“MALARIA”

• Parasitic, endemic disease

• Malaria is a single cell protozoan

• It is caused by sporozoa of plasmodium

• Transmitted to human by bite of female

Anopheles mosquito .

• Symptoms become apparent only 7-10days

Plasmodium species which infect humans

Plasmodium vivax (tertian)©

Plasmodium ovale (tertian)

Plasmodium falciparum (tertian) © (d)

Plasmodium malariae (quartian)

Symptoms

• Fever• Shivering• Pain in joints• Headache• Repeated vomiting• Severe convulsions, coma

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 (“rosettes”) P.F

Pre erythrocytic (hepatic) cycle10-14days

Sporozoites

Mosquito Salivary Gland

Malaria Life Cycle

Male & Female Gametocytes

Oocyst

Erythrocytic Cycle

Zygote

Schizogony

Sporogony

Hypnozoites(for P. vivax and P. ovale) para/exo erythrocytic cycle

Sporozoites

Mono nucleated merozoites

Motile trophozoites

Multi nucleated merozoites

Liver- Tissue schizonts

RBC- Blood schizoints

sexual cycle in mosquito

Asexual cycle in human

Types of Infections• Recrudescence

– All merozoites are not completely eradicated– Surviving merozoites enter erythrocytic phase again (P.f.,

P.m.)

• Relapse– Reactivation of hypnozoites forms of parasite in liver(P.v&

P.o)

• Recurrence or reinfection – exo-erythrocytic forms infect erythrocytes

Classification of antimalarials: Based on clinical use (Based on stage of parasite they affect) • True causal prophylactics: • Causal prophylactics: Primaquine (3Ps)

Pyrimethamine, Proguanil

– Maturation of sporozoites Schizonts in liver• Supressives prophylactics :Quinine (MCQ-P)

(chemoprophylaxis) 4-aminoquinolines (Chloroquinine)Mefloquine Proguanil

– Destroy the merozoites so errythrocytic stage is prevented.

• Clinical cure: Chlorquinine, Pyrimethamine, Sulfadoxine (CPS)– Blood schizonticides

• CQ resistance: Qunine, Mefloquinine , Artesunate • Radical curatives: Primaquine (P.v& P.o)

Antimalarial drugs1. Chincona alkaloids- Quinine

2. 4 aminoquionoline- Chloroquine, Hydroxychloroquine, 3. 8 aminoquionolines- Primaquine

4. Biguanides- proguanil

5. Diaminopyridines- Pyrimethamine

6. Quinoline methanol- Mefloquine

1. Phenanthrene- Halofantherine

• Artemisinin derivatives Artesunate, Artemether, Arteether

• Acridine Mepacrine, Quinacrine

10. Misellaneous- sulfonamides Teracycline

Atavaquone

4 aminoquinolines :Chloroquine

• Synthetic available as chloroquine phosphate Pharmacokinetics• Rapidly and completely absorbed oral/IM/IV slow.• Peak conc. 2-3 hrs after oral dose.• Highly conc. in liver, spleen ,lung, kidney.• Vd high• Drug persist for longer period after discont. • t½ 3-4days but terminal t½1-2months • Metabolised to 4hydroxychloroquine.

Actions & Clinical use

Antimalarial• Potent blood schizonticidal • Gametocidal P.Vivax, P.Ovale• Relapse common so therapy followed by

primaquine 15mg OD for 15days • P.falciparum is resistance

Uses & Dose1.Malaria2.Ameobiasis - Hepatic 3.Acute manifestations of Lepra reaction.4.Arthritis Rheumatoid5.Infectious mononucleosis6. Autoimmune disorder- Discoid lupus erythematousDoses-antimalarial vd-high Tab. Chloroquine 250 mg- 4tab stat

2tab after 6hrs2tab daily for 2days2 tab once a week

Others Hydroxychloroquine & Amidoquine

Amodiquine

• Spectrum and clinical use are same• A/E: Agranulocytosis • Cheap• Respond to chloroquine resistance P.falciparum

Quinine

• Obtained from cinchona bark -1820• P.K: Orally/slow IV for severe P.falciparum

malaria • Wide distribution • t½- 10-11hrsMechanism of action:• Being a protoplasmic poison to parasite• Hampers the supply of aminoacids and

peptides

Clinical use

• Erythrocytic state• Gametocidal activity in P.Vivax, P.Ovale • Main drug for treating chloroquine resistant

P.falciparum malaria • Loading dose.• Require IV slow infusion in severe conditions• Patient condition improve shifted to oral • Present indication-cerebral malaria• Nocturnal leg cramps

