3)PLASMODIUM VIVAX PRESENTATION FOR STUDENT

MALARIA

1. Malaria Objectives – To prevent clinical attack [prophylactic] To treat clinical attack[curative] To completely eradicate the parasite [radical] from pts body To cut down human to mosquito transmission

2. Life cycle – Infect man Vivax – benign tertian malaria every third day – temp Falciparum – no pre erythrocyte phase – malignant tertian fulminating type Ovule mild – every 4 th day – temp →persistent Malaria hepatic (benign quarten ) cycle → Hypnozoites

3. Transmission of disease → Mosquito bite Blood transfusion (infected) Tissue schizonts → RBC Retculo Endothelial cells Merozoites Sporozoites Gametocytes Male – Macro Female – micro

4. Clinical Symptoms Fever with rigor Female anaphelis Anaemia Spleenomegaly Wide spread resistance to DDT – mosquitoes ↑ prevalence of falciparum Caused by parasite protozoa – genus Plasmodium Commen in india – fever with rigor Anaemia , Spleenomegaly

5. During Maturation in RBCs Host Hb – digested – remains accumulated of Malarial pigment Haemozoin P- falciparum – Toxic factors produced by merozoites → fulminating infection overwhelming paracyhama capillary permeability – DIC

6. Infected RBCs (all ages) develop receptors for adhesions Knobs or rosettes ,obstruction-- Molecules on vascular endothelial cells Adhere and pack the vessels (Microcirculation) Results into ↓↓ blood flow to tissues – causing organ damage Renal failure, encephalopathy (Cerebral malaria) Relapses may occur Inadequate treatment – recrudescence , merozoites -fresh RBCs,reapear ,-- Immunity – present – remains for 6 months after leaving the place,exoerytrocytic ---re-entry of schzogony in hepatic cells,

7. True casual prophylaxis – Destroy the sporozoites before their invasion in host reticulo endothelia cells Casual prophylaxis – Prevent maturation of or destroy the sporozoites before enter in RBCS Primaquine , Pyramethamine , Proguanil

8. Suppressive – Schizontisides [chemoprophylaxis] ↓ RBC – schizogony No effect – hepatic cycle Chloroquine 600mg weekly – Ist & last day Mefloquine Resistant 200mg weekly 4 weeks leave Artemisinin Proguanil Tetracyclin Pyrimethamine

9. Radical cure – Eradication of both –hepatic & erythrocytes Primaquine Gametocides – Primaquine , quinine Chloroquine artesunate or Pyrimethamine Clinical cure – chloroquine – 600mg base ↓ 8 hrs – 300mg ↓ 300mg x next 2 days

10. Chloroquine & Congeners Most widely used – most versatile but restricted due to resistance.. blood schizonticidal action – all four types 400 years – ago quinine Pharmacokinetics – Rapidly & completely absorbed from GIT – Parental – emergency & unconscious Very large apparent volume of distribution Plasma protein binding 50% Narrow safety margin L.M.E. – metabolism unchanged 50% - 25% - metabolism Acidification of urine ↑- excretion

11. Tissue selectivity – 200-900 time – infested R.B.C. Liver spleen, skin, kidney, lungs, retina (melanin containing tissue) ,collagen Traces present 5 years after cessation of therapy Spinal cord & brain –less Loading dose – essential Peak plasma levels – 3 – 5 hrs t1/2 – 50 hrs initial Later on – 30 -60 days terminal ½ life Superior to quinine – less toxic more potent → as suppressive weekly.

12. Pharmacological effects Antimalarial – Asexual erythrocyte forms – highly effective 24 – 48 hrs M.A. – weak base get concentrated in infected RBCS ↑ pH in acidic food vacuoles of sensitive parasites Unable to utilize host Hb -histological changes in sensitive parasite → rapid clumping of pigments

13. Releases heme A toxic compound ( ferri protoporqurine ) having membrano lytic properties Free radicle Haemeazoin – a harmless malarial pigment is released → ↑↑ - concentration of drug in suceptible parasites & infected RBC – Ca dependent Energy dependant Saturable , competitive

14. Drug resistance can be minimize → by using Ca channel blocking- verapamil Resistance is due to ↑ - efflux of drugs from parasite Other – inexpensive & safe (extra-ordinary) Hepatic Amoebiasis – extra intestinal

