Malaria ANISH FINAL

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1 MALARIA Dr. ANISH JOSHI Jaslok Hospital

MALARIA : 

2 MALARIA MALARIA ( AGUE )Mal – BadAria – Air Protozoal Infection Transmission requires temperature between 16-33 oC Rainfall provides breeding site for mosquito. Humidity favours mosquito survival.

EPIDEMIOLOGY : 

3 EPIDEMIOLOGY Sporadic - A few scattered cases. Endemic - Hypoendemic - Spleenic Rate < 10% Mesoendemic - Spleenic Rate 10-50% Hyperendemic - Spleenic Rate 50-75% Holoendemic - Spleenic Rate > 75% Epidemic - Disease with high morbidity Stable transmission: Constant frequent year round infection Unstable transmission: Low, erratic or focal transmission

TRANSMISSION : 

4 TRANSMISSION Mosquito Bite (Female Anopheles) Blood Maximum with fresh blood upto 5 days. No infection - stored blood > 5 days. No infection - Plasma Transfusion Syringes Drug Addict / Iatrogenic. Congenital Malaria Mother to Child ( Rare ) ( AIDS )

VIDEO : 

5 VIDEO

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P. falcipuram : 

8 P. falcipuram Young trophozoites Old trophozoites Pigment in polymorphonuclear cells and trophozoites Mature schizonts Female gametocytes Male gametocytes

P. vivax : 

9 P. vivax Young trophozoites Male gametocytes Female gametocytes Old trophozoites Mature schizonts

TISSUE DAMAGE : 

10 TISSUE DAMAGE Mechanical Obstruction Permeability Changes Immunological Changes Release of Cytokines Metabolic Changes

1 MECHANICAL OBSTRUCTION : 

11 1 MECHANICAL OBSTRUCTION CYTOADHERENCE : Parasitised RBC adhere to microvascular endothelium by “sequestrin” protein. SEQUESTRATION : Parasitised RBC disappears from circulation. Starts at middle of asexual cycle. Sequestration occurs mainly venules of vital organs [Brain, Heart, Liver, Kidney, Intestine, Adipose Tissues]

MECHANICAL OBSTRUCTION[ Contd.. ] : 

12 MECHANICAL OBSTRUCTION[ Contd.. ] Rossette Formation Microcirculation obstruction. Hypoxia, Anaerobic Glycolysis, Lactic Acidosis. Parasitised RBC adhere to uninfected RBC. Parasites derived Histidine rich protein produce hump on the surface of RBC. Knob is attached to vascular endothelium Sticky protein ( Thrombospondin ) binds to Parasitised RBC.

MECHANICAL OBSTRUCTION[ Contd.. ] : 

13 MECHANICAL OBSTRUCTION[ Contd.. ] RBC Deformity Parasitised RBC become spherical & Rigid due to : Decreased Membrane fluidity Increased Sphericity Enlarged RBC Less filterable in spleen

2 PERMEABILITY CHANGETissue damage by Parasitised RBC : 

14 2 PERMEABILITY CHANGETissue damage by Parasitised RBC Increased Capillary permeability Outward leakage of plasma [ Haemoconcentration reduces microcirculation ] Oedema of organs [ Brain – Intestine – Lungs ]

3 IMMUNOLOGICAL CHANGESTissue damage by Parasitised RBC : 

15 3 IMMUNOLOGICAL CHANGESTissue damage by Parasitised RBC Parasite & Parasitised RBC act as antigen. Cellular & Humoral immune responses. Complement activation. Immune Complex Vasculitis : EFFECT :Proliferative glomerulonephritis spleenomegaly

4 RELEASE OF CYTOKINES : 

16 4 RELEASE OF CYTOKINES TNF IFN has antiparasitic activity IL-1 , IL-6 Good Effect : Killing parasite by Leukocyte Proliferation (Release of Nitric oxide, Lipid Peroxidase) Bad Effect : Paroxysm of Malaria - Cytoadherence - Inhibit Gluconeogenesis - Suppresses Erythropoesis

5 METABOLIC CHANGES : 

17 5 METABOLIC CHANGES Hypoglycemia  Metabolic Demand ↓ Hepatic gluconeogenesis by cytokines ↓ Glycogenolysis Hyperinsulinemia (Quinine induced) Anaerobic glycolysis (Pregnant female /severe infection & non-immune patient)

METABOLIC CHANGES : 

18 METABOLIC CHANGES Lactic acidosis Hypoxia Anaerobic glycolysis Decreased Microcirculation Cytokines, Hypotension Faliure of Hepatic Lactate clearance

METABOLIC CHANGESTissue damage by Parasitised RBC : 

