9/2/2012                                      By- Jitendra Bhangale                                    Assistant Professor...
9/2/2012     Plasmodium vivax (tertian)     Plasmodium ovale (tertian)     Plasmodium falciparum (tertian)     Plasmod...
9/2/2012The life cycle of all species that infect humans is basicallythe same.There is an exogenous asexual phase in the...
9/2/2012                                Oocyst                                             Sporogony                      ...
9/2/2012Blood is infected with sporozoites about 30 minutesafter the mosquito biteThe sporozoites are eaten by macrophag...
9/2/2012P. vivax and P. ovale hypnozoites remain dormant formonthsThey develop and undergoe pre-erythrocytic sporogenyT...
9/2/2012Stages of parasite in RBCTrophozoites are early stages with ring form theyoungestTropohozoite nucleus and cytopl...
9/2/2012Schizogenic periodicity is length of asexual erythrocyticphase    48 hours in P.f., P.v., and P.o. (tertian)    ...
9/2/2012Infection is by mosquitobiteInfects liver,then blood cells                                                        ...
9/2/20124-Aminoquinolines                            Sulfonamides and sulfone      Chloroquine                         ...
9/2/2012The drug is effective against all four types of malaria     with the exception of chloroquine-resistant P.     fa...
9/2/2012Mefloquine is a 4-quinolinemethanol derivative used         both prophylactically and acutely against resistant  ...
9/2/2012Quinine is used for the prevention and treatment ofnocturnal leg muscle cramps, especially those resultingfrom   ...
9/2/2012It inhibit the parasite’s ability to synthesize folic acid.Sulfonamides should always be coadministered withpyri...
9/2/2012Pyrimethamine                inhibits        plasmodial           dihydrofolatereductase, for which it has a high...
9/2/2012Pyrimethamine                is    combined           with       dapsone          forprophylaxis of Plasmodium fa...
9/2/2012Artemisinin which is isolated from the leaves of theChinese herb qinghao (Artemisia annua).They act against the ...
9/2/2012It is lipid-soluble and is administered orally or i.m., butnot i.vOral absorption is slower taktng 24 hours, but...
9/2/2012                               By Jitendra Bhangale                                                               ...
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Malaria by JITENDRA BHANGALE

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Antimalarial agent, life cycle of malaria

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Malaria by JITENDRA BHANGALE

  1. 1. 9/2/2012 By- Jitendra Bhangale Assistant Professor & Head, Department of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad 1 © 2010 Delmar, Cengage LearningMalaria is a parasite that enters the blood.This parasite is a protozoan called plasmodium.3 to 700 million people get malaria each year, but only kills 1 to 2 million40% of the worlds population lives in malaria zones 2 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad 1
  2. 2. 9/2/2012  Plasmodium vivax (tertian)  Plasmodium ovale (tertian)  Plasmodium falciparum (tertian)  Plasmodium malariae (quartian) 3 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’badFalciparum: Almost 80% of cases and 90% of malaria deaths. Primarily found in South America and Africa.Ovale: Rarest form. Found in West Africa. Can be up to four years before and symptoms occur.Malariae: Can infect other mammals. Found in Africa and SE Asia.Vivax: 20% of infections. Widest geographic distribution. 4 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad 2
  3. 3. 9/2/2012The life cycle of all species that infect humans is basicallythe same.There is an exogenous asexual phase in the mosquito calledsporogony during which the parasite multiplies.There is also an endogenous asexual phase that takes placein the vertebrate or human host that is called schizogeny.This phase includes the parasite development that takesplace in the red blood cell, called the erythrocytic cycle. 5 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’badSchizogeny phase includes the parasite development that takes place in the red blood cell, called the erythrocytic cycle and the phase that takes place in the parencymal cells in the liver, called the exo-erythrocytic phase.The exo-erthrocytic phase is also called the tissue phase.The schizogeny that takes place here can occur without delay during the primary infection or can be delayed in the case of relapses of malaria.I will focus on the development of the parasite in the human host. 6 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad 3
