Antimalaria drugs

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  • I am giving the old names for these malarias in parentheses to give some historical perspective in case you see these terms again. I will also explain how these old terms relate to the pathogenesis of these respective diseases and the associated fever patterns.
  • Hemoglobinuria  digest the blood  it provide amino acid source
  • The life cycle of all species that infect humans is basically the same. There is an exogenous asexual phase in the mosquito called sporogony during which the parasite multiplies. There is also an endogenous asexual phase that takes place in the vertebrate or human host that is called schizogeny. This phase includes the parasite development that takes place in the red blood cell, called the erythrocytic cycle and the phase tthat takes place in the parencymal cells in the liver, called the exo-erythrocytic phase. The exo-erthrocytic phase is also called the tissue phase. The schizogeny that takes place here can occur without delay during the primary infection or can be delayed in the case of relapses of malaria. I will focus on the development of the parasite in the human host.
  • Infectious mononucleosis- viral disease, Discoid –skin, Systemic , Used to indicate reactions that occurs in leprosy patients
  • Hampers= adduthagulu
  • Nocturnal leg cramps - night
  • Thrombophelbitis- inflammation of vein in conjunction with thrombus
    water fever-
  • Stomatitis-
  • Parasitic protophorphrin IV – catalyses breakdown of endoperoxides (-0-0-) bridges of artemesin molecules generation high free radicals.
  • Antimalaria drugs

    1. 1. “MALARIA”
    2. 2. • 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
    3. 3. Plasmodium species which infect humans Plasmodium vivax (tertian)© Plasmodium ovale (tertian) Plasmodium falciparum (tertian) © (d) Plasmodium malariae (quartian)
    4. 4. Symptoms • • • • • • Fever Shivering Pain in joints Headache Repeated vomiting Severe  convulsions, coma
    5. 5. 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)
    6. 6. Classification of Malaria • Severe Malaria – Cerebral malaria (seizures, coma) – Severe anemia – Hemoglobinuria – Abnormalities in blood coagulation – Cardiovascular collapse and shock (“rosettes”) P.F
    7. 7. Malaria Life Cycle Liver- Tissue schizonts RBC- Blood schizoints Sporogony Oocyst Sporozoites sexual cycle in mosquito Mosquito Salivary Gland Zygote Asexual cycle in human Sporozoites Male & Female Gametocytes Schizogony Multi nucleated merozoites Pre erythrocytic (hepatic) cycle 10-14days Hypnozoites (for P. vivax and P. ovale) para/exo erythrocytic cycle Erythrocytic Cycle Motile trophozoites Mono nucleated merozoites
    8. 8. 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
    9. 9. 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)
    10. 10. Antimalarial drugs 1. 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 Atavaquone Teracycline
    11. 11. 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.
    12. 12. 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
    13. 13. Uses & Dose 1.Malaria 2.Ameobiasis - Hepatic 3.Acute manifestations of Lepra reaction. 4.Arthritis Rheumatoid 5.Infectious mononucleosis 6. Autoimmune disorder- Discoid lupus erythematous Doses-antimalarial vd-high Tab. Chloroquine 250 mg4tab stat 2tab after 6hrs 2tab daily for 2days 2 tab once a week Others Hydroxychloroquine & Amidoquine
    14. 14. Amodiquine • Spectrum and clinical use are same • A/E: Agranulocytosis • Cheap • Respond to chloroquine resistance P.falciparum
    15. 15. quinine • Obtained from cinchona bark -1820 • P.K: Orally/slow IV for severe P.falciparum malaria • Wide distribution • t½- 10-11hrs meChAnism of ACtion: • Being a protoplasmic poison to parasite • Hampers the supply of aminoacids and peptides
    16. 16. 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
    17. 17. 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
    18. 18. 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
    19. 19. Antifolates: PyriMethaMine, SulPhadoxine, SulPhoneS, Proguanil • Pyrimethamine + Sulphadoxine  Chloroquine resistant amlaria • Oral • Initial loading dose require • 87% PB • Half life 3-4days • Sulphones Dapsone
    20. 20. PABA DHF SYNTHETASE DHF DHF REDUCTASE THF
    21. 21. PyriMethaMine • Slow acting blood schizonticide • Resistance rapid so combination with sulfonamide • Sulfadoxine500mg+ Pyrimethamine25mg combination adjunct with quinine to treat chloroquinine resistance P.falciparum malaria
    22. 22. A/E: • At high dose it inhibits mammalian folate synthesis • CNS stimulation causes seizures • Large dose of Pyrimethamine+ Dapsone combination cause anaemia, agranulocytosis
    23. 23. 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
    24. 24. Proguanil AE: 1.Git:stomatitis, mouth ulcers 2.CVS:depression 3.Blood:leucopenia,megaloblastic anaemia. DOSE:100 mg tab. USE: For causal prophylaxis MALARONE-proguanil(100mg)+atovaquone(250mg),used for multi drug resistance malaria. Dose-4 tab od for 3 days
    25. 25. 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.
    26. 26. 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
    27. 27. • • • • 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 drugs Therapeutic uses • Clinical cure of severe malaria, chloroquine resistance malaria
    28. 28. • ADR:• Very few adverse reactions • Common side effects include – Nausea – Vomiting – Anorexia – dizziness • Safe for pregnant women
    29. 29. TREATMENT • In patients who can take drugs orally Chloroquine 250mg 4 tab stat (600mg base) 300mg after 12hrs 300mg OD for 2nd and 3rd day Note: chloroquine phosphate 250mg =150mg base OR Quinine salts- 600mg tab TDS for 7days
    30. 30. In patients who cannot take drugs orally Chloroquine IM 2.5mg/kg every 4 hrly Chloroquine IV 10mg/kg over 4 hrs 5mg/kg over every 12 hrly
    31. 31. Chloroquine resistant malaria 1.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.
    32. 32. Cerebral malaria • Serious disease-P.falciparum with strongly marked CNS symptoms, impaires consciousness Treatment -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.

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