Pharmacology PPT

1. DRUG THERAPY FOR
MALARIA
PRESENT BY,
DR.Chintan Doshi

2. INTRODUCTION
DEFINITION:--
• Protozoal disease
• Caused by infection with parasites of the
genus Plasmodium.
• Transmitted to man by certain species of
infected female anopheline mosquito.

3. Problem statement
• At present malaria is a major public health
in the tropical developing world.
• Those at greatest risk of dying from the
disease are:
• Children under age 5 years in malaria
endemic areas,
• Pregnant women,
• Travelers who visit endemic countries and
return home with the disease.

4. AGENT FACTORS
common & severe
• Plasmodium falciparum
• Plasmodium vivax
• Plasmodium ovale
• Plasmodium malariae
rare & mild

5. • A fifth species, P. knowlesi is primarily a
pathogen of monkeys, but has recently
been recognized to cause illness in
humans in Asia.

6. CLINICAL PRESENTATION
• c/f:-high spiking fevers, chills, headache, myalgia,
malaise, and gastrointestinal symptoms
• Malarial Paroxysm—3 distinct stages
– Cold stage
– Hot stage
– Sweating stage

8. • Each Plasmodium species causes a distinct
illness:
• (1) P. falciparum is the most dangerous---
invading erythrocytes of any age---
sequestering in the vasculature, and
producing vasoactive products--- cause an
overwhelming parasitemia, hypoglycemia,
and shock with multiorgan failure, including
cerebral malaria.
• Treatment delay may lead to death.

9. • If treated early, the infection usually
responds within 48 hours.
• If treatment is inadequate, recrudescence
of infection may result.

10. MANIFESTATIONS OF SEVERE FALCIPARUM
MALARIA
• Signs Manifestations
• Unarousable coma/cerebral malaria
• Acidemia/acidosis
• Severe normochromic,Normocytic anemia.
• Renal failure
• Pulmonary edema/
• adult respiratory distress syndrome
• Hypoglycemia
• Hypotension/shock
• Bleeding/disseminated Intravascular coagulation
• Hemoglobinuria
• Impaired consciousness/arousable
• Jaundice

11. Diagnosis
• Thick and thin blood smears are gold standard
– Identify species and quantify density.
• Rapid diagnostic tests for detection of parasites:-
• Combo Test targeting the Plasmodium falciparum
specific antigen histidine-rich protein (HRP-2) and
the pan-Plasmodium antigen lactate
dehydrogenase (pLDH)
• Microtube concentration methods with acridine
orange staining using fluorescence microscopy.

12. DRUG THERAPY FOR MALARIA
• ANTIMALARIALS DRUGS CLASSIFY
BASED ON ATTACKING PARASITES AT
ITS VARIOUS STAGES OF LIFE CYCLE IN
THE HUMAN HOST.
• Erythrocytic schizontocides:- act on
erythrocytic schizogony;
• Tisuue schizontocides :- act on
preerythrocytic and exoerythrocytic stages in
liver.
• Gametocides.:-kill gametocytes in blood.

13. ANTIMALARIAL DRUGS
CLASSIFICATION
• 4-Aminoquinolines:-
chloroquine,amodiaquine,piperaquine.
• Quinoline-methanol:- mefloquine
• Cinchona alkaloid:- quinine, quinidine
• Biguanides:- proguanil, chlorproguanil
• Diamiopyrimidines:-pyrimethamine
• 8-Aminoquinoline:-primaquine,Tafenoquine.

14. • Sulfonamides and sulfone:-sulfadoxine,
sulfamethopyrazine, dapsone
• Tetracyclines:-tetracycline, doxycycline
• Sesquiterpine lactones :-artesunate,
artemether,arteether,arterolane.
• Amino alcohols :- halofantrine, lumefantrine
• Naphthyridine:- pyronaridine
• Naphthoquinone :-atovaquone.

15. OBJECTIVES AND USE OF
ANTIMALARIALS
• AIMS OF TREATMENT:-
1. To prevent and treat clinical attack of
malaria.
2. To completely eradicate the parasite from the
patient’s body.
3. To reduce the human reservoir of infection –
cut down transmission to mosquito.

