1. ANTIMALARIAL DRUGS

2. Plasmodium species which
infect humans
Plasmodium vivax
Plasmodium ovale
Plasmodium falciparum
Plasmodium malariae

3. Classification of Malaria
• Uncomplicated Malaria
• Cold stage (sensation of cold, shivering)
• Hot stage (fever, headaches, vomiting; seizures
in young children)
• Sweating stage (sweats, return to normal
temperature, tiredness)

4. Classification of Malaria
• Severe Malaria
– Cerebral malaria (seizures, coma)
– Severe anemia
– Hemoglobinuria
– Abnormalities in blood coagulation
– Cardiovascular collapse and shock

5. Types of Infections
• Recrudescence
– exacerbation of persistent undetectable parasitemia, due to survival
of erythrocytic forms, no exo-erythrocytic cycle (P.f., P.m.)
• Relapse
– reactivation of hypnozoites forms of parasite in liver, separate from
previous infection with same species (P.v. and P.o.)
• Recurrence or reinfection
– exo-erythrocytic forms infect erythrocytes, separate from previous
infection (all species)
• Can not always differentiate recrudescence from reinfection

6. CLASSIFICATION OF ANTIMALARIALS
• Based on stage of parasite they affect:
– Causal prophylactics: Primaquine, Pyrimethamine,proguanil
– Supressives: Quinine, 4-aminoquinolines, mefloquine,artemisinin
– Radical curatives: Primaquine,pyrimethamine
– Gametocidal:
• Supressives – Pl Vivax ,
• Primaquine – against all,
• Proguanil ,pyrimethamine – prevent development also
prevent development of sporozoites

7. • Based on chemical structure:
– Cinchona alkaloids: Quinine, quinidine
– 4 aminoquinolines: Chloroquine, hydroxychloroquine,
amodiaquine, pyronaridine
– 8 aminoquinolines: Primaquine, tafenoquine, bulaquine
– Quinoline-methanol: Mefloquine, halofantrine, lumefantrine
– Antifolates:
• Diaminopyrimidine: pyrimethamine
• Biguanides: proguanil
• Sulfonamides: sulfadoxine

8. – Antibiotics: Tetracycline, doxycycline, clindamycin
– Hydronaphthoquinone: Atovaquone
– Artemisinin Derivatives: Artesunate, artemether,
arteether

9. Malaria Life Cycle
Life Cycle
Sporogony
Oocyst
Sporozoites
Mosquito Salivary
Gland
Zygote
Exoerythrocytic
(hepatic) cycle
Gametocytes
Erythrocytic
Cycle
Schizogony
Hypnozoites
(for P. vivax
and P. ovale)

10. Malaria Transmission Cycle
Exo-erythrocytic (hepatic) Cycle:
Sporozoites infect liver cells and
develop into schizonts, which release
merozoites into the blood
Sporozoites injected
into human host during
blood meal
Parasites
mature in
mosquito
midgut and
migrate to
salivary
glands
MOSQUITO
Parasite undergoes
sexual reproduction in
the mosquito
HUMAN
Some merozoites
differentiate into male or
female gametocyctes
Dormant liver stages
(hypnozoites) of P.
vivax and P. ovale
Erythrocytic Cycle:
Merozoites infect red
blood cells to form
schizonts

11. Components of the Malaria Life Cycle
Sporogonic cycle
Infective Period
Mosquito bites
uninfected
person
Mosquito bites
gametocytemic
person
Mosquito Vector
Parasites visible
Prepatent Period
Human Host
Symptom onset
Recovery
Incubation Period
Clinical Illness

12. Exo-erythrocytic (tissue) phase
• Blood is infected with sporozoites about 30
minutes after the mosquito bite
• The sporozoites are eaten by macrophages or
enter the liver cells where they multiply –
pre-erythrocytic schizogeny
• P. vivax and P. ovale sporozoites form parasites
in the liver called hypnozoites

13. Exo-erythrocytic (tissue) phase
• P. malariae or P. falciparum sporozoites do not
form hypnozites, develop directly into preerythrocytic schizonts in the liver
• Pre-erythrocytic schizogeny takes 6-16 days post
infection
• Schizonts rupture, releasing merozoites which
invade red blood cells (RBC) in liver

14. Exo-erythrocytic (tissue) phase
• P. vivax and P. ovale hypnozoites remain
dormant for months
• They develop and undergo pre-erythrocytic
sporogeny
• The schizonts rupture, releasing merozoites
and producing clinical relapse

