Post on 07-May-2015
“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.