15. Anti-inflammatory – Rheumatoid arthritis Get concentrated in lysosome stabilizes the lysosome Discoid lupus erythematosis Lepra reactions Infectious mononucleosis Giardiasis Photogenic reaction Porphyries cutanea tarda Severe polymorph lesions Sarcoidosis

16. M.A. interfere with plasmodium DNA synthesis Hemingferriproto porphyrin release by parasites – Hb digestion acts as receptor for chloroquine & complex cause ↑ - pH

17. Uses Acute attack of Malaria 600 mg – base loading dose 300 mg – 6 hrs later 300 mg – II day 300 mg – III day Suppressive prophylaxis – 300 mg / weakly – till the person is in endemic area start 2 weeks before 8 weeks after leaving the area

18. Rheumatoid arthritis Extra intestinal amoebiasis Lupus erythematosus Porphyria cutanea tarda Photogenic skin reactions Infections mononucleosis- symptomatic relief Lepra – reactions

19. Side effects Safe in pregnancy & children GIT – Nausea, vomiting, visual disturbances, Puraritus , headache, skin eruptions Acute toxicity – IV in children – cardiovascular collapse Vasodilatation – direct cardiac depressant action G6PD → Heamolytic anemia

20. High Doses- Retinopathy, toxic Myopathy , peripheral neuropathy Psychiatric illness, cardiomyopathy Precautions & Contraindications Epilepsies & myasthenia Gravis Cautions – with hepatic, GIT, Neurological, or blood disorders

21. Quinine Not getting concentrated in infected RBC, more – toxicity and less effective Cinchonism CVS Idiosyncrasy Black water fever → acute intravascular haemolysis Hypoglycaemia nausea, Fever Quinine & Doxycycline → for – Glucocorticoids & quinine resistant Alkilinization of Urine

22. Use Cerebral Malaria – 250 to 500 mg IV slowly (Infusion) Drug of choice Drug resistance – Malaria Myoclonic congenital – hereditary myopthy Cramps – 200-300 mg Spermicidal in vaginal creams Varicose veins – as irritants thrombosis fibrosis

23. Pharmacological actions Protoplasmic poison Local action – irritant – vascular damage Interferes with parasite feeding mechanism Accumulation of heme – more like action of Proguanil , Mefloquine , Pigment changes Skeletal muscle – ↓ excitability at motor end place, alarming respiratory distress in myasthenic Patients

24. Primaquine Most effective → only agent available for radical lest toxic cure ( Gemetocidal ) Hypnozoites Highest therapeutic index Primaquine → electrophones – oxidation reduction ↓ converted mediators Interfer with electron transport of energy to parasites

25. Used – For radical cure – except falciparum (relapses due to pre-erythrocyte cycles) with chloroquine – Bulaquine Started – Before or after suppressive treatment 15mg/day – 14 day G6PD – Heamolysis (Intravascular) GIT – irritation GIT – Epigastric distress, abdominal cramps Bulaquine - drug is under evalution Tafenoquine new long acting potent 3 days treatment

26. Mefloquine For chloroquine resistant – High cost Less potent Toxic Mechanism Action –like quinine blood schizontocide Acts on erythrocyte stage Highly effective with single dose – chloroquine resistant Can be given 12 hrs after quinine No action on persistant tissue forms

27. Pharmacokinatics Slow good, rapidly absorbed – t1/2 – 20 days – excreted in bile (2-3 weeks) – ( entero - hepatic circulation) tissue binding ADRs – GI – dizziness, nausea, vomiting Neuropsychiatric – Anxiety disorders Hallucinations Sleep disturbances CVS – like chloroquine Teratogenicity A single dose 750 mg tab 250 mg plenty of water

28. Use should be restricted to Repeat after hrs in some cases M.D.R. malaria Prophylaxis travelers to MDR malaria Contraindications Cardiac conduction abnormality, liver impairment H/o psychiatric or neurological disorder – epilepsy I trimester Pregnancy

29. Halofantrine Chlorquine sensitivity parasites Also – resistant, Pyrimethamine & quinine Slowly & variably absorbed peak concentration – 4-6 hrs Fatty food – interferes the absorption metabolite – longer t1/2 active (N- desbutyl ) Three doses – 500 mg with 6 hrs internal – repeated after one week ADR – prolongation of QT – – ventricular arrhythmias due to toxicity the drug is rarely used