15. Erythrocytic phase
• Pre-patent period – interval between date
of infection and detection of parasites in
peripheral blood
• Incubation period – time between infection
and first appearance of clinical symptoms
• Merozoites from liver invade peripheral
(RBC) and develop causing changes in the
RBC
• There is variability in all 3 of these features
depending on species of malaria

16. Erythrocytic phase
stages of parasite in RBC
• Trophozoites are early stages with ring form the
youngest
• Tropohozoite nucleus and cytoplasm divide forming a
schizont
• Segmentation of schizont’s nucleus and cytoplasm
forms merozoites
• Schizogeny complete when schizont ruptures,
releasing merozoites into blood stream, causing fever
• These are asexual forms

17. Erythrocytic phase
stages of parasite in RBC
• Merozoites invade other RBCs and
schizogony is repeated
• Parasite density increases until host’s
immune response slows it down
• Merozoites may develop into gametocytes,
the sexual forms of the parasite

18. •
•
Quinine
Oldest antimalarial alkaloid isolated from barks of chinchona tree.
Present indication-cerebral malaria
-chloroquine resistant p. falcifarum
Pharmacological actions
1.Antimalarial :Suppressive agent
2.Local irritational action: General protoplasmic poison
-decrease cilliary actvity
-Inhibit phagocytosis & fibroblast growth
Local anesthetic action, At high conc. edema , pain at site of inj.
3.GI tract- bitter, nausea ,vomiting
4.CVS- myocardial depression, decrease excitability and conductivity
iv. dose- hypotension
5. Miscellaneous- analgesic, antipyretic, sk. muscle relaxant
P/K-well absorbed ,peak 1-3 hrs, cross placenta, metabolized in liver,
excreted in urine

19. Adverse effect
1.Cinchonism:
Mild - ringing in ears, nausea, vomiting, headache, visual impairment.
Large doses-Tinnitus, deafness, vertigo, blurring,photophobia, delirium,
confusion.
Poisoning progress- Skin pale, cold, resp. depress,BP falls, comma,
death.
2.Idiosyncrasy
3.CVS toxicity-cardiac arrest
4.Black Water Fever
-acute intravascular haemolysis,haemoglobinuria,fever, acute renal
failure,focal hepatic necrosis
5.Hypoglycemia
6.Acute renal Failure

20. Uses & Dose
1.Malaria:
• schizontocidal drug
• very active against erythrocytic phase.
• No effect against proerythrocytic, sexual gametocytes,
exoerythrocytic phase, relapse.
2.Myotonia Congenita
3.Nocturnal muscle cramps
4.Cerebral malaria
IV Quinine 600mg in 500ml of 5% dextrose slowly over 4 hrs
repeated every 8 hrs till patient is conscious followed by oral
treatment to complete 7 day coarse.
Dose:300-600mg orally

21. Chloroquine
• It is a 4-aminoquinolone
• It was produced in USA as a less toxic alternative to
mepacrine.
• It is rapidly acting erythrocytic schizontocide against
all species of plasmodia.it is highly efficacious drug.
• It controls most clinical attack in 1-2 days.
• It does not prevent relapses in vivax & ovale malaria.

22. Mechanism of action
• It is actively concentrated by sensitive intraerythrocytic
plasmodia
• It interfers with degradation of Hb by parasitic lysosomes
• Heme itself or its complex with chloroquine damages
plasmodial membrane
• Clumping of pigment & changes in parasite membrane
follows
• It has anti-inflamatory, local irritant, local anaesthetic, weak
smooth muscle relaxant, anti-histaminic & anti-arrhythmic

23. Resistance
• Chloroquine resistance among P. vivax has been slow
in developing.
• However P. falciparum has acquired significant
resistance
• Resistance in P. falciparum is associated with a
decreased ability of parasite to accumulate
chloroquine

24. Pharmacokinetics
• Oral absorption of chloroquine is excellent , about
50% gets bound in plasma
• It gets bound to melanin & nuclear chromatin and is
concentrated in liver, spleen, kidney, lungs, skin,
leucocyte
• Absorption after i.m. injection is also good
• Plasma concentration is 15-30ng/ml
• Chloroquine is partly metabolised by liver & slowly
excreted in urine
• Plasma t-1/2 varies from 3-10 days

25. Toxic effects
• Toxicity of chloroquine is low but side
effects are frequent & unpleasant:
• nausea
• vomiting
• anorexia
• uncontrollable itching
• epigastric pain
• uneasiness
• headache

26. …contd.
Parenteral administration can cause
• hypotension
• cardiac depression
• arrythmias
CNS toxicity including convulsions.
• Prolonged use of high doses can cause loss of
vision.

