Antimalarial drugs

1. Antimalarial drug

2. Global Situation Of Malaria
• According to WHO,
• A significant public health problem
• More than 90 countries inhabited by some
2400 million people (about 40% of the world's
population).
• The disease causes an estimated 300 million
acute illnesses each year and at least 1 million
deaths.
• More than 90% of these occur in sub-Saharan
Africa, and it is estimated that the disease kills
an African child every 30 seconds.

3. Situation Of Malaria In Bangladesh
• The prevalence of malaria in the 13 endemic
districts is 3.97%.
• In five south-eastern districts weighted
average prevalence rate is 6.00% and in the
eight north-eastern districts weighted
average prevalence rate is 0.40%.
• The highest prevalence is observed in
Khagrachari district. The majority of the
cases (90.18%) are P. falciparum infections.
• Malaria morbidity rates in five south-eastern
districts is 2.94%.

4. Ref. Goodman & Gilman’s

5. Ref. Rang&Dales

6. • Infection usually is transmitted by the bite of
infected female Anopheline mosquitoes.
• Sporozoites from the mosquito salivary glands
rapidly enter the circulation after a bite and
localize in hepatocytes, where they transform,
multiply, and develop into tissue schizonts
• This primary asymptomatic tissue
(preerythrocytic or exoerythrocytic) stage of
infection lasts for 5 to 15 days, depending on
the Plasmodium species.
• Tissue schizonts then rupture, each releasing
thousands of merozoites that enter the
circulation, invade erythrocytes, and initiate the
erythrocytic cycle.

7. • Once the tissue schizonts burst in P.
falciparum and P. malariae infections, no
forms of the parasite remain in the liver.
treatment that eliminates erythrocytic
parasites will cure these infections.
• However, in P. vivax and P. ovale infections,
tissue parasites (hypnozoites) persist that can
produce relapses of erythrocytic infection
months to years after the primary attack.
Eradication of both erythrocytic and hepatic
parasites is required to cure these infections.

8. • In erythrocytes, most parasites undergo
asexual development & finally to mature
schizonts.
• Schizont-containing erythrocytes rupture,
each releasing 6 to 32 merozoites depending
on the Plasmodium species. Only erythrocytic
parasites cause clinical illness. It is this
process that produces febrile clinical attacks.
• The merozoites invade more erythrocytes to
continue the cycle

9. • Sexual stage gametocytes also develop in
erythrocytes before being taken up by
mosquitoes, where they develop into
infective sporozoites. which invade the
salivary gland of the mosquito. The insect
then can infect a human host by taking a
blood meal.

10. Ref. Rang&Dales

11. Symptomatic malaria is typified by high spiking fevers that
may have a periodic pattern chills, headache, myalgias,
malaise, and gastrointestinal symptoms. In addition, each
Plasmodium species causes a distinct illness:
(1) P. falciparum is the most dangerous. By invading
erythrocytes of any age, sequestering in the vasculature, and
producing endotoxin-like products, this species can cause an
overwhelming parasitemia, hypoglycemia, and shock with
multiorgan failure.
Delay in treatment may lead to death. If treated early, the
infection usually responds within 48 hours. If treatment is
inadequate, recrudescence of infection may result.
Cerebral malaria:
Organism residesin the RBC, red cell become sticky,adhere to
another RBC,Rouleux formation –cerebralcapillary blocks-
ischemia, convulsion.

12. (2) P. vivax & P. ovale infection has a low
mortality rate in untreated adults and is
characterized by relapses caused by the
reactivation of latent tissue forms.
(4) P. malariae causes a generally
indolent infection that is common in
localized areas of the tropics. Clinical
attacks may occur years or decades after
infection.

13. Classification
• Antimalarials can be categorized by the stage
of the parasite that they affect and by
their intended use for either prophylaxis
or treatment.
• The various stages of the malaria life cycle that
occur in humans differ from one another not
only in their morphology and metabolism but
also in their drug sensitivity. For this reason, the
classification of antimalarial drugs is best done
in the context of the life cycle.

14. • Prophylaxis:
Since none of the drugs kills sporozoites, it is not
truly possible to prevent infection but only to
prevent the development of symptomatic malaria
caused by the asexual erythrocytic forms.
• Treatment of an established infection:
None of the antimalarials is effective against all
liver and red cell stages of the life cycle that may
coexist in the same patient. Complete cure
therefore may require more than one drug.