16. • Antimalarial therapy is given in the following
forms:-
1.Causal prophylaxis:- covers the preerythrocytic
phase in liver.
2.Suppressive prophylaxis:-covers the
erythrocytic phase and attack of malarial fever.
3.Clinical cure:-terminates the episode of
malarial fever.

17. 4.Radical cure:- needed in relapsing malaria
to covers the exoerythrocytic
stage(hypnozoites)
5.Gametocidal:- cover male and female
gametes of plasmodia formed in the
patient’s blood.

18. Chloroquine
 4-amino quinoline
 Rapidly acting erythrocytic schizontocide
 No effect on pre and exo-erythrocytic phases
of the parasite- does not prevent relapses in
vivax and ovale malaria.
 P/K:-oral absorption excellent.
plasma t1/2:-3-10 days
highly concentrated in liver,spleen,
kidney,retina,lung etc.

19. Mechanism

20. Adverse Effects
• Nausea, vomiting, headache, blurred
vision
• Prolonged use of high doses cause loss of
vision due to retinal damage.
• Iv use causes hypotension, cardiac
depression
• safe for children and in pregnancy

21. Other actions
• Anti-inflammatory, local irritant
• Local anaesthetic (on injection),
• Weak smooth muscle relaxant,
• Antihistaminic
• Antiarrhythmic

22. Uses
 Drug of choice for clinical cure and suppressive
prophylaxis of all types of malaria, except
resistant p. falciparum
 Extra intestinal amoebiasis
 Rheumatoid arthritis
• Discoid lupus erythematosus
• Lepra reaction
• Photogenic reactions.
• Infectious mononucleosis

23. MEFLOQUINE
Relatively fast acting erythrocytic
schizontocide.
P/K:-
 Good but slow oral absorption
 Highly protein bound and concentrated in
liver, lung etc.
 Enterohepatic circulation
 Tissue binding ---longer t1/2 of 2-3 weeks.

24. Adrs.:-
 Nausea,
 Vomiting,
 Dizziness,
 Sinus tachycardia,
 Abdominal pain.
 Neuropsychiatric reactions

25. • Contraindication:-h/o seizure and acute
neuropsychiatric disorders.
• Safe in children and pregnancy except the
first trimester
• Drug interaction:- not given with
halofantrine and quinine—prolonged QTc
interval-cardiac arrests.

26. Use:-
1)Along with the artemisinin derivatives for
uncomplicated chloroquine as well as s/p
resistant falciparum malaria.
2)for prophylaxis of malaria among travellers
to areas with multidrug resistance

27. QUININE
• Derived from the bark of the cinchona tree.
• Erythrocytic schizontocide for all species of
plasmodia.
• No effect on preerythrocytic stage and on
hypnozoites of relapsing malaria but kills
vivax gametes.
• P/K:-rapidly and completely absorbed orally.
70% bound to alfa-1 acid glycoprotein.
metabolised in liver by CYP3A4.
t1/2:- 10-12 hours.

28. CINCHONA PUBESCENS

29. • ADRs:-toxicity of quinine –high and dose related .
- Cinchonism:- at large single dose .
-ringing in ear
-nausea, vomiting
-headache
-mental confusion
-Difficulty in hearing and vision
-vertigo etc.
- hypoglycemia.
- idiosyncratic/hypersensitive reaction-Purpura,
rashes, itching, angioedema of face and
bronchoconstriction
- hypotension and cardiac arrhythmias on rapid i.v.
injection

30. • Safe in pregnancy.
• Uses:-
- uncomplicated resistant falciparum malaria:-
quinine given orally.
- complicated and severe malaria including
cerebral malaria:- i.v. quinine with 5%
dextrose infusion.(to prevent hypoglycemia)
- Nocturnal muscle cramps
• Amplification of the pfmdr1 gene is
associated with resistance to quinine.

