Dr Farah Manger,Dr.Prashant,MD

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• Dr Farah Manger,Dr.Prashant,MD
• www.pharmacology4students.com
• Drprashant.editor_at_gmail.com
• 
  

A Powerpoint presentation on.
ANTI-MALARIAL DRUGS
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INTRODUCTION

• TYPES OF MALARIA AND THEIR CAUSES
• MALARIA IS CAUSED BY 4 SPECIES OF PROTOZOAL
  PARASITES
• PLASMODIUM VIVAX
• PLASMODIUM OVALE
• PLASMODIUM FALCIPARUM
• PLASMODIUM MALARIAE

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LIFE CYCLE OF MALARIAL PARASITE
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• MALARIAL PARASITES EXHIBIT A COMPLEX LIFE CYCLE
• THEY HAVE ALTERNATING CYCLE OF ASEXUAL DIVISION
  (SCHIZONY) IN HUMANS
• SEXUAL DEVELOPMENT (SPOROGONY) OCCURS IN FEMALE
  MOSQUITOES.

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ANTIMALARIAL DRUGS

• CLASSIFICATION
• 4-AMINOQUINOLONES
• CHLOROQUINE
• AMODIAQUINE
• QUINOLINE METHANOL
• MEFLOQUINE

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• ACRIDINE
• MEPACRINE
• CINCHONA ALKALOID
• QUININE
• BIGUANIDES
• ROGUANIL
• DIAMINOPYRAMIDINES
• PYRIMETHAMINE

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• 8-AMINOQUINOLONES
• PRIMAQUINE
• BULAQUINE
• SULFONAMIDES AND SULFONES
• SULFODOXINE
• SULFAMETHOPYRAZINE
• DAPSONE
• TETRACYCLINES
• TETRACYCLINE
• DOXYCYCLINE

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• SESQUITERPINE LACTONES
• ARTESUNATE
• ARTEMETHER
• ARTEETHER
• PHENANTHRENE METHANOL
• HALOFANTRENE
• NAPTHOQUINONE
• ATIVAQUONE

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OBJECTIVES AND USE OF ANTIMALARIAL DRUGS

• THE AIMS OF USING DRUGS IN A MALARIAL INFECTION
  ARE
• (a)TO PREVENT AND TREAT CLINICAL ATTACK OF
  MALARIA
• (b)TO COMPLETELY ERADICATE THE PARASITES FROM THE
  PATIENTS BODY
• (c)TO REDUCE THE HUMAN RESERVOIR OF INFECTION

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• ANTIMALARIAL THERAPY IS GIVEN IN THE FOLLOWING
  FORMS-
• 1)CASUAL PROPHYLAXIS
• -IN THIS THE PREERYTHROCYTIC STAGE IS THE
  TARGET.
• -FOR THIS PURPOSE THE DRUGS THAT CAN BE GIVEN
  INCLUDE
• (a)PROGUANIL
• (b)PRIMAQUINE

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• 2)SUPPRESSIVE PROPHYLAXIS
• THE SCHIZONTOCIDES WHICH SUPPRESS THE
  ERYTHROCYTIC PHASE AND THUS ATTACKS OF MALARIAL
  FEVER CAN BE USED FOR THIS PURPOSE.
• THEY INCLUDE-
• (a)CHLOROQUINE-300mg WEEKLY

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• (b)PROGUANIL-200mg DAILY WITH
  CHLOROQUINE 300mg
• (c)MEFLOQUINE-250mg WEEKLY
• (d)DOXYCYCLINE-100mg DAILY
• 3)CLINICAL CURE
• THE ERYTHROCYTIC SCHIZONTOCIDES ARE USED
  TOTERMINATE AN EPISODE OF MALARIAL FEVER

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• THESE ARE-
• (A)FAST ACTING HIGH EFFICACY DRUGS
• (a)CHLOROQUINE
• (b)MEPACRINE
• (c)MEFLOQUINE
• (d)HALOFANTRINE
• (e)ATOVAQUONE
• (B)SLOW ACTING LOW EFFICACY DRUGS
• (a)PROGUANIL
• (b)PYRIMETHAMINE
• (c)SULFONAMIDES
• (d)TETRACYCLINES

