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ANTIMALARIALANTIMALARIAL
DRUGSDRUGS
Prof. Dr. V. SATHYA NARAYANAN M.D
MALARIAMALARIA
Caused by protozoa - plasmodium
species
Endemic in India–12-15 million cases/year
Cinchona bark – quinin...
ANTIMALARIAL DRUGSANTIMALARIAL DRUGS
Drugs used for
prophylaxis,
treatment and
 prevention of relapses
of malaria
CLASSIFICATION OFCLASSIFICATION OF
ANTIMALARIAL DRUGSANTIMALARIAL DRUGS
Cinchona alkaloid - Quinine
4 Aminoquinolines – ...
CLASSIFICATIONCLASSIFICATION
Sulfonamides – sulfadoxine
Sulfone - dapsone
Tetracyclines – Tetracycline,doxycycline
Ses...
CHLOROQUINECHLOROQUINE
Rapidly acting erythrocytic schizontocide
No effect on other phases
Effective on all forms of pl...
CHLOROQUINE RESISTANCECHLOROQUINE RESISTANCE
P. falciparum developed Resistance
Modulated by p-glycoprotein pumps
out c...
OTHER ACTIONSOTHER ACTIONS
Active against E. histolytica,
 Giardia lamblia
Anti inflammatory
PKPK
Excellent oral absorption
Given parenterally attains toxic
concentration In very short time  used
only when defin...
ADRADR
Poorly tolerated
Intravenous – hypotension , arrhythmias,
respiratory arrest, cardiac arrest
Nausea, vomiting qu...
PRECAUTIONSPRECAUTIONS
Liver damage
GI, Neurological, hematological diseases
Retinal diseases
Avoid parenteral adminis...
DRUG INTERACTIONSDRUG INTERACTIONS
Mefloquine  increased seizures,
therapeutic failure
Halofantrine  arrhythmias
USESUSES
Drug of choice for treatment of all 4 types of
malaria due to sensitive strains ( 1g at 0
followed by 0.5 g at 6...
AMODIAQUINEAMODIAQUINE
Same as chloroquine
Less bitter = Palatable
Used in uncomplicated falciparum malaria
Not recomm...
MEFLOQUINEMEFLOQUINE
Slower acting than chloroquine
Erythrocytic schizontocide
Effective against chloroquine sensitive,...
PKPK
Slow , good oral absorption
Highly protein bound
Enterohepatic cycling occur
t1/2 – 20 – 30 days
ADRADR
GI –nausea, Vomiting, dizziness
Neuropsychiatric reactions – ataxia,
hallucinations, impaired psychomotor
skills,...
DRUG INTERACTIONS, C/IDRUG INTERACTIONS, C/I
QTc prolongation with quinine/
halofantrine  cardiac arrest
Arrhythmias
E...
USESUSES
Multi drug resistant P. falciparum malaria
– 20 mg/kg single dose
Currently in ACT
Prophylaxis of malaria amon...
QUININEQUININE
Alkaloid obtained from cinchona bark
Erythrocytic schizontocide for all species
Kills vivax gametes
Cau...
ADRADR
I.V  Cardiac depression, hypotension,
arrhythmias, cardiac arrest
 hypoglycemia
 Cinchonism – ringing in ear, n...
USESUSES
Orally- uncomplicated falciparum malaria
i.v – complicated falciparum /cerebral
malaria ( caution – hypoglycemi...
PROGUANILPROGUANIL
Slow acting erythrocytic schizontocide
Cyclized  cycloguanil  inhibits plasmodial DHF
reductase
Re...
PYRIMETHAMINEPYRIMETHAMINE
Slow acting erythrocytic Schizontocide
Inhibit DHF reductase
Resistance rapidly develops
AD...
PYRIMETHAMINE- SULFA/PYRIMETHAMINE- SULFA/
DAPSONEDAPSONE
Synergistic due to sequential blockade
Clinical curative for f...