19 METABOLIC CHANGESTissue damage by Parasitised RBC Hyperkalemia due to hemolysis of RBC Hyponatremia Hypoalbuminemia Capillary leakage Hepatic dysfunction  TG, FA Sick Euthyroid syndrome Hypoparathyoidism Cal. PO4

CARDIO-VASCULAR CHANGES : 

20 CARDIO-VASCULAR CHANGES Cardiac dysfunction Primary Coronary embolism by Parasitised RBC Secondary Hypovolemia – Lactic acidosis - Septicemia Orthostatic – Hypotension (Falciparum) Cardiac arrhythmia – Quinine/Chloroquine/Lactic acidosis Circulatory collapse (Due to) Pyrogen medicated vasodilation (Kinine Effect) Pulmonary oedema Metabolic acidosis Endotoxaemia – Gram -ve septicemia Dehydration ( intake, loss, vomiting)

PULMONARY CHANGES : 

21 PULMONARY CHANGES Pathogenesis Disturbance in microcirculation Pulmonary vasculature microembolisation Capillary leak – Oedema Compliment activation – Immunological reaction Fluid overload – Renal failure Histolgy Thickening of alveolar septa endotoxin effect Deposition of pigment (Hemazoin) Produce inflammation Cellular infiltration Hyaline membrane formation

PULMONARY CHANGES : 

22 PULMONARY CHANGES Clinical Symptoms Acute pharyngitis Acute bronchitis Pleural effusion Acute pulmonary Oedema (Paroxysmal) ARDS Always associated with cerebral malaria 3 – 10 % of malarial cases - 80% mortality.

GASTRO INTESTINAL PATHOLOGY : 

23 GASTRO INTESTINAL PATHOLOGY Parasites sequestation in capillaries of Gl tract. Interferes with absorption producing malabsorption Malabsorption of Sugar – Fat – Aminoacid Chloroquine – Quinine Endotoxaemia (serious complication of malaria) Originates from gut Entry of GNB – Enteric Fever Failure of hepatic clearance of toxin

GASTRO INTESTINAL PATHOLOGY : 

24 GASTRO INTESTINAL PATHOLOGY Clinical Features Acute gastritis AGE & Acute bacillary dysentery Choleratic diarrhoea Hematemesis – malena Malabsorption

SPLEEN IN MALARIA : 

25 SPLEEN IN MALARIA Acute stage – Soft tender spleenomegaly (Falciparum) (1st week) – Splenic infarction Left shoulder pain Acute stage (Vivax – 2nd week) Reticuloendothelial hyperplasia Non tender firm spleen Chronic Stage Massive spleenomegaly Tropical spleenomegaly Immune mediated hypertrophy response Burkitt’s Lymphoma Continuous stimulation of Lymphoid system Neoplastic transformation (Presence of EBV)

HEPATIC CHANGES : 

26 HEPATIC CHANGES Pre-erythrocytic stage – Reactive Hepatitis Erythrocytic stage (Falciparum) Severe hepatic necrosis Hepatomegaly is more common than spleenomegaly Liver regresses after effective Antimalarial therapy Cirrhosis of liver - NEVER

JAUNDICE IN MALARIA : 

27 JAUNDICE IN MALARIA Intravascular Hemolysis Hepatitis: Pre-Erythrocytic phase D.I.C. Septicemia Associated viral Hepatitis Cholestasis in Black-water fever

HEMATOLOGICAL ABNORMALITY( more in young children & pregnant females ) : 

28 HEMATOLOGICAL ABNORMALITY( more in young children & pregnant females ) SEVERE ANAEMIA Hemolysis of Parasitised red cell. Schizont releases merozoites by rupture of RBC. Hemolysis of non-parasitised red cell. Immune complex [ AB + AG ] Hemolysis Dyserythropoiesis Impairment of bone marrow function. Decreased iron incorporation.[Plenty of iron available but not producing haemoglobin] Severe infection / secondary bacterial inf.

HEMATOLOGICAL ABNORMALITY [ Contd. ] : 

29 HEMATOLOGICAL ABNORMALITY [ Contd. ] Thrombocytopenia Bone marrow depression. Consumption coagulopathy. Hypersplenism. DIC Fibrin degradation product.  Plasma fibrinogen. Cytokines are procoagulant

BRAIN ( CEREBRAL MALARIA ) : 

30 BRAIN ( CEREBRAL MALARIA ) Commonest in falciparum, sometime in vivax Capillaries & small blood vessels – blocked Ring hemorrhage around blocked vessels Petechial hemorrhage in subcortical white matter of cerebrum – cerebellum – brain stem HISTOLOGY OF BRAIN : Rosette formation in brain ( Rose like appearance due to vacuole – Monocyte & Parasitised RBC ) Necrosis with glial reaction leads to malaria granuloma Acute cerebral oedema

CEREBELLAR INVOLVEMENTPt. recovering from malaria 3rd – 4th Day. : 

31 CEREBELLAR INVOLVEMENTPt. recovering from malaria 3rd – 4th Day. Direct effect of parasite Vascular – mechanical obstruction. Oedema – Increased capillary permeability. Inflammation due to parasitemia. Delayed immune response. Drug toxicity – Antimalarial & Antiemetics. Activation of neurotropic virus. Rubella – Varicella.

