Malaria - caused by sporozoites of Plasmodium

Transmitted by infected female Anopheles

Symptoms: chills, rigor, fever, headache,

sweating

Chronic- progressive spleenomegaly

Sym appear after 7-10 days of mosquito bite

Incubation period 10-30 days.

Clinically important species of plasmodium

P.falciparum, P.vivax, P.ovale, P.malariae

Definitive host- female anapheles mosquito

Intermediate host- human being

P.vivax:

causes benign tertian malaria

Relapse can occur due to hypnozoites in liver

P.ovale:

Has periodicity & relapses, milder

P.falciparum:

Malignant tertian malaria

Forms RBC rosettes

Blocks vital organs-renal failure &

encephalopathy

Exo-erythrocytic stage absent

Relapse do not occur, recrudescence can occur

P.malariae:

Quartan malaria,Exo-erythrocytic stage absent

relapse can occur, rare.

1) 4-Aminoquinolines – Chloroquine

Amodiaquine

Piperaquine.

pyronaridine

2) Quinoline-methanol – Mefloquine.

3) Cinchona alkaloid - Quinine

Quinidine

4) Biguanides –------- Proguanil

Chlorproguanil

5) Diaminopyrimidines – Pyrimethamine

6) 8-Aminoqunilones–---- Primaquine

Bulaquine

7) Sulfonamides and sulfones – Sulfadoxine

SulfamethopyrizoneDapsone

8) Tetracyclines –---------- Tetracycline

Doxycycline

9) Sesquiterpinelactones –----- Artesunate

Artemether

Arteether

10) Amino alcohols –------------ Halofantrine

Lumefantrine

11) Acridine –--------------- Mepacrine

Quinacrine

12) Naphthoquinone –-----------Atovaquone

Schizonticides

1)Tissue (Hepatic) schizonticides:

Primary- proguanil & pyrimethamine

Active against pre-erythrocytic state of P.Falc

Secondary- primaquine

Acts on both pre & exo erythrocytic cycle of all

Ps

Destroy blood schizonts

Prevent erythrocytic schizogony

1) Fast acting high efficacy-

Chloroquine, quinine, mefloquine,

lumefantrine, atremisinin & atovaquone

Used to terminate attack of malaria promptly

2) Slow acting low efficacy-

Pyrimethamine+sulfadoxine, proguanil &

doxycycline.

Used in combination to terminate clinical attack

Gametocides

Destroy gametocytes so mosquito can’t transmit

Primaquine for all species

Chloroquine & quinine- except P.falciparum

Sporontocides

Makes gametocytes ineffective in mosquito

proguanil & pyrimethamine

No clinical advantage

Causal prophylactics

Prevent pre-erythrocytic phase

proguanil & pyrimethamine – P.Falciparum only

Primaquine- all Ps, toxic

If G6PD levels are normal 0.5mg/Kg daily till

stay in endemic region.

Blood schizonticides are used - kills merozoites

Prevents erythrocytic phase

No effect on hepatic phase

Following drug regimens are used.

1) Areas with CQ-sensitive P. falc or P. viv only

Tab.Chloroquine 300mg(free base)

[500mg chl. phosphate contains 300mg free base]

Begin 1–2 weeks before travel to malariousareas. Take weekly on the same day of the week while in the malarious areas and for 4 weeks after leaving such areas.

Primaquine 15mg/d X 14 days after leaving

2) Areas with chloroquine-resistant P. falciparum

T.Mefloquine 250 mg once weekly, 1 week

before and 4 weeks after travel.