30. Proguanil Prodrug – No Hypoglacaemic action Prophylactic ↓ - dihydro folate reductase Suppressive ↓ - DNA synthesis Not used alone, used in combination and of schizogony Active metabolite – cycloguanil Prophylactic Suppressive

31. No action against persistent tissue forms Schizonticide – P.vivax P.falciiparam Primary pre-erythrocyte forms Prevents development of gametes t1/2 -12- 21 hrs – oral absorption – better Side effects – free from ADRs GIT – disturbances, stomatitis , mouth ulcers afovanquone 250 mg + 100 mg proguanil – multi resistant falciparam Safe during pregnancy 4 tablet /OD / 3 days

32. Pyrimethamine More potent than proguanil Like trimthoprim – potency greater – Anti malarial revertase [sequential block] given in combination with sulfonamide Prolong t1/2 – 80 -95 hrs Acts – directly Single dose – therapeutic concentration – 2 weeks High affinity to dihydro folate reductase No action on tissue parasites like 1400 more than mammalian, no action on tissue parasites like proguanil

33. Combination delays – resistance (supra- aditive ) Sulfadoxine + Pyrimethamine + Dapsone (Sometime 500 mg 25 mg 100mg combined) Toxicity – rash ↓ - haemopoetic system Megaloblastic anemia reversible, stopping Malaria Toxoplasmosis 25 mg – twice / day and followed by once / day Polycythemia vera Early diagnosis → symptoms are – nonspecific – PS – short – duration of free parasites in blood

34. Pyrethrum Compounds Pyrethroids Neuropoisons for muscle Mosquito repellant – Diethylmeta tolamide Chemoprophylaxis – 1-2 weeks before 2-3 weeks after Cerebral Malaria – quinine J.R. slow – emergency treat – Hypoglycaemia Children – Same as adult Quinine – better tolerated – primaquine – avoide in prenatal Pyrimethmine → 12.5 mg/once a week Pregnant – chloroquine , quinine Mefloquine safe II & III trimesters

35. Tetracycline & doxycycline Slowly acting, weak erythrocytic schizontocidal Combination – quinine – chloroquine resistant F

36. Artemisinin Derivatives Active against P. falciparum , resistant to all Potent, rapid blood schizonticide action quicker .ferrous protophyrin4 present in parasitic vacuole..generates highly reactive free radical—damages parasites.– parasitaemia , clearance fast Action on wide range of stages Broadest time window Derivatives Artesunate , artemether , arteether ( iminoil ) Short duration – monotherapy – more than 5 days

37. Mechanism of Action Endoperoxide bridge – interact with haeme in parasite ↑↑ highly reactive free radicle binds to membrane proteins – damages Endoplasmic reticulum – lysis ↓ sarcoplasmic calcium AT Pase Emerged no resistance

38. Pharmacokinetics Poorly soluble – water & oil Oral absorption + ve invariable after food – better Combined 3 days, single 5-7 days Oral, rectal, i.m ., i.v . Protein binding variable Artesumate Water soluble Oral, prodrug Repeated doses causes Auto induction – own metabolism Artemether – Lipid soluble, oral only

39. Use Uncomplicated falciparum malaria- Potent antimalarial ( chloroquine resistant) Combination – better - ↓↓ recrudescence Vivax – only chloroquine resistant Severe & complicated falceparum – Cerebral, Pregnancy Better tolerated , safer, lower mortality No use for prophylaxis – short acting

40. ADRs Safe High doses Ist degree heart block ↓ reticulocyte , neutrophils Neurotoxicity Bone marrow ↓↓

41. Antimalarial Combination Therapy Independent modes of action ↑↑ therapeutic efficacy Delay resistance sulphadoxine – pyrimethamine , Proguanil - dapsone

42. Rationale Often more effective Mutual protection to prevent or delay emergence of resistance

43. Chemoprophylaxis Non-immune travellers Pregnant (II & III trimester) Army units – high risk areas Chloroquine sensitive – 300 mg base - / week start 1-2 weeks before continue – 4 weeks after leaving Drug resistant Mefloquine -/ week 1-2 week before 4 weeks later Doxycycline – 100 mg/ day