15. P. falciparum
P. ovale,p. vivax
Ref. Goodman & Gilman’s

16. • The patterns of clinically useful activity fall into three
general classes
• Class I agents action is directed against the
asexual erythrocytic forms. These drugs will
treat, or prevent, clinically symptomatic malaria.
Prophylactically,must be taken for several weeks
after exposure until parasites complete the liver
phase and become susceptible to therapy.
• The class II agents, which target not only the
asexual erythrocytic forms but also the primary liver
stages of P. falciparum. This additional activity
shortens to several days the required period
for postexposure prophylaxis.

17. • Finally, primaquine is unique in its
spectrum of activity, which includes
reliable efficacy against primary and
latent liver stages (Hypnozoites) as
well as gametocytes.
• Primaquine has no place in the
treatment of symptomatic malaria but
rather is used most commonly to
eradicate the hypnozoites of P. vivax
and P. ovale, which are responsible
for relapsing infections.

18. • Quinine and Primaquine - short half-lives and
common toxicities, generally are reserved for Rx
of bvestablished infection & not used for
prophylaxis in a healthy traveler.
• In contrast, chloroquine is relatively safe and
has a one-week half-life that is convenient for
prophylactic dosing (in those few areas still
reporting chloroquine-sensitive malaria).
Briefly, causal prophylactics act on the initial
hepatic stages, drugs for terminal prophylaxis
and radical cure target hypnozoites, and agents
for suppressive prophylaxis or cure target the
asexual red cell forms.

19. • Tissue schizonticide:
To kill the hypnozoites. Dormant paracyte in liver.
Clinical fever due to hypnozoites.
-Primaquine
Proguanil
• Blood schizonticidal:
Responsible for acute attack. Release ofmerozoites –
Acute fever. Red cell debris – IL,TNF- Fever
↓
Cause rigor
- Chloroquine
Quinine
Mefloquine
Halofantrine

20. • Gametocidal:
That prevent transmission of P. falciparam. gametocyte
responsible for transmission.
-Primaquine
Proguanil,
Trimethoprim,
Chloroquine
• Antimetabolite:
Pyrimethamine,
Sulphadoxine
Proguanil
Dapsone
Trimethoprim
• Antibiotic:
Tetracycline
Doxycycline
Azythromycin

21. • Drugs used for chemoprophylaxis (also known as
causal prophylactic drugs) block the link between
the exoerythrocytic stage and the erythrocytic
stage, and thus prevent the development of
malarial attacks.
• True causal prophylaxis-the prevention of
infection by the killing of the sporozoites on entry
into the host-is not feasible with the drugs at
present in use, although it may be achieved in the
future with vaccines.

22. • Chemoprophylactic agents are given to
individuals who intend travelling to an area
where malaria is endemic.
• Administration should start 1 week before
entering the area and should be continued
throughout the stay and for at least a month
afterwards.
• No chemoprophylactic regimen is 100% effective,
and the choice of drug is difficult.
• Chemoprophylexis with mefloquine should not
be used unless high chance of chloroqine
resistance.

23. Chemo
prophylaxis
Antimalarial
tablet
Adult prophylactic
dose
Regimen
Chloroquine
resistance
high
Mefloquine
Or
Doxycycline
Or
Malarone
250 mg
100 mg
1 tab from 1-2 d
before travelling to
1 week after return
One tablet weekly
Daily
Daily
Chloroquine
resistance
moderate
Chloroquine
Plus
proguanil
150 mg base
100 mg
Two tablet weekly
Two tablets daily
Chloroquine
resistance
absent
Chloroquine
Or
Proguanil
150 mg base
100 mg
Two tablets
weekly
One or two
tablets daily

25. Anti malarial drugs
Malaria Drugs
Acute attack Chloroquine, quinine,
mefloquine, halofantrine,
sulphones, pyrimethamine,
doxycycline
Chemoprophylaxis Chloroquine, mefloquine,
proguanil, maloprim,
pyrimethamine, doxycycline
Radical cure Primaquine
Prevent
transmission
Primaquine, proguanil,
pyrimethamine

26. Selection of drug
• The selection of antimalarial drug depends on
–Whether it is to be used for
chemoprophylaxis or for treatment
–The species of Plasmodium
–The area of infection where it is used
• It also depends on
–The adverse effects of the drug
–Age of the patient
–Pregnancy
–Lactating mother
–Hepatic or renal impairment

27. Selection of drug

32. • Among the antimalarial drugs chloroquine is
commonly used.
• Pyrimethamine, sulfones, & tetracyclines are
slower acting, less effective, & nearly always
used in combination with other antimalarial
drugs
• The artemisinins are potent and fast-acting
antimalarials with no clinical evidence of
resistance.
They are particularly well suited for the
treatment of severe P. falciparum malaria and
now play a key role in the combination therapy
of drug-resistant infections.