27. …contd.
• Loss of hearing , rashes, photo allergy, mental
disturbance, myopathy and graying of hairs
can occur as long term use.
• Attack of seizures, porphyria & psoriasis may
be precipitated.

28. Routes of administration & dosage
• Chloroquine phosphate is given orally
• As prophylaxis –
Dose: adults – 500mg once each week
children – 5mg/kg weekly
• For treatment –
Initial dose - 600mg
followed by 300mg after 6-8 hrs
then 300mg on 2 consecutive days

29. Indications
• Chloroquine is drug of choice for malaria
• It completely cures sensitive falciparum
disease, but relapses in vivax and ovale are
not prevented .
Other uses
• Extra intestinal amoebiasis
• Rheumatoid arthritis

30. …contd.
• Discoid lupus erythematosus
• Lepra reactions
• Photogenic reactions
• Infectious mononucleosis

31. Mefloquine
Introduction
It is a quinoline methanol derivative
It is a drug developed to deal with problem of
chloroquine resistant P.falciparum
It is rapidly acting erythrocytic schizontocide.
It is effective against chloroquine sensitive as
well as resistant plasmodia
It has not been extensively used in India.

32. Mechanism of action
 Acts on erythrocytic stage
 Highly effective in a single dose against
P.falciparum including chloroquine resistant
strains.
 Appears to bind to heme and the complex
damages membrane of the parasite
 No action on persistant tissue form.

33. Pharmacokinetics
 Given orally
 Rapidly and completely absorbed
 Highly bound to plasma protein
 Eliminated slowly with plasma half life of 20
days

34. Adverse effects
GIT
Dizziness, nausea, vomiting, diarrhoea, abdominal
pain
Neuropsychiatric disturbances
Anxiety, halloucination, sleep disturbances,
Single dose may cause light headedness and loss
of concentration

35. …Contd.
CVS
Causes bradycardia
Sinus arrhythmia
Teratogenicity
Should be avoided in 1st trimester of pregnancy
May be used in 2nd and 3rd trimester
Miscellaneous
Allergic skin reaction
Blood dyscriasis
Hepatitis

36. Uses
 Effective drug for multiresistant P.falciparum
 Treatment of uncomplicated falciparum
malaria in areas with multidrug resistance
 Dose -25 mg per kg (maximum 1.5 g)
 Prophylaxis of malaria among travellers to
areas with multidrug resistance
 Dose -5 mg per kg (adult 150 mg)

37. Proguanil
Introduction
Commonly used salt of these drug is proguanil
hydrochloride
Has negligible antiplasmodial action in vitro
Slow acting erythrocytic schizonticide
Cyclized in body to triazine derivative

38. Actions
 Effective schizonticide against P.vivax and
P.falciparum
 Effective against primary pre-erythrocytic
forms of P.falciparum
 Prevents development of gametes encysted in
gut wall of mosquito
 No action against persistant tissue forms
P.vivax

39. Pharmacokinetics
 Slowly absorbed from gut
 Partly metabolized and excreted in urine
 Non-cumulative
 Plasma half life- 16-20 hrs

40. Adverse effects
 GIT disturbance
 Stomatits
 Mouth ulcers
 Reduction in leucocyte count
 Rarely megaloblastic anaemia
 Dosage
 Tab Proguanil hydrochloride 100mg

41. Uses
 Use dependent on sensitivity of strain
 In multiresistant falciparum malaria
 Combination of proguanil 100mg and
atovaqoune 250mg
 Used prophylactically (in dose of 1 tablet
taken with food)

42. PRIMAQUINE
 Poor erythrocytic schizontocide : has weak
action of P. vivax.
 In contrast it is more active against preerythrocytic stage of P. falciparum than that
of P. vivax
 Highly active against gametocytes &
hypnozoites.

43. PHARMACOKINETICS
 Readily absorbed by oral ingestion.
 Oxidized in liver with a plasma t1/2 of 3-6 hrs.
 Excreted in urine within 24 hrs.
 Not a cumulative drug.

44. Mechanism of action :• Mechanism of action of primaqunine is not known.
However it is difficult from that of chloroquine.
Uses :• Radical cure of relapsing malaria : 15 mg daily for 2
weeks is given with full curative dose of chloroquine.
• Falciparum malaria : single 45 mg dose of primaquine
is given with curative dose of chloroquine to kill
gametes & cut down transmission to mosquito.

