2. INTRODUCTION
• Cause: Plasmodium
6 species: P falciparum (Severe)
P. vivax
P. ovale curtisi
P. ovale wallikeri
P. malariae
P. knowlesi (Monkey parasite)
• Transmission: female anopheles mosquito:
Sporozoites
5. CLASSIFICATION
Agents not effective against primary or
latent liver stage:
Artemisinin
Chloroquine
Mefloquine
Quinine
Quinidine
Pyrimethamine
Sulfadoxine
Tetracycline
Agents targeting both erythrocytic form
and primary liver stage of falciparum
Atovaquone
Proguanil
Agent effective against primary and
liver stage and also gametocytes
Primaquine
Taefnoquine
6.
7. ANTIMALARIAL
• NO ANTIMALARIAL KILLS SPOROZOITES
• Cant prevent infection
• Can only prevent development of symptomatic
malaria by targeting asexual exo-erythrocytic forms
8. ARTEMISININ AND ITS DERIVATIVES
1. Dihydro-artemisinin(oral)
2. Artemether(oral/ IM/ Rectal)
3. Artesunate(oral/IV/IM/Rectal)
Not effective against primary or latent liver stage
Some activity against gametocytes
9. ARTEMISININ AND ITS DERIVATIVES
Uses:
First line antimalarial
• Treatment of severe P. falciparum and asexual
erythrocytic stage of vivax
• ACT: to avoid emergence of resistance (delayed
parasite clearance time)
• Reason: mutation in Pfk13 gene encoding kechl 13
protein( how? UK)
• Resistance of non falciparum species to artemisinin-
not reported
10. ARTEMISININ AND ITS DERIVATIVES
Mechanism of action: cleavage of endoperoxide
bridge – generation of reactive oxygen species -
oxidative stress- protein damage via alkylation
ADME: oral/IM/IV/Rectal
Bioavailability (Oral) : 30%
Plasma protein bound: 40- 80%
Half life: 1-2 hr - NOT for prophylaxis
Induce their own metabolism via CYP2B6, CYP3A4
11. ARTEMISININ AND ITS DERIVATIVES
Side effect:
• GI side effect
• Neutropenia
• Hemolysis
• Anaphylaxis
• Urticaria
• Fever
• Not indicated in pregnancy and Children <5 YR age
(increased embryo lethality in rats)
13. LUMEFANTRINE
• First line of treatment
• Large volume of distribution
• Half life 4-5 days
• Fatty meal increase absorption
• No major side effect
• Artemether-lumefantrine (1.5/9 mg/kg bid for 3 days
with food)
14. AMODIAQUINE
• Half life: 3 hr
• Metabolite half life: 9- 18 days
• Side effect: Agranulocytosis
Hepatitis
Artesunate (4 mg/kg qd for 3 days) plus amodiaquine
(10 mg of base/kg qd for 3 days)
15. PIPERAQUINE
• Half life: 21- 28 days(longest among partner drugs)
• Resistance seen in some places: mutation in Pfk13
gene
• No major side effect
• DHA-piperaquine 4/18 mg/kg qd for 3 days in
persons weighing ≥25 kg)
17. ATOVAQUONE
• 250 mg atovaquone and 100 mg proguanil
hydrochloride * 3days
• FDC for prophylaxis, uncomplicated falciparum, resistant
falciparum
• Vivax malaria: but may reoccur- No activity against
hypnozoites
18. ATOVAQUONE
• Mechanism of action: inhibits electron transport,
inhibits regeneration of
ubiquinone
• Not toxic to human: structural differences in the amino
terminal regions of plasmodial and human cytochrome b
19. ATOVAQUONE
• ADME: Slow and variable oral absorption (fatty meal)
• 99% plasma protein bound
• Enterohepatic circulation
• Excreted in bile and feces
• Half life – 2-3 days
No major side effect
Rarely elevation of transaminases or amylase
20. DIAMINOPYRIMIDINES
• Sulfadoxine and pyrimethamine: was primary
treatment for falciparum
• Artesunate (4 mg/kg qd for 3 days) plus sulfadoxine
(25 mg/kg)/pyrimethamine (1.25 mg/kg) as a single
dose
• No longer recommended
21. DIAMINOPYRIMIDINES
• Mechanism of action: inhibit folate biosynthesis-
schizontocide
• No activity against hepatic form, hypnozoites,
gametocytes- increased transmission
• Dihydropteroate synthase and inhibited by
sulfonamides
• Reduction of dihydrofolate to tetrahydrofolate, which
is catalyzed by dihydrofolate reductase and inhibited
by pyrimethamine
22. DIAMINOPYRIMIDINES
• ADME: 90% Plasma protein bound
• Half life pyrimethamine: 85-100 hr
• Supressive concentration last for 2 wk
• Enter milk : contraindicated in lactation
• Teratogenic in animal : contraindicated in pregnancy
24. PROGUANIL
• Mechanism of action: inhibit dihydrofolate
reductase- thymidylate synthetase
Required for purine and pyrimidine synthesis
• Active against primary liver stage and asexual blood
cell stage
• No activity against latent stage and gametocyte (may
recur)
25. PROGUANIL
Uses: chemoprophylaxis(100mg) along with
atovaquone(250 mg)* 3 days
May be used for treatment in resistant cases
Side effect: no severe side effect, nausea, diarrhea,
abdominal pain
26. PROGUANIL
ADME:
• HALF LIFE 180-200hr
• Metabolized by CYP2C19 - active cycloguanil and
inactive 4- chlorophenyl biguanide
• Resistance due to non conversion to active metabolite
• Excreted in urine
• Concentration in RBC is 3 times higher than plasma
27. CHLOROQUINE
• DOC for treatment and prophylaxis(if sensitive)
• Mechanism of action: Inhibit heme polymerase-
free heme is toxic
• No action on liver stage
• Given with primaquine to eliminate hepatic forms
28. CHLOROQUINE
• Resistance: mutation in pfcrt gene- encodes a
transporter which resides membrane of site of action
of chloroquine
• Pfmdr 1 – p. falciparum multidrug resistance
associated protein
29. CHLOROQUINE
ADME: well absorbed
• Oral/IM/ SC/ IV
• SLOW INFUSION TO AVOID TOXICITY
• Converted to active metabolite by CYP-
desethylchloroquine and bisdesethylchloroquine.