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• SEVERE AND COMPLICATED FALCIPARUM MALARIA
• THIS INCLUDES P. FALCIPARUM INFECTION ATTENUATED
  BY-
• HYPERPARASITAEMIA
• HYPERPYREXIA
• FLUID AND ELECTROLYTE
  IMBALANCE
• HYPOGLYCAEMIA
• CARDIOVASCULAR COLLAPSE
• PULMONARY OEDEMA

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• HAEMOGLOBINURIA
• PARENTRAL FEVER
• RENAL FAILURE AND
• CEREBLAR MALARIA
• TREATMENT-
• PARENTRAL ADMINISTRATION(I.M/I.V) HAVE TO BE USED
• DRUGS GIVEN ARE-
• QUININE
• ARTESUNATE/ARTEEMETHER
• CHLOROQUINE

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• RADICAL CURE
• A RADICAL CURATIVE IS NEEDED IN RELAPSING MALARIA
  WHILE IN FALCIPARUM MALARIA ADEQUATE TREATMENT OF
  CLINUCAL ATTACK LEAVES NO PARASITE IN THE BODY.
• DRUGS-
• PRIMAQUINE-15mg DAILY FOR 2 WEAKS

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• CHLOROQUINE
• CHLOROQUINE IS A RAPIDLY ACTING
  SCHIZONTOCIDE.
• IT BELONGS TO AMINOQUINOLONES
• MECHANISM OF ACTION
• BY ACCUMULATING IN ACIDIC VESCICLES OF
  PARASITE AND BECAUSE OF ITS WEAKLY BASIC NATURE
  IT RAISES THE

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• VESCICULAR PH AND THEREBY INTERFERES WITH
  DEGRADATION OF HAEMOGLOBIN BY PARASITIC
  LYSOSOMES.
• RESISTANCE-
• RESISTANCE TO P. FALCIPARUM IS ASSOCIATED WITH
  A DECREASED ABILITY OF PARASITE TOACCUMULATE
  CHLOROQUINE

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• PHARMACOKINETICS
• ROUTE- ORAL ADMINISTRATION
• 50 BOUND TO PLASMA PROTEIN
• IT IS CONCENTRATED IN LIVER,SPLEEN, KIDNEY,
  LUNGS, AND RETINA.
• ITS ACCUMULATION IN RETINA IS RESPONSIBLE FOR ITS
  OCULARTOXICITY.

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• ADVERSE EFFECTS
• PARENTRAL ADMINISTRATION CAN CAUSE HYPOTENSION,
  CARDIAC DEPRESSION, ARRYTHMIAS AND CNS TOXICITY.
• LOSS OF VISION DUE TO RETINAL DAMAGE
• LOSS OF HEARING
• RASHES
• PHOTOALLERGY
• MENTAL DISTURBANCE

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• USES-
• SUPPRESSIVE PROPHYLAXIS OF ALL TYPES OF MALARIA
  EXCEPT THAT CAUSED BY RESISTANT P FALCIPARUM
• EXTRAINTESTINAL AMOEBIASIS
• RHEUMATOID ARTHRITIS
• DISCOID LUPUS ERYTHMATOSUS
• LEPRA REACTIONS
• PHOTOGENIC REACTIONS
• INFECTIOUS MONONUCLEOSIS

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• MEFLOQUINE
• INTRODUCTION-
• IT IS A DRUG THAT DEALS WITH CHLOROQUINE
  RESISTANT P. FALCIFARUM
• IT HAS EMERGED FROM REINVESTIGATION OF QUINOLONE
  METHANOLS.