RENAL DYSFUNCTION : 

32 RENAL DYSFUNCTION ATN Pre-renal (Dehydration/fluid loss) Black-water fever (Haemoglobin is nephrotoxic) Massive hemolysis Quinine – Primaquine - G6PD Deficient Acute Cortical ischaemia Dehydration, shock Lactic acidosis Quartan nephropathy by Pl. Malariae

MALARIA IN PREGNANCY : 

33 MALARIA IN PREGNANCY (Falciparum – highest mortality) Immunosupression of pregnancy Placenta – Good source for parasite growth Encourages parasite multiplication Microcirculation obstruction Placental insufficiency Foetal distress Abortion Low birth weight baby Child rarely affected except AIDS

MALARIA IN PREGNANCY : 

34 MALARIA IN PREGNANCY Mother Acute pulmonary oedema Severe hypoglycemia Severe metabolic acidosis Secondary bacterial infection Infant – Less frequent malaria due to : Transfer of maternal immunity. High Haemoglobin (fetal Hb)Does not allow parasite to grow.

BLACKWATER FEVERPathophysiology : 

35 BLACKWATER FEVERPathophysiology Plasmodium Falciparum only (Parasite not seen in blood) Massive intravascular hemolysis Autoimmune reaction Repeated infection - Partially treated infection Massive infection - Quinine therapy Infected red cells become antigenic to RBC Quinine - Increase fragility of sensitised RBC Effect of Hemolysis of red cells Blood - Oxyhaemoglobin Methemoglobin + Albumin Unconjugated billirubin ( Indirect positive Van den bergh ) Urine - Oxyhemoglobinuria – Red urine Methemoglobinuria – Black / Brown urine Urobilinogen - Increased

BLACKWATER FEVERSymptoms : 

36 BLACKWATER FEVERSymptoms Fever + Chills + Bodyache Joint pain – vomiting – diarrhoea Red or black colour urine Polyuria  Anuria Uraemic symptoms Jaundice – liver cell failure Shock Severe anaemiaPrecipitating factors Irregular antimalarial therapy Quinine therapy Primaquine in G6PD Extreme cold temperature Alcohol Exertion - Mental or Physical strain

IMMUNITY IN MALARIA : 

37 IMMUNITY IN MALARIA Natural immunity (Humoral or red cell factor) Duffy blood group negative Deficiency of glycophorin – A Sickle cell – Parasite cannot grow (Low O2 – sickling – spleen trapping) Ovalocytosis – Resist penetration Thalassemia – Prevent growth G6PD – (?) Prevents invasion by Competitive Inhibitor

IMMUNITY IN MALARIA : 

38 IMMUNITY IN MALARIA Acquired Immunity Passive: Mother to child (upto 6 mths) lgG Active: Humoral & Cellular Sporozoite – “T” Cell Merozoite – “B” Cell Gametocyte – lgG, lgA, lgM Antibody production Antigen: (Merozoite + Schizont) L (Labile) immunity R (Resistant) S (Stable) Acute falciparum

CLINICAL FEATURES : 

39 CLINICAL FEATURES Incubation Period (Mosquito Bite – onset of symptom) Pl. Falciparum – 12 days Pl. Vivax-ovale – 14 days Pl. Malariae – 18-42 days Malarial Prophylaxis Temporate climate Inadequate antimalarial Immune adult in endemic zone [mild symptoms] Symptoms (General) : Fever + Rigors + Chills + Myalgia Headache – Bodyache – lassitude - fatigue malaise Perspiration, anorexia, vomiting and worsening Urticaria Delayed Pl. Vivax – 6 mths Pl. Falciparum – 1 mth

MALARIAL PAROXYSM : 

40 MALARIAL PAROXYSM Erythrocytic schizogony. Rupture of Schizont & RBC – Sporulation. Release of toxic product of parasite. Endogenous Pyrogens acts on posterior hypothalamus. Release prostaglandins Sympathetic nerve stimulation. Vasoconstriction - Decreased heat dissipation. [Commonly seen in Pl. vivax] [Absent in falciparum]

MALARIA PAROXYSM : 

41 MALARIA PAROXYSM Cold stage (20-60 min) Rigors- chills convulsion in children Hot stage (3-8 hrs) 38.5oC Headache, Vomiting 40oC Delirium 42oC Coma Wet stage Perspiration, Exhaustion, Hypothermia

