Malaria

• 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
 Malaria Endemic Areas

Chloroquine resistant-PF Chloroquine sensitive-PF

Resistant PV Mexico, Central America west of Panama canal,
Indonesia,Papua New Carribean, South America, middle east
Guinea, Burma
 Types

• P.vivax - Benign tertian

• P.Falciparum - Malignant tertian

• P.ovale -Benign tertian

• P.Malariae -Benign Quartan

 Transmission
• “ Bite of Infected Female Anopheles
Mosquito”

• Blood transfusion

• Congenital

• Sharing needles
Life Cycle
 Hepatic 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 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?
• Binds-RBCs all ages
• P.Palciparum
• Alters surface
• Grows in low o2

• Micro-vascular blocks
• Produces • Cytokine release
• Endotoxin release

• High parasitemia
• Leads to • Cerebral malaria
• Hypoglycemia
• Shock, Multi organ failure
• Death
 Classification of Drugs
• Cinchona alkaloids: Quinine &
Quinidine
• Quinolines:
1. 4-Aminoquinolines- Chloroquine
Hydroxychloroquine
Amodiaquine
Piperaquine
2. 8-Aminoquinolines- Primaquine
Tafloquine
Bulaquine
 Classification……
• Quinolines..
3. Quinoline methane-Mefloquine
Halofentrine
Lumefantrene
• Antifolates:
1. Biguanides- Proguanil
2. Diaminopyrimidine- Pyremethamine
3. Sulfonamides- Sulfadoxine
Dapsone
 Classification……
• Artemisinin compounds:
Artesunate
Artemether
Arteether

• AMA: Doxycycline,
Clindamycin,
• Others Atovaquone,
Pyoronaridine
 Spor Liver RBC forms
Class I Asex Gam
P.E Hypno

Chloroquine - - - + (±)
Mefloquine - - - + -
Quinine - - - + (±)
Pyrimethamine+ - ± - + _
Sulfadoxin
T.C - - - ± -
Class II
Atovaquone+Proguanil - [+]
- + -
Class III
Primaquine - + + - +
 Lesson!

• No drug acts on • True prevention not

Sporo possible, only
suppress
symptomatic malaria.

• Complete cure
• None very effective
against both liver & requires more than
RBC stages one drug
 Clinical 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……

• 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 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 Cycle
And
Drugs

Primaquine

NONE

Chloroquine
Quinine
[not F.P.]

Pyrimethamine
Most of the drugs Proguanil
Except Primaquine
 Quinine
• 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…
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…
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…

• Chloroquine,
• Amodiaquine,
• Mefloquine, Lumefantrine
• Halofantrine & Pyronaridine
• Have similar MOA
 Quinine contd…
• Skeletal muscles: Decreases contractile force &
excitability

• Antagonize physostigmine.
• Myesthenia gravis?

• Myotonia congenita?

• Local-Inflammatory and anesthetic

• Uterus-Stimulant
 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:
• Severe and resistant malaria
• Nocturnal leg cramps
• Spermicidal-Vaginal creams
• Sclerosing agent-V.V.
• Quinidine used as anti-
arrhythmic
 Quinine ….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 ….Caution

• Hypersensitivity

• Hemolysis- discontinued

• Cardiac arrhythmia, tinitus, optic neuritis

• Irritant
• Fairly safe in pregnancy
 Quinine (DI)

• Antacids

• Reduces absorption of digoxin

• Elevates plasma conc.of Warfarin

• Enhances effect of NM blockers

• Acidification of urine ↑ clearance

 Chloroquine
• 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… 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
 Chloroquine- Uses
• Clinical cure & Chemoprophy.(Sensitive strains)
• Hepatic amoebiasis
• RA
• Discoid lupus,SLE
• Lepra reaction, Sarcoidosis With other agents
• Photosensitivity reaction
• Porphyria cutanea tarda
• Chikengunya? [HCQ]
 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… 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… 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…
• Preperations:
• Tab, Syp, Injection
• Oral- Chl.Po4 ( 250mg salt=150 mg base)

Dose

Curative:

Prophylactic
 Mefloquine
• 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…
• 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…
• 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
 Primaquine
• 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…

• Radical cure of P.V. & P.O.

• Terminal prophylaxis (just before
or soon after leaves endemic area)
• P.jiroveci with clindamycin
 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
Defeciency

Glucose-6- 6-Phoshogluconate
Glucose Phospate

NADP NADPH
Hexokinase

GSH DEF.
GSH
GSSG

No protection
For RBC’s
Against
Oxidative
Hemolysis substances
 Proguanil(Chloroguanide)
• Proguanil Cycloguanil (Triazine)
• Anti-malarial:
PF- Primary tissue stage & Erythrocytic
forms
P.V.- Only erythrocytic stage
 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
 Atovaquone
• 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]
 Atovaquone

• Uses:
• Treatment and prophylaxis of resistant
PF malaria,
• T.gondii,
• P.carinii
• Babesia
• Proguanil : Atovaquone – 100:250mg
 Pyrimethamine
• 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 Derivatives
• Sesquiterpine Lactone Endoperoxide
derived from weed ARTIMISIA ANNUA
(QING HAO)

• Used by Chinese for 2000 yrs.