• High volume of distribution
• half life 1-2 months
• 60% plasma protein bound
• Excreted in kidney
• Inhibit CYP2D6- DIGOXIN TOXICITY
30. CHLOROQUINE
Dose
Prophylaxis in chloroquine sensitive area- 300 mg oral
once a wk
Start 2 wk before travel and upto 4 wk after return
• Treatment of falciparum and vivax in sensitive areas:
600 mg base
300 mg at 6, 4, 48 hr
TO PREVENT REPLPSE : GIVEN ALONG WITH
PRIMAQUINE
• Other uses: hepatic amebiasis
32. QUININE AND QUINIDINE
• Uncomplicated falciparum- parenteral treatment of
severe illness, resistant cases
• Quinidine is more potent and more toxic (cardiotoxic)
• No activity against hepatic form
• Mechanism same as chloroquine
• Not for prophylaxis- short half life and toxic
• Resistance : transporter genes involved
34. QUININE AND QUINIDINE
Half life- 11- 13 hr
Increase in malaria - high levels of plasma α1-acid
glycoprotein produced in severe malaria may prevent
toxicity by binding quinine and thereby reducing the
free fraction of drug
Metabolized by CYP 3A4
Excreted in urine
35. QUININE AND QUINIDINE
Side effect:
Triad of cinchonism, hypoglycaemia(stimulate beta cell), and
hypotension(alpha blockage)
Cinchonism - tinnitus, high-tone deafness, visual
disturbances, headache, dysphoria, nausea, vomiting, and
postural hypotension
36. QUININE AND QUINIDINE
Side effect:
Cutaneous- flushing rash angioedema
Rarely cardiac arrhythmias – potassium channel
blockage, Qunidine more cardiotoxic
Hemolysis in G6PD Deficient
Blackwater fever-triad of massive hemolysis,
hemoglobinemia, and hemoglobinuria
37. MEFLOQUINE
• Drug resistant falciparum
• Not first line agent
• Mechanism- same as chloroquine
• Given with artesunate to prevent resistance
• Artesunate (4 mg/kg qd for 3 days) plus mefloquine
(24–25 mg of base/kg—either 8 mg/kg qd for 3 days
or 15 mg/kg on day 2 and then 10 mg/kg on day 3)
• Oral
• Parental: local reaction
39. MEFLOQUINE
Side effect:
• Neuropsychiatric reaction- black box warning
• Full dose repeated if vomiting occurs
• Teratogenic in rodents
• Avoid pregnancy for 3 month after use- long half life
40. PRIMAQUINE
• Act on liver stage – prevent and cure relapsing malaria
• Gametocidal
• USE: prophylaxis and radical cure of vivax and ovale
• Given with blood schizonticide- chloroquine
• Screen G6PD deficiency
• Half life – 7 hr
• Metabolised by CYP2D6
• Induce CYP1A2
• Mild side effect- abdominal distress
• Not safe in pregnancy
42. SULFONAMIDE AND SULFONES
• Inhibit dihydropteroate synthase
• Mutation – resistance
• Blood schizonticide – falciparum and ovale
43. TETRACYCLIN
CLINDAMYCIN
DOXYCYCLINE
• Schizonticide- weak activity
• Chloroquine resistant falciparum and vivax
• Containdicated in pregnancy and children
• Doxycycline -100 mg oral BD 7 DAYS
• Clindamycin- 20 mg base/kg/d orally divided 3 times daily
× 7 d
• Tetracycline: 250mg qid 7days
Side effect-
• Doxycycline: esophagitis- prevent by taking with large
amount of fluid
• Clindamycin- no major side effect, renal failure in impaired
renal function
44. TREATMENT
• Radical cure: eliminate hepatic and erythrocytic form
• Causal prophylaxis: prevent erythrocytic infection
45. TREATMENT
Aims Causation Therapy Drugs
To alleviate
symptoms
Symptoms are
caused by blood
forms of the
parasite
Blood
schizonticidal
drugs
Chloroquine,
quinine,
artemisinin
combinations
To prevent
relapses
Relapses are
due to
hypnozoites
of P. vivax/ P.