33. Rational therapy for Malaria
• Rx of Acute clinical Attack
• Prevention of clinical attack
• Radical cure.
Rx of Acute clinical Attack
 First try to diagnose the case.
 Dx should be confirmed by examination of RBC
 Quick detection of malaria parasite by deep stick
Ag assay for P. vivax.
 Sensitivity of this test depends upon the no. of
parasite. Parasite > 60/microgm per L is 100%
sensitive.

34.  Sensivity decreases to 10-60% if parasite
count < 10 microgm per L
 So, blood film study is appropriate for
detection of malaria.
 Thin blood film (parasite may be absent)
 Thick blood film (more parasite)
 Malaria parasite embaded in
lymphocyte,so from head to tail –whole
PBF must be examined.
 Whenever detection of parsite,
P.falciparum/P.Vivax , start RX of
P.falciparum

35. • Drug acting faster shouldbe given in Rx of
malaria.
• Blood schizonticidal Chloroquine given, if
sensitive
• Quinine,
meflaoquine,Artemethar,Artesunate
• Artemethar,Artesunate- clear parasite from
blood v. quickly than quinine( 7days)
• Slower acting- pyrimethamine, proguanil,
doxycycline, sulphadoxine,tetracycline
• They are never given alone.

36.  Any fever in malaria zone should be treated as malaria
 If there is doubt either chloroquine resistant /Not Rx
as resistant malaria.
 Pt must be aware of Recrudence & Relapse.
 Halofantrine is contraindicated in pregnancy or in
female who might become pregnant within the next 3
months

37. Clinical Setting Drug Therapy
Chloroquine-sensitive P
falciparum & P
malariae infections
Chloroquine phosphate, 1gm,
followed by 500 mg at 6, 24, &
48 hours
Or-
Chloroquine phosphate, 1g at 0
& 24 hours, then 0.5 g at 48
hours
P vivax &
P ovale infections
Chloroquine (as above), then (if
G6PD normal) primaquine, 26.3
mg daily for 14 days

38. Cl. Setting Drug Therapy Alternative Drugs
Uncomplicated
infections with
chloroquine
resistant P
.falciparum
Quine Plus one of
the following-
Doxycycline, 100 mg
twice daily for 7 days
Or-
Clindamycin, 600 mg
twice daily for 7 days
Or-
Fansider, 3 tabs once
Artesunate or artemether, single
daily doses of 4 mg/kg on day
0, 2 mg/kg on days 2 & 3,
1 mg/kg on days 4-7
Or
Coartem (coartemether 20 mg,
lumefantrine 120 mg), 4 tablets
twice daily for 3 days
Severe or
complicated
infections with
P falciparum
Quinine gluconate, 10
mg/kg IV over 1-2
hours, then 0.02
mg/kg IV/minute
Or-15 mg/kg IV over
4 hours, then 7.5
mg/kg IV over 4
hours every 8 hrs
Artesunate, 2.4 mg/kg IV or IM,
then 1.2 mg/kg every 12 hours
for 1 day, then every day
Or-
Artemether, 3.2 mg/kg IM, then
1.6 mg/kg/d IM

39. Malaria Treatment Regimens
• Uncomplicated Malaria Confirmed:
–Tab. Co-artem (Artemether 20 mg + Lumefantrine
120 mg Combination): The total recommended
treatment is a 6-dose regimen of artemether-
lumefantrine twice daily for 3 days. The second
dose on the first day should be given any time
between 8 h & 12 h after the first dose. Dosage
on the second & third day is twice a day (morning
& evening)
–OR
• If for any reason co-artem can not be given
–Pregnancy in 1st trimester
–Children < 5 kg of body weight
–Tab. Quinine sulfate (300 mg). 600 mg 8 hourly
for 7 days

40. • Alternative regimen may be:
–Quinine for 7 days + Tetracycline 250 mg 6 hourly
for 7 days or
Quinine for 7 days + Doxycycline 100 mg 12
hourly for 7 days
–Artesunate (50 mg) + mefloquine (500 mg)
–Dose in mg (no. of tablets)
Artesunate Mefloquine
–Day 1 Day 2 Day 3 Day 1 Day 2 Day 3
–200 (4) 200 200 - 1000 (2) 500 (1)