TYPES OF FEVER IN MALARIA : 

42 TYPES OF FEVER IN MALARIA Flu like fever – initial stage (1st week). Intermittent – 2nd week of Malarial paroxysm Continuous fever (Enteric Type) – falciparum Remittent fever (irregular Sporulation – falciparum) Low grade evening fever (like TB) Chronic malaria. Apyrexia (Malaria without fever) (Latent malaria – Gametocytes)

Uncomplicated malaria : 

43 Uncomplicated malaria Symptomatic malaria without signs of severity or evidence of vital organ dysfunction.

ALGID MALARIA : 

44 ALGID MALARIA Peripheral circulatory failure Gram Negative Septicemia(Sequestration of Parasitised RBC in internal organs) Gastric form Choleric form Dysentric form Haemorrhagic form Syncopal form Sudden death due to cardiac failure Coronary artery thrombosis

CEREBRAL MALARIA(10% all malaria – 80% mortality) : 

45 CEREBRAL MALARIA(10% all malaria – 80% mortality) Delirium – Agitation – Confusion- Coma Decerebrate rigidity Focal or generalised convulsion Cranial N-palsy, Hemiplegia, Blindness, Polyneuropathy GBS, Mononeuritis multiplex Retinal haemorrhage – NO papilloedema Conjugate gaze – Divergent squint Reflexes Brisk jaw jerk + Pout reflex, DTR – Brisk + Clonus +  Tone Absent abdominal reflex. Plantars extensor Occulogyric crisis Cerebellar ataxia – hypotonia + nystagmus Psychosis – Encephalopathy

W.H.O. CRITERIA FOR SEVERE MALARIA : 

46 W.H.O. CRITERIA FOR SEVERE MALARIA Major - Cerebral malaria Repeated convulsion Pulmonary oedema / ARDS Renal failure Hypoglycemia (Severe – Repeated) Circulatory collapse – shock Lactic acidosis Severe anaemia (Hematocrit < 20%) Bleeding disorder/DIC Haemoglobinuria Minor - Impaired consciousness Extreme weakness Hyperparasitemia > 5% in nonimmune, > 20% in any pt. Jaundice

POOR PROGNOSTIC GUIDE : 

47 POOR PROGNOSTIC GUIDE Clinical Agitation – irritable pt. Hyperventilation Hypothermia Bleeding – severe anaemia Deep coma – convulsion Anuria, Shock

POOR PROGNOSTIC GUIDE : 

48 POOR PROGNOSTIC GUIDE Laboratory Hypoglycemia High Lactate Metabolic Acidosis Azotemia Hyperbillirubinemia High SGOT, SGPT (3 times N), nucleotidase PT > 3 sec  PTT High CPK, Myoglobin WBC > 12,000/CMM PCV < 15% Fibrinogen < 200 mg Parasite Index > 20% RBC

DIAGNOSIS : 

49 DIAGNOSIS CLINICAL : Fever in last 72 hours (Risk low)/24 hours + anaemia (Risk high) PARASITOLOGICAL Light Microscopy : Smear for Malarial Parasite Collection of specimen: During fever & 4-6 hrly. 3 days. Thick Smear – Diagnosis of malaria( Drying, no fixing ) Thin Smear Fix with alcohol Species identification Staining Giemsa stain – prepared by mixing Lieshman’s stain – Fixing and staining Field’s stain – Rapid method, thick smear. False Negative Smear Low parasite count. Sequestration of parasite Partially treated Technical fault

PARASITOLOGICAL DIAGNOSIS : 

50 PARASITOLOGICAL DIAGNOSIS Improved Microscopy Microtube concentration & Fluorescent staining with flurochrome, Acridine orange of centrifuged heparinised blood.

Slide 51: 

51 QBC [ Quantified Buffy Coat ] : Heparinised tube coated with acridine Parasite DNA stained with acridine.

PARASITOLOGICAL DIAGNOSIS : 

52 PARASITOLOGICAL DIAGNOSIS Dipstick Technology Tip of dipstick detecting Malarial Parasite “Parasight F” dipstick or “ICT Malaria Pf”Parasite specific histidine rich protien II [HRP II] Rapid test – 20 min – Result Highly Sensitive – specific Measured by colour change “Parasite LDH-optimal stick” Parasite Derived nucleic acid detection PCR

CHEMOTHERAPHY OF MALARIA : 

53 CHEMOTHERAPHY OF MALARIA Causal Prophylaxis : Preerthyrocytic stage Suppressive Prophylaxis : Erythrocytic stage Prevention of acute attack.(Kill Schizont in blood) Clinical Cure : Erythrocytic stage Treatment of acute attack.(Rapid clearance of parasite from blood) Radical Cure : Exoerythrocytic cycle Complete eradication of parasite from body. (blood – tissue) Suppressive cure Form of radical cure by extended suppressive therapy Slow action on hypnozoites by exhaustion as soon as they enter the bloodstream Gametocidal Reduces the transmission to the mosquito

