ANTIMALARIAL DRUGS

Plasmodium species which infect humans

Plasmodium vivax

Plasmodium ovale

Plasmodium falciparum

Plasmodium malariae

Classification of Malaria

• Uncomplicated Malaria

• Cold stage (sensation of cold, shivering)

• Hot stage (fever, headaches, vomiting; seizures

in young children)

• Sweating stage (sweats, return to normal

temperature, tiredness)

Classification of Malaria

• Severe Malaria

– Cerebral malaria (seizures, coma)

– Severe anemia

– Hemoglobinuria

– Abnormalities in blood coagulation

– Cardiovascular collapse and shock

Types of Infections• Recrudescence

– exacerbation of persistent undetectable parasitemia, due to survival of erythrocytic forms, no exo-erythrocytic cycle (P.f., P.m.)

• Relapse– reactivation of hypnozoites forms of parasite in liver, separate from

previous infection with same species (P.v. and P.o.)

• Recurrence or reinfection – exo-erythrocytic forms infect erythrocytes, separate from previous

infection (all species)

• Can not always differentiate recrudescence from reinfection

• Based on stage of parasite they affect:

– Causal prophylactics: Primaquine, Pyrimethamine,proguanil

– Supressives: Quinine, 4-aminoquinolines, mefloquine,artemisinin

– Radical curatives: Primaquine,pyrimethamine

– Gametocidal:

• Supressives – Pl Vivax ,

• Primaquine – against all,

• Proguanil ,pyrimethamine – prevent development also

prevent development of sporozoites

CLASSIFICATION OF ANTIMALARIALS

• Based on chemical structure:

– Cinchona alkaloids: Quinine, quinidine

– 4 aminoquinolines: Chloroquine, hydroxychloroquine,

amodiaquine, pyronaridine

– 8 aminoquinolines: Primaquine, tafenoquine, bulaquine

– Quinoline-methanol: Mefloquine, halofantrine, lumefantrine

– Antifolates:

• Diaminopyrimidine: pyrimethamine

• Biguanides: proguanil

• Sulfonamides: sulfadoxine

– Antibiotics: Tetracycline, doxycycline, clindamycin

– Hydronaphthoquinone: Atovaquone

– Artemisinin Derivatives: Artesunate, artemether,

arteether

Exo-erythrocytic (hepatic) cycle

Sporozoites

Mosquito Salivary Gland

Malaria Life Cycle

Life Cycle

Gametocytes

Oocyst

Erythrocytic Cycle

Zygote

Schizogony

Sporogony

Hypnozoites(for P. vivax and P. ovale)

Malaria Transmission Cycle

Parasite undergoes sexual reproduction in the mosquito

Some merozoites differentiate into male or female gametocyctes

Erythrocytic Cycle: Merozoites infect red blood cells to form schizonts

Dormant liver stages (hypnozoites) of P. vivax and P. ovale

Exo-erythrocytic (hepatic) Cycle: Sporozoites infect liver cells and develop into schizonts, which release merozoites into the blood

MOSQUITO HUMAN

Sporozoites injected into human host during blood meal

Parasites mature in mosquito midgut and migrate to salivary glands

Components of the Malaria Life Cycle

Mosquito Vector

Human Host

Sporogonic cycle

Infective Period

Mosquito bitesgametocytemic person

Mosquito bitesuninfected person

Prepatent Period

Incubation Period

Clinical Illness

Parasites visible

Recovery

Symptom onset

Exo-erythrocytic (tissue) phase

• Blood is infected with sporozoites about 30 minutes after the mosquito bite

• The sporozoites are eaten by macrophages or enter the liver cells where they multiply –

pre-erythrocytic schizogeny• P. vivax and P. ovale sporozoites form parasites

in the liver called hypnozoites

Exo-erythrocytic (tissue) phase

• P. malariae or P. falciparum sporozoites do not

form hypnozites, develop directly into pre-

erythrocytic schizonts in the liver

• Pre-erythrocytic schizogeny takes 6-16 days post

infection

• Schizonts rupture, releasing merozoites which

invade red blood cells (RBC) in liver

Exo-erythrocytic (tissue) phase

• P. vivax and P. ovale hypnozoites remain

dormant for months

• They develop and undergo pre-erythrocytic

sporogeny

• The schizonts rupture, releasing merozoites

and producing clinical relapse

Erythrocytic phase

• Pre-patent period – interval between date of infection and detection of parasites in peripheral blood