• Derivatives:
1. Artesunate
2. Artemether
3. Arteether
4. Dihydroartimisinin
 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…..
• MOA:
• I Step
Heme iron in parasite
Cleaves endoperoxide bridge,

• II Step
Carbon centerd radical is produced
Toxic to parasites
 Artimisinin
• PK
Oral, i.v., Rectal-routes
Induce their own CYP450
• Resistance
No resistance
Resistance to Chlo. Paradoxically
increases sensitivity to Artimisinin
• ADE:
Allergic
Embryotoxic in animals, Cardiotoxic
 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 Artimisinin
• Quinine DOC in severe/complicated
malaria
• Artimisinin---
Faster parasitic clearance
Safe, better tolerated
Simple dosing schedule
High efficacy, low mortality
ACT-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 cure
 Low recrudescence
 No resistance(Combination prevents)
 Good tolerability
• Combination regimens: Ref.KDT 6th Ed.
 Chemoprophylaxis
Type Drug Before After
Entering Leaving
Chloroquine Chloroquine 1-2weeks 4 weeks
Sensitive po4 500mg
once a week
Pro+Ato(Mala 1-2 days 7 days
rone) 1tab/d
Resistant Mefloquine 1-2 weeks 4 weeks
strains 250mg/week

Doxycycline 1 day before 4 weeks

100mg 1Tab
o.d.
 Chemoprophylaxis: Indications

• Special risk groups:

• Non-immune travellers
• Non-immune persons living in endemic
areas
• Pregnancy- After 1 trimester
(Chloroquine, Proguanil, Quinine)
• 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 Pregnancy

• Travellers
• Avoid travel[Pregnant or likely to become pregnant!!]
• Chlo or Proguanil+F.A
• Or Meflo in II, III trimester
• Doxy, Ato, Prim. CI.
• Mosquito net

8. Intermittent Preventive Treatment [IPT]:

9. Pregnant in endemic areas
10. Pyr+Sulfa
11. 2-3 doses
12. I dose after quickening-II trimester
13. Further at 1 month intervals
 Treatment 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….

• 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
Non-Falciparum Falciparum Severe malaria
Oral not
P.Vivax P.Vivax possible
Chlo Chlo F.P.
Sensitive Resistant Chlo F.P. Any species
Sensitive Chlo
Resistant

Primaquine for
Radical cure
 Treatment-Chloroquine sensitive:P.V.
• Chloroquine po4 1 Tab=250mg salt or
150mg base

• Clinical cure- 0h - 4Tab stat

6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs

• Radical cure: Primaquine 15mg/d X 14

days. Primaquine C.I in G6PD def.
 Treatment-Chloroquine
Resistant:P.V.[Rare]
• Quinine 600mg 8th hrly X 7 days
•+
• Doxy 100mg daily X 7 days
•+
• Primaquine
 Treatment-Chloroquine
Sensitive:FP.[Rare]
• Chloroquine:[250mg]
• 0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
• +
• Primaquine 45 mg single dose[gametocidal]
• OR
• Sulfadoxine/Pyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
 Treatment-Chloroquine Resistant:FP
1. Artesunate 100mg BDx3days
• +
• Sulfadoxine/Pyrimethamine 3 tab single dose
• OR
• Mefloquine 750mg on ii day-500mg on iii day.

(Sulfadoxine500/Pyrimethamine25)

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

• Quinine 600mg 8th hrly x 7 days

• + Doxycycline 100mg daily x 7 days
 Severe malaria
• Cerebral malaria:
• Severe anemia
• Renal failure
• Pulmonary edema
• Shock
• Metabolic acidosis
• Hemoglobinuria, jaundice
• Hyperpyrexia
• Hyperparasitemia
 Severe
• The single most important step in the
management of severe malaria is IMMEDIATE
INITIATION OF APPROPRIATE
PARENTERAL TREATMENT
 Severe 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
 Treatment-Severe malaria
Quinidine gluconate-
• 10mg/kg in 300ml of N.S over 2-3h (max600mg)
↓
• 0.02mg/kg/.mt infusion for 24 h
↓
• Oral quinine sulfate 600mg tid X 7 days
AND Adjunctive therapy oral
• Doxy 100mg bd
• or
• Clindamycin 20mg/kg/day X 7days
or
• Pyr+Sulfa 3 tab on last day of quinine
 Treatment-Chloroquine resistance

• Quinine 10mg/kg/day tid X 7 days

• or
• Mefloquine 750mg, repeat 500mg after
12 h.
• or
• Artesunate 100mg bid followed by 100mg
od X 5 days [ACT?]
• or
• Pro + Ato 4 tab od X 3 days
 Malaria Vaccine

• Reduce severity and

complications of malaria
• Tried in children less than 5yrs,
in Africa
• Reduces mortality and
morbidity
 Malaria 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 gut
Prevents development
• Vaccines against toxins-Disease
attenuation
• Multiantigen, Multistage vaccine
 Other drugs
• Halofentrene
} Drug resistant
• Lumefentrene

• Bulaquine……Primaquine

• Amodiaquine…..Chloroquine

• Dapsone….With pyremethamine
• Fosmidomycin-apicoplast inhibitor
 MDR 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