  4. 4. 9/2/2012 Oocyst Sporogony Sporozoites Mosquito Salivary Zygote Gland Hypnozoites Exo- (for P. vivax erythrocytic and P. ovale) (hepatic) cycle Gametocytes Erythrocytic CycleSchizogony 7 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad Exo-erythrocytic (hepatic) Cycle: Sporozoires injected Sporozoites infect liver cells and into human host develop into schizonts, which during blood meal release merozoites into the bloodParasitesmature inmosquitomidgut and Dormant liver MOSQUITO HUMANmigrate to stages (hypnozoites)salivary of P. vivax and P.glands ovale Erythrocytic Cycle: Merozoites infect red blood cells to Some merozoites form schizonts Parasite undergoes sexual reproduction differentiate into male in the mosquito or female gametocyctes 8 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad 4
  5. 5. 9/2/2012Blood is infected with sporozoites about 30 minutesafter the mosquito biteThe sporozoites are eaten by macrophages or enter theliver cells where they multiply – -pre-erythrocytic schizogenyP. vivax and P. ovale sporozoites form parasites in theliver called hypnozoites 9 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’badP. malariae or P. falciparum sporozoites do not formhypnozites, develop directly into pre-erythrocyticschizonts in the liverPre-erythrocytic schizogeny takes 6-16 days postinfectionSchizonts rupture, releasing merozoites which invadered blood cells (RBC) in liver 10 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad 5
  6. 6. 9/2/2012P. vivax and P. ovale hypnozoites remain dormant formonthsThey develop and undergoe pre-erythrocytic sporogenyThe schizonts rupture, releasing merozoites andproducing clinical relapse 11 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’badPre-patent period – interval between date of infectionand detection of parasites in peripheral bloodIncubation period – time between infection and firstappearance of clinical symptomsMerozoites from liver invade peripheral (RBC) anddevelop causing changes in the RBCThere is variability in all 3 of these features dependingon species of malaria 12 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad 6
  7. 7. 9/2/2012Stages of parasite in RBCTrophozoites are early stages with ring form theyoungestTropohozoite nucleus and cytoplasm divide forming aschizontSegmentation of schizont’s nucleus and cytoplasmforms merozoitesSchizogeny complete when schizont ruptures, releasingmerozoites into blood stream, causing feverThese are asexual forms 13 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’badStages of parasite in RBCMerozoites invade other RBCs and schizongeny isrepeatedParasite density increases until host’s immuneresponse slows it downMerozoites may develop into gametocytes, the sexualforms of the parasite 14 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad 7
  8. 8. 9/2/2012Schizogenic periodicity is length of asexual erythrocyticphase 48 hours in P.f., P.v., and P.o. (tertian) 72 hours in P.m. (quartian)Initially may not see characteristic fever pattern ifschizogeny not synchronousWith synchrony, periods of fever or febrile paroxsymsassume a more definite 3 (tertian)- or 4 (quartian)- daypattern 15 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’badEarly symptoms Headache Malaise Fatigue Nausea Muscular pains Slight diarrhea Slight fever, usually not intermittentCould mistake for influenza or gastrointestinalinfection 16 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad 8
  9. 9. 9/2/2012Infection is by mosquitobiteInfects liver,then blood cells 17 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’badAcute febrile illness, may have periodic febrile paroxysmsevery 48 – 72 hours withTendency to recrudesce or relapse over months to yearsAnemia, thrombocytopenia, jaundice, hepatosplenomegaly,respiratory distress syndrome, renal dysfunction,hypoglycemia, mental status changes, tropical splenomegalysyndrome 18 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad 9