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• MECHANISM OF ACTION
• LIKE CHLOROQUINE IT RAISES THE INTRAVASCULAR PH.
• IT BINDS TO THE HAEM AND THE COMPLEX DAMAGES
  MEMBERANES OF THE PARASITE.
• RESISTANT ORGANISMS ACCUMULATE LESS MEFLOQUINE

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• PHARMACOKINETICS
• ORAL ABSORBTION OF MEFLOQUINE IS QUITE GOOD.
• HIGHLY PLASMA PROTEIN BOUND
• T1/2 IS 2-3 WEEKS
• EXTENSIVE METABOLISM OCCURS IN LIVER AND IS
  EXCRETED IN BILE.

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• ADVERSE EFFECTS
• BITTER IN TASTE
• NAUSEA
• VOMITING
• DIARRHOEA
• DIZZINESS
• ABDOMINAL PAIN AND
• SINUS BRADYCHARDIA

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• INTERACTIONS-
• HALOFANTRINE OR QUINIDINE GIVEN TO PATIENTS WHO
  HAVE RECEIVED MEFLOQUINE CAUSE QTc LENGHTHENING
  AND CARDIAC ARRESTS ARE REPORTED.
• EXAGGERATED BRADYCHARDIA OR ARRYTHMIAS HAVE BEEN
  RPORTED WHEN MEFLOQUINE IS GIVEN TO PATIENTS
  RECEIVING B-BLOCKERS AND Ca CHANNEL BLOCKERS

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• USES-
• TREATMENT OF UNCOMPLICATED FALCIPARUM MALARIA IN
  AREAS WITH MULTIDRUG RESISTANCE
• PROPHYLAXIS OF MALARIA AMONG TRAVELLERS

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• QUININE
• QININE IS A LEVO ROTATORY AQLKALOID OBTAINED FROM
  CINCHONA BARK.
• IT IS AN ERYTHROCYTIC SCHIZONTICIDE FOR ALL
  SPECIES OF PLASMODIA

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• MECHANISM OF ACTION
• IT GETS CONCENTRAATED IN THE ACIDIC VACUOLES OF
  THE BLOOD SCHIZONTS AND CAUSES PIGMENT CHANGES
• ALSO INHIBITS THE POLYMERIZATION OF HAEM TO
  HEMOZOIN
• FREE HEME OR HEMOZOIN COMPLEX DAMAGES PARASITE
  MEMBERANE AND KILLS IT.

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• PHARMACOKINETICS
• QUININE IS RAPIDLY ABSORBED ORALLY
• IT IS 70 BOUND TO PLASMA PROTEIN
• CSF CONCENTRATIONS ARE LOW
• LARGE FRACTION OF DOSE IS METABOLISED IN THE
  LIVER
• T1/2 10-12 HRS

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• ADVERSE EFFECTS-
• CINCHONISM
• THE SYMPTOMS ARE AS FOLLOWS-
• RINGING IN EARS, NAUSEA, VOMITING, HEADACHE,
  MENTAL CONFUSION, VERTIGO, DIFFICULTY IN HEARING
  AND VISUAL DEFECTS.
• IN ADDITION DELIRIUM, FEVER, TACHYPNOEA, FOLLOWED
  BY RESPIRATORY DEPRESSION AND CYANOSIS.

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• USES-
• MALARIA
• CEREBRAL MALARIA
• NOCTURNAL MUSCLE CRAMPS
• DIAGNOSIS OF MYASTHENIA GRAVIS
• SPERMICIDAL IN VAGINAL CREAMS
• INJECTED ALONG WITH URETHANE IT CAUSES THROMBOSIS
  AND FIBROSIS OF THE VARICOSE VEIN MASS

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• PYRIMETHAMINE
• IT IS DIRECTLY ACTING INHIBITOR OF DHFrase NOT
  REQUIRE CONVERSION TO A CYCLIC TRIAZINE.
• MECHANISM OF ACTION-
• MECHANISM OF ACTION RESEMBLES PROGUANIL BUT IS
  MORE POTENT

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• PHARMACOKINETICS-
• ABSORPTION OF PYRIMETHAMINE FROM GIT IS GOOD BUT
  SLOW.
• CONCENTRATED IN CERTAIN ORGANS LIKE LIVER, BRAIN
• T1/2 4 WEEKS
• PROPHYLACTIC CONC REMAIN IN BLOOD FOR 2 WEEKS

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• ADVERSE EFFECTS-
• OCCASIONAL NAUSEA
• RASHES
• FOLATE DEFICIENCY
• USES-
• IN COMBINATION WITH A SULFONAMIDE IT IS USED IN
  TREATMENT OF MALARIA.