A/E• GIT: Quinine inc. gastric acid secretion by

irritation• CVS: Depress myocardium and cause hypotension• Sk. Muscle : neuromuscular blockade • CNS: In therapeutic dose – Hearing and vision

disturbance.• IV it cause thrombophelbitis• Stimulation of insulin Hypoglycaemia • Black water fever – Rare characterized by

haemolysis, Haemoglobinemia, Haemoglobinuria renal failure

Quinoline methanol : Mefloquine• 4 aminoquiniline derivative, haem poly. inhibitor • Highly effective against erythrocytic cycle• Orally. No parental Local irritation• High protein binding• t½-20days• It is used as Prophylaxis or clinical cure• Avoided during pregnancy• Should not be co-administered with quninie • Reserve drug for prophylaxis and R

chloroquinine resistant malaria

Antifolates: Pyrimethamine, Sulphadoxine, Sulphones, Proguanil

• Pyrimethamine + Sulphadoxine Chloroquine resistant amlaria

• Oral • Initial loading dose require• 87% PB• Half life 3-4days• Sulphones Dapsone

PABA DHF SYNTHETASE

DHF

DHF REDUCTASE

THF

Pyrimethamine

• Slow acting blood schizonticide • Resistance rapid so combination with

sulfonamide• Sulfadoxine500mg+ Pyrimethamine25mg

combination adjunct with quinine to treat chloroquinine resistance P.falciparum malaria

A/E:• At high dose it inhibits mammalian folate

synthesis• CNS stimulation causes seizures• Large dose of Pyrimethamine+ Dapsone

combination cause anaemia, agranulocytosis

Proguanil

• Same mech of action folate synthesis inhibitor• Produrg liver cycloguanil• Half life 16hrs• Alone resistance combination with Chloroquine • Effective schizontocide• Prevents maturation of fertilized gametes

ProguanilAE:1.Git:stomatitis, mouth ulcers2.CVS:depression3.Blood:leucopenia,megaloblastic anaemia.

DOSE:100 mg tab.

USE:For causal prophylaxisMALARONE-proguanil(100mg)+atovaquone(250mg),used

for multi drug resistance malaria.

Dose-4 tab od for 3 days

Primaquine• 8- Aminoquinoline derivative• Oral t½ 3-6hrs• Mech: Inhibits respiratory process of parasite

in its erythrocytic state• Use in radical cure and prevent relapse for P.

vivax & ovale• CI : In pregnancy . foetus G6PD Risk of

haemolysis• Dose:15 mg daily x 14 days for radical cure of p. vivax.

Artemesin(Qinghaosu) derivatives

• artemisinin isolated from the verb Artemisia annua (1972)

• Parasitic protophorphrin IV – catalyses breakdown of endoperoxides (-0-0-) bridges of artemesin molecules generation high free radicals.

• Killing of malaria parasite is mediated by production free radicals

• Inhibit hemoglobin digestion by malaria parasites• Artemether

• Arteether • Artesunate

• Artemisinin induce rapid killing of parasites• Fast clearance rate• Very few side effects• Artemsinin-resistant parasites have not been

identified• Should be used in combination with other

antimalarial drugsTherapeutic uses• Clinical cure of severe malaria, chloroquine

resistance malaria

• ADR:-• Very few adverse reactions• Common side effects include

– Nausea– Vomiting– Anorexia– dizziness

• Safe for pregnant women

TREATMENT• In patients who can take drugs orallyChloroquine 250mg 4 tab stat (600mg base)

300mg after 12hrs

300mg OD for 2nd and 3rd dayNote: chloroquine phosphate 250mg =150mg base

ORQuinine salts- 600mg tab TDS for 7days

In patients who cannot take drugs orallyChloroquine IM 2.5mg/kg every 4 hrlyChloroquine IV 10mg/kg over 4 hrs 5mg/kg over every 12 hrly

Chloroquine resistant malaria1.Quinine 600mg TDS for 7 days along with Pyrimethamine 75mg+sulfadoxine 1500mg

2. Quinine 600mg TDS + Teracycline 250mg qid -7 days.

3.Mefloquine 750mg stat followed by 500mg 12hr later.

4. Artesunate 100mgBD on 1stday followed by 100mg OD -5 days

5.Artesunate iv/im 120mg on 1st day followed by 60mg daily-4 days

6.Artemether (im)-80mg BD 1st day followed then OD -4 days.

7.Arteether (im)-150mg od -3 days.

Cerebral malaria• Serious disease-P.falciparum with strongly marked CNS

symptoms, impaires consciousnessTreatment-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 course.-Antipyretic for fever-IV Diazepam-If fatal hypoglycemia -5%iv dextrose cont. infusion.-correction of fluid and electrolyte balance, treatment of acidosis

Rapid iv can cause• fall in BP• Cardiac arrythmias.