• Incubation period – time between infection and first appearance of clinical symptoms

• Merozoites from liver invade peripheral (RBC) and develop causing changes in the RBC

• There is variability in all 3 of these features depending on species of malaria

Erythrocytic phasestages of parasite in RBC

• Trophozoites are early stages with ring form the youngest

• Tropohozoite nucleus and cytoplasm divide forming a schizont

• Segmentation of schizont’s nucleus and cytoplasm forms merozoites

• Schizogeny complete when schizont ruptures, releasing merozoites into blood stream, causing fever

• These are asexual forms

Erythrocytic phasestages of parasite in RBC

• Merozoites invade other RBCs and

schizogony is repeated

• Parasite density increases until host’s

immune response slows it down

• Merozoites may develop into gametocytes,

the sexual forms of the parasite

Quinine• Oldest antimalarial alkaloid isolated from barks of chinchona tree.• Present indication-cerebral malaria

-chloroquine resistant p. falcifarumPharmacological actions1.Antimalarial :Suppressive agent2.Local irritational action: General protoplasmic poison

-decrease cilliary actvity-Inhibit phagocytosis & fibroblast growth

Local anesthetic action, At high conc. edema , pain at site of inj.3.GI tract- bitter, nausea ,vomiting4.CVS- myocardial depression, decrease excitability and conductivity iv. dose-

hypotension5. Miscellaneous- analgesic, antipyretic, sk. muscle relaxant

P/K-well absorbed ,peak 1-3 hrs, cross placenta, metabolized in liver, excreted in urine

Adverse effect1.Cinchonism:

Mild - ringing in ears, nausea, vomiting, headache, visual impairment.

Large doses-Tinnitus, deafness, vertigo, blurring,photophobia, delirium, confusion.

Poisoning progress- Skin pale, cold, resp. depress,BP falls, comma, death.

2.Idiosyncrasy

3.CVS toxicity-cardiac arrest

4.Black Water Fever

-acute intravascular haemolysis,haemoglobinuria,fever, acute renal failure,focal hepatic necrosis

5.Hypoglycemia

6.Acute renal Failure

Uses & Dose1.Malaria:• schizontocidal drug• very active against erythrocytic phase.• No effect against proerythrocytic, sexual gametocytes,

exoerythrocytic phase, relapse.2.Myotonia Congenita3.Nocturnal muscle cramps4.Cerebral malaria

IV Quinine 600mg in 500ml of 5% dextrose slowly over 4 hrs repeated every 8 hrs till patient is conscious followed by oral treatment to complete 7 day coarse.

Dose:300-600mg orally

Chloroquine

• It is a 4-aminoquinolone

• It was produced in USA as a less toxic alternative to

mepacrine.

• It is rapidly acting erythrocytic schizontocide against

all species of plasmodia.it is highly efficacious drug.

• It controls most clinical attack in 1-2 days.

• It does not prevent relapses in vivax & ovale malaria.

Mechanism of action• It is actively concentrated by sensitive intraerythrocytic

plasmodia

• It interfers with degradation of Hb by parasitic lysosomes

• Heme itself or its complex with chloroquine damages

plasmodial membrane

• Clumping of pigment & changes in parasite membrane follows

• It has anti-inflamatory, local irritant, local anaesthetic, weak

smooth muscle relaxant, anti-histaminic & anti-arrhythmic

properties

Resistance

• Chloroquine resistance among P. vivax has been slow

in developing.

• However P. falciparum has acquired significant

resistance

• Resistance in P. falciparum is associated with a

decreased ability of parasite to accumulate

chloroquine

Pharmacokinetics • Oral absorption of chloroquine is excellent , about

50% gets bound in plasma • It gets bound to melanin & nuclear chromatin and is

concentrated in liver, spleen, kidney, lungs, skin, leucocyte

• Absorption after i.m. injection is also good• Plasma concentration is 15-30ng/ml• Chloroquine is partly metabolised by liver & slowly

excreted in urine• Plasma t-1/2 varies from 3-10 days

Toxic effects• Toxicity of chloroquine is low but side effects

are frequent & unpleasant:• nausea • vomiting • anorexia • uncontrollable itching • epigastric pain• uneasiness• headache

…contd.

Parenteral administration can cause• hypotension• cardiac depression • arrythmias CNS toxicity including convulsions.• Prolonged use of high doses can cause loss of

vision.