ANTIMALARIAL DRUGS : 

54 ANTIMALARIAL DRUGS 4-Aminoquinoline Chloroquine, Amodiaquine. Hydroxychloroquine 8-Aminoquinoline Primaquine, Arylamine Alcohol – Quinine 4-Quinoline Methanol – Mefloquine 9-Phenanthrene Methanol - Halofantrine,Lumefantrine Biguanide – Proquanil Diaminopyrimidine – Pyrimethamine Sulfonamides & sulfone: Sulfadoxine, Sulfamethopyrazine, Dapsone Sesquiterpene lactones / Endoperoxidase – Artesunate, Artemether, Arteether. Antibiotics Tetra, Doxy, Macrolide

1. CHLOROQUINE : 

55 1. CHLOROQUINE Schizonticidal – Large ring & trophozoite No Effect on pre-erythrocytic & Exoerythrocytic Mode of Action Influence Hb Digestion by raising intravesicular pH Interferes Nucleoprotien synthesis Half Life: 3-10 days Metabolite: Monodesethylchloroquine (Active) Toxicity G.I. Disturbances Visual Disturbances: Keratopathy, retinopathy Orthostatic Hypotension Neuropsychiatric Reaction Neuropathy, Myopathy Arrhythmia Pruritus, Alopecia Useful for treatment or prophylaxis Safe for children and in pregnancy

CHLOROQUINE[ Contd. ] : 

56 CHLOROQUINE[ Contd. ] Tab: 250 mg = 150 mg base Ampoule: 40mg(base)/ml in 2 & 5 ml, 30 ml vial as HCl salt

2. AMODIAQUINE : 

57 2. AMODIAQUINE Action as same as chloroquine More active against resistant strain of P. falciparum. Metabolite: Desethylamodiaquine (Active) Toxicity Agranulocytosis Hepatotoxicity Peripheral Neuropathy Precaution : Regular CBC, LFT, Ophthalmic check. Tab: 200 mg = 150 mg base as HCl Dosage : 10 mg/kg single dose or 5 mg/kg OD x 2 days.

3. MEFLOQUINE : 

58 3. MEFLOQUINE Action : Schizonticidal – Mature Trophozoite, schizont. Similar to Quinine Mode of action : Forming Toxic complex with Haem. Damages parasite membrane Half life : 3 weeks Toxicity Nausea, Vomitting, Dizziness(4 days after last dose) Orthostatic Hypotension Neuro-psychiatric reaction(Convulsion, Psychosis, Encephalopathy)

MEFLOQUINE : 

59 MEFLOQUINE Never Use with Quinine Dosage – Acute Attack 15 mg/kg stat 750 mg 3 TabsFollowed By 10 mg/kg 500 mg 2 Tabs12 hrs laterOR 25 mg/kg non immune 1 dose (5 tabs) Chemoprophylaxis – 5 mg/kg ( 250mg Tab.) wkly Trade Name : Meflam, Meflotas 250 mg Tab.

4. QUININE : 

60 4. QUININE Levo rotatory main alkaloid, bitter powder from bark of Cinchona tree Action : Erythrocytic schizonticidal - PV, PF. Gametocyte of P. vivax Mode of Action : Gets concentrated in the acidic vacuoles of blood schizonts & causes pigment changes Inhibits polymerization of heme to hemozoin Accumulation of Haem - cytotoxic Half Life : 11-18 hrs. Safe in pregnancy – does not induce labour.

QUININE(contd..) : 

61 QUININE(contd..) Toxicity : Gl disturbances, bitter taste Cinchonism – tinnitus, deafness, vertigo, nausea, vomiting, dysphoria ECG : Arrhythmia, Prolongation QT interval. Visual disturbances, blindness Stimulate pancreas. ↑ insulin – Hypoglycemia Blackwater fever: Haemolysis with renal failure Dosage : Oral – 300-600mg TDS x 7 Days IV–Infusion Never Bolus ( Hypotension & cardiac arrest), 20mg/kg infusion over 4 hrs f/b 10mg/kg. over 4 hrs. TDS. Deep IM (careful) on thigh only. DIL 1:3, 1:5Injection on buttock→ Sciatic nerve damage

5. PRIMAQUINE : 

62 5. PRIMAQUINE Acts on : Erythrocytic stage of parasite – Acute stage Hypnozoite of P.vivax (prevent relapse) Gametocyte of P.falciparum (prevent transmission) Mode of action : Disrupts mitochondria & binds to DNA Half life: 7 hrs. Toxicity : Nausea, vomitting, headache Visual disturbances Hemolysis in G6PD deficiency Methaemoglobinaemia Formulation: Tab. 5.0 mg, 7.5 mg or 15.0 mg Primaquine diphosphate 26 mg = 15 mg Dose : Radical cure – 15mg daily x 14 days, India x 5 days

