MalariaMalaria

• Types• Lifecycle• Drugs-classification• Individual drugs• Dosage regimen• Chemo-prophylaxis• Newer anti-malarials• Vaccine

•Devastating parasitic infection

•Attacks-500 million•Mortality –2 million[1million children].

•Except N.America, Europe, Russia

Chloroquine resistant-PF Chloroquine sensitive-PF

Malaria Endemic Areas

Mexico, Central America west of Panama canal,Carribean, South America, middle east

Resistant PVIndonesia,Papua New Guinea, Burma

Types

• P.vivax - Benign tertian

• P.Falciparum - Malignant tertian

• P.ovale -Benign tertian

• P.Malariae -Benign Quartan

TransmissionTransmission

• “ Bite of Infected Female Anopheles Mosquito”

• Blood transfusion

• Congenital

• Sharing needles

Life Cycle

Hepatic StageHepatic Stage

• P.F and P.M No persistent tissue phase

No Hypnozoites

No relapse

No Radical cure required

• P.V and P.O.- Persistent tissue phase +

Erythrocytic PhaseErythrocytic Phase

• Most of the drugs act in this stage

• Leads to clinical cure

• Most of the drugs do not prevent transmission

• Chemoprophylaxis

Why P.F. Serious?Why P.F. Serious?

• P.Palciparum

• Produces

• Leads to

• Binds-RBCs all ages• Alters surface• Grows in low o2

• Micro-vascular blocks• Cytokine release• Endotoxin release

• High parasitemia• Cerebral malaria• Hypoglycemia• Shock, Multi organ failure• Death

Classification of DrugsClassification of Drugs• Cinchona alkaloids: Quinine &

Quinidine• Quinolines:1. 4-Aminoquinolines- Chloroquine

Hydroxychloroquine

AmodiaquinePiperaquine

2. 8-Aminoquinolines- PrimaquineTafloquineBulaquine

Classification……Classification……

• Quinolines..3. Quinoline methane-Mefloquine

Halofentrine Lumefantrene

• Antifolates:1. Biguanides- Proguanil2. Diaminopyrimidine- Pyremethamine3. Sulfonamides- Sulfadoxine

Dapsone

Classification……Classification……• Artemisinin compounds:

ArtesunateArtemetherArteether

• AMA: Doxycycline, Clindamycin,

• Others Atovaquone, Pyoronaridine

Spor Liver RBC forms

Class I P.E Hypno Asex Gam

Chloroquine - - - + (±)

Mefloquine - - - + -

Quinine - - - + (±)

Pyrimethamine+Sulfadoxin

- ± - + _

T.C - - - ± -

Class II

Atovaquone+Proguanil - [+] - + -

Class III

Primaquine - + + - +

Lesson!Lesson!

• No drug acts on Sporo

• None very effective against both liver & RBC stages

• True prevention not possible, only suppress symptomatic malaria.

• Complete cure requires more than one drug

Clinical utilityClinical utility• Class I:

Liver and sexual forms- No action. Active against RBC stage Only Hence- used in the tt and prevention

of clinical malaria

• Prophylaxis-Takes several weeks to exhaust liver

stages

Clinical utility……Clinical utility……

• Class II: Act against early Liver & RBC forms, Reduces period of post exposure in prophylaxis

• Class III: Unique! Radical cure, No place in Symptomatic treatment.

Use and ClassificationUse and Classification• Causal prophylactics-

Target early liver forms• Eg.?????????• Terminal prophylaxis and radical cure-

Target hypnozoites• Eg.????????• Suppressive prophylactics and clinical

cure-Target asexual RBC forms

• Eg.?????

Life CycleAndDrugs

NONE

PyrimethamineProguanil

Primaquine

Most of the drugsExcept Primaquine

ChloroquineQuinine[not F.P.]

QuinineQuinine

• Holy bark, Cardinal’s bark, Jesuit’s• Quinine & Quinidine-Alkaloids from

Cinchona bark. Cheapest source

• H/O 350 yrs.

• Even today d.o.c severe and resistant malaria

Quinine contd…Quinine contd…

Anti-malarial action:• Active against asexual erythrocytic

forms

• Against gametocytes of P.V & P.M(Not P.F.)