PRIMAQUINEPRIMAQUINE
Highly active against gametocytes, hypnozoites
Weak activity on erythrocytic forms
Marked effect o...
BULAQUINEBULAQUINE
Congener of primaquine
Developed in india
Similar to primaquine
Better tolerated in G-6-PD deficien...
TETRACYCLINESTETRACYCLINES
Combined with other antimalarials for
chloroquine resistant falciparum malaria
 Multi Drug Re...
ARTEMISININ DERIVTIVESARTEMISININ DERIVTIVES
Derivative of Artemisia annua ( Quinghaosu)
Effective on falciparum resista...
ARTEMISININ DERIVTIVESARTEMISININ DERIVTIVES
PK – artesunate (oral, IM, IV, rectal ), artemether
( oral, IM, rectal )  p...
ADVANTAGES OF I.VADVANTAGES OF I.V
ARTESUNATEARTESUNATE
Faster parasite clearance
Safer
Better tolerated
Simpler dosin...
HALOFANTRINEHALOFANTRINE
Activity comparable to mefloquine
t1/2 – 1 day
ADR – GI effects, itching, rash, elevated
liver...
ATOVAQUONEATOVAQUONE
Rapidly acting schizontocide
M.O.A – collapses mitochondrial
membranes, interferes with ATP
product...
OBJECTIVES OF USEOBJECTIVES OF USE
Prevent, treat clinical attack
Complete eradication of the parasite
from the patient
...
ANTIMALARIALSANTIMALARIALS
Erythrocytic schizontocides
Tissue schizontocides
gametocides
TREATMENT OF MALARIATREATMENT OF MALARIA
CAUSAL PROPHYLAXIS – pre
erythrocytic phase in liver is the target –
PROGUANIL, ...
TREATMENT OF MALARIATREATMENT OF MALARIA
CLINICAL CURE –erythrocytic schizontocide –
Fast acting -CHLOROQUINE, MEFLOQUINE...
TREATMENT OF MALARIATREATMENT OF MALARIA
RADICAL CURE – hypnozoites/
exoerythrocytic phase – PRIMAQUINE
+CLINICAL CURATIV...
ARTEMISININ-BASEDARTEMISININ-BASED
COMBINATION THERAPY-ACTCOMBINATION THERAPY-ACT
Combining one of the artemisinin
compou...
LUMEFANTRINELUMEFANTRINE
Orally active, high efficacy, long acting
erythrocytic schizontocide
Acts in the food vacuole o...
PREVENTION OF MALARIAPREVENTION OF MALARIA
Chloroquine, Proguanil and Maloprim
Malarone (atovaquone/proguanil )
Doxycyc...
Prevention is better than cure
If you have built castles in the air, yourIf you have built castles in the air, your
work need not be lost; that is where ...
THANK YOU…THANK YOU…
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Antimalarial drugs satya

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an interesting and exhaustive presentation for medical undergraduates and postgraduates on antimalarial drugs... and also helpful to physicians for learning new concepts like ACT, for treating resistant malaria and knowing important ADR of antimalarial drugs..