41. • Uncomplicated Malaria Presumptive:
–The drug should be Chloroquine – 3 days
• Drug Day Weight in kg
• Chloroquine Day-1 4
Tab. 150 mg Day-2 4
base Day-3 2
But all efforts should be made for confirming the
diagnosis as soon as possible by Blood Slide
Examination (BSE) or Rapid Diagnostic Test (RDT). If
BSE/RDT is positive treatment should be started in
the line of uncomplicated malaria confirmed

42. • Treatment of Severe Malaria:
–IV Quinine drip/ IM Quinine followed by oral
Quinine for a total of 7 days
or
–IM Artemether / IV Artesunate followed by oral
Artesunate tablet
• Quinine:
– Loading dose: Quinine dihydrochloride 20
mg salt/kg of body weight (loading dose) by
infusion over 4 hours, in 5% dextrose saline
(5-10 ml/kg of body weight depending on
the patient’s overall fluid balance).

43. – Maintenance dose: Eight hours after the
start of the loading dose, maintenance dose
of quinine 10 mg salt/kg of body weight in
dextrose saline diluted as above over 4
hours. This maintenance dose should be
repeated every 8 hours & up to six doses
(including loading dose). Thereafter the
quinine dose will be reduced to 15 – 20 mg
salt/kg body weight, until the patient can
take oral medication
• If the patient can take orally properly:
– Oral quinine: Quinine sulphate 10 mg
salt/kg, 8 hourly to complete a 7 day course
of treatment

44. • Artesunate:
–2.4 mg/kg (loading dose) IV, followed by 1.2
mg/kg at 12 hours, then 1.2 mg/kg daily for 6
days, if the patient is able to swallow, the daily
dose can be given orally
–Oral Artesunate:
• 1st day – 2 mg/kg/dose
• 2nd day – after 12 hours
• 3rd dose – 8th – daily (total duration of
treatment 7 days & total 8 doses)
• Artemether:
–3.2 mg/kg (loading dose) IM followed by 1.6
mg/kg daily for 5 days
• Arteether:
–150 mg deep IM once daily for 3 days for adults

45. • Treatment of plasmodium Vivax case:
–Chloroquine 3 days + Primaquine 14 days
(Primaquine: 1 tablet daily for 14 days in
adults & 0.3 mg/kg daily for 14 days in
children)
• Management of Severe Malaria In Pregnancy:
–Quinine in the doses advocated for the
treatment of life-threatening malaria, is safe
in pregnancy. Quinine is not an abortificient
in therapeutic doses & safe in all trimester in
pregnancy. It has been shown that the initial
IV infusion of quinine in woman who are >
30 weeks pregnant is not associated with
uterine stimulation or fetal distress. Its major
adverse effect if hypoglycemia. Artesunate &
Artemether should not be used in first
trimester of pregnancy

46. Blood schizontocide: Chloroquine
• A very potent blood schizontocidal drug,
effective against all 4 plasmodial species
(if sensitive to the drug), but it does not
have any effect on sporozoite, hypnozoite
or gametocytes
• A synthetic, 4-aminoquinoline that has
been the mainstay of antimalarial therapy
–It has a complex mechanism of action
that is not fully understood.

47. Mechanism of action:
• Acts mainly on heme disposal by preventing digestion
of hemoglobin by the parasite & thus reducing the
supply of amino acids necessary for parasite viability.
• During the digestion process, large amounts of soluble
heme (ferriprotoporphyrin IX) are released, which is
toxic to the parasite.
• To protect itself, the parasite ordinarily polymerizes
the heme to hemozoin (a pigment), which is
sequestered in the parasite’s food vacuole.
• Chloroquine specifically binds to heme, preventing its
polymerization to hemozoin.
• the accumulation of heme result in oxidative damage
to the membranes, leading to lysis of both the
parasite & the red blood cell.

48. • Pharmacokinetics:
– Route of administration – oral, parenteral
– Absorption – well absorbed from the GIT
– Distribution – rapidly distributed to the tissues.
Volume of distribution 100 – 1000 L/kg (due to
extensive accumulation in organs – liver, spleen,
lungs, heart, kidney, pancreas, brain, eyes,
erythrocyte & skin) & is slowly released from
tissues & metabolized in the liver
– Excretion – mainly in the urine with a initial t½ of 3-
5 days but a much longer terminal elimination t½ of
1-2 months

49. • Indications:
–Chemoprophylaxis & treatment of malaria
where there is no chloroquine resistance
–Hepatic amoebiasis (effective amoebicidal as
it reaches high concentration in the liver)
–Rheumatoid arthritis -anti inflammatory
action is due to –
• inhibition of lymphocyte proliferation, decrease
leukocyte chemotaxis,
• decrease lysosome enzyme release
• & inhibit phospholpase A2 which decrease
prostaglandin & thus decreased inflammation

50. • Contraindications:
–Psoriasis
–Patient with retinal or visual field
abnormality or myopathy
–History of liver disease or neurologic or
hematologic disorders
• Adverse effects:
–Corneal deposits of chloroquine may be
asymptomatic or may cause halos
around lights or photophobia (these
reverse when the drug stopped).