6. SULPHADOXINE + PYRIMETHAMINE : 

63 6. SULPHADOXINE + PYRIMETHAMINE Dihydrofolate Reductase Inhibitor – Sequential block High affinity (2000 times) for plasmodial over mammalian enz. Slow acting : Schizonticidal, Erythrocytic stage Sporonticidal action Half life : 3 to 7 Days Toxicity : Megaloblastic AnaemiaBone Marrow Depression: Pancytopenia Sulpha: Skin rash, Hepatitis Methhaemoglobinemia Steven Johnson’s Syndrome Dose : Acute Attack Sulfadoxine 500mg 3 tab. Single dose Pyrimethamine 25mg Chemoprophylaxis 1 tab. weekly

7. ARTEMISININ DERIVATIVES : 

64 7. ARTEMISININ DERIVATIVES 2000 yrs. Old Chinese medicine. Rediscovered in 1971 – used since 1987 Rapid resolution of symptoms Inhibits Ca ATPase and thus inhibiting protein synthesis during growth of parasite Sesquiterpene lactone extracted from the leaves of Artemisia annua (sweet wormwood) Active against all stages from young rings to schizonts of all species Gametocidal for P. falciparum

ARTEETHER(ARTEMOTIL) : 

65 ARTEETHER(ARTEMOTIL) Toxic Effects : Not known Dose : IM inj. 150mg daily x 3 Days Tradename : EMAL inj., FALCY inj., RAPITHER inj.

ARTHEMETHER : 

66 ARTHEMETHER Toxic Effects : Prolongs QT interval (Not advisable to use with medicines which ↑ QT interval) viz. Quinidine,Quinine,Amiodarone,Bretylium Disopyramide Erythromycin,Terfenadine,Phenothiazine,TCA Dose : Orally : 160 mg in two divided doses on 1st Day Then 80mg daily for next 4 Days Injections : 80 mg TDS on 1st Day Then 80 mg OD X 4 Days OR 80 mg BD X 3 Days Trade name : LARITHER – 40 mg capsule, PALUTHER – Injection 80 mg Amp. Coformulation of 20 mg of artemether and 120 mg of lumefantrine

ARTESUNATE : 

67 ARTESUNATE M.O.A . : Fastest Antimalarial drug Activate parasite haem generating free radicals Promoting cytotoxicity Metabolite: Dihydroartemisinin (active) Toxicity : Nausea, Vomiting, Itching, Dizziness, Occ convulsion Contra-Indication : G6PD, Immunodeficient pt. Tab: 50 mg or 200 mg of sodium artesunate. Amp: 60 mg of anhydrous artesunic acid with a separate ampoule of 5% NaHCO3 solution i.m, i.v. Rectal capsules containing 100 mg or 400 mg of sodium artesunate. Dosage : Orally : 100 mg BD 1st Day f/b 100 mg OD for 5 days Injection : 120 mg stat followed by 60 mg daily for 4 days Interaction : Potentiates the action of Mefloquine,Primaquine & Tetracyclines Additive Effect with Chloroquine Antagonistic Effect with Sulpha-Pyrimethamine. ↓ dose in hepatic dysfunction Name : FALCIGO

8. HALOFANTRINE : 

68 8. HALOFANTRINE More potent than Quinine,Mefloquine Poor & Erratically absorbed Absorption Increased by Fatty food Half life: 3-4 Days Toxicity : Gl. disturbances, Diarrhoea Cardiac Arrhythmia, Prolonged QT interval Sudden death due to VT Toxicity increases if Mefloquine given before Tradename : HALFAN, 250 mg tablet SHOULD NOT BE GIVEN IN MEFLOQUINE RX PT.

ANTIBIOTICS AND ANTIMALARIAL ACTIVITY : 

69 ANTIBIOTICS AND ANTIMALARIAL ACTIVITY Tetracyclines, Doxycycline : Slow Schizonticidal used with Quinine, Primaquine Macrolides – Azithromycin, Clarithromycin, Clindamycin Rifampicin Quinolone – Norfloxacilin, Ciprofloxacilin

ANTIMALARIAL in PREGNANCY : 

70 ANTIMALARIAL in PREGNANCY Chloroquine Quinine Artesunate & Artemether – may be given Sulpha-Pyrimethamine – only in severe cases Never in last trimester of pregnancy NEVER Tetracyclines, Primaquines, Amodiaquine, Mefloquine, Halofantrine Safe in pregnancy

WHO Recommendations : 