3) Areas with chloroquine or mefloquine-resistant

Plasmodium falciparum

Atovaquone/proguanil 1 adult tablet daily 1-2

days before & 7 days after travel

An adult tablet contains 250 mg of atovaquone

and 100 mg of proguanil hydrochloride. (or)

Doxycycline: 100mg daily, a day before travel

and taken till 4 weeks after return from endemic

area.

a)Vivax (ovale, malariae) malaria

1.Chloroquine 600mg stat followed by

300mg after 8 hrs and for next 2

days(total 25mg/kg over 3 days) +

Primaquine 15mg (0.25mg/kg daily) for 14 days

In chloroquine resistance

2) Quinine- 600mg 8 hourly x7 days+

Doxycycline- 100mg daily x 7days+

Primaquine- 15mg daily X 14 days

B) Chloroquine sensitive falciparum malaria

Chloroqiuine as above +

Primaquine- 45 mg single dose as gametocide

C) Chloroquine resistant falciparum malaria

1.Artesunate- 100mgBD(4mg/kg daily) x 3 days+

Sulfadoxine-1500mg(25mg/kg)+

Pyrimethamine- 75mg(1.25mg/kg) single dose

First line ACT

2.Artesunate- 100mgBD(4mg/kg daily) x 3 days+

Mefloquine- 750mg(15mg/kg)on 2nd day and

500mg(10mg/kg) on 3rd day

3. Artemether- 80mg +

Lumefantrine- 480 mg B.D X 3days

4. Arterolane 150 mg +

Piperaquine 750mg od X3 days

5.Quinine 600mg 8hly X 7 days+

Doxycycline100mg daily X 7days or

Clindamycin 600mg 12hly X 7 days

In India irrespective of CQ – resistance status

are treated with ACT.

1. Artesunate- 2.4mg/kg i.v or i.m, f/b

2.4mg/kg after 12 and 24 hrs

Then OD for 7 days.

2. Artemether- 3.2mg/kg i.m on 1st day f/b

1.6mg/kg for next 7 days

3. Arteether- 3.2mg/kg on 1st day f/b

1.6mg/kg for next 4 days

Switch over to 3 day oral ACT in between

whenever the patient is able to take oral med

4. Quinine diHCL-20mg/kg(loading dose) diluted in 10ml/kg 5%dextrose/dextrose-saline and infused i.v over 4 hours, f/b

10mg/kg(maintenance dose) i.v infusion over 4 hours(adults) or 2 hours (children) every 8 hours, until patient can swallow.

Switch over to oral quinine 10mg/kg 8hourly to complete 7 day course.

Falciparum malaria during pregnancy

Q 600mgTDS 7d+ clindamycin 300md 7d all tri

3 day ACT regimen in 2nd & 3rd tri alt to above

Radical cure:

Drugs which attack the exo-erythrocytic stage given together with a clinical curative achieve total eradication of parasite.

Drug of choice for vivax and ovale malaria is

Primaquine: 15mg daily for 14 days.

It should given with or immediately after chloroquine or other schizonticide only to persons who test negative to G6PD deficiency.

Anti relapse treatment is restricted to:

a) Areas with low levels of transmission.

b) Patients treated during an epidemic along with effective vector measures to cut down transmission.

Chloroquine

Available as Cl.Phosphate for oral use

PK

A-almost completely absorbed from GIT.

D-large aVd, extensively tissue bound.

M- liver, initial t1/2- 3-4 days, terminal t1/2- 1-2mts

E-urine

ROA- oral/ I.M/ slow I.V infusion

MOA

Preferentially accumulates in Parasitized RBC

Being basic diffuses freely in to parasite

lysosome

Gets ionized in acidic pH of lysosome

Inhibits peptide formation & AA synthesis

Inhibits parasite haem polymerase→

Host haem is not converted to haemozoin

Free haem is toxic to malarial parasite

Antimalarial action & clinical use

It is rapidly acting erythrocytic schizonticide

against all species of plasmodia.

Uses

1) Drug of choice for clinical cure and prophylaxis

of all types of malaria.

2) Extra-intestinal amoebiasis

3) Rheumatoid arthritis

4) DLE- very effective. Less effective in SLE.

5) Lepra reactions.

6) Photogenic reactions

7) Infectious mononucleosis – symptomatic relief.

Resistance

Most common in P.falciparum

Due to mutation in putative chloroquine

transporter (PfCRT).

Adverse effects

Nausea, anorexia, uncontrollable vomiting,

epigastric pain, difficulty in accommodation, and

headache.