51. – Retinal toxicity is more serious, & may be
irreversible. In early stage it takes the form of
visual field defects; late retinopathy classically
gives the picture of macular pigmentation
surrounded by a ring of pigment (the ‘bull’s eye’
macula.
– In the extreme case, blindness
– Pruritus
– Nausea, vomiting, abdominal pain, headache,
anorexia, malaise, blurring of vision & urticaria –
uncommon

52. – Rare – hemolysis in G-6-PD deficiencient
patient.
– impaired hearing, confusion, psychosis,
seizure, agranulocytosis, exfoliative dermatitis,
alopecia, bleaching of hair, hypotension
– Long term administration of high doses of
chloroquine for rheumatoid disease can result
in – irreversible ototoxicity, retinopathy,
myopathy & peripheral neuropathy
– Larger I.M. injection or rapid I.V. infusion of
chloroquine hydrochloride can result in severe
hypotension & respiratory & cardiac arrest

53. • Chloroquine is the drug of choice because –
– Rapidly causes remission of fever &
parasitemia within 24-48 hours after receiving
therapeutic dose
– Well tolerated & more reliably administered
than quinine
– No toxic synergism when given with
primaquine
– Duration of treatment shorter with choroquine
(3 days) than quinine (7 days)
– As a both suppressive & therapeutic agent
chloroquine is superior to quinine i.e. more
potent & less toxic than quinine
– Hypoglycemia less with chloroquine
– Quinine cause more GI upset
– Quinine narrow therapeutic index

54. Blood schizontocide: Quinine
• Quinine & Quinidine remain first-line therapies for
falciparum malaria- specially severe disease
• Chemistry & pharmacokinetics:
– Quinine is derived from the bark of cinchona tree, a
traditional remedy for intermittent fevers from South
America
– Orally active. Rapidly & completely absorbed from
the GIT.
– Widely distributed in body tissues.
– Highly bound (90%) to plasma proteins.
– The pharmacokinetics of quinine varies among
populations. Individuals with malaria develop higher
plasma levels of the drug than healthy controls, but
toxicity is not increased, apparently because of
increased protein binding.

55. • The half-life is longer in those with severe malaria
(18 hours) than in healthy controls (11
hours).Quinidine has a shorter half-life (6 hours)
than quinine, mostly as a result of decreased
protein binding.
• metabolize in the liver & excreted in the urine.
• Readily cross placental barrier
• CSF concentration is only 2-5 % of that in the
plasma
• Mechanism of action:
– Unknown.Quinine is a rapidly acting, highly
effective blood schizontocide against the four
species of human malarial parasites. The drug is
gametocidal against P vivax & P ovale but not
P.falciparum. It is not active against liver stage
parasites.

56. • Pharmacological action:
– Antiplasmodial action: quinine binds with
plasmodial DNA & thus inhibit protein synthesis. It
also inhibit hemoglobin metabolism by parasite
– Antimalarial action: blood schizontocide.
– Heart “quinidine like action”: a depressant action
on heart. Antidysrhythmic action.
– Skeletal muscle: a slight blocking action on the
neuromuscular junction used in mytonia & muscle
cramp because it prolongs the muscle refractory
period
– Pancreas: stimulate insulin secretion –
hypoglycemia
– Others:
• Weak antipyretic action.
• Mild oxytocic action on the gravid uterus

57. • Clinical use:
– Parenteral treatment of severe falciparum
malaria
– First-line therapy for uncomplicated falciparum
malaria & Chloroquine resistant malaria
– Malarial chemoprophylaxis: not generally used
owing to toxicity, although a daily dose of 325
mg is effective
– Babesiosis: first-line therapy in combination
with clindamycin, in the treatment of infection
with Babesia microti or other human babesial
infection
– Myotonia congenita
– Nocturnal muscle cramp
• Contraindication:
– Hypersensitivity to quinine
– Pregnancy
– Evidence of hemolysis, cinchonism
– Optic neuritis
– Myasthenia