…contd.

• Loss of hearing , rashes, photo allergy, mental

disturbance, myopathy and graying of hairs

can occur as long term use.

• Attack of seizures, porphyria & psoriasis may

be precipitated.

Routes of administration & dosage

• Chloroquine phosphate is given orally• As prophylaxis – Dose: adults – 500mg once each week children – 5mg/kg weekly• For treatment – Initial dose - 600mg followed by 300mg after 6-8 hrs then 300mg on 2 consecutive days

Indications

• Chloroquine is drug of choice for malaria• It completely cures sensitive falciparum

disease, but relapses in vivax and ovale are not prevented .

Other uses• Extra intestinal amoebiasis • Rheumatoid arthritis

…contd.

• Discoid lupus erythematosus

• Lepra reactions

• Photogenic reactions

• Infectious mononucleosis

Mefloquine

Introduction It is a quinoline methanol derivativeIt is a drug developed to deal with problem of chloroquine resistant P.falciparum It is rapidly acting erythrocytic schizontocide.It is effective against chloroquine sensitive as well as resistant plasmodiaIt has not been extensively used in India.

Mechanism of action

Acts on erythrocytic stageHighly effective in a single dose against

P.falciparum including chloroquine resistant strains.

Appears to bind to heme and the complex damages membrane of the parasite

No action on persistant tissue form.

Pharmacokinetics

Given orally

Rapidly and completely absorbed

Highly bound to plasma protein

Eliminated slowly with plasma half life of 20

days

Adverse effects

GITDizziness, nausea, vomiting, diarrhoea, abdominal

pain

Neuropsychiatric disturbancesAnxiety, halloucination, sleep disturbances,

Single dose may cause light headedness and loss of concentration

…Contd.CVS

Causes bradycardiaSinus arrhythmia

Teratogenicity Should be avoided in 1st trimester of pregnancyMay be used in 2nd and 3rd trimester

MiscellaneousAllergic skin reactionBlood dyscriasisHepatitis

Uses

Effective drug for multiresistant P.falciparumTreatment of uncomplicated falciparum

malaria in areas with multidrug resistanceDose -25 mg per kg (maximum 1.5 g)Prophylaxis of malaria among travellers to

areas with multidrug resistanceDose -5 mg per kg (adult 150 mg)

Proguanil

IntroductionCommonly used salt of these drug is proguanil hydrochlorideHas negligible antiplasmodial action in vitroSlow acting erythrocytic schizonticideCyclized in body to triazine derivative

Actions

Effective schizonticide against P.vivax and P.falciparum

Effective against primary pre-erythrocytic forms of P.falciparum

Prevents development of gametes encysted in gut wall of mosquito

No action against persistant tissue forms P.vivax

Pharmacokinetics

Slowly absorbed from gut

Partly metabolized and excreted in urine

Non-cumulative

Plasma half life- 16-20 hrs

Adverse effects

GIT disturbanceStomatitsMouth ulcersReduction in leucocyte count Rarely megaloblastic anaemiaDosageTab Proguanil hydrochloride 100mg

Uses

Use dependent on sensitivity of strainIn multiresistant falciparum malariaCombination of proguanil 100mg and

atovaqoune 250mgUsed prophylactically (in dose of 1 tablet

taken with food)

PRIMAQUINE

Poor erythrocytic schizontocide : has weak action of P. vivax.

In contrast it is more active against pre-erythrocytic stage of P. falciparum than that of P. vivax

Highly active against gametocytes & hypnozoites.

PHARMACOKINETICS

Readily absorbed by oral ingestion.

Oxidized in liver with a plasma t1/2 of 3-6 hrs.

Excreted in urine within 24 hrs.

Not a cumulative drug.

Mechanism of action :-

• Mechanism of action of primaqunine is not known. However it is difficult from that of chloroquine.

Uses :- • Radical cure of relapsing malaria : 15 mg daily for 2

weeks is given with full curative dose of chloroquine. • Falciparum malaria : single 45 mg dose of primaquine

is given with curative dose of chloroquine to kill gametes & cut down transmission to mosquito.

Adverse effect

• Abdominal pain

• GI upset

• Weakness or uneasiness in chest

• CNS & cardiovascular symptoms are infrequent

leucopenia

• Haemolysis, methemoglobinemia, cyanosis

TETRACYCLINES Introduction

• Broad spectrum antibiotic having a nucleus of four

cyclic ring.

