The document discusses antimalarial drugs and protozoal infections. It provides information on common protozoal infections including malaria, amoebiasis, and trypanosomiasis. It then focuses on malaria, describing the four Plasmodium species that infect humans and their life cycles. The document outlines the different chemical classes of antimalarial drugs and their effects on parasite viability. It provides details on specific antimalarial drugs including chloroquine, quinine, and primaquine, covering their mechanisms of action, pharmacokinetics, uses, and adverse effects.
The document discusses antimalarial drugs and protozoal infections. It provides information on common protozoal infections including malaria, amoebiasis, and trypanosomiasis. It then focuses on malaria, describing the four Plasmodium species that infect humans and their life cycles. The document outlines the different chemical classes of antimalarial drugs and their effects on parasite viability. It provides details on specific antimalarial drugs including chloroquine, quinine, and primaquine, covering their mechanisms of action, pharmacokinetics, uses, and adverse effects.
The document discusses antimalarial drugs and protozoal infections. It provides information on common protozoal infections including malaria, amoebiasis, and trypanosomiasis. It then focuses on malaria, describing the four Plasmodium species that infect humans and their life cycles. The document outlines the different chemical classes of antimalarial drugs and their effects on parasite viability. It provides details on specific antimalarial drugs including chloroquine, quinine, and primaquine, covering their mechanisms of action, pharmacokinetics, uses, and adverse effects.
DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES
Protozoal infections Protozoa Eukaryotes & unicellular organisms Most protozoal infections due to unhygienic conditions Less easily treated than bacterial infections & antiprotozoal drugs are more toxic
DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES
Protozoal infections Common protozoal infections include Malaria Amoebiasis Trypanosomiasis Giardiasis Leishmaniasis Trichomoniasis Toxoplasmosis
DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES
DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES
Effect of drug on parasite viability
Liver stages Blood stages
Hypno- Gameto- Group Drugs Sporozoite Primary Asexual zoite cyte 1 Artemisinins - - - + + Chloroquine - - - + +/- Mefloquine - - - + - Quinine / - - - + +/- Quinidine Pyrimethamine - - - + - Sulfadoxine - - - + - Tetracycline - - - + - Atovaquone / 2 - + - + +/ Proguanil 3 Primaquine - + + - + DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES Chloroquine Synthesized by Germans in 1934 ( resochin) d & l isomers, d isomer is less toxic Cl at position 7 confers maximal antimalarial efficacy Antimalarial activity: High against erythrocytic forms of vivax, ovale, malariae & sensitive strains of falciparum Gametocytes of vivax
DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES
Chloroquine Mechanism of action
DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES
Chloroquine Other parasitic infections: Giardiasis, taeniasis, extrainstestinal amoebiasis Other actions: Depressant action on myocardium, direct relaxant effect on vascular smooth muscles, anti-inflammatory, antihistaminic , local anaesthetic Resistance develops due to efflux mechanism Well absorbed, tmax 2-3 hrs , 60 % protein bound Concentrated in liver , spleen, kidney, lungs , leucocytes Selective accumulation in retina: ocular toxicity T1/2 = 3-10 days increases from few days to weeks DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES Chloroquine Pharmacokinetics Chloroquine is administered in loading dose in malaria Chloroquine is well absorbed after oral administration. It is extensively tissue bound & sequestrated by tissues particularly liver, spleen, kidney it has got large apparent volume of distribution So it is given in loading dose to rapidly achieve the effective plasma conc. 600 mg of base stat 300 mg base after 8 hours 150 mg of base BD for 2 days 200 mg oral tablet of chloroquine phosphate consists of 150 mg base DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES Chloroquine Adverse drug reactions Intolerance: Nausea, vomiting, anorexia skin rashes, angioneurotic edema, photosensitivity, pigmentation, exfoliative dermatitis's Long term therapy may cause bleaching of hair Rarely thrombocytopenia, agranulocytosis, pancytopenia
DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES
