude, headache, nausea
and chilly sensation followed by rigors. The stage lasts for ¼ -
1 hour
b) Hot stage- The patient feels burning hot, the skin is hot
and dry to touch. Headache is intense. Pulse rate is high. The
stage lasts for 2-6 hours
c) Sweating stage- Fever comes down with profuse
sweating. The pulse rate gets slower, patient feels relieved.
The stage lasts 2-4 hours
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6. Relapse Vs Recrudesence
• Depending upon the cause , recurrence can be classified either as
recrudescence or relapse
• Recrudescence is when symptoms return after a symptoms free period. It is
due to parasites surviving in the blood as a result of inadequate or
ineffective treatment.
• Relapse is when symptoms reappear after the parasites have been
eliminated from blood but persist as dormant hypnozites in liver cells.
• Relapse is common in P.ovale and P.vivax infection
• Recrudescence is commonly seen in P.falciparum
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7. Classification
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8. Primaquine
• Primaquine [PRIM-a-kwin], an 8-aminoquinoline, is an oral
antimalarial drug
• Eradicates primary exoerythrocytic (tissue) forms of plasmodia
and the secondary exoerythrocytic forms of recurring malarias (P.
vivax and P. ovale).
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9. MOA/Pharamcokinetics
• Primaquine – Metabolites – Toxicants
• Responsible for the schizonticidal action
• Well absorbed
• It is rapidly oxidized to many compounds, primarily the deaminated
drug.
• The drug is minimally excreted in the urine
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10. ADR
• Drug-induced hemolytic anemia in patients with glucose-6-
phosphate dehydrogenase deficiency.
• Abdominal discomfort
• Occasional methemoglobinemia.
• Primaquine should not be used during pregnancy.
• All Plasmodium species may develop resistance to primaquine.
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11. Chloroquine
• Rapidly acting erythrocytic schizontocide against all species of
plasmodia including the senstive strains of P. falciparum
• Controls most clinical attacks in 1-2 days with disappearance of
parasites from peripheral blood in 1-3 days.
• No effect on Pre-erythrocytic and exo-erythrocytic phases of
the parasite does not prevent relapses in vivax and ovale malaria.
Only for clinical cure.
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12. MOA 12

13. Pharmacokinetics
• Oral
• Widely distributed & concentrated in tissues
like liver, spleen, kidney, lungs (several hundred-fold), skin,
leucocytes and some other tissues
Its selective accumulation in retina is responsible for the ocular
toxicity seen with prolonged use
• metabolized by liver
• excreted in urine.
• The early plasma t1/2 varies from 3-10 days. Because of tight
tissue binding, small amounts persist in the body for longer time.
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14. ADR
• GI intolerance
• Nausea, vomiting, abdominal pain, headache, anorexia,
malaise, and urticaria are common. Dosing after meals may
reduce some adverse effects.
• The long-term administration - loss of vision due to retinal
damage.
• Corneal deposits may occur affect vision: reversible
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15. Contra indication
• Chloroquine can ppt attacks of seizures, psoriasis
• or porphyria
• Cautious use
• Liver damage
• Severe GI, neurological, retinal & haematological
• diseases
• Safe in pregnancy and for young children
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16. Other action
• E. histolytica & Giardia lambia
• Anti-inflammatory
• Local irritant
• Local anaesthetic (on injection)
• Weak smooth muscle relaxant
• Anti-histaminic
• Anti-arrythmic properties
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17. Mefloquine
• Chemically related to quinine
• Fast acting Erythrocytic schizonticidal
Hepatic stage ×
Gametocyte stage ×
• Mechanism same as chloroquine
• Active against chloroquine sensitive as well resistant P.vivax and
falciparum
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18. Pharmacokinetic
• Single dose: 15mg/kg controls fever & eliminates circulating
parasites(both P. vivax & pf)
• Well absorbed orally, absorption enhances by food
• Not used parentally
• Excreted in bile and urine
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19. Therapeutic use
Mefloquine is effective therapy for many chloroquine resistant
strains of P falciparum
Chemoprophylactic drug for most malaria-endemic regions with
chloroquine-resistant strains
Sporadic resistance to mefloquine has been reported from many
areas
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20. Quinine
• 1820 Pelletier & caventou isolated quinine
• from cinchona bark.
• • Mechanism of action:
• – Similar to chloroquine
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21. • 1. Antimalarial action:
• – Erythrocytic forms of all
malarial parasites including
• resistant falciparum strains .
• – Gametocidal for vivax &
malariae
• 2. Local irritant effect:
• – Local pain sterile abcess.
3. Cardiovascular:
– depresses myocardium, ↓ excitability, ↓
conductivity,
↑ refractory period, profound hypotension
IV.
4. Miscellaneous actions:
– Mild analgesic, antipyretic activity ,
stimulation of
uterine smooth muscle, curaremimitic
effect
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22. ADR
• Cinchonism:
• • Tinnitus, nausea & vomiting
• • Headache mental confusion, vertigo,
• difficulty in hearing & visual disturbances
• • Diarrhoea , flushing & marked perspiration
• • Still higher doses , exagerated symptoms
• with delirium , fever, tachypnoea,
• respiratory depression , cyanosis.
Idiosyncrasy : similar to
cinchonism but
occurs in therapeutic doses
• Cardiovascular toxicity:
cardiac
arrest, hypotension ,fatal
arrhytmias
• Black water fever:
• Hypoglycemia:
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23. Use
• Malaria:
• – uncomplicated resistant falciparum malaria
• – Cerebral malarial
• • Myotonia congenita: 300 to 600 mg BD/ TDS
• • Nocturnal muscle cramps: 200 – 300 mg
• before sleeping
• • Spermicidal in vaginal creams
• • Varicose veins: along with urethane causes
• thrombosis & fibrosis of varicose vein mass
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24. Dihydrofolate reductase inhibitors
• Proguanil :
• – Biguanide converted to cycloguanil active compound
• – Act slowly on erythrocytic stage of vivax & falciparum
• – Prevents development of gametes
• Adverse effects:
• Stomatitis, mouth ulcers, larger doses depression of myocardium
, megaloblastic anemia
• Not a drug for acute attack
• Causal prophylaxis: 100 – 200 mg daily
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25. Pyrimethamine
• Diaminopyrimidine more potent than proguanil
• & effective against erythrocytic forms of all species.
• • Tasteless so suitable for children
• Adverse events:
• megaloblastic anemia,
• thrombocytopenia,
• agranulocytosis
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26. Artemisinin
• Artemisinin is the active principle of the plant Artimisia
annua
• • Sesquiterpine lactone derivative
• • Most potent and rapid acting blood schizonticides
• • Short duration of action
• • high recrudescence rate
• • Poorly soluble in water & oil
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27. Pharmacokinetics
• Poorly soluble in water & oil
• Derivatives
• Artemether: soluble in oil; oral; i.m
• Artesunate: water soluble; oral; i.m + i.v
• Active metabolite generated in the body DHA is also
used orally
• Arte-ether (injectable; i.m in oil) was produced in India
• Arterolane : totally synthetic has been developed here
• Collectively k/a Artemesinins
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28. MOA
• 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
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29. ADR
• Leucopenia
• • Hypersensitivity: Drug fever, itching
• • GIT: nausea, vomiting, abdominal pain (common)
• • ECG changes: ST-T changes, QT prolongation
• • Abnormal bleeding, dark urine
• • Reticulocytopenia
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