• More toxic, less effective than chloroquine(If suceptible to both)

• Chlo. & MDR strains respond. • Parenteral treatment

Quinine contd…Quinine contd…Anti-malarial action ( M.O.A.)• Asexual parasites digest Hb in ACIDIC

food vacuoles• Quinine(Alkaline) Concentrated in

vacuoles• Raises pH ‘ALKALINE‘• Free radicals and heme generated• These Toxic sub. sequestered by

parasite as non toxic hemozoin• Prevents hemozoin formation• May also bind to heme- Toxic

Quinine contd…Quinine contd…

• Chloroquine,• Amodiaquine,• Mefloquine, Lumefantrine• Halofantrine & Pyronaridine • Have similar MOA

Quinine contd…Quinine contd…

• Skeletal muscles: Decreases contractile force & excitability

• Antagonize physostigmine. • Myesthenia gravis?

• Myotonia congenita?

• Local-Inflammatory and anesthetic

• Uterus-Stimulant

Quinine contd…Quinine contd…

• PK: well absorbed from GIT, i.m.• Metabolized by CYP3A4• Acidic urine ↑ excretion

• α1-acid glycoprotein in malaria protects from toxicity of high plasma concn.!

Therapeutic uses:Therapeutic uses:

1. Severe and resistant malaria2. Nocturnal leg cramps3. Spermicidal-Vaginal creams4. Sclerosing agent-V.V.5. Quinidine used as anti-

arrhythmic

Quinine ….ADEQuinine ….ADE

• Fatal dose 2-8g.• Cinchonism: Tinitus, high tone deafness,

visual disturb., nausea, vomiting• Hypoglycemia• Cardiac: Arrhythmia, AV block,

Hypotension more with quinidine• Blackwater fever: Hypersensitivity: • “Hemolysis-hemoglobinemia -

hemoglobinuria” Anuria Renal failure and death.

• Purpura

Quinine ….CautionQuinine ….Caution

• Hypersensitivity

• Hemolysis- discontinued

• Cardiac arrhythmia, tinitus, optic neuritis

• Irritant• Fairly safe in pregnancy

Quinine (DI)Quinine (DI)

• Antacids

• Reduces absorption of digoxin

• Elevates plasma conc.of Warfarin

• Enhances effect of NM blockers

• Acidification of urine ↑ clearance

ChloroquineChloroquine

• Anti-malarial spectrum: Erythrocytic forms of all species, Gametocyte of all except P.F,No activity against tissue forms

• MOA: As before• Resistance: Resistant strains concentrate

chloroquine less in vacuoles.• Crt-Chloroquine resistant transporter and

Pfmdr transporters

Chloroquine contd… Chloroquine contd… PK: PK:

• Well absorbed by oral , s.c, i.m.

• Extensively sequestrated in tissues-Large V (100L/k.g)

• Loading dose is required-Wide dist.

• Half life-1 week

• Slow IV-slow dist.• Oral-PK of absorption and dist. matched

• Clinical cure & Chemoprophy.(Sensitive strains)

• Hepatic amoebiasis• RA• Discoid lupus,SLE• Lepra reaction, Sarcoidosis• Photosensitivity reaction• Porphyria cutanea tarda• Chikengunya? [HCQ]

Chloroquine- UsesChloroquine- Uses

With other agents

Chloroquine contd… ADE: Chloroquine contd… ADE:

• Remarkably safe in th. doses. Safety margin is narrow

• Parenteral - Rapid infusion → Arrhythhmia, Hypotension, arrest.

• More than 5g fatal

• Oral- GIT, headache, VISUAL disturbances, blurring, rashes

Chloroquine contd… ADEChloroquine contd… ADE::

• Chronic therapy: Accumulates in melanin rich tissues(↑ 250mg/day)

• Irreversible retinopathy, ototoxicity [Total cumulative dose of more than 1G/Kg]

• Discolouration of nail bed& m.m., bleaching of hair

• Myopathy, neuropathy, neuropschiatric, cardiopathy

• Optho and Neuro exam PERIODICALLY

Chloroquine contd… ADEChloroquine contd… ADE::•Caution:• Not used with Mefloquine