71 WHO Recommendations First trimester: ACT Quinine + clindamycin for 7 days. Second and third trimesters: ACT Quinine + clindamycin for 7 days Artesunate + clindamycin for 7 days Lactation: All safe except tetracyclines & dapsone

Antimalarial combination therapyArtemisinin-based combination therapy (ACT) : 

72 Antimalarial combination therapyArtemisinin-based combination therapy (ACT) Simultaneous use of two or more blood schizontocidal drugs with independent modes of action and thus unrelated biochemical targets in the parasite. Rationale More effective If a mutant parasite that is resistant to one of the drugs arises de novo then it will be killed by the other drug Disadvantages  adverse effects  cost

Slide 73: 

73 Currently recommended by WHO: Artemether + lumefantrine Artesunate + mefloquine Artesunate + amodiaquine Artesunate + sulfadoxine–pyrimethamine. Drug combinations such as sulfadoxine–pyrimethamine which rely on synergy or non-antimalarial medicine to enhance the antimalarial effect of a blood schizontocidal drug (e.g. chloroquine & chlorpheniramine) What is not considered to be combination therapy South east Asia

UNCOMPLICATED MALARIA : 

74 UNCOMPLICATED MALARIA Chloroquine : Tab. Total dose 25 mg/kg 10 mg/kg followed by 10 mg/kg after 24 hrs & 5 mg/kg after 48 hrs. OR 10 mg/kg loading dose foll. by 5 mg/kg at 6 hr, 24 hr, 48 hr For P.Vivax, ovale add T. Primaquine 15 mg (0.25 mg/kg) daily for 14 days. Sulphadoxine + Pyrimethamine : 1500 mg + 75 mg (3 Tabs) Single Dose. Quinine : Tab. 10 mg/kg TDS + Cap. Tetracycline 250 mg QID Or Cap. Doxycycline 200 mg OD. All for 7 days.

Slide 75: 

75 Artemether-lumefantrine Co-formulated tablets: 20 mg artemether + 120 mg lumefantrine BD × 3 days > 5 kg of patients Should be taken with milk/fat containing foods Artesunate + mefloquine Separate tablets:50 mg artesunate, 250 mg base mefloquine 4 mg/kg of artesunate OD × 3 days, 25 mg base/kg of mefloquine usually split over 2 or 3 days (15 mg/kg usually on the second day followed by 10 mg/kg one day later, or as 8.3 mg/kg per day for 3 days Artesunate + sulfadoxine–pyrimethamine Separate tablets:50 mg artesunate, 500 mg of sulfadoxine + 25 mg of pyrimethamine. 4 mg/kg artesunate OD × 3 days and a single administration of sulfadoxinepyrimethamine 25/1.25 mg base/kg on day 1 Artesunate + amodiaquine Separate tablets:50 mg of artesunate, 153 mg base of amodiaquine 4 mg/kg artesunate and 10 mg base/kg of amodiaquine OD × 3 days

WHO Recommendations for uncomplicated malaria : 

76 WHO Recommendations for uncomplicated malaria Rx is with combination of two or more antimalarials with different mechanisms of action ACTs are the recommended Artemisinin derivative components of the combination must be given for atleast 3 days for an optimum effect Amodiaquine + sulfadoxine-pyrimethamine may be considered as an interim option in situations where ACTs cannot be made available

Severe falciparum Malaria (WHO) : 

77 Severe falciparum Malaria (WHO) Chloroquine Sensitive Chloroquine 10mg base/kg in Isotonic IVF over 8 hrs. Followed by 15mg/kg in next 24 hrs. OR 5 mg base/kg in Isotonic IVF over 6 hrs. Every 6 hrs. for total 5 doses ( i.e 25 mg/kg) OR 3.5 mg/kg every 6 hrs IM. Or SC. Chloroquine Resistant Malaria Artesunate : 2.4 mg/kg loading dose IVf/b 2.4 mg/kg at 12 hr. , 24 hr. & daily x 6 days. OR Artemether : 3.2 mg/kg loading dose IM Followed by 1.6mg/kg daily for 6 days OR Quinine : 20 mg/kg dil. In 10ml/kg IVf over 4 hrs f/b 10mg/kg over 2-8 hrs TDS until pt. can swallow.Then Quinine Tab. 10mg/kg TDS for 7 days. OR Quinidine : 10 mg/kg over 1-2 hrs f/b 1.2mg/kg/hr with ECG monitoring

Slide 78: 

78 Recrudescence. The recurrence of asexual parasitaemia after treatment of the infection with the same infection that caused the original illness. Incomplete clearance of parasitaemia by treatment. Relapse. The recurrence of asexual parasitaemia in P. vivax and P. ovale malaria deriving from persisting liver stages (hypnozoites). Recurrence. The recurrence of asexual parasitaemia following treatment. This can be caused by Recrudescence Relapse New infection.