45. Adverse effect
• Abdominal pain
• GI upset
• Weakness or uneasiness in chest
• CNS & cardiovascular symptoms are infrequent
leucopenia
• Haemolysis, methemoglobinemia, cyanosis

46. TETRACYCLINES
Introduction
• Broad spectrum antibiotic having a nucleus of four
cyclic ring.
• All are obtained from soil actinomycetes
• Slowly acting & weak erythrocytic schizontocidal
action against all plasmodial species

47. Mechanism of action
• Tetracyclines are primarily bacteriostatic, inhibit
protein synthesis by binding 30 s ribosomes in
susceptible organism. To such binding attachment of
aminoactyl – t- RNA to the m – RNA ribosomes
complex is interfered with. Thus peptide chain fails
to grow.

48. Adverse effects
• Irritative effects :- epigastric pain, N, V & D
• Dose related toxicity
Liver damage :- fatty infiltration of liver &
jaundice.
Kidney damage :- It is prominent only in the
presence of existing kidney disease.
Phototoxicity:- A sun like or other severe skin
reaction on exposed parts is seen
Teeth & bones:- Tetracyclines have chelating
property.

49. Cont…
 Given between 3 months to 6 years of age affect
permanent anterior dentition.
 Antianabolic effect:- Reduce protein synthesis & have
an overall catabolic effect
 Increased intracranial pressure
 Diabetes insipidus
 Hypersensitivity
 Super infection :- Tetracyclines are most common
antibiotics response for superinfections

50. Uses
• Used in combination with quinine or pyrimethamine
sulfadoxine for the treatment of chloroquine
resistant falciparum malaria.
• Doxycycline 100 mg /day in used as a 2nd line
prophylactic for travelers to chloroquine resistant p.
falciparum areas.

51. Precautions
• Should not given during pregnancy, lactation
& in children.
• Should be avoided in patients on diuretics
• Do not inject tetracycline intrathecally.

52. PYRIMETHAMINE
Mechanism of action
 It is a directly acting inhibitor of plasmodial
DHFRase.
 It gradually reduces the schizogony of malarial
parasite in blood.
 It is slowly acting erythrocytic schizontocide.

53. Pharmacokinetics
 Absorption from the gut is good but slow.
 It is excreted in urine.
 Half life time = 4 days.
Adverse Effects
 Nausea & rashes,
 Folate deficiency,
 Megaloblastic anemia & granulocytopenia.

54. Uses
• Used only in combination with
sulfonamide/dapsone to treat P.falciparum
malaria.
S/P Combination
• Sulfonamide has some inhibitory action on
erythrocytic phase of P.falciparum like
pyrimethamine..
• It is a supra-additive synergistic combination
by sequential block.

55. Cont….
•
•
•
•
PABA
Folate synthetase
DHFA
DHFRase reductase
THFA
Combination acts faster than individual drug.
Efficacy against P.vivax is low.
When ultra long acting sulfonamides are used ;
exfoliative dermatitis , Stevens-Johnson syndrome
are seen.
Used only as a single effective dose.

56. Contraindications
• Infants
• Individuals allergic to sulfonamide
• Cautious use in pregnancy
Uses
• Chloroquine resistant falciparum malaria.
• Toxoplasmosis
Resistance
• Pyrimethamine develops resistance quickly & cross
resistance to biguanides is seen.
• It decreases due to sulfonamide & no cross
resistance seen

57. Cont…
• Resistance was first noted in 1980.
• It is more in south-east asia,s.america, southern
Africa.
• It is sporadic in India except for north-east
Some Combinations
• Sulfonamide(500mg)+pyrimethamin(25mg
• Sulfamethapyrasine+pyrimethamine
•
(500mg)
(25mg)
• Dapsone(100mg)+pyrimethamine(25mg)
• As clinical curative- sulfadoxine(1500mg)
+pyrimethamine(75mg)

58. Artemisia annua
• Also known as sweet wormwood
• Origin from northern parts of China
• Artemisinin present in leaves and flower of
the plant in 0.01-0.08% dry weight

59. Artemisia annua
• Used in Traditional Chinese Medicine for more
than 2000 years
• First antimalarial application described in “The
Handbook of Prescriptions for Emergencies”
in the 4th century by a Chinese chemist

60. Artemsia annua
“take a handful of sweet
wormwood, soak it in a
sheng (liter) of water, and
squeeze out the juice and
drink it all”
• Li Shizhen, a great
Chinese herbalist
• Use of wormwood is also
recorded in the “Great
Compendium of Herbs”
in 1596

61. Artemisinin
• One of the most novel discoveries in recent
medicinal plant research
• 1967- extracts of Artemisia was found to have
antimalarial activity
• 1972- artemisinin isolated from the plant
• 1979- structure of artemisinin determined by
X-ray analysis

62. Key Features
• Rapid onset of actions
•
Effective against severe malaria
• Rapid clearance rate
•
Slow development of artemisinin resistance
•
Frequent recurrence of infections