Chloroquine Adverse drug reactions Ocular toxicity: High dose prolonged therapy Temporary loss of accommodation Lenticular opacities, sub capsular cataract Retinopathy: constriction of arteries, edema, blue black pigmentation , constricted field of vision. CNS: Insomnia, transient depression seizures, rarely neuromyopathy & ototoxicity CVS: ST & T wave abnormalities, abrupt fall in BP & cardiac arrest in children reported DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES Chloroquine Therapeutic uses Hepatic Amoebiasis: Giardiasis Clonorchis sinensis Rheumatoid arthritis Discoid Lupus Erythematosus Control manifestation of lepra reaction Infectious mononucleosis
DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES
4-aminoquinolones HYDROXY CHLOROQUINE: Less toxic, properties &uses similar AMODIAQUINE: As effective as chloroquine Pharmacological actions similar May be effective in Chloroquine resistant strains Adverse events: GIT, headache , photosensitivity, rarely agranulocytosis Not recommended for prophylaxis Pyronaridine: effective in resistant cases DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES Quinine 1820 Pelletier & caventou isolated quinine from cinchona bark. Mechanism of action: Similar to chloroquine General protoplasmic poison Pharmacokinetics-Administered orally is completely absorbed Tmax = 1-3 hrs , crosses placental barrier Metabolized in liver degradation products excreted in urine t = 10 hrs
DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES
Pharmacological actions Antimalarial action: Erythrocytic forms of all malarial parasites including resistant falciparum strains . Gametocidal for vivax & malariae Local irritant effect: Local pain sterile abscess. 3. Cardiovascular: depresses myocardium, excitability, conduc vity, refractory period, profound hypotension IV. 4. Miscellaneous actions: Mild analgesic, antipyretic activity , stimulation of uterine smooth muscle, curare mimetic effect DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES Uses Malaria: uncomplicated resistant falciparum malaria Cerebral malarial Myotonia congenita: 300 to 600 mg BD/ TDS Nocturnal muscle cramps: 200 300 mg before sleeping Spermicidal in vaginal creams Varicose veins: along with urethane causes thrombosis & fibrosis of varicose vein mass DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES Adverse drug reactions Cinchonism: (resembles salicylism) Tinnitus, nausea & vomiting Headache mental confusion, vertigo, difficulty in hearing & visual disturbances Diarrhoea , flushing & marked perspiration Still higher doses , exaggerated symptoms with delirium, fever, tachypnoea, respiratory depression , cyanosis.
DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES
Adverse drug reactions Idiosyncrasy : similar to Cinchonism but occurs in therapeutic doses-pruritis, urticaria, hemolytic anemia and agranulocytosis Cardiovascular toxicity: cardiac arrest, hypotension fatal arrhythmias Hypoglycemia Black water fever-intravascular hemolysis, hemoglobinuria, fever & acute renal failure DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES Primaquine Primaquine-Converted to electrophiles Generates reactive oxygen species Liver Hypnozoites Weak action against erythrocytic stage of vivax, so used with suppressive in radical cure No action against erythrocytic stage of falciparum Has gametocidal action & is most effective antimalarial to prevent transmission disease against all 4 species DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES Pharmacokinetics Readily absorbed, t1/2 = 3-6 hrs Oxidized in liver excreted in urine Uses-Primary use is radical cure of relapsing malaria 15 mg daily for 14 days with dose of chloroquine Falciparum malaria 45 mg of single dose with chloroquine curative dose to kill gametes & cut down transmission of malaria. DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES Adverse effects Gastrointestinal: epigastric distress, abdominal cramps , Hemopoetic: mild anemia, methaemoglobinemia, cyanosis, hemolytic anemia in G6PD deficiency Avoided during pregnancy, G6PD deficient DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES Tafenoquine & Bulaquine Tafenoquine: More active slowly metabolized analog of primaquine, has advantage that it can be given on weekly basis. Tried for radical cure in 3 days Bulaquine: Congener of primaquine developed in India Comparable antirelapse activity when used for 5 days Partly metabolized to primaquine Better tolerated in G6PD deficiency
DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES
Mefloquine Quinoline methanol derivative developed to deal with chloroquine resistant malaria & MDR-Muti Drug resistant species Rapidly acting erythrocytic schizonticide, slower than chloroquine & quinine Mechanism of action similar to chloroquine Neither gametocidal, nor kills Hypnozoites
DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES
Pharmacokinetics Good but slow oral absorption High protein binding Concentrated in liver, lung, intestine Extensive metabolism in liver, primarily secreted in bile , under goes enterohepatic circulation Long t1/2 = 2 3 weeks Caution- minimum of 12hr interval after quinine administration as both are cardiotoxic
DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES
Uses Effective drug for MDR falciparum T/t of uncomplicated falciparum in MDR malaria should be used along with Artesunate (ACT) Prophylaxis in MDR areas 250 mg per week started 2-3 weeks before to assess side effects Due to fear of drug resistance mefloquine should not be used as drug for prophylaxis in residents of endemic area
DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES
Adverse events GIT: bitter in taste, nausea, vomiting, abdominal pain, diarrhoea Neuropsychiatric disturbances: anxiety, hallucinations, sleep disturbances, psychosis, errors in operating machinery, convulsions CVS: Bradycardia, sinus arrhythmia, & QT prolongation Teratogenicity: Avoided in first trimester Miscellaneous: allergic skin reactions, hepatitis & blood dyscrasias DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES Halofantrine Quinoline methanol Used in chloroquine resistant malaria since 1980 Erratic bioavailabilty, lethal cardiotoxicity & cross- resistance to mefloquine limited its use Now a days used only when no other alternative available can act against chloroquine, quinine & pyrimethamine resistant strains Adverse events; Nausea, vomiting, QT prolongation, diarrhoea, itching , rashes C/I: along with quinine, chloroquine, antidepressants, antipsychotics DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES Atovaquone Synthetic naphthoquinone Rapidly acting erythrocytic schizonticide for plasmodium falciparum & other plasmodia MOA: Collapses mitochondrial membrane & interferes ATP production Proguanil potentiates action of atovaquone and prevents development of resistance Also used in P. Jiroveci & Toxoplasma gondi infections DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES Dihydrofolate reductase inhibitors Proguanil : Biguanide converted to cycloguanil active compound Act slowly on erythrocytic stage of vivax & falciparum Prevents development of gametes Adverse effects: Stomatitis, mouth ulcers, larger doses cause depression of myocardium, megaloblastic anemia Not a drug for acute attack Causal prophylaxis: 100 200 mg daily DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES Sulfonamide + pyrimethamine Pyrimethamine is diaminopyrimidine more potent than proguanil & effective against erythrocytic forms of all species, toxoplasmosis, polycythemia vera Inhibits dihydrofolate reductase enzyme Tasteless so suitable for children Used in uncomplicated chloroquine resistant malaria Sulfadoxine(1500mg)+ Pyrimethamine(75mg)-single dose Adverse events: sulfa related megaloblastic anemia, thrombocytopenia, agranulocytosis. DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES Artemisinin Artemisinin is the active principle of the plant Artemisia annua Sesquiterpene lactone derivative Most potent & rapid acting blood schizonticides Short duration of action Poorly soluble in water & oil Artesunate Artemether Arteether Arterolane DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES Mechanism of action
These compounds have presence of endoperoxide
bridge Endoperoxide bridge interacts with heme in parasite Heme iron cleaves this endoperoxide bridge There is generation of highly reactive free radicals which damage parasite membrane by covalently binding to membrane proteins
DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES
MOA- 2) Artemisinin free radicals specifically inhibit a plasmodial sarcoplasmic-endoplasmic calcium ATPase Water soluble ester of dihydroartemisinin Dose: can be given oral, IM,IV, rectal t1/2- 1-2hrs Oral -100 mg BD on day 1, 50 mg BD day 2 to day 5 Parenteral-120 mg on day 1 (2.4 mg/kg BD ) 60 mg OD ( 2.4 mg/kg) for 7 days
DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES
Artemisinin
Conventional treatment
Artemisinin
DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES
Artemether Methyl ether of dihydroartemisinin Converted to DHA-dihydroartemisinin, not given IV