Rx failures : 

79 Rx failures Failure after 14 days Recrudescence → first-line treatment However, reuse of mefloquine within 28 days is associated with an increased risk of neuropsychiatric sequelae use second-line treatment. Second-line antimalarial treatment/Imported malaria Alternative ACT Artesunate (2 mg/kg OD) + tetracycline (4 mg/kg QID) or doxycycline (3.5 mg/kg OD) or clindamycin (10 mg/kg BD) for 7 days Quinine (10 mg salt/kg TDS) + tetracycline or doxycycline or clindamycin for 7 days

CHEMOPROPHYLAXIS : 

80 CHEMOPROPHYLAXIS Chloroquine : 300 mg (2 tabs) once a week Mefloquine : 250 mg salt (1 tab) once a week Doxycycline : 100 mg once daily Proguanil : 200 mg once daily (combined with Chloroquine once weekly) Primaquine : 15 mg daily 14 days (Post Exposure) Sulphadoxine + Pyrimethamine : SMP 500mg + PYR 25 mg (1 Tab) Wkly

MANAGEMENT OF CEREBRAL MALARIA : 

81 MANAGEMENT OF CEREBRAL MALARIA ABC GCS Nursing care I/O Chart – Urethral Catheter RT feeding Convulsion: diazepam, Do Not Use Doubtful Corticosteroids Mannitol, Urea Heparin Prostacycline Pentoxyphylline NSAIDS Low Molecular Wt Dextran Epinephrine Low Molecular Heparin Cyclosporine A. Hyperimmune Globulin

ANAEMIA : 

82 ANAEMIA Blood Transfusion Hb < 7 gm, PCV < 20% Fresh blood, Packed Cell Frusemide after B.T. Folic Acid – Tab, Inj. RENAL FAILURE Exclude & Treat Hypovolemia Fluid & Electrolyte Balance Monitor JVP – Central Line Dialysis – Hemodialysis, Peritoneal Dialysis ( After Adequate Hydration & Diuretics )

HYPOGLYCEMIA : 

83 HYPOGLYCEMIA Regular blood sugar check – HGT I.V. 25% - 50% Dextrose 50 ml – 100 ml Frequently Follow with I.V. 5% Dextrose METABOLIC ACIDOSIS Treat Hypoglycemia, Hypovolemia, Septicemia. Sodabicarb No Ringer Lactate

FLUID & ELECTROLYTE DISTURBANCES : 

84 FLUID & ELECTROLYTE DISTURBANCES Look for dehydration MM, SKIN, TEMP, BP, JVP, Urine, Output, SP.GR., Na+ IV Isotonic fluid – Central Line Monitor for over-hydration Urine, BP, JVP Improve Oxygenation Clear airway, O2 Ventilator support.

PULMONARY OEDEMA : 

85 PULMONARY OEDEMA PUP > 45o Give – O2 Nasal cath/mask Diuretics – Frusemide – 40-200 mg IV Mechanical ventilatory support, PEEP Vasoactive drugs – monitor haemodynamics If overhydration Stop I.V. Fluid Diuretics

SHOCK – CIRCULATORY COLLAPSE(ALGID MALARIA) : 

86 SHOCK – CIRCULATORY COLLAPSE(ALGID MALARIA) Correct Hypovolemia I.V Fluid, Blood Transfusion Plasma expander Blood C/S Broad Spectrum Antibiotics Monitor CVP

BLEEDING : 

87 BLEEDING BT Inj. VIT. K. 10 mg I.V. OTHER COMPLICATIONS Hyperpyrexia Hemoglobinuria Aspiration Pneumonia

HYPER-REACTIVE MALARIAL SPLENOMEGALY(Tropical Spleenomegaly) : 

88 HYPER-REACTIVE MALARIAL SPLENOMEGALY(Tropical Spleenomegaly) Exaggerated immune response Anaemia, Leucopenia, Thrombocytopenia with normal or hypercellular bone – marrow. Low Parasitemia with high antibody tite IgM level 3-20 times. Increased Susceptibility to Bacterial Inf. Treatment : T. Proguanil 100 mg daily – lifetime. Folic acid 5 mg OD Malarial Chemoprophylaxis – 6 months. Spleenectomy (Failure of Medical Treatment)

MALARIA VACCINE : 

89 MALARIA VACCINE HIGHLY EFFECTIVE VACCINE ? P. Vivax P. Falciparum Sporozoite Merozoite Trophozoite Heat Labile Heat Stable

THANKYOU : 

90 THANKYOU Ref: HARRISON KDT PHARMACOLOGY WHO GUIDELINES 2006 Dr. BHARAT SHAH’s PRESENTATION ON MALARIA CDC GUIDELINES