ovale
Tissue
schizonticidal
drugs
Primaquine
To prevent
spread
Spread is
through the
Gametocytocida
l drugs
Primaquine
for P.
47. SEVERE
MALARIA
Artemesinin
avaliable
Artesunate iv/im 2.4mg/kg at
0,12,24,48 hr
ACT + primaquine 0.75 mg/kg
on day2
Artemisinin
not available
Quinine 20mg/kg infusion
Then 10 mg/kg 8 hrly
Quinine 10mg/kg 8 hrly
Doxycycline 100mg OD
Clindamycin 10 mg/kg BD
7DAYS
48. Malaria in
pregnancy
Vivax
Weekly 300 mg
chloroquine
No primaquine
Falciparum/ mixed
First trimester
Quinine 10 mg/kg
TDS
Clindamycin
10mg/kg BD
Second and
third trimester
ACT
49. PROPHYLAXIS
• Atovaquone /proguanil
• Chloroquine in sensitive area
• Mefloquine
• Doxycycline in chloroquine and mefloquine resistance
• Primaquine
50. PREVENTION
• Insecticide treated nets
• Insecticide
RTS,S/AS01 (Mosquirix TM)
Genetically engineered vaccine
Vaccine target against P.falciparum
It is a fusion protein of malaria antigen with Hepatitis B
antigen.
• Vaccine targeting placental malaria: against VAR2CSA –
UNDER RESEARCH
51. TAKE HOME MESSAGE
Chloroquine sensitive falciparum Chloroquine
Chloroquine resistant falciparum ACT
Vivax malaria Chloroquine with primaquine
Severe malaria IV Artesunate
First trimester pregnancy
(falciparum)
Quinine with clindamycin
Second and third trimester
pregnancy (falciparum)
ACT
Pregnancy vivax malaria Weekly chloroquine
(Primaquine contraindicated)
Prophylaxis (travel <6 week) Doxycycline
Prophylaxis (travel >6 week) Mefloquine
52. NEW DRUGS
• TE3
A prodrug of bis-ammonium compound.
Inhibit phosphatidylcholine synthesis → Heme detoxification hampered
• FOSMIDOMYCIN- Inhibit lipid and haem synthesis of plasmodium
• ARTEROLANE and TRIOCXOLANE- free radical damage
• ARTEMISONE a drug in Phase II trials, is 10 times more potent than
artesunate
• SPIROINDOLONES Phase II trials
• ALBITIAZOLIUM inhibiting the transport of choline into the parasite-
PHASE 2
• SEVUPARIN To prevent vasoocclusion , antiadhesive
• Actelion reported ACT-213615 - fast-acting against all asexual
erythrocytic stages
When a red blood cell (RBC) becomes infected with P falciparum, the organism produces proteinaceous knobs that bind to endothelial cells. The adherence of these infected RBCs causes them to clump together in the blood vessels in many areas of the body, causing microvascular damage and leading to much of the damage incurred by the parasite.
P. vivax binds to receptors on young red cells. The Duffy blood-group antigen Fya or Fyb plays an important role in invasion. Most West Africans and people with origins in that region carry the Duffy-negative FyFy phenotype and are generally resistant to P. vivax malaria
ONLY PRIMAQUINE- AGAINST HYPNOZOITES
FOR RELAPSE PREVENTION
When a red blood cell (RBC) becomes infected with P falciparum, the organism produces proteinaceous knobs that bind to endothelial cells. The adherence of these infected RBCs causes them to clump together in the blood vessels in many areas of the body, causing microvascular damage and leading to much of the damage incurred by the parasite.
Artesunate and mether are biotransform to dihydroartemisinin
Chosen for longer half life
Heme polymerase converts heme to hemazoin
Reisistance reversal by verapamil, desipramine, chlorpheniramine
Cinchonism – derived from bark of cinchona plant
Also used for nocturnal leg cramps, Safe in pregnancy
Quinine inhibit Tat2p transporter
Transport tryptophan - precursor of of 5HT
Inhibit 5HT biosynthesis- inhibit tryptophan hydroxylase
Avoid in methhb
Avoid in pt on myelosuppression- coz cause neutropenia
G6pd def – 8 wk wkly treatment with monitoring
Fetus g6pd deficient