(Siezures)• Cautiously in liver disease renal

failure, G6PD def• CI- Epilepsy, myesthenia gravis, • Opposes anticonvulsants,

arrhythmogenic with halofentrine and amiodarone

Chloroquine contd…Chloroquine contd…

• Preperations:• Tab, Syp, Injection

• Oral- Chl.Po4 ( 250mg salt=150 mg base)

Dose

Curative:

Prophylactic

MefloquineMefloquine

• Antimalarial action- Against blood schizonts

• MOA: Exactly not known. Similar to chloroquine

• PK: Slow oral absorption. Food ?. Excretion fecal• No parenteral (Local reaction)

• t1/2-2-3 weeks –enterohepatic circulation

• Uses: Prophy. & Tt of drug resistant malaria[With Artimisinin]

Mefloquine ADE contd…Mefloquine ADE contd…

• Vomiting( repeat if within 1 h.)

• CNS- seizures, confusion or decreased sensorium, acute psychosis, and disabling vertigo.[reversible]

• CI: Pregnancy(avoided for 3 mo. After stopping), Epilepsy, psychotics, pilots

• H/O ADE to other quinolines

Mefloquine Caution contd…Mefloquine Caution contd…• Pregnancy• CI with Halofantrine or within 2

months of mefloquine• Compromizes typhoid vaccine• Not with drugs which affect cardiac

conduction• CI in jobs require motor coordination

PrimaquinePrimaquine

• History: Lead to Identification of G6PD def.

• Antimalarial action: • Effective against tissue forms[Bothe] and

gametocytes. • Not against erythrocytic forms

• Moa: Not known[Metabolites are toxic to parasites ?]

• PK: only oral. Parenteral cause Hypotension

Primaquine contd…Primaquine contd…

•Radical cure of P.V. & P.O. •Terminal prophylaxis (just before

or soon after leaves endemic area)

•P.jiroveci with clindamycin

Primaquine contd…Primaquine contd…• ADE: Hemolysis in G-6-PD def., anemia,

methemoglobinemia• G-6-PD Def-200 million• India-Tirbals-Jharkhand, AP, MP, Assam• Spot tests available • Passage of dark urine-Stop• Pregnancy-Fetus deficient in G6PD• Risk is more with RA, SLE

• Offers protection against severe malaria• More than 30mg/day repeated blood

counts/urine for Hb.

G6PD

Glucose Glucose-6-Phospate

6-Phoshogluconate

HexokinaseNADP NADPH

GSSGGSH

Defeciency

GSH DEF.

Hemolysis

No protectionFor RBC’sAgainstOxidative substancesHemolysis

Proguanil(Chloroguanide)Proguanil(Chloroguanide)

• Proguanil Cycloguanil (Triazine)

• Anti-malarial:PF- Primary tissue stage & Erythrocytic formsP.V.- Only erythrocytic stage

Proguanil(Chloroguanide)Proguanil(Chloroguanide)• MOA: • Inhibits DHFR• Proguanil-intrinsic antimalarial

activity• Accentuates action of Atovaquane• Therapeutic use: In combination

with atovaquone-against resistant strains- prophylactic and curative (uncomplicated)

• Safe in pregnancy

AtovaquoneAtovaquone• Antiparasitic effect:• RBC forms of plasmodia, Early liver

forms of FP, T.Gondii, P.Carinii, Babesia• MOA: Inhibits ATP and pyrimidine

synthesis, collapse of mitochondrial membrane potential[Potentiated by Proguanil]

• Resistance: Common when used alone• PK: Absorption increased by fatty food.

94% excreted unchanged in bile [E.H.circculation]

AtovaquoneAtovaquone

• Uses: • Treatment and prophylaxis of

resistant PF malaria,• T.gondii,• P.carinii• Babesia• Proguanil : Atovaquone – 100:250mg

PyrimethaminePyrimethamine

• Antiprotozoal action:• RBC forms –plasmodia, Pre-erythrocytic• T.Gondii [with S.D, high doses with Leucovorin]• MOA: DHFR inhibitor• Use: • Along with( 25 : 500 ) sulfadoxine (folate

synthetase inhibitor). Synergistic• Not for prophylaxis

Only tt of resistant strains of P.F. With sulfadiazine for T.Gondii.