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  1. 1. ANTIMALARIALANTIMALARIAL DRUGSDRUGS Prof. Dr. V. SATHYA NARAYANAN M.D
  2. 2. MALARIAMALARIA Caused by protozoa - plasmodium species Endemic in India–12-15 million cases/year Cinchona bark – quinine – till 1942 Chloroquine – 1934 - Germans Primaquine – 1920s  pyrimethamine - 1951
  3. 3. ANTIMALARIAL DRUGSANTIMALARIAL DRUGS Drugs used for prophylaxis, treatment and  prevention of relapses of malaria
  4. 4. CLASSIFICATION OFCLASSIFICATION OF ANTIMALARIAL DRUGSANTIMALARIAL DRUGS Cinchona alkaloid - Quinine 4 Aminoquinolines – chloroquine, amodiaquine 8 Aminoquinolines – Primaquine, Bulaquine Quinoline-methanol – Mefloquine Biguanides – proguanil Diamino pyrimidines - pyrimethamine
  5. 5. CLASSIFICATIONCLASSIFICATION Sulfonamides – sulfadoxine Sulfone - dapsone Tetracyclines – Tetracycline,doxycycline Sesquiterpine lactones – Artesunate, Artemether, Arteether Amino alcohols – Halofantrine Mannich base - pyronaridine Naphthoquinone - Atovaquone
  6. 6. CHLOROQUINECHLOROQUINE Rapidly acting erythrocytic schizontocide No effect on other phases Effective on all forms of plasmodia Rapidly acting M.O.A enters RBC  Concentrated inside plasmodial acidic food vacuole  inhibit haeme polymerase  accumulation of toxic haeme  parasite membrane lysis  death Also prevents digestion of hemoglobin
  7. 7. CHLOROQUINE RESISTANCECHLOROQUINE RESISTANCE P. falciparum developed Resistance Modulated by p-glycoprotein pumps out chloroquine out of food vacuole – may cause serious infection Verapamil – restore sensitivity
  8. 8. OTHER ACTIONSOTHER ACTIONS Active against E. histolytica,  Giardia lamblia Anti inflammatory
  9. 9. PKPK Excellent oral absorption Given parenterally attains toxic concentration In very short time  used only when definitely needed Concentrated in liver, kidneys, lungs, spleen, retina t1/2 – 6-7 days, high Vd Tight tissue binding – persists in the body for months - CUMULATIVE
  10. 10. ADRADR Poorly tolerated Intravenous – hypotension , arrhythmias, respiratory arrest, cardiac arrest Nausea, vomiting quite severe in some Pruritus, headache, visual disturbances, insomnia, rashes, precipitates porphyria High doses  peripheral neuropathy, hearing loss, convulsions, mental disturbances Long term tt  Retinal damage, corneal deposits, Graying of hair, myopathy NOT TERATOGENIC
  11. 11. PRECAUTIONSPRECAUTIONS Liver damage GI, Neurological, hematological diseases Retinal diseases Avoid parenteral administration ( if required give slow infusion )
  12. 12. DRUG INTERACTIONSDRUG INTERACTIONS Mefloquine  increased seizures, therapeutic failure Halofantrine  arrhythmias
  13. 13. USESUSES Drug of choice for treatment of all 4 types of malaria due to sensitive strains ( 1g at 0 followed by 0.5 g at 6, 24, 48 hr) Prophylaxis – 2 tab/ week Extra intestinal amoebiasis Rheumatoid arthritis, DLE Lepra reactions Photogenic reactions Symptomatic relief of Infectious mononucleosis
  14. 14. AMODIAQUINEAMODIAQUINE Same as chloroquine Less bitter = Palatable Used in uncomplicated falciparum malaria Not recommended for prophylaxis( fatal toxic hepatitis) Similar S/E, itching less common, neutropenia in children
  15. 15. MEFLOQUINEMEFLOQUINE Slower acting than chloroquine Erythrocytic schizontocide Effective against chloroquine sensitive, resistant malaria, MDR malaria  single dose Resistance, cross resistance seen Relapses occur M.O.A probably act by inhibiting haeme polymerase  binds with heme  complex damages plasmodial membranes
