A vector-borne disease is one in which the pathogenic microorganism is transmitted from an infected individual to another individual by an agent

The name comes from the Italian mal (bad) and aria (air) – it was originally thought the disease was spread by the damp air from swamps

The link between the disease and the Anopheles Mosquito was first made by Ronald Ross, a Scottish army doctor, working in India

Malaria

Plasmodium falciparum is responsible for most morbidity and mortality

4 distinctive species

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

Malaria

Malaria - deadly disease

Malaria kills 1.5-2.7 million people every year

Additional 300-500 million people suffer from malaria attacks but survive

Malaria is a major cause of death equal with AIDS and tuberculosis

The mortality and morbidity associated with malaria have a crippling effect on the economies of endemic countries

-100 nations at risk

- 1 death every 30 seconds

- 2.7 millions death / year

- 1 in 3 below five years

- 10 times killer than AIDS

Malaria – global scenario

NVBDCP - 2 million cases

WHO estimate – 70 million cases

45-50% falciparum cases

2 lakh deaths / year

Increasing drug resistance

Malaria – Indian scenario

NVBDCP – National Vector Borne Disease Control Programme

Malaria triad

AGENTAGENT

(Plasmodium)(Plasmodium)

VECTORVECTOR(Female anopheles (Female anopheles

mosquito)mosquito)

HOSTHOST

(Man)(Man)

Eleven Steps in ‘Slow Motion’

Life Cycle of

A Malarial Parasite

Why Falciparum Malaria is serious?

Vivax malaria seldom kills, Falciparum does

In Falciparum life cycle, each liver schizont can release upto 40,000 merozoites (only 10,000 in Vivax)

In Falciparum life cycle, merozoites attack young RBC, and even older RBC (Vivax merozoites preferentially attack immature RBC).

In Falciparum life cycle, a large number of infected RBC get sequestered i.e. get secluded by leaving the general circulation and move to peripheral circulation (microvascular circulation), causing multiple organ damage.

Falciparum parasitizes upto 35 per cent of RBCsWHEREAS

Parasitization with Vivax rarely exceeds 5% 0f RBCs

Parasitemia in Vivax ranges between 20,000 to 50,000 RBCs per

micro-litre (1/1000th of a liter) whereas in Falciparum it can go upto 20,000,000 RBCs per micro-litre

Why Falciparum Malaria is serious?

PCT & FCT

Parasitic clearance time is the time between beginning antimalarial treatment and the first negative blood slide.

Fever clearance time is the time taken by an antimalarial drug to bring down the body temperature of a patient with malarial fever to normal temperature (i.e. 37.5oC or below).

Other common terms

Tissue schizontocide

Kills hypnozoites or tissue schizonts which leads to relapse. e.g. Primaquine

Blood schizontocide

Acts on malaria parasites (which are in various stages like trophozoites, schizonts, merozoites) inside RBCs. e.g. Chloroquine,Quinine, Artemisinins

Gametocytocidal

Kills gametocytes & hence prevents spread of disease

Resistance

R1

(Low grade)

Recrudescence of infection (i.e. reappearance of malaria) between 7 and 28 days of completing treatment following initial resolution of symptoms and parasite clearance

R2

(High grade)

Reduction of parasitaemia by >75% at 48 hours, but failure to clear parasites within the 7 days

R3 Parasitaemia does not fall below >75% within 48 hours

Improper treatment and inadequate dosage of antimalarials lead to development of resistance

Antimalarial therapy

Vivax malaria

LARIAGO (Chloroquine Tablets/Suspension/Injection)

Drug of choice in the treatment and prophylaxis of malaria caused by P. vivax

Rapid schizontocidal effect

No effect on malarial parasites present in the liver cells

Mode of Action

Accumulates selectively in parasitized erythrocytes

Alters the pH of the food vacoules of the parasites, resulting in severe metabolic disturbances

Also interferes with the parasites’ ability to utilize haemoglobin

These disturbances ultimately leads to destruction of the membrane of the parasite, causing its death

MALIRID(Primaquine Tablets )

Tissue schizonticidal agent for radical cure of vivax malaria

Acts at liver stage of vivax parasite

Exact mechanism of action is not known but the drug appears to interfere with the function of plasmodial DNA

Gametocytocidal against gametocytes of P. falciparum

Falciparum malaria- traditional antimalarials

LARIDOX (Sulphadoxine and Pyrimethamine Tablets/Susp.)

Effective against P. falciparum

As a single dose of therapy

Should not be used alone for the treatment of malaria having P. vivax presence

Ineffective in P. vivax infection

Lariago to be added along with Laridox in cases of mixed malaria

LARIMEFMefloquine Tablets

Blood schizontocidal

Active against all forms of malaria parasites including multidrug resistant strains of P. falciparum

Ensures both suppression and cure of infections with multidrug resistant P. falciparum.