58. • Adverse effects:
–Hearing & vision are particularly disturbed.
• Tinnitus, vertigo, decreased auditory acuity,
blurred vision, disturbed color perception,
photophobia, diplopia, night blindness,
mydriasis
–Skin – hot & flushed. Sweating is prominent
–Nausea, vomiting, abdominal pain & diarrhoea,
hypoglycemia – more in children, pregnant
woman & the elderly patient
–Black water fever is a rare severe illness that
includes marked hemolysis & hemoglobinuria
due to hypersensitivity reaction to the drug,
though its pathogenesis is uncertain

59. Points Chloroquine Quinine
Chemical nature 4-aminoquinoline Cinchona alkalloid
Effective against P falciparum
sensitive strains,
P malariae, P
ovale, P vivax
P falciparum
resistant strain, P
vivax, P ovale, P
malariae
Effect on
sporozoite &
pre-erythrocytic
form of parasite
No action Little action
On relapse Does not prevent
relapse of vivax
malariae
Prevent relapse of
vivax malariae
Potency More potent Less potent
Toxicity Less More

60. Points Chloroquine Quinine
Duration of
treatment
Shorter (3 days) Longer (7 days)
Patient
compliance
Well tolerated,
reliable
Not well tolerated
t½ 50 hours 10 hours
Plasma protein
binding
50-65% 90%
Adverse effect Large dose
causes –
retinopathy,
ototoxicity,
cardiovascular
toxicity
Hypoglycemia,
cinchonism

61. Blood schizontocide: Mefloquine
• Mefloquine is effective therapy for many
chloroquine-resistant strains of P falciparum &
against other species
• One of the recommended chemoprophylactic drugs
for use in most malaria-endemic regions with
chloroquine-resistant strains
• It is a synthetic 4-quinoline methanol that is
chemically related to quinine
• It can only be given orally because severe local
irritation occurs with parenteral use
• Pharmacokinetics:
–Well absorbed
–Highly protein bound, extensively distributed in
tissues, & eliminated slowly, allowing a single-
dose treatment regimen

62. – t½ 15-30 days, allowing weekly dosing for
chemoprophylaxis. Prolonged t½ probably
due to fact that it undergoes extensive
enterohepatic cycle & it has high tissue
storage
– Mefloquine & acid metabolites of the drug
are slowly excreted, mainly in the feces
– The drug can be detected in the blood for
months after the completion of therapy

63. • Advantage for chemoprophylaxis:
–It is active against multi-drug-resistant P
falciparum
–It has extended duration of action &
–It has relatively minor adverse effects
• Simultaneous administration of mefloquine &
chloroquine increase the chance of convulsion, so
this is not encouraged
• Clinical uses:
–Chemoprophylaxis: against most strains of P
falciparum & probably all other human malarial
species as well except for those with no
chloroquine resistance (where chloroquine is
preferred). Eradication of P vivax & P ovale
requires a course of primaquine
–Treatment: most falciparum malaria

64. • Adverse effects:
–GI disturbance: nausea, vomiting, abdominal
pain, diarrhoea & loss of appetite
–Transient CNS toxicity: giddiness, confusion,
dysphoria & insomnia
–Cardiac conduction defect, arrhythmia &
bradycardia
–Rash
–Leukocytosis, thrombocytopenia, &
aminotransferase elevations
–Rarely neuropsychiatric reactions: depression,
confusion, seizure, acute psychosis &
hallucination
• Disadvantage for treatment of acute malaria –
–Expensive, about 50% of the patient complain of
GI disturbances, transient CNS toxicity.

65. • Contraindication & cautions:
–if history of epilepsy, psychiatric disorders,
arrhythmia, cardiac conduction defects, or
sensitivity to related drugs
–It should not be co administered with quinine,
quinidine, or halofantrine, & caution is required if
quinine or quinidine is used to treat malaria after
mefloquine chemoprophylaxis
–Now considered safe in young children
–should not be used in pregnant woman or in
woman liable to become pregnant within 3
months of stopping the drug

66. Tissue schizontocide: Primaquine
• Is the drug of choice for the eradication of dormant
liver forms of P vivax & P ovale
• It is a synthetic 8-aminoquinoline
• Well absorbed orally. t½ is 3-8 hours.
• Widely distributed to the tissues, but a small
amount is bound there.
• It is rapidly metabolized & excreted in the urine.
• Its three major metabolites appears to have less
antimalarial activity but more potential for inducing
hemolysis than the parent compound

67. • Primaquine is also gametocidal against the four human
malarial species.
• Clinical uses:
– Therapy (radical cure) of acute vivax & ovale malaria
– Terminal prophylaxis of vivax & ovale malaria
– Chemoprophylaxis of malaria
– Gametocidal action
– Pneumocystis jiroveci infection
• Adverse effects:
– Primaquine in recommended doses is generally well
tolerated. Infrequently causes nausea, epigastric
pain, abdominal cramps, & headache (with higher
dosages & in empty stomach)