  10. 10. 9/2/20124-Aminoquinolines Sulfonamides and sulfone Chloroquine Sulfadoxine Amodiaquine Sulfamethopyrazine Piperaquine DapsoneQuinoline-methanol Tetracyclines Mefloquine. TetracyclineCinchona alkaloid Doxycycline Quinine Sesquiterpine lactones Quinidine ArtesunateBiguanides Artemether Proguanil Arteether (Chloroguanide) Amino alcohols Chlorproguanil HalofantrineDiaminopyrimidines Lumefantrine Pyrimethamine Mannich base8-Aminoquinoline Pyronaridine Primaquine Naphthoquinone Bulaquine Atovaquone 19 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’badChloroquine is one of several 4-aminoquinoline derivatives that display antimalarial activity.Chloroquine is particularly effective against intraerythrocytic forms because it is concentrated within the parasitized erythrocyte.This preferential drug accumulation appears to occur as a result of specific uptake mechanisms in the parasite.Chloroquine appears to work by intercalation with DNA, inhibition of heme polymerase or by interaction with Ca–calmodulin mediated mechanisms.It also accumulates in the parasite’s food vacuoles, where it inhibits peptide formation and phospholipases, leading to parasite death. 20 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad 10
  11. 11. 9/2/2012The drug is effective against all four types of malaria with the exception of chloroquine-resistant P. falciparum.Chloroquine also can be used prophylactically in areas where resistance does not exist.The absorption of chloroquine from the gastrointestinal tract is rapid and complete.The drug is distributed widely and is extensively bound to body tissues.Adverse effect:-Dizziness, headache, itching (especially in darkskinnedpeople), skin rash, vomiting, and blurring of vision 21 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’badAmodiaquine is another 4-aminoquinoline derivative whose antimalarial spectrum and adverse reactions are similar to those of chloroquine, although chloroquine-resistant parasites may not be amodiaquine- resistant to the same degree.Prolonged treatment with amodiaquine may result in pigmentation of the palate, nail beds, and skin.There is a risk of agranulocytosis and hepatocellular dysfunction when the drug is used prophylactically. © 2010 Delmar, Cengage Learning 22By J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad 11
  12. 12. 9/2/2012Mefloquine is a 4-quinolinemethanol derivative used both prophylactically and acutely against resistant P. falciparum malaria.It is ineffective against the liver stage of P. vivax malaria.It is an effective blood schizonticide.Adverse effect:-Vertigo, visual alterations, vomiting, and such CNSdisturbances as psychosis, hallucinations, confusion,anxiety, and depression 23 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’badQuinine is the levo rotatory alkaloid obtained fromcinchona bark. Its d-isomer quinidine is used as anantiarrhythmic.Quinine is an erythrocytic schizontocide for all speciesof plasmodia.Like chloroquine, it is a weak base: gets concentratedin the acidic vacuoles of the blood schizonts and causespigment changes; inhibits polymerization of haeme tohemozoin; free haeme or haeme-quinine complexdamages parasite membranes and kills it. 24 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad 12
  13. 13. 9/2/2012Quinine is used for the prevention and treatment ofnocturnal leg muscle cramps, especially those resultingfrom arthritis, diabetes, thrombophlebitis,arteriosclerosis, and varicose veins.Adverse effect:-sweating, ringing in the ears, impaired hearing, blurredvision, nausea, vomiting, and diarrohea.Quinine is a potent stimulus to insulin secretion andirritates the gastrointestinal mucosa 25 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’badChloroguanide hydrochloride is activated to a triazine metabolite, cycloguanil, which also interferes with parasite folic acid synthesis.It is a dihydrofolate reductase inhibitor that is used for the prophylaxis of malaria caused by all susceptible strains of plasmodia.Chloroguanide is rapidly absorbed from the gastrointestinal tract.Adverse effect:-Mild abdominal upset, vomiting, occasional stomatitis,haematuria, rashes and transient loss of hair. 26 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad 13