Rapidly absorbed and long elimination half life of 21 days

Add on to Artemisinin injection as a follow up to prevent recrudesence

Falciparum malaria

Increasing incidences Rising resistance Fast progression towards complicated malaria Morbidity & mortality

NEED - new treatment approach

ARTEMISININS

Potent antimalarial activity

Immediate onset and rapid reduction of parasitaemia with complete clearance in most cases within 48 hours

Clinical recovery of the patient, e.g. defervescence is faster than with other antimalarials

Efficacy is high even in areas with multi-drug resistant strains

Well tolerated and efficacious in adults and children

Artemisinin

Dihydroartemisinin

Methyl ether Hemisuccinate Ethyl ether

Artemether Artesunate Arteether

Parameter Artemether Artesunate Arteether

Solubility Oil soluble Water soluble Oil soluble

Dosage forms Oral/Inj Oral/inj Inj

Route of admin. Oral/IM Oral/IM/IV IM

Blood/tissue schizonticidal

Blood Blood Blood

Action on rosetting & cytoadherence

Reduces Faster action than others

Reduces

Plasma half life Rapidly eliminated

3-6 hrs 23 hrs

Stability Stable Unstable Stable

Mechanism of action

Drug is concentrated in parasitized erythrocytes

The functional group responsible for antimalarial activity of drug is endoperoxide bridge

Iron from the digested haemoglobin of the parasite’s victim reduces this bridge, releasing a highly reactive free radical iron species, which causes lysis of the parasitic cell

It is also proposed that artemisinins inhibit the protein synthesis and alters the ribosomal organization and endoplasmic reticulum.

A

A

A

A

A

MPMP

MP

MPMP

MP MPMP

A

MP

RE

MP

Hb Hb Hb Hb Hb

Intracellular Mechanism of Action

of Artemisinin compounds

A Artemisinin derivatives MP Malaria ParasiteHb HaemoglobinRE Reticular Endothelial Cells

Concept of ACT

Lumerax Larinate kit

WHO initiative

Combinations of drugs

First line tratment for uncomplicated falciparum malaria

The aim is to improve efficacy and to retard the development of resistance to the individual components of the combination

Fixed-combination and multiple-drug therapies are used to exploit the synergistic and additive potential of individual drugs

Ideal ACT features

Drugs having unrelated mode of action on the parasite

Fast acting & Long acting

No negative pharmacological interactions

Short duration & well tolerated

WHO Initiative

Artesunate + amodiaquine

• Artemether/lumefantrine

Artesunate + SP

Artesunate + mefloquine

FDC

KIT

Amodiaquine + SP

Lumerax represents a new approach in Antimalarial treatment called Artemisinin-based Combination Therapy (ACT)

Lumerax is fixed dose combination of Artemether with Lumefantrine

Lumerax is the first ACT introduced in the Indian market

LUMERAX

Larinate Kit is a combo-pack of an artemisinin derivative, Artesunate, along with a separate strip of Sulfadoxine and Pyrimethamine (‘SP’) tablets

Larinate Kit is the WHO-endorsed combination for Uncomplicated Falciparum Malaria

Larinate Kit also serves as a ‘switch oral therapy’ when patients on injectable Artemisinins (injectable artesunate, artemether or arteether who are able to swallow an oral dosage form)

LARINATE KIT

RAPITHER-AB

Combination of alpha and beta isomers (A and B) of Arteether, the ethyl ether of artemisin. Hence Rapither AB

Rapither AB is recommended for Falciparum Malaria, including drug-resistant Malaria

Short 3-dose treatment

Larither contains Artemether and belongs to the Artemisinin group of Antimalarial drugs.

Larither is recommended for the treatment of severe Falciparum Malaria, as a complete 7-day IM injection therapy especially in area where falciparum cases are on rise

The elimination half-life is approximately 1 hour, but following intramuscular administration the elimination phase is prolonged because of continued absorption.

LARITHER

Complicated Malaria Treatment

Hospital settings

OPD, Casualty

Ward care

ICU care

Criticality of disease

Why complications?

High degree of parasitemia

Severity of illness

Cytoadherence - rosseting

One to multi organ failure

Predisposing factors for complications

Extremes of age

Pregnancy

Immunosuppressed - patients on steroids, anti-cancer drugs, immunosuppressant drugs

Lack of previous exposure to malaria (non-immune)

Pre-existing organ failure.

Complications of Malaria

Cerebral malariaSevere anemiaJaundiceRenal failurePulmonary edemaHypoglycemiaBleeding and clotting disturbancesHyperpyrexia

HyperparasitemiaComplicating or associated infectionsVomiting of oral drugsImpaired consciousnessExtreme weakness

CINKONA(Quinine Tablets/Injection)

A cinchona alkaloid that is a time tested drug

Mode of action: May interfere with nucleic acid synthesis in the malaria parasite

Activity against all four forms of malaria

Rapidly acting blood schizontocide

Effective against resistant strains

Adverse effect - Hypoglycemia, Cinchonism i.e. tinnitus, headache, nausea and diarrhoea

LARINATE INJECTION(Artesunate inj.)

The primary objective of antimalarial treatment in severe malaria is to prevent death

IV artesunate is more rapidly acting than IV quinine in terms of parasite clearance, is safer, and is simpler to administer

Reduces mortality in complicated malaria cases

Larinate for injection is available as a combi-pack containing:

a) 5 ml vial containing sterile Artesunate powderb) Sodium Bicarbonate 1 ml. for reconstitutionc) Sodium Chloride 5 ml

All the three components i.e. one vial and two ampoules are embedded in a specially designed three-compartment tray

LARINATE INJECTION(Artesunate inj.)

MANAGEMENT OF MALARIA

Management of clinical malaria (febrile episode)

Prevention of relapse in vivax and spread in falciparum

UncomplicatedComplicated

P. Vivax / P. falciparum Chloroquine Sulphadoxine/Pyrimethamine Mefloquine ACT Inj. Artemisinin derivatives

P. falciparum Inj. Artemisinin derivatives Inj. Quinine

Primaquine

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