63. Site of Action
Artemisinin
Conventional
Treatment
Artemisinin

64. Mechanism of Action
• Killing of malaria parasite is mediated by
production free radicals
– Artemisinin derivatives lacking endoperoxide
bridge are devoid of antimalarial activity
– Addition of free radical generating compounds
enhances antimalarial activity
– Antioxidants block antimalarial activity

65. ARTEMISININ
• Oral formulation - 250mg capsule
• Dosage
Adults and children: 25mg/Kg on the first day followed by 12.5mg/Kg
on the second and third day in combination with mefloquine
(15mg/Kg) in a single dose on the second day. In some areas, a
higher dose (25mg/Kg) of mefloquine may be required for a cure to
be obtained.

66. DERIVATIVES OF ARTEMISININ USED
IN TREATMENT OF MALARIA
• Artemether
• Arteether
• Artesunate

67. ARTEMETHER
•
Methyl ether of dihydroartemisinin
• Superior to intravenous quinine with respect to
survival and parasite clearance
• Available as tablets, capsules and as IM injectable form
• In India, available as 40mg capsules and 80mg/ml
ampoule

68. ARTEETHER
• Ethyl
ether of dihydroartemisinin
• Therapeutically equivalent to quinine in cerebral malaria
• Available as β arteether and α/β arteether
• β arteether developed by WHO and The Special
Programme for Research and Training in Tropical
Diseases (TDR)
• α/β arteether developed by CDRI

69. ARTEETHER
• A longer t1/2 beta and more lipophilic properties than
artemether favouring accumulation in brain tissue and thus
the treatment of cerebral malaria were regarded as
advantages over the other compounds.
• Available as 150mg per 2ml ampoule

70. ARTESUNATE
• Water soluble hemisuccinate derivative
• Used for oral, rectal, intravenous and intramuscular
administration.
• Available as tablets and as powder with separate vial
containing 5% sodium bicarbonate
• In India, available as 50mg tablets and 60mg/ml injection
• In China also available as 100mg suppository and in
Switzerland available as 200mg rectocap

71. • Artemisinin based combination therapy:
• WHO has recommended that acute uncomplicated Pl
Falciparum be treated only by combining one
Artemisinin with other effective erythrocytic
schizonticide
• ACT Regimens in use:
– Artesunate – Sulfadoxine, pyrimethamine:
• Adopted as first line in India under NMP
• Not effective against MDR strains which are non responsive to S/P
• ARTESUNATE 100 mg BD for 3 days with S-P, 3 tablets
– Artesunate Mefloquine:
–
Highly effective, well tolerated, first line of treatment
for uncomplicated falciparum malaria
• By combining artesunate further spread of mefloquine resistance
can be prevented
• Artesunate 100 mg BD for 3 days, + mefloquine 750 mg on second
day & 500 mg on third day

72. • Artemether & lumefantrine:
– Lumefantrine is highly effective , long acting oral
erythrocytic schizonticide related to mefloquine
– Same mechanism of action
– Highly lipophilic onset delayed , peak 6 hrs
– Slower acting than chloroquine, 99 % bound ,
metabolized by CYP3A4, T1/2= 2-3 days
– Available as fixed dose combination
– Adverse events: headache, dizziness, sleep disturbances,
abdominal pain, arthralgia, pruritis & rash
– 80 mg artemether BD with 480 mg lumefantrine BD for 3
days
• DHA – Piperaquine, Artesunate- pyronaridine

73. Resistance
• Currently no evidence for clinically relevant
artemisinin resistance
• Reasons for delay of artemisinin resistance:
– Short half-life
– Reduces transmission potential
– Used in combination with other antimalarial drugs

74. PHARMACOKINETICS
• Absorption of orally administered artemisinin or its derivatives seems to
be rapid but incomplete
• Substantial hydrolysis of artesunate (probable complete) and artemether
into dihydroartemisinin probably occurs even before absorption
• Elimination is mainly by hepatic metabolism
• Arteether has much slower elimination
• Artesunate, artemether, arteether and probably also artemisinin itself are
transformed into dihydro-artemisinin, which is subsequently
converted into inactive metabolites

75. ARTEMISININ DERIVATIVES
IN PREGNANCY
• Very limited data on the use of artemisinin group in pregnant women.
• Artemisinin and derivatives should be avoided during first
trimester of pregnancy, but in case of severe malaria the risks have to
be balanced against the benefits.
• No congenital malformations were detected in six children born to
mothers who received intramuscular artemisinin or artemether at 17 to
27 weeks of gestation.