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Antiprotozoal drugs

  1. Antiprotozoal drugs Dr. Karun Kumar Senior Lecturer Dept. of Pharmacology
  2. Antimalarial Drugs • Aims of using drugs 1. To prevent clinical attack of malaria (prophylactic) 2. To treat clinical attack of malaria (clinical curative) 3. To completely eradicate the parasite from the patient’s body (radical curative) 4. To cut down human-to-mosquito transmission (gametocidal)
  3. Classification
  4. • When a person is bitten by an infected mosquito, Plasmodium sporozoites enter the liver, form tissue schizonts, and undergo exoerythrocytic schizogony to produce merozoites • The merozoites released from the liver invade erythrocytes and form trophozoites that undergo erythrocytic schizogony
  5. • Some trophozoites develop into male and female gametocytes, which must subsequently pass back into a mosquito before they can develop into sporozoites and repeat the infection cycle
  6. • Erythrocytic schizontocides  Act on erythrocytic schizogony • Tissue schizontocides  Act on preerythrocytic as well as exoerythrocytic (P. vivax) stages in liver • Gametocides  Kill gametocytes in blood • Primaquine blocks exoerythrocytic schizogony (tissue schizontocide)  Causal prophylaxis • Symptoms of malaria (fever, chills & rigors) correspond to erythrocytic stage
  7. Causal prophylaxis • Pre erythrocytic phase (in liver), which is the cause of malarial infection and clinical attacks, is the target for this purpose • Primaquine ; not used in mass programmes, because of its toxic potential • Proguanil for P.f., but not used in India, because of weak activity against liver stages of P.v., and rapid development of resistance when used alone
  8. Suppressive prophylaxis • The schizontocides which suppress the erythrocytic phase and thus attacks of malarial fever can be used as prophylactics • Though the exoerythrocytic phase in case of vivax and other relapsing malarias continues, clinical disease does not appear • Mefloquine & Doxy. are used for malaria prophylaxis by travellers
  9. Clinical cure • The erythrocytic schizontocides are used to terminate an episode of malarial fever 1. High-efficacy drugs  Artemisinin, CQ, Amodiaquine, quinine, mefloquine, halofantrine, Lumefantrine and Atovaquone 2. Low-efficacy drugs  Proguanil, pyrimethamine, sulfonamides, tetracyclines and clindamycin
  10. • The faster acting drugs are preferred, particularly in falciparum malaria where delay in treatment may result in death even if the parasites are cleared from blood by the drug • The exoerythrocytic phase (hypnozoites) of vivax and ovale persists which can cause relapses subsequently without reinfection
  11. • Erythrocytic schizontocides are radical curatives for falciparum, but not for vivax or ovale malaria • However, recrudescences occur in falciparum infection if the blood is not totally cleared of the parasites by the drug
  12. Erythrocytic schizontocides (cl.cure) • Kill schizonts in the blood (T/t of acute attacks & suppressive prophylaxis)  MACHAR Pe attack • Mefloquine • Atovaquone • Chloroquine • Halofantrine (and Lumefantrine) • Artemisinins • ResQ (Quinine) • Proguanil, Pyrimethamine
  13. T/t of uncomplicated malaria A. Vivax (also ovale, malariae) malaria 1. Chloroquine 600 mg (10 mg/kg) followed by 300 mg (5 mg/kg) after 8 hours and then for next 2 days (total 25 mg/kg over 3 days) + Primaquine 15 mg (0.25 mg/kg) daily × 14 days • In CQ resist., Quinine 600 mg (10 mg/kg) 8 hourly × 7 days + Doxycycline 100 mg daily × 7 days or + Clindamycin 600 mg 12 hourly × 7 days + Primaquine (as above) or ACT + Primaquine (as above)
  14. B. Chloroquine-sensitive falciparum malaria  Chloroquine (as above) + Primaquine 45 mg (0.75 mg/kg) single dose (as gametocidal) C. Chloroquine-resistant falciparum malaria Artesunate 100 mg BD (4 mg/kg/day) × 3 days + Sulfadoxine 1500 mg (25 mg/kg) + Pyrimethamine 75 mg (1.25 mg/kg) single dose • In India (including under NVBDCP) all P.f. cases, irrespective of CQ-resistance status, are treated with artemisinin based combination therapy (ACT)
  15. Radical cure • In case of vivax and ovale malaria, drugs which attack the exoerythrocytic stage (hypnozoites) given together with a clinical curative achieve total eradication of the parasite from the patient’s body • A radical curative is needed in relapsing malaria, while in falciparum malaria — adequate treatment of clinical attack leaves no parasite in the body • DOC for radical cure of vivax and ovale malaria is Primaquine 15 mg daily for 14 days
  16. Gametocidal • Elimination of the male and female gametes of Plasmodia formed in the patient’s blood • Gametocidal action is of no benefit to the patient being treated, but will reduce the transmission to mosquito • Primaquine is gametocidal to all species of Plasmodia, while artemisinins have weak lethal action on early-stage but not mature gametes
  17. Stage Clinical use Pre-erythrocytic Causal prophylaxis Erythrocytic Cl. Cure & supp. prophyl. Exo-erythrocytic Radical cure Gametocidal Prev. of trans.