68. –Serious but rare adverse effects include
leukopenia, agranulocytosis, leukocytosis, &
cardiac arrhythmias
–Standard dose of primaquine may cause hemolysis
or methemoglobinemia (manifested by cyanosis),
especially in persons with G6PD deficiency or
other hereditary metabolic defects
Contraindication & cautions:
– History of granulocytopenia or methemoglobinemia,
in those receiving potentially myelosuppressive drugs
(e.g. quinidine)
– Never given parenterally because it may induce
marked hypotension
– Avoided in patients with G6PD deficiency
– Avoided in pregnancy because the fetus is relatively
G6PD-deficient & thus at risk of hemolysis

69. • Pyrimethamine
–Pyrimethamine is a 2,4-diaminopyrimidine
related to trimethoprim
–Effect a radical cure as a blood schizontocide &
strong sporontocide in the mosquito’s gut when
the mosquito ingests it with the blood of human
host
–Has an elimination half-life of about 3.5 days.
Therefore it can be given once a week
• Proguanil
–Is a biguanide derivative
–Has an elimination half-life of about 16 hours,
therefore it must be administered daily for
chemoprophylaxis
–is a prodrug; only its metabolite, cycloguanil, is
active
• Both drugs are slowly but adequately absorbed from
the GIT

70. • Mechanism of action of folate antagonist:
–Selectively inhibit plasmodial dihydrofolate
reductase, a key enzyme in the pathway for
synthesis of folate
–Sulfonamides & sulfones inhibit another enzyme
in the folate pathway, dihydropteroate
synthetase. Combinations of inhibitors of these
two enzymes provide synergistic activity
• Clinical uses:
–Chemoprophylaxis; Treatment of chloroquine
resistant falciparum malaria; Presumptive
treatment of falciparum malaria; Toxoplasmosis;
pneumocystosis

71. • Adverse effects & caution:
–Well tolerated
–GI symptoms, skin rash & itching are rare
–Mouth ulcer & alopecia (proguanil)
–Fansider is no longer recommended for
chemoprophylaxis because of uncommon but
severe cutaneous reactions, including erythema
multiforme, Stevens-Johnson syndrome, & toxic
epidermal necrolysis
–Folate antagonists should be used cautiously in the
presence of renal or hepatic dysfunction
– Proguanil is considered safe in pregnancy
– With the use of any folate antagonist in pregnancy,
folate supplements should be co administered

72. Halofantrine
• A phenanthrene-methanol related to quinine, is
effective against erythrocytic (but not other) stages
of all four human malarial species
• Rapidly effective against most chloroquine-resistant
strains of P falciparum
• Generally well tolerated, but use is limited by
irregular absorption & cardiac toxicity
• Most common adverse effects are abdominal pain,
diarrhoea, vomiting, cough, rash, headache,
pruritus, & elevated liver enzymes
• Contraindicated in patients with cardiac conduction
defects & should not be used in those who have
recently taken mefloquine;
• contraindicated in pregnancy

73. Lumefantrine
• An aryl alcohol related to halofantrine
• Available as a fixed-dose combination with
artemether as Coartem
• Half-life, in combination, is 4.5 hours
• Coartem is highly effective in the treatment of
falciparum malaria, but it is expensive & requires
twice-daily dosing
• Despite these limitations, due to its reliable efficacy
against falciparum malaria, Coartem has recently
been selected as the first-line therapy for malaria in
African countries
• Coartem does not appear to cause the cardiac
toxicity as seen with halofantrine

74. Artemisinin & its derivatives
• Artemisinin (qinghaosu) is a sesquiterpene lactone
endoperoxide, the active component of an herbal
medicine that has been used as an antipyretic in
China for over 2000 years
• Artemisinin can only be used orally
• Analogs have been synthesized to increase solubility &
improve antimalarial activity. Most important of these
analogs are –
– Artesunate (water-soluble; useful for oral, IV, IM, &
rectal administration) & Artemether (lipid-soluble;
useful for oral, IM, & rectal administration)
• Rapidly absorbed, half-life of 1-3 hours after oral
administration
• Compounds are rapidly metabolized to the active
metabolite dihydroartemisinin