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• PRIMAQUINE
• IT IS A POOR ERYTHROCYTIC SCHIZONTOCIDE
• IT DIFFERS FROM ALL THE OTHER ANTIMICROBIALS IN
  HAVING A MARKED EFFECT ON PRIMARY AS WELL AS
  SECONDARY TISSUE PHASES OF MALARIAL PARASITE.

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• PHARMACOKINETICS-
• READILY ABSORBED AFTER ORAL ABSORBTION
• OXIDISED IN LIVER
• PLASMA T1/23-6 HRS
• EXCRETED IN URINE WITHIN 24 HRS.

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• ADVERSE EFFECTS
• ABDOMINAL PAIN
• GI UPSET
• WEAKNESS OR UNEASINES
• DOSE RELATED HAEMOLYSIS, METHHAEMOGLOBINAEMIA,
  TACHYPNOEA,CYANOSIS

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• USES
• USED FOR RADICAL CURE OF RELAPSING MALARIA
• ALSO USED IN TREATMENT OF FALCIPARUM MALARIA
• DOSE 15 mg DAILY FOR TWO WEAKS
• OTHER DRUGS INCLUDED IN THIS GROUP ARE-
• BULAQUINE
• TETRACYCLINES

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• ARTEMESENIN DERIVATIVES
• ARTEMESENIN IS THE ACTIVE PRINCIPLE OF PLANT
  ARTEMESIA ANNUA
• IT IS USED IN CHINESE TRADITIONAL MEDICINE AS
  QUINGHAOSU
• ARTEMESENIN IS POORLY SOLUBLE IN WATER AS WELL AS
  OIL

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• MECHANISM OF ACTION
• THE ENDOPEROXIDE BRIDGE IN ITS MOLECULE
  INTERACTS WITH HEME IN THE PARASITE
• IRON MEDIATED CLEAVAGE OF THE BRIDGE RELEASES A
  HIGHLY REACTIVE FREE RADICAL SPECIES

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• THIS BINDS TO MEMBERANE PROTEINS CAUSES LIPID
  PERODIXATION,DAMAGES ENDOPLASMIC RETICULUM,
  INHIBITS PROTEIN SYNTHESIS, AND ULTIMATELY LYSIS
  OF THE PARASITE.

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• PHARMACOKINETICS
• ARTENSUATE AND ARTEETHER ARE PRODRUGS
• RAPIDLY ABSORBED AND CONVERTED INTO THE ACTIVE
  METABOLITE DIHYDRO-ARTEMISININ
• T1/2 OF ARTENSUATE lt 1 hr
• T1/2 OF ARTEETHER 3-11 HOURS

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• ADVERSE EFFECTS
• NAUSEA
• VOMITING
• ABDOMINAL PAIN
• ITCHING
• ABNORMAL BLEEDING
• DARK URINE
• S-T SEGMENT CHANGES
• FIRST DEGREE A-V BLOCK
• TRANSIENT RETICULOPENIA AND LEUCOPENIA

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• INTERACTION
• CONCURRENT ADMINISTRATION OF ARTEMISIN COMPOUNDS
  WITH TERFENADINE, ASTEMIZOLE, ANTIARRYTHMATICS,TRI
  CYCLIC ANTIDEPREEANTS AND PHENOTHIAZINES

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• USES
• TREATMENT OF ACUTE ATTACKS OF SEVERE FALCIFARUM
  MALARIA
• CEREBRAL MALARIA
• CHLOROQUINE/OTHER MULTIDRUG RESISTANT MALARIA
• THEIR USE FOR PROPHYLAXIS OF MALARIA IS
  IRRATIONAL AND NOT ALLOWED

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