Parenterally – hypotension, cardiac depression,

arrhythmias, convulsions

Prolonged use: loss of vision due to retinal

damage.

CI

Retinal & visual field abnormalities.

Aggravates psoriasis & porphyria.

G6PD deficiency- haemolytic anemia.

DI

Antacids ↓ absorption

C+ metoclopramide precipitates extra pyramidal

side effects.

Safe in pregnancy and children >2yrs

Amodiaquine

Similar to chloroquine

Withdrawn-risk of agranulocytosis, hepatotoxic.

Reintroduced in chloroquine resistant areas

Resistant P.falciparum responds to

amodiaquine combination regimens

Artesunate + amodiaquine or

Pyrimethamine-sulfadoxine + amodiaquine.

Toxicity is rare with combination.

Piperaquine

Piperaquine is chloroquine analogue.

Used for Rx of P.falciparum malaria in fixed dose

combination with dihydroartemisinin

Longer t1/2- 35 days, reduces rate of relapse

Pyronaridine

Amodiaquine analogue used in china.

Combined with artesunate for chloroquine

resistant falciparum & vivax malaria

Effective orally & has low toxicity.

Quinine

Alkaloid derived from cinchona bark

Rx and prevention of malaria since 1820

PK

A- well absorbed from GIT.

D-large aVd, extensively tissue bound.

M- liver, t1/2- 10-11 hrs

E- urine

ROA- oral/ slow I.V infusion

MOA

Not clear

Like chloroq inhibits parasite haem polymerase.

Acts as a protoplasmic poison to parasite &

hampers supply of AA & peptides.

Antimalarial action & clinical use

Similar to chloroquine.

No effect on pre-erythtocytic stages and on

hypnozoites of relapsing malaria, but kills vivax

gametes.

Main drug for chloroquine resistant P.fal malaria

Other uses

Nocturnal leg cramps- varicose veins

Diabetes mellitus

Arthritis

Quinine + clindamycin- 1st line Rx of Babesiosis

Resistance

To P.falciparum reported in Thailand.

Due to ↑ expression of P-glycoprotein

Adverse effects

Bitter taste- poor compliance

Gastric irritant – nausea, vomiting

Bolus I.V admin- hypotension & arrhythmias

Stimulates insulin release- Hypoglycemia.

Hence quinine usually infused with 5%dextrose.

May lead to hypoglycemic coma in P.f malaria.

Black water fever- erratic use in other fever.

Leads to marked haemolysis & renal failure.

Cinchonism

A syndrome due to intake of a large single dose

or higher therapeutic doses taken for a few

days.

Characterized by

Sweating

Tinnitus

Blurred vision

Headache

Diarrhoea

Cardiac arrhythmias

Neurotoxicity (higher doses)

Hematological toxicity (hemolysis in G6PD def)

Contraindications (CI)

Visual & auditory problems

Cardiac abnormalities

Drug interactions (DI)

Antacids ↓ absorption

Quinine raises plasma levels of digoxin

Shouldn’t be given concurrently with mefloquine

both effect cardiac conduction- arrhythmias

Mefloquine

PK

A- orally well absorbed

D- highly protein bound, extensively distributed

M- liver, undergoes enterohepatic circulation.

E- feces, t1/2- 20 days, weekly dosing in

chemoprophylaxis, single dose regimen for

clinical cure.

ROA- oral, can’t give parenterally-pain, irritation

MOA & Resistance

Similar to quinine

Antimalarial action & uses

Blood schizonticide

used for chemoprophylaxis and clinical cure

Not useful in severe & complicated malaria

Adverse effects

Nausea

Vomiting

Neuropsychiatric side effects in 0.5% patients

Vertigo, Confusion, vivid dreams, seizures

Abnormal AV conduction

CI with quinine or halofantrine

Primaquine

PK

A- orally well absorbed.

D- wide, not extensively tissue bound.

M- liver, active metabolites- toxic.

E- urine, t1/2-3-6 hrs.