  16. 16. PKPK Slow , good oral absorption Highly protein bound Enterohepatic cycling occur t1/2 – 20 – 30 days
  17. 17. ADRADR GI –nausea, Vomiting, dizziness Neuropsychiatric reactions – ataxia, hallucinations, impaired psychomotor skills, errors in operating machinery, ataxia, disturbed sense of balance Rarely Hepato, hemato, cutaneus Teratogenic in animals
  18. 18. DRUG INTERACTIONS, C/IDRUG INTERACTIONS, C/I QTc prolongation with quinine/ halofantrine  cardiac arrest Arrhythmias Epileptics Psychiatric patients
  19. 19. USESUSES Multi drug resistant P. falciparum malaria – 20 mg/kg single dose Currently in ACT Prophylaxis of malaria among travellers to areas of multidrug resistance (250 mg/week)
  20. 20. QUININEQUININE Alkaloid obtained from cinchona bark Erythrocytic schizontocide for all species Kills vivax gametes Cause incomplete clearance Less effective and more toxic Exact mechanism not known, probably as chloroquine Non-cumulative
  21. 21. ADRADR I.V  Cardiac depression, hypotension, arrhythmias, cardiac arrest  hypoglycemia  Cinchonism – ringing in ear, nausea, vomiting, hearing loss, visual defects, diarrhea, marked sweating Convulsions,  hypersensitivity reactions Black water fever  Hemolytic anemia, hemoglobinuria Fatal dose – 2-8 grams
  22. 22. USESUSES Orally- uncomplicated falciparum malaria i.v – complicated falciparum /cerebral malaria ( caution – hypoglycemia ) Nocturnal muscle cramps Babesiosis Myotonia congenita Spermicidal in vaginal creams
  23. 23. PROGUANILPROGUANIL Slow acting erythrocytic schizontocide Cyclized  cycloguanil  inhibits plasmodial DHF reductase Resistance develops rapidly Non-cumulative ADR- stomatitis, rash, N,V,D, transient loss of hair CAUTION – poor renal function Prophylaxis of malaria with chloroquine Along with atovaquone for treating MDR falsiparum malaria Safe in pregnancy
  24. 24. PYRIMETHAMINEPYRIMETHAMINE Slow acting erythrocytic Schizontocide Inhibit DHF reductase Resistance rapidly develops ADR- relatively safe, rash, nausea, megaloblastic anemia in high doses Caution –give folic acid during pregnancy Use –only in combination for falciparum malaria
  25. 25. PYRIMETHAMINE- SULFA/PYRIMETHAMINE- SULFA/ DAPSONEDAPSONE Synergistic due to sequential blockade Clinical curative for falciparum ADR – serious cutaneous reactions C/I –pregnancy, infants, sulfa allergy Uses – single dose therapy in chloroquine resistant malaria (Pyri 25 mg+ sulfa 500 mg or dapsone 100 mg) , toxoplasmosis ( 1st choice ), pneumocystosis
  26. 26. PRIMAQUINEPRIMAQUINE Highly active against gametocytes, hypnozoites Weak activity on erythrocytic forms Marked effect on Primary, secondary tissue phases Non-cumulative Mechanism not known ADR – GIT, uneasiness in chest, hemolysis in G- 6-PD deficiency, methemoglobinemia C/I – pregnancy Use –radical cure of relapsing malaria (vivax ), pneomocystis jiroveci infection
  27. 27. BULAQUINEBULAQUINE Congener of primaquine Developed in india Similar to primaquine Better tolerated in G-6-PD deficients Used in relapsing malaria
  28. 28. TETRACYCLINESTETRACYCLINES Combined with other antimalarials for chloroquine resistant falciparum malaria  Multi Drug Resistant malaria  2nd line drug for prophylaxis in travelers
  29. 29. ARTEMISININ DERIVTIVESARTEMISININ DERIVTIVES Derivative of Artemisia annua ( Quinghaosu) Effective on falciparum resistant to all drugs Rapidly acting schizontocide with short duration of action Do not kill hypnozoites Arteether – developed in India, for institutional use only M.O.A – interact with heme  release free radical species  binds to plasmodial membrane protein  lysis