44. Acute attack of Malaria Chloroquine sensitive 600 mg base – 6-8 hrs later 10mg/kg 300 mg base II day 300 mg III day 300 mg Resistant Quinine – 600 mg – 8 th hrly + doxycycline 100 mg/day x 7 days Artesumate 100 mg B.d . + mefloquine 1250 mg for three days only Complicated Severe Artesunate 2.4 mg/kg iv or im 12 hrly once a day x 7

45. Resistance to Anti- malarials Ability of parasite strain to survive and / or multiply despite the proper anti-malarial treatment Treatment failure – different P- falciparum – lethal potential

46. Parasitic Diseases Protozoa Helminths Ectoparasites Less developed countries, most prevalent health & economic burden Expanded due to Deforstation Population shifts Global warming Other climatic changes

47. Human response to invading parasites Cell mediated immune response T helper pathway ( Th )1 Cytokines – interleukin2 TNF – β , interferon's IFN- α Active macrophages, Cytotoxic CD8+T Kill intracellular parasites ( Th )1 pathway – down regulated by Th2 pathway Leishmania →↑↑ Th2 pathway – TGF- β

48. Protozoa Single celled organisms Free living or parasite Entamoeaba , Giardia , Leishmania Plasmodium Transmission – Faecal oral route Arthropod vector Lactacystin – ↓↓ of 20G proteosome ↓↓ erythrocytic stage of falciparum & reduces replication of amoeba

49. Parasite enzyme – cysteine / aspartate proteinases degrade Hb – potential target Cytokine receptor based – Host cytokines & chemokines mutant cytokines – protect animals Vaccines – Destroy sporozoites & infected hepatocytes Attacking parasites

50. Helminths Large multicellular organism Trematodes – flukes Cestodes – tapeworms Nematodes - roundworms

51. Ectoparasites Ticks, fleas, lice, mites attach or burrow – into skin Blood sucking, vectors / transmitters

52. Trypanosomiasis Only in America & Africa Stages – Haemo lymphatic – lymph node enlargement Meningo encephalopathy fever headache Africa Suramine Pentamidine Mental disturbances Drowsiness – sleeping sickness

53. American – Cardio myopathy (Chagas D) Mega – Colon Esophagus Oral – Benznidazole Nifurtimox

54. Drugs for Trichomoniasis Metronidazole – 200 mg TDS x 7 other – 2G single dose Tinidazole Secnidazole Local Clofrimazole 100 mg –deep intravaginal at night x 6 days Econazole – 150 mg – 3 days at night

55. Visceral leishmaniasis or kala azar Protozoan Genus leishmania 20 – different species Caused by – L donovani Transmitted by – Phebotomus sandflies Hepatomegaly , irregulars fever, anemia, leukopenia , Hyperglobulinemia India – Assam, Bihar, Orissa, Bengal

56. Cutaneus / oriental sore Muco cutaneous & diffuse Visceral ↓ Human

57. Female sandfly 10 days REC – Human of liver, spleen & lung Form is GIT ↓ Humen being by bite ↓ Attack the REC → Phagocytosed by macrophages L. Forms ( amastigotes ) – non flagellated → Humen ↓→ 10 days Leptomonad form ( Promastigotes ) flagellated

58. Drugs Pentavalent antimony compounds Sodium stibogluconate Meglumine Diamidine D – Pentamidine isethionate Miscellaneous – Amphotericin B Aminocillin Allopurinol Miltefosine

59. Liposomal AMB – suitable, it delivers the drugs inside REC Na stiboglucomate – SH dependant enzymes are ↓ & bioenergetics of the parasite interfered Injection – IM – excreted unchanged in urine a small fraction enters tissue → stored for long period 10mg/kg/day for 20-30 days daily or alternate Toxic drugs – Pancreatitis, myelosuppression

60. Pentamidine – interacts with kinetoplast DNA →↓ topoisomerase II interferes with Gesobic glycolysis Only for antimony failure cases Pneumocono carnie in AID pt Treatment is undergoing major changes Miltefosine → most successful → oral drugs 28 day is anticancer drug – side effects – vomiting diarrhea, I st line 4 weeks course – t1/2 7 days terminal – 4 weeks with meals 100 mg /day – 30 day other wise I.V. Amphoterisin B – liposomal – most imp. Costly