  14. 14. 9/2/2012It inhibit the parasite’s ability to synthesize folic acid.Sulfonamides should always be coadministered withpyrimethamine (or trimethoprim), since the combinedantimalarial activity of the two drugs is significantlygreater than when either drug is used alone.Adverse effect:-Anorexia, vomiting, anemia, leukopenia,thrombocytopenia, and atrophic glossitis.CNS stimulation, including convulsions, may follow anacute overdose 27 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’badPrimaquine is the least toxic and most effective of the 8- aminoquinoline antimalarial compounds.Antimalarial effects is thought to be through a quinoline–quinone metabolite that inhibits the coenzyme Q–mediated respiratory chain of the exoerythrocytic parasite.Primaquine is an important antimalarial because it is essentially the only drug effective against the liver (exoerythrocytic) forms of the malarial parasite.The drug also kills the gametocytes in all four species of human malaria.Primaquine is relatively ineffective against the asexual erythrocyte forms.Adverse effect:- G-6-PD deficiency, haemolysis, methaemoglobinaemia, tachypnoea and cyanosis 28 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad 14
  15. 15. 9/2/2012Pyrimethamine inhibits plasmodial dihydrofolatereductase, for which it has a high affinity. It is wellabsorbed from the gastrointestinal tract and isextensively metabolised.Pregnant women should receive supplementary folicacid when taking pyrimethamine.Adverse effectsAnorexia, abdominal cramps, vomiting, ataxia, tremor,seizures and megaloblastic anaemia. 29 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’badPyrimethamine acts synergistically with sulfadoxine toinhibit folic acid metabolismSulfadoxine is excreted in the urine.The combination is chiefly used with quinine to treatacute attacks of malaria caused by susceptible strains ofPlasmodium falciparum; a single dose of pyrimethamine75 mg plus sulfadoxine 1.5 g (3 tablets) usually suffices.Adverse effectsErythema multiforme, Stevens-Johnson syndrome andtoxic epidermal necrolysis © 2010 Delmar, Cengage Learning 30By J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad 15
  16. 16. 9/2/2012Pyrimethamine is combined with dapsone forprophylaxis of Plasmodium falciparum malaria.Adverse effects Erythema multiforme Stevens-Johnson syndrome Toxic epidermal necrolysis 31 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’badAtovaquone is a naphthoquinoneMechanism of actionIt inhibit the mitochondrial electron transport system in the protozoa.Malaria parasites depend on pyrimidine biosynthesis through dihydroorotate dehydrogenase coupled to electron transport.Atovaquone has good initial activity against the blood but not the hepatic stage of P. vivax and P. ovale malaria parasites.It is effective against erythrocytic and exoerythrocytic P. falciparum.Adverse effect:-Nausea, vomiting, diarrhea, abdominal pain, headache, and rash 32 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad 16
  17. 17. 9/2/2012Artemisinin which is isolated from the leaves of theChinese herb qinghao (Artemisia annua).They act against the blood, including sexual forms, ofplasmodia and may also reduce transmissibilityArtemisinins do not kill hypnozoites.E.g. Artemether, Artesunate, ArteetherArtemisininis poorly soluble in water as well as oil.Artemether is soluble in oil, while Artesunate (sod.) issoluble in water. 33 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’badIts sodium salt is water-soluble and administered by oral, i m or i v. routesAfter oral ingestion, absorption is incomplete.It is rapidly converted to the active metabolite dihydroartemisinin (DHA).Adverse effect:-Nausea, vomiting, abdominal pain, itching and drugfever. Abnormal bleeding, dark urine, S-T segmentchanges, Q-T prolongation, first degree A-V block 34 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad 17
  18. 18. 9/2/2012It is lipid-soluble and is administered orally or i.m., butnot i.vOral absorption is slower taktng 24 hours, but isenhanced by food.It undergoes substantial first pass metabolism and isconverted to DHA.Adverse effect:-Nausea, vomiting, abdominal pain, itching and drugfever. Abnormal bleeding, dark urine, S-T segmentchanges, Q-T prolongation, first degree A-V block 35 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’badHalofantrine is active against the erythrocytic forms of all four Plasmodium species, especially Plasmodium falciparum and Plasmodium vivax, and at the schizont stage.It is metabolised to an active metabolite and no unchanged drug is recovered in the urine.Halofantrine is used for the treatment of uncomplicated chloroquine-resistant Plasmodium falciparum and Plasmodium vivax malaria.It should not be given for prophylaxis. 36 © 2010 Delmar, Cengage LearningBy J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad 18
  19. 19. 9/2/2012 By Jitendra Bhangale 37Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 19

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