  18. Chloroquine • Rapidly acting erythrocytic schizontocide against all species of plasmodia; controls most clinical attacks in 1–2 days with disappearance of parasites from peripheral blood in 1–3 days • Actively concentrated by sensitive intraerythrocytic plasmodia; higher concentration is found in infected RBCs than in noninfected ones • DOC for T/t & prophyl. of non-falciparum malaria & CQ sensitive P. falciparum malaria
  19. Mechanism of action • By accumulating in the acidic vacuoles of the parasite and because of its weakly basic nature, it ↑ vacuolar pH and thereby interferes with degradation of haemoglobin by parasitic lysosomes • Polymerization of toxic haeme generated from digestion of haemoglobin to nontoxic parasite pigment haemozoin is inhibited by the formation of CQ-haeme complex
  20. • Haeme itself or its complex with CQ then damages the plasmodial membranes • Clumping of pigment and changes in parasite membranes follow • Other related antimalarials like quinine, mefloquine, lumefantrine, pyronaridine appear to act in an analogous manner
  21. Other uses (RED LIP Mahatma Gandhi) 1. Rheumatoid arthritis 2. Extraintestinal amoebiasis 3. Discoid lupus erythematosus 4. Lepra reaction 5. Infectious mononucleosis 6. Photogenic reactions 7. Malaria (DOC in pregnant women) 8. Giardiasis
  22. Adverse effects • Nausea, vomiting, anorexia, uncontrollable itching, epigastric pain, uneasiness, difficulty in accommodation and headache are frequent and quite unpleasant • Prolonged use of high doses can result in blindness due to retinal damage
  23. Mefloquine • Fast acting erythrocytic schizontocide, but slower than CQ or quinine due to prolonged absorption after oral ingestion. • Effective against CQ-sensitive as well as resistant plasmodia • A single dose controls fever and eliminates circulating parasites in infections caused by P. falciparum or P. vivax
  24. • However, relapses occur frequently subsequently in vivax malaria • Also an efficacious suppressive prophylactic for multiresistant P. falciparum and other types of malaria • Bitter in taste • S/E  Dizziness, nausea, vomiting, diarrhoea, abdominal pain, sinus bradycardia and Q-T prolongation
  25. Use • MDR P. falciparum • Due to potential toxicity, cost and long t½, use is restricted • In combination with artesunate as ACT for uncomplicated falciparum malaria, including CQ- resistant and CQ + sulfa-pyrimethamine (S/P) resistant cases • For prophylaxis of malaria among travellers to areas with multidrug resistance
  26. Sulfonamide-Pyrimethamine (S/P) • Pyrimethamine has high affinity for the plasmodial DHFRase enzyme • Sulfadoxine and sulfamethopyrazine are ultralong acting sulfonamides — attain low blood concentrations, but are able to synergise with pyrimethamine which also has long t½
  27. • Combination has the potential to cause serious adverse effects (exfoliative dermatitis, Stevens Johnson syndrome, etc.) due to the sulfonamide • Use is restricted to single dose t/t of uncomplicated CQ-resistant falciparum malaria • 1st line ACT regimen used under NVBDCP in India
  28. Primaquine • Has a marked effect on primary as well as secondary hepatic phases of the malarial parasite • Highly active against gametocytes and hypnozoites • A/E  Abd. pain, g.i. upset, weakness or uneasiness in chest (S/E); can be minimized by taking the drug with meals. CNS and CV symptoms are infrequent. • Leucopenia occurs rarely with larger doses. • Most imp. toxic potential is dose related haemolysis, methaemoglobinaemia, tachypnoea and cyanosis