75. • Artimisins have no effect on hepatic stages
• The antimalarial effect may result from the
production of free radicals that follows the iron-
catalyzed cleavage of the artemisinin endoperoxide
bridge in the parsite food vacuole or from inhibition
of a parasite calcium ATPase
• Artesunate & artemether are playing an increasingly
important role in the treatment of multidrug-
resistant P falciparum malaria
• They are the only drugs reliably effective against
quinine-resistant strains
• The efficacy of artemisinins is limited by their short
plasma half-life
• Also because of their short-half-lives, they are not
useful in chemoprophylaxis

76. • Artesunate has also been effective in the treatment of
severe malaria when administered rectally, offering a
valuable treatment modality when parenteral therapy is
not available
• In the setting of multidrug resistance, combination
therapy with an artemisinin are: Artemether +
lumefantrine, artesunate + amodiaquine, artesunate +
mefloquine, artesunate + sulfadoxin + pyrimethamine
• Most commonly reported adverse effects – nausea,
vomiting & diarrhoea
• Artemisinins should be avoided in pregnancy because
tertogenicity seen in animal studies

77. Fansidar
• Pyrimethamine (25 mg) acts synergistically with
sulfadoxin (500 mg) as Fansidar to inhibit folic acid
metabolism
• It is used with quinine to treat acute attack of malaria
caused by susceptible strains of P falciparum resistant
to chloroquine
• Mechanism of action:
– Acts by reciprocal potential of its two components,
achieved by a sequential blockade of two enzymes
involved in the biosynthesis of folinic acid in the
parasites
– Dosage: a single dose of pyrimethamine 75 mg +
sulfadoxin 1.5 gm (3 tablets) usually suffices
– Sulfadoxin is excreted in the urine

78. • Indication:
– All forms of malaria
• Toxoplasmosis
– Pneumonia due to pneumocystis carinii
– For chemoprophylaxis of malaria
• Contraindications:
– During pregnancy (because of antifolate action)
– Pre mature or new born infants during 1st few
weeks of life (due to immaturity of enzyme system)
– Sulfonamide hypersensitive patient
• Adverse effects:
– Any sulfonamide induced allergic reaction can be
severe, e.g. erythema multiforme, Stevens Johnson
syndrome & toxic epidermal necrolysis.

79. Drugs to prevent transmission
• Some drugs (e.g. primaquine, proguanil &
pyrimethamine) have the additional action of
destroying the gametocytes, preventing
transmission by the mosquito & thus
preventing the increase of the human
reservoir of the disease – but they are rarely
used for this action alone

80. Last minute traveler
• 500 mg of chloroquine phosphate (Tab 250
mg) (300 mg base) taken daily for 2-3 days
then once weekly during staying in the malaria
zone & continued for 4 weeks after leaving the
area
• Or
• Mefloquine (Tab 250 mg) 250 mg daily for 2-3
days & then weekly continued up to 4 weeks
after leaving the area

81. Management of cerebral malaria
• Diagnosis is made from cerebral manifestation –
–Convulsion, hypoglycemia, difficulty in breathing
or pulmonary edema, oliguria or acute renal
failure, hyperpyrexia, hyperparasitemia, change
of behavior, drowsiness, altered consciousness,
coma, severe anemia, circulatory collapse or
shock, hemoglobinuria, jaundice, acidosis
• Exclusion of other causes of encephalopathy
• Focal neurological signs absent
• Neck rigidity & kernigs sign absent
• Microscopic confirmation
• CSF normal

82. • Injection chloroquine 5 mg/kg in 500 ml of 5%
dextrose aqua over 4 hours stat & 8 hourly upto
patient can take orally for 7 days orally
• Or if chloroquine resistant –
• IV quinine dihydrochloride loading dose 20
mg/kg if not treated with quinine before
• If treated then give 10 mg/kg body weight
• It is given with 500 ml of 5% (10%) dextrose
over 4 hours & 8 hourly until patient can take
the drug orally. Total duration for 7 days
• Treatment of convulsion – diazepam IV 0.2
mg/kg
• For hypoglycemia – IV glucose 10% or 25%
• Correct fluid & electrolyte balance
• If hemoglobin < 6 gm/dl – blood transfusion
with packed red cell
• Ryles tube down for feeding

83. • Proper nursing care –
–Clean airway
–Frequently change of posture
–Urethral catherization
–Careful record of input/output chart
–Check speed of infusion frequently
–Monitoring of vital signs
• Treatment of pulmonary edema – propped up
position, frusemide
• Hyperpyrexia – sponging, antipyretic
• Hyparasitemia: if > 10% RBC are infected –
exchange blood transfusion
• Antibiotic – if associated infection
• If oliguria develops, frusemide or an infusion of
mannitol may forestall renal failure
• Dialysis may be needed if renal failure develops