• Toxicity: due to Sulfa

Artemisinin DerivativesArtemisinin Derivatives

• Sesquiterpine Lactone Endoperoxide derived from weed ARTIMISIA ANNUA (QING HAO)

• Used by Chinese for 2000 yrs.

• Derivatives:1. Artesunate2. Artemether3. Arteether4. Dihydroartimisinin

Artemisinin Derivatives…..Artemisinin Derivatives…..

Anti-malarial action: 1.Only against RBC forms and

gametocytes

2.Not against tissue forms

3.Short acting, Recrudescence high, therapy prolonged even after disappearance of parasites from blood.

Artemisinin Derivatives…..Artemisinin Derivatives…..

• MOA: • I StepHeme iron in parasiteCleaves endoperoxide bridge,

• II StepCarbon centerd radical is producedToxic to parasites

ArtimisininArtimisinin

• PKOral, i.v., Rectal-routesInduce their own CYP450• ResistanceNo resistanceResistance to Chlo. Paradoxically

increases sensitivity to Artimisinin• ADE:AllergicEmbryotoxic in animals, Cardiotoxic

Artemisinin Derivatives….Artemisinin Derivatives….

Therapeutic uses:• Oral: Uncomplicated Chloroquine/MDR

malaria• Parenteral: Severe complicated

F.P.Malaria• Not for prophylaxis, or P.V. or

chloroquine sensitive F.P.• Only with combinations-longer acting

drug.

Quinine Vs ArtimisininQuinine Vs Artimisinin

• Quinine DOC in severe/complicated malaria

• Artimisinin---Faster parasitic clearanceSafe, better toleratedSimple dosing scheduleHigh efficacy, low mortality

ACT-Artemisinin based Combination TherapyACT-Artemisinin based Combination Therapy

• To exhaust parasite burden• Short acting high efficacy drug to quickly

kill 95% of parasites• Long acting drug for 7 days[Small parasite

load, reduced chances of selecting mutants• ACT is the choice. Why?Rapid clinical, parasitological cureLow recrudescenceNo resistance(Combination prevents)Good tolerability• Combination regimens: Ref.KDT 6th Ed.

ChemoprophylaxisChemoprophylaxis

Type Drug BeforeEntering

AfterLeaving

ChloroquineSensitive

Chloroquinepo4 500mg once a week

1-2weeks 4 weeks

Resistant strains

Pro+Ato(Malarone) 1tab/d

1-2 days 7 days

Mefloquine 250mg/week

1-2 weeks 4 weeks

Doxycycline 100mg 1Tab o.d.

1 day before 4 weeks

Chemoprophylaxis: IndicationsChemoprophylaxis: Indications

• Special risk groups:1. Non-immune travellers2. Non-immune persons living in endemic

areas3. Pregnancy- After 1 trimester

(Chloroquine, Proguanil, Quinine)4. Terminal prophylaxis-Primaquine

30mg/day during last 14 days of chloroquine prophylaxis Or Chloro500+Prim45mg/week X 8 weeks

• Standby Tt.[?Presumptive Tt.]: • Travellers within 24 h of

symptoms[Presumed as malaria] No chlo. prophylaxis →Chlo or

Meflo Chlo →Meflo or quinine Meflo →Quinine Doxy →Meflo Malarone →Doxy+Quinine

Prophylaxis in PregnancyProphylaxis in Pregnancy

• Travellers1. Avoid travel[Pregnant or likely to become

pregnant!!]2. Chlo or Proguanil+F.A3. Or Meflo in II, III trimester4. Doxy, Ato, Prim. CI.5. Mosquito net

1. Intermittent Preventive Treatment [IPT]:2. Pregnant in endemic areas3. Pyr+Sulfa4. 2-3 doses5. I dose after quickening-II trimester6. Further at 1 month intervals

Treatment GuidelinesTreatment Guidelines

• Malaria-Med.emergency• Clinical exp is the guide• Chloroquine d.o.c for sensitive strains • Oral route preferred, chlo.can be given iv

with precautions• 48-72 h-clinical improvement. • Parasites cleared within 7 days• If not-drug resistance• In Chlo. Resistance- d.o.c is

quinine/Artimisinin• MDR-quinine & antifolates,T.c• Iv until tolerates oral route

Guidelines….Guidelines….