  29. Use 1. Vivax malaria  Radical cure of relapsing (vivax) malaria. G-6-PD status of the patient should be tested before giving 14 day primaquine course. It is to be taken with food to reduce g.i. side effects. 2. Falciparum malaria  Single 45 mg dose is given with the curative dose of CQ or ACT to kill the gametes and cut down transmission to mosquito
  30. Artemisinin derivatives • Fastest acting drugs against malaria • Used for t/t of MDR malaria & cerebral malaria • Short acting drugs, monotherapy needs to be extended beyond the disappearance of the parasites to prevent recrudescence • Recrudescence can be totally prevented by combining 3 day artemisinin with a long acting drug
  31. • A/E  N, V, abd. pain, itching and drug fever. Headache, tinnitus, dizziness, bleeding, dark urine, S- T segment changes, Q-T prolongation subside when the patient improves or drug is stopped • Use  Uncomplicated falciparum malaria (CQ- resistant as well as sensitive). DCGI has prohibited use of oral artemisinins as single drugs. FDCs are encouraged • Severe and complicated falciparum malaria  Artesunate (i.v. or i.m.) OR Artemether (i.m.) OR Arteether (i.m.) given till the patient is fit to take oral medication, followed by 3 day oral ACT
  32. ACT regimens for uncomplicated falciparum malaria 1. Artesunate-mefloquine (AS/MQ)  Artesunate 100 mg BD (4 mg/kg/day) × 3 days + mefloquine 750 mg (15 mg/kg) on 2nd day and 500 mg (10 mg/kg) on 3rd day (total 25 mg/kg) 2. Artesunate-sulfadoxine + pyrimethamine (AS/S/P)  Artesunate 100 mg BD (4 mg/kg/day) × 3 days + sulfadoxine 1500 mg (25 mg/kg) and Pyrimethamine 75 mg (1.25 mg/kg) single dose
  33. Summary
  34. Antiamoebic drugs • Drugs useful in infection caused by the anaerobic protozoa Entamoeba histolytica • Diloxanide furoate  DOC for asympt. Intest. Amebiasis & carriers • Metronidazole  DOC for amoebic liver abscess & intestinal wall disease
  35. Classification

Notas del editor

  1. The malaria parasite life cycle involves two hosts. During a blood meal, a malaria-infected female Anopheles mosquito inoculates sporozoites into the human host . Sporozoites infect liver cells and mature into schizonts , which rupture and release merozoites
  2. All doses expressed in terms of base, e.g. chloroquine phosphate 250 mg = 150 mg base. It is sold under the brand name Aralen, and it is also sold as a generic medicine. It is available in tablets of two sizes: 150mg base (250mg salt) and 300mg base (500mg salt). 150mg base tablet is the same as the 250mg salt tablet and the 300mg base tablet is the same as the 500mg salt tablet. It is just two different ways of describing the same thing.
  3. recurrence of an undesirable condition; same as relapse
  4. Hypnozoites are dormant forms in the life cycles ;relapse in human malarial infections caused by Plasmodium ovale and P. vivax
  5. Haemozoin is a disposal product formed from the digestion of blood by some blood-feeding parasites.
  6. produced or precipitated by light photogenic dermatitis
  7. Exfoliative dermatitis is widespread erythema and scaling of the skin caused by preexisting skin disorders, drugs, cancer, or unknown causes
  8. Methemoglobin (British: methaemoglobin) (pronounced "met-hemoglobin") is a hemoglobin in the form of metalloprotein, in which the iron in the heme group is in the Fe3+ (ferric) state, not the Fe2+ (ferrous) of normal hemoglobin. Methemoglobin cannot bind oxygen, which means it cannot carry oxygen to tissues.