  30. 30. ARTEMISININ DERIVTIVESARTEMISININ DERIVTIVES PK – artesunate (oral, IM, IV, rectal ), artemether ( oral, IM, rectal )  prodrugs Arteether – longer acting, IM ADR – GI effects, itching, fever, ST changes, Q-T prolongation arrhythmias  close monitoring required Bone marrow toxicity – rare, reversible D/I – with astemizole, terfenadine, TCAs  risk of arrhythmias Use cautiously in pregnancy Use – restricted use in severe forms of malaria, Chloroquine/MDR falciparum malaria
  31. 31. ADVANTAGES OF I.VADVANTAGES OF I.V ARTESUNATEARTESUNATE Faster parasite clearance Safer Better tolerated Simpler dosing shedule Higher efficacy Lower mortality
  32. 32. HALOFANTRINEHALOFANTRINE Activity comparable to mefloquine t1/2 – 1 day ADR – GI effects, itching, rash, elevated liver enzymes, prolongation of QTc interval C/I - pregnancy Not approved in India Use –alternative in MR falciparum malaria ( 1500 mg in 3 divided doses )
  33. 33. ATOVAQUONEATOVAQUONE Rapidly acting schizontocide M.O.A – collapses mitochondrial membranes, interferes with ATP production Uses- chloroquine resistant malaria, 2nd line drug in toxoplasmosis, Pneumocystis carinii in AIDS ADR – headache , rash, fever, vomiting, diarrhoea C/I - pregnancy
  34. 34. OBJECTIVES OF USEOBJECTIVES OF USE Prevent, treat clinical attack Complete eradication of the parasite from the patient Reduce human reservoir of infection
  35. 35. ANTIMALARIALSANTIMALARIALS Erythrocytic schizontocides Tissue schizontocides gametocides
  36. 36. TREATMENT OF MALARIATREATMENT OF MALARIA CAUSAL PROPHYLAXIS – pre erythrocytic phase in liver is the target – PROGUANIL, PRIMAQUINE SUPPRESSIVE PROPHYLAXIS – Suppress erythrocytic phase- CHLOROQUINE, PROGUANIL, MEFLOQUINE, DOXYCYCLINE
  37. 37. TREATMENT OF MALARIATREATMENT OF MALARIA CLINICAL CURE –erythrocytic schizontocide – Fast acting -CHLOROQUINE, MEFLOQUINE, QUININE, HALOFANTRINE, ARTEMISININ- given or combinations of slow acting drugs like proguanil,pyrimethamine, sulfonamides CHL .RES.MALARIA, MR FALCIPARUM – MEFLOQUINE, QUININE, ARTESUNATE Severe falciparum – PARENTERAL QUININE/ ARTESUNATE/ARTEMETHER/ARTEETHER
  38. 38. TREATMENT OF MALARIATREATMENT OF MALARIA RADICAL CURE – hypnozoites/ exoerythrocytic phase – PRIMAQUINE +CLINICAL CURATIVE GAMETOCIDAL – elimination of gametes – PRIMAQUINE,ARTEMISININ – all species,  CHLOROQUINE, QUININE - vivax
  39. 39. ARTEMISININ-BASEDARTEMISININ-BASED COMBINATION THERAPY-ACTCOMBINATION THERAPY-ACT Combining one of the artemisinin compounds with another effective erythrocytic schizontocide for uncomplicated resistant falciparum malaria – AS/S/P, AS/MQ, A/L Rapid clinical, parasitological cure Absence of resistance Good tolerability
  40. 40. LUMEFANTRINELUMEFANTRINE Orally active, high efficacy, long acting erythrocytic schizontocide Acts in the food vacuole of plasmodia to inhibit haeme polymerization Only ACT available as fixed dose combination Used in multi drug resistant, mefloquine resistant malaria Given with food C/I – PREGNANCY, Prolonged QTc interval
  41. 41. PREVENTION OF MALARIAPREVENTION OF MALARIA Chloroquine, Proguanil and Maloprim Malarone (atovaquone/proguanil ) Doxycycline
  42. 42. Prevention is better than cure
  43. 43. If you have built castles in the air, yourIf you have built castles in the air, your work need not be lost; that is where theywork need not be lost; that is where they should be. Now put foundations undershould be. Now put foundations under them.them. Henry David ThoreauHenry David Thoreau
  44. 44. THANK YOU…THANK YOU…

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