• Children are small adults! Reduced dose, No TC

• Ato-Pro. Only for more than 11 kg.• Pregnancy-Chlo, proguanil• Quinine with precautions for hpoglycemia• Antifolates, TC, artemisinin, atovaquone,

primaquine avoided• Mefloquine if necessary• Lactating mother- all except ato-prog.,

tested for G6PD if primaquin to be used

Severe malariaOral not possible

Any species

Non-Falciparum Falciparum

P.VivaxChloResistant

F.P.ChloSensitive

F.P.ChloResistant

P.VivaxChlo

Sensitive

Primaquine forRadical cure

Treatment-Chloroquine sensitive:Treatment-Chloroquine sensitive:P.VP.V..

• Chloroquine po4 1 Tab=250mg salt or 150mg base

• Clinical cure- 0h - 4Tab stat6h - 2 Tabs24h - 2 Tabs48h - 2 Tabs

• Radical cure: Primaquine 15mg/d X 14 days. Primaquine C.I in G6PD def.

Treatment-Chloroquine Treatment-Chloroquine Resistant:Resistant:P.VP.V.[Rare].[Rare]

• Quinine 600mg 8th hrly X 7 days• +• Doxy 100mg daily X 7 days• +• Primaquine

Treatment-Chloroquine Treatment-Chloroquine Sensitive:Sensitive:FPFP.[Rare].[Rare]

• Chloroquine:[250mg]• 0h - 4Tab stat

8h - 2 Tabs24h - 2 Tabs48h - 2 Tabs

• +• Primaquine 45 mg single dose[gametocidal]• OR• Sulfadoxine/Pyrrimethamine 3 Tab +

Primaquine[Chlo not tolerated]

Treatment-Chloroquine Resistant:Treatment-Chloroquine Resistant:FPFP1. Artesunate 100mg BDx3days• +• Sulfadoxine/Pyrimethamine 3 tab single dose• OR• Mefloquine 750mg on ii day-500mg on iii day.

(Sulfadoxine500/Pyrimethamine25)

2. Artemether 80mg• + Lumefantrine 480mg BD x 3 days

3. Quinine 600mg 8th hrly x 7 days• + Doxycycline 100mg daily x 7 days

Severe malariaSevere malaria• Cerebral malaria:• Severe anemia• Renal failure• Pulmonary edema• Shock• Metabolic acidosis• Hemoglobinuria, jaundice• Hyperpyrexia• Hyperparasitemia

SevereSevere• The single most important step in the

management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT

Severe and complicated F.P.MalariaSevere and complicated F.P.Malaria• Artesunate 2.4mg/Kg i.v or i.m. » 12 hrs » 24 hrs

» OD x 7days [Change to oral ACTx3days, if possible]

• Or• Artemether: 3.2mg/Kgi.m » 1.6mg/Kg x 7days

[change….]• Or• Arteether: Same as above. But 4 days• Or• Quinine diHCL:20mg/Kg in 10ml/Kg of dextrose

infused 4hrs » 10mg/Kg for 4hrs every 8hrs » Oral quinine10mg/kgx 7days

• + doxy 100mg od oral or 3day oral ACT or pyrimethamine/Sulfadoxine

Malaria VaccineMalaria Vaccine

•Reduce severity and complications of malaria

•Tried in children less than 5yrs, in Africa

•Reduces mortality and morbidity

Malaria VaccineMalaria Vaccine• Sporozoite vaccine-Prevents infection-

RTS,S/ASO2A• Asexual RBC form[Merozoite] Vaccine-

Reduces severity-MSP-1• Transmission blocking Vaccine-Against

sexual forms in mosquito gutPrevents development• Vaccines against toxins-Disease

attenuation• Multiantigen, Multistage vaccine

Other drugsOther drugs

• Halofentrene } Drug resistant• Lumefentrene

• Bulaquine……Primaquine

• Amodiaquine…..Chloroquine

• Dapsone….With pyremethamine• Fosmidomycin-apicoplast inhibitor

MDR MalariaMDR Malaria• “Resistance to more than 3 or more

anti-malarials of different chemical classes of which 2 are 4-aminoquinolines and diaminopyrimidine”(Wernsdorfer et al, 1994).

• Exposure of Plasmodium falciparum to sub-lethal doses of antimalarial drugs