ROA- oral

MOA

Not clear

Quinone metabolite inhibits coenzyme-Q in

parasite, also hemolysis in host.

Antimalarial action & uses

Tissue schizonticide, gametocidal.

Effective on both pre & exo erythrocytic state

Not effective on erythrocytic state.

Mainly used for radical cure and to prevent

relapse in P.vivax & P.ovale

Other use- primaquine + clindamycin in

Pneumocystis jiroveci pneumonia

Improved tolerance over cotrimoxazole

Adverse effects

Git distress, nausea

Head ache

Pruritis

Leukopenia

G6PD def pt- fatal haemolytic anemia

CI in pregnancy

Other congeners-

Bulaquine, etaquine, tafenoquine

Bulaquine : developed in India,

Prodrug for primaquine

Dose- 25mg/d starting on 2nd day of chloroquine

therapy

primaquine or bulaquine not given parenterally

Produces marked hypotension

Etaquine & tafenoquine more potent and longer

acting

Tafenoquine –orally once weekly.

Pyrimethamine-sulfonamide/dapsone

Pyrimethamine selectively inhibits plasmodialfolate reductase enzyme.

Slow acting erythrocytic schizonticide

Sulfonamides are added to prevent resistance.

Sulfadoxine/sulphamethopyrazine/dapsone

Inhibit dihydropteroate synthase enzyme

Used for clinical cure of P.falciparum malaria.

Q+Sd+P- chloroquine resistant P.falc .

Other uses:

Toxoplasmosis : in immunodeficient P(50-75mg/d)+sulfadiazine(2-4g/d) 1-3 wk 1st line therapy.

Adverse effects

Pyrimethamine -megaloblastic anemia

Folinic acid is added to therapy to prevent this

Anorexia, vomiting, atrophic glossitis, seizures

P+Sd- exfoliative dermatitis

stevens johnson syndrome.

Allergic alveolitis, blood dyscrasias

P+D- Haemolytic anemia,

Agranulocytosis

Eosinophilic alveolotis

Tetracycline & Doxycycline

Slow acting & weak erythrocytic schizonticides

Effective against all species.

Use – combination with quinine for CQ resistant

falciparum & vivax malaria.

Dose: Tetracycline- 250mg QID

Doxycycline- 100mg OD

Doxycycline 100mg/day is 2nd line prophylactic

treatment for travellers to chloroquine resistant

P.falciparum areas.

Proguanil (Chloroguanide)

Inhibitor of plasmodial dihydrofolate reductase

PK

A- rapid, t1/2 16hrs, administered OD.

Antimalarial action

Slow acting erythrocytic schizonticide for all Ps.

Acts on pre-erythrocytic stage of P.vivax

No effect on exoerythrocytic cycle & gametes

Resistance develops rapidly when used alone

Hence used in combination

250 mg Atovaquone + Prouguanil 100mg OD X

2days prior to & 7 days after exposure for

chemoprophylaxis of P.falciparum malaria.

AQ 1000mg + PG 400 mg OD X3 days

preferred for Rx of CQ R P.viv & MDR P.fal

Combined formulations should be taken with

food

AE: less severe

Atovaquone

Used in combination with proguanil

FDC prevent resistance & better tolerated

MOA

Not clear, disrupts plasmodial mitochondrial electron transport

Inhibits pyrimidine & ATP synthesis

PK

A-BA poor & erratic, ↑ with fatty meal

D- PB-99%

M- long t1/2 (2-3 d) partly due to EH recycling

E- feces

Uses

Chemoprophylaxis & Rx of P.fal with PG

Other- mild to mod Pneumocystis.carinii

pneumonia in pt intolerant to cotrimoazole

Rx or suppression of Toxoplasma gondii

encephalitis

AE

Abd pain, N, V, Headache, rash

Reversible elevation in liver enzymes

DI

Metoclopramide, tetracycline, rifampicin ↓AQ

plasma levels

Artemether, Artesunate, Arteether are

Sesquiterpinelactone endoperoxidases

Artemisinin is active principle of the plant

Artemisia annua used in Chinese traditional

medicine as” Quinghaosu.”