31. PROGUANIL
• Slow acting erythrocytic schizontocide
• Inhibits DHFRase
• Use :-prophylaxis of malaria in combination
with chloroquine in areas of low level
chloroquine resistance among p.falciparum
• Safe in pregnancy
• Resistance due to mutations in plasmodial
dihydrofolate reductase

32. Primaquine
-Poor erythrocytic schizontocide
-it is only available agent active against the
dormant hypnozoite stages of P. vivax and P.
ovale.
- P/K:-readily absorbed after oral ingestion.
plasma t1/2:-3-6 hours
-Dose:- 15 mg (children 0.25 mg/kg ) daily for 2
weeks with full curative dose of choloquine.

33. • Adrs.:-g.i. upset ,abdominal pain
haemolysis,methaemoglobinaemia,
tachypnoea and cyanosis.(G6PD
deficient patient)
• Avoid during pregnancy .
• Use:-1) radical cure (therapy) and terminal
prophylaxis of vivax and oval malaria.
2) chemoprophylaxis of malaria.

34. PYRIMETHAMINE
• Slowly acting blood schizontocide
• Pyrimethamine resistance results from
mutations in dihydrofolate reductase–
thymidylate synthetase.
• S/E:occasional nausea and rashes.
• Folate deficiency is rare

35. Sulfonamide-pyrimethamine
(S/P)
• Supra-additive synergistic combination with
pyrimethamine due to sequential block
• Sulfadoxine 1500 mg + pyrimethamine 75 mg
• Use:efficacy against CQ-resistant P. falciparum.
• Decrease resistance

36. ATOVAQUONE
• Malarone, a fixed combination of
atovaquone and proquanil , is highly
effective for both the treatment and
chemoprophylaxis of falciparum malaria.

37. ANTIBIOTICS
• Act by inhibiting protein synthesis in a
plasmodial prokaryote like organelle,
apicoplast.
• These groups includes:-
-tetracycline
-doxycycline
-clindamycin
-azithromycin

38. • Tetracycline and doxycycline are active
against erythrocytic schizonts of all human
malaria parasites.---no active against liver
stages.
• Use:- 1) treatment of falciparum malaria in
conjunction with quinine.
2) To complete treatment courses of 1 week
after initial treatment of severe malaria
with i.v. quinine or artesunate.

39. • Clindamycin is slowly active against
erythrocytic schizonts and be used after
treatment courses of quinine or artesunate
in those for whom doxycycline is not
recommended ( i.e. children and pregnant
women)
• Azithromycin – under study as an
antimalarial agent.
• Fluoroquinolones – efficacy as a
antimalarial is suboptimal.

40. HALOFANTRINE
• Effective against P.falciparum and P.vivax
resistant to chloroquine
• Prolongation of QTc interval at therapeutic
doses and few cases of serious ventricular
arrhythmia.
• Not approved in india.

41. LUMEFANTRINE
• Orally active, high efficacy,long acting
erythrocytic schizontocide
• P/K:-plasma protein binding -99%
metabolised predominantly by CYP3A4
• Use:-only in combination with artemether
and is the only ACT currently available as
fixed dose combination tablets.
• High cure rate >95%
• Active against multidrug resistant areas
including mefloquine resistant.

42. • Well tolerated with minimum side effects.
• Contraindicated in first trimester of
pregnancy and during breastfeeding.

43. ARTEMISININ DERIVATIVES
• Active principle of the plant artemisia
annua used in chinese traditional medicine
as ‘QUINGHAOSU’
• Active against P. falciparum resistant to all
other antimalarial drugs as well as
sensitive strains.
• Potent and rapid blood schizontocide
action – quicker defervescence and
parasitaemia clearance < 48 hours than
chloroquine or any other drug.

44. ARTEMISININ PLANT

45. • Artemisinins of 3 types are:-
-artemether prodrugs
-artesunate
-arteether
-arterolane –developed in india

46. Mechanism of Action

47. • Use:-
oral therapy:- for the treatment of
uncomplicated chloroquine/multidrug
resistant falciparum malaria.
parenterally:- severe and complicated
falciparum malaria.
rectally:-artesunate and artemether both
use for severe falciparum malaria when
parenteral therapy is not available.