• All are obtained from soil actinomycetes

• Slowly acting & weak erythrocytic schizontocidal

action against all plasmodial species

Mechanism of action

• Tetracyclines are primarily bacteriostatic, inhibit

protein synthesis by binding 30 s ribosomes in

susceptible organism. To such binding attachment of

aminoactyl – t- RNA to the m – RNA ribosomes

complex is interfered with. Thus peptide chain fails

to grow.

Adverse effects • Irritative effects :- epigastric pain, N, V & D• Dose related toxicity

Liver damage :- fatty infiltration of liver & jaundice.

Kidney damage :- It is prominent only in the presence of existing kidney disease.

Phototoxicity:- A sun like or other severe skin reaction on exposed parts is seen

Teeth & bones:- Tetracyclines have chelating property.

Cont…

Given between 3 months to 6 years of age affect permanent anterior dentition.

Antianabolic effect:- Reduce protein synthesis & have an overall catabolic effect

Increased intracranial pressure Diabetes insipidus Hypersensitivity Super infection :- Tetracyclines are most common

antibiotics response for superinfections

Uses

• Used in combination with quinine or pyrimethamine

sulfadoxine for the treatment of chloroquine

resistant falciparum malaria.

• Doxycycline 100 mg /day in used as a 2nd line

prophylactic for travelers to chloroquine resistant p.

falciparum areas.

Precautions

• Should not given during pregnancy, lactation

& in children.

• Should be avoided in patients on diuretics

• Do not inject tetracycline intrathecally.

PYRIMETHAMINE

Mechanism of action

It is a directly acting inhibitor of plasmodial

DHFRase.

It gradually reduces the schizogony of malarial

parasite in blood.

It is slowly acting erythrocytic schizontocide.

Pharmacokinetics

Absorption from the gut is good but slow. It is excreted in urine. Half life time = 4 days.

Adverse Effects Nausea & rashes, Folate deficiency, Megaloblastic anemia & granulocytopenia.

Uses

• Used only in combination with sulfonamide/dapsone to treat P.falciparum malaria.

S/P Combination• Sulfonamide has some inhibitory action on

erythrocytic phase of P.falciparum like pyrimethamine..

• It is a supra-additive synergistic combination by sequential block.

PABA Folate synthetase

DHFA DHFRase reductase

THFA• Combination acts faster than individual drug.• Efficacy against P.vivax is low.• When ultra long acting sulfonamides are used ;

exfoliative dermatitis , Stevens-Johnson syndrome are seen.

• Used only as a single effective dose.

Cont….

Contraindications• Infants• Individuals allergic to sulfonamide• Cautious use in pregnancyUses• Chloroquine resistant falciparum malaria.• ToxoplasmosisResistance• Pyrimethamine develops resistance quickly & cross

resistance to biguanides is seen.• It decreases due to sulfonamide & no cross

resistance seen

Cont…

• Resistance was first noted in 1980.• It is more in south-east asia,s.america, southern

Africa.• It is sporadic in India except for north-eastSome Combinations • Sulfonamide(500mg)+pyrimethamin(25mg• Sulfamethapyrasine+pyrimethamine• (500mg) (25mg)• Dapsone(100mg)+pyrimethamine(25mg)• As clinical curative- sulfadoxine(1500mg)

+pyrimethamine(75mg)

Artemisia annua

• Also known as sweet wormwood

• Origin from northern parts of China

• Artemisinin present in leaves and flower of

the plant in 0.01-0.08% dry weight

Artemisia annua

• Used in Traditional Chinese Medicine for more

than 2000 years

• First antimalarial application described in “The

Handbook of Prescriptions for Emergencies”

in the 4th century by a Chinese chemist

Artemsia annua

• Li Shizhen, a great Chinese herbalist

• Use of wormwood is also recorded in the “Great Compendium of Herbs” in 1596

“take a handful of sweet wormwood, soak it in a sheng (liter) of water, and squeeze out the juice and drink it all”