Active against P.falciparum resistant to all

drugs as well as sensitive strains.

Artemether, Artesunate, Arteether

semisynthetic derivatives of Artemisinin with

improved potency better BA

Pk

Artemisinin is poorly soluble in water & oil,

Artemether is soluble in oil , given orally, i.m, t1/2

4-11 hrs.

Artesunate is water soluble , given orally, i.m, i.v

t1/2<1 hr . Both are prodrugs.

Active metabolite Dihydroartemisinin also used

orally

Arteether (i.m in oil) was produced in India in

1990. longer t1/2 23 hrs

Arterolane –synthetic compound given orally.

Antimalarial action

Potent and rapid blood schizonticide and

parasitemia clearance is<48 hrs.

Action on a wide range of forms – from ring

forms to early schizonts, thus have the broadest

time window of anti-malarial action.

Do not kill hypnozoites but some action on

gametes.

Recrudescence depends on dose, duration, as

well as severity of disease.

MOA

Involves two steps

Initially intraparasitic protoporphyrin –IV

catalyses break down of endoperoxide bridge

(-O-O-) of artemisinin molecule

Generation of highly reactive free radicals ->

Damage parasite membrane by covalently

binding to proteins

Free radicals specifically inhibit plasmodial

sarcoplasmic-endoplasmic Ca ATPase labelled

PfATP6

AE:

N, V, Abd pain, itching

Temp QT prolongation may occur

Transient reticulopenia and leucopenia are rare

Halofantrine

Potent blood schizonticide

A- erratic, ↑with food

MOA possible inhibition of proton pump

Manifests lethal cardiotoxicity & cross

resistance with mefloquine

USE: restricted for MDR P.fal 500mg QID X 1 d

repeated after 1wk

AE:

Abd pain, Vomiting cough, rash, prutitis

Transient elevation in liver enzymes

Cardiotoxicity: prolong QT & PR interval, dose

related defects in cardiac conduction

Worsens with mefloquine

Embryotoxic in animals avoided in pregnancy

Lumefantrine

Used in combination with Artemether for MDR P.fa

BD X 3days

Combination not cardiotoxic

Given with fatty meal ↑ BA

Artemisinin based combination therapy (ACT)

WHO recommended that acute uncomplicated

resistant falciparum malaria should be treated

by combining artemisinin compounds with

another erythrocytic schizonticide.

Most important consideration for companion

drug is elimination half life as effective

concentrations in blood must be maintained for

at least 3asexual cycles.

Short half life drugs Ad. for 7 days.

Long half life drugs Ad. for 1-3days.

Advantages of ACT over other drugs:

Rapid clinical and parasitological cure.

High cure rates(>95%) and low recrudescence rate.

Absence of parasitic resistance.

Good tolerability profile.

ACT regimens in use are:

1.Artesunate- 100mgBD(4mg/kg daily) x 3 days+

Sulfadoxine-1500mg(25mg/kg)+

Pyrimethamine- 75mg(1.25mg/kg) single dose

First line ACT

But not effective against multidrug resistant strains.

2.Artesunate- 100mgBD(4mg/kg daily) x 3 days+

Mefloquine- 750mg(15mg/kg)on 2nd day and 500mg(10mg/kg) on 3rd day

First line treatment for uncomplicated falciparummalaria in S-E Asia.

Further spread of mefloquine resistance is prevented.

3. Artemether- 80mg +

Lumefantrine- 480 mg B.D X 3days

components protect each other from plasmodialresistance.

Active in multidrug resistance areas.

Artemether reduces symptoms and lumefantrineprevents recrudescence.

4. Arterolane 150 mg +

Piperaquine 750mg od X3 days

5. Dihydroartemisinin 120mg +piperaquine 750mg

daily X 3days

Well tolerated even in children

6. Artesunate 200mg + Amodiaquine 600mg/day X

3days.

7. Artesunate 100-200mg + pyronaridine 300 -

600mg/day X 3days.

Thank you