48. • i.v. artesunate now become a drug of
choice for severe complicated resistant P.
falciparum malaria because of
• i.v artesunate offers several advantages.:-
1. faster parasite clearance than i.v. quinine
2. safer and better tolerated than i.v. quinine.
3. simple dosing schedule
4. higher efficacy and lower mortality.

49. Adverse Effects
• Nausea, vomiting, abdominal pain, itching
and drug fever.
• Headache, tinnitus, dizziness, bleeding,
dark urine,
• S-T segment changes, Q-T prolongation,
• First degree A-V block,
• Transient reticulopenia
• Leucopenia are rare

50. Artemisinin based
combination therapy(ACT)
• WHO has recommended that acute
uncomplicated resistant falciparum malaria
should be treated only by combining one
of the artemisinin compounds(short acting)
with another effective long acting
erythrocytic schizontocide.

51. • Advantages of ACT over other
antimalarials are:-
a)Rapid clinical and parasitological cure.
b)High cure rates(>95%) and low
recrudescence rate.
c)Absence of parasite resistance (the
components prevent development of
resistance to each other.)
d)Good tolerability profile.

53. Causal prophylaxis:
• Primaquine is a causal prophylactic for all
species of malaria
• Proguanil is a causal prophylactic, primarily for
P.f
• Atovaquone (250 mg) + proguanil (100 mg) is
commonly used as a prophylactic by Americans
and other western travelers visiting malaria
endemic areas

54. Suppressive prophylaxis
• Mefloquine 250 mg started 1–2 weeks before
and taken weekly till 4 weeks after return from
endemic area
• Chloroquine (CQ) 300 mg weekly:
• Start one week before with a loading dose of 10
mg/kg and continue till one month after return
from endemic area.

55. Contd.
• Doxycycline 100 mg daily:
• Starting day before travel
• Taken till 4 weeks after return from
endemic area for CQ-resistant P.f.,

56. • Chemoprophylaxis of malaria limited to
short-term use in special risk groups
• Nonimmune travelers
• Nonimmune Persons living in endemic areas for
fixed periods(army units, labour forces)
• Infants, children and pregnant women

57. Radical cure
• Primaquine 15 mg daily for 14 days

58. Gametocidal
• Primaquine is gametocidal to all species of
Plasmodia
• Single 45 mg (0.75 mg/kg) dose of
primaquine

59. Treatment of Malaria:
Vivax (also ovale, malariae) malaria
• Chloroquine + Primaquine 15 mg (0.25
mg/kg) daily × 14 days
Chloroquine-sensitive falciparum
malaria
• Chloroquine + Primaquine 45 mg (0.75
mg/kg) single dose (as gametocidal)

60. Chloroquine-resistant
falciparum malaria
• Artesunate 100 mg BD (4 mg/kg/day) × 3 days
+
• Sulfadoxine 1500 mg (25 mg/kg) +
Pyrimethamine 75 mg (1.25 mg/kg) single dose

61. • Artesunate 100 mg BD (4 mg/kg/day) × 3 days
+
• Mefloquine 750 mg (15 mg/kg) on 2nd day and
500 mg (10 mg/kg) on 3rd day.

62. • Arterolane (as maleate) 150 mg +
Piperaquine 750 mg once daily × 3 days

63. • Quinine 600 mg (10 mg/kg) 8 hourly × 7
days
+
• Doxycycline 100 mg daily × 7 days or +
Clindamycin 600 12 hourly × 7 days

64. Treatment of severe and complicated
falciparum malaria
• Artesunate: 2.4 mg/kg i.v. or i.m., followed
by 2.4 mg/kg after 12 and 24 hours, and
then once daily for 7 days

65. Contd.
• Artemether: 3.2 mg/kg i.m. on the 1st day,
followed by 1.6 mg/kg daily for 7 days.

66. Contd.
• Quinine diHCl: 20 mg/kg (loading dose) diluted
in 10 ml/kg 5% dextrose/dextrose-saline
• Infused i.v. over 4 hours, followed by 10 mg/kg
(maintenance dose) i.v. infusion over 4 hours (in
adults) or 2 hours (in children) every 8 hours

67. THANK YOU