Artemisinin• One of the most novel discoveries in recent

medicinal plant research

• 1967- extracts of Artemisia was found to have

antimalarial activity

• 1972- artemisinin isolated from the plant

• 1979- structure of artemisinin determined by

X-ray analysis

Key Features

• Rapid onset of actions

• Effective against severe malaria

• Rapid clearance rate

• Slow development of artemisinin resistance

• Frequent recurrence of infections

Site of Action

Artemisinin

Artemisinin

Conventional Treatment

Mechanism of Action

• Killing of malaria parasite is mediated by

production free radicals

– Artemisinin derivatives lacking endoperoxide

bridge are devoid of antimalarial activity

– Addition of free radical generating compounds

enhances antimalarial activity

– Antioxidants block antimalarial activity

ARTEMISININ

• Oral formulation - 250mg capsule

• Dosage

Adults and children: 25mg/Kg on the first day followed by 12.5mg/Kg

on the second and third day in combination with mefloquine

(15mg/Kg) in a single dose on the second day. In some areas, a

higher dose (25mg/Kg) of mefloquine may be required for a cure to

be obtained.

DERIVATIVES OF ARTEMISININ USED IN TREATMENT OF MALARIA

• Artemether

• Arteether

• Artesunate

ARTEMETHER

• Methyl ether of dihydroartemisinin

• Superior to intravenous quinine with respect to

survival and parasite clearance

• Available as tablets, capsules and as IM injectable form

• In India, available as 40mg capsules and 80mg/ml ampoule

ARTEETHER

• Ethyl ether of dihydroartemisinin

• Therapeutically equivalent to quinine in cerebral malaria • Available as arteether and / arteether

• arteether developed by WHO and The Special Programme for Research and Training in Tropical

Diseases (TDR)

• / arteether developed by CDRI

ARTEETHER

• A longer t1/2 beta and more lipophilic properties than

artemether favouring accumulation in brain tissue and thus

the treatment of cerebral malaria were regarded as

advantages over the other compounds.

• Available as 150mg per 2ml ampoule

ARTESUNATE

• Water soluble hemisuccinate derivative

• Used for oral, rectal, intravenous and intramuscular administration.

• Available as tablets and as powder with separate vial containing 5% sodium bicarbonate

• In India, available as 50mg tablets and 60mg/ml injection

• In China also available as 100mg suppository and in Switzerland available as 200mg rectocap

• Artemisinin based combination therapy:• WHO has recommended that acute uncomplicated Pl

Falciparum be treated only by combining one Artemisinin with other effective erythrocytic schizonticide

• ACT Regimens in use:– Artesunate – Sulfadoxine, pyrimethamine:

• Adopted as first line in India under NMP • Not effective against MDR strains which are non responsive to S/P• ARTESUNATE 100 mg BD for 3 days with S-P, 3 tablets

– Artesunate Mefloquine:– Highly effective, well tolerated, first line of treatment

for uncomplicated falciparum malaria• By combining artesunate further spread of mefloquine resistance

can be prevented • Artesunate 100 mg BD for 3 days, + mefloquine 750 mg on second

day & 500 mg on third day

• Artemether & lumefantrine: – Lumefantrine is highly effective , long acting oral

erythrocytic schizonticide related to mefloquine – Same mechanism of action – Highly lipophilic onset delayed , peak 6 hrs – Slower acting than chloroquine, 99 % bound ,

metabolized by CYP3A4, T1/2= 2-3 days – Available as fixed dose combination – Adverse events: headache, dizziness, sleep disturbances,

abdominal pain, arthralgia, pruritis & rash – 80 mg artemether BD with 480 mg lumefantrine BD for 3

days

• DHA – Piperaquine, Artesunate- pyronaridine

Resistance

• Currently no evidence for clinically relevant

artemisinin resistance

• Reasons for delay of artemisinin resistance:

– Short half-life

– Reduces transmission potential

– Used in combination with other antimalarial drugs

PHARMACOKINETICS

• Absorption of orally administered artemisinin or its derivatives seems to

be rapid but incomplete

• Substantial hydrolysis of artesunate (probable complete) and artemether

into dihydroartemisinin probably occurs even before absorption

• Elimination is mainly by hepatic metabolism

• Arteether has much slower elimination

• Artesunate, artemether, arteether and probably also artemisinin itself are

transformed into dihydro-artemisinin, which is subsequently

converted into inactive metabolites

ARTEMISININ DERIVATIVES

IN PREGNANCY

• Very limited data on the use of artemisinin group in pregnant women.

• Artemisinin and derivatives should be avoided during first

trimester of pregnancy, but in case of severe malaria the risks have to

be balanced against the benefits.

• No congenital malformations were detected in six children born to

mothers who received intramuscular artemisinin or artemether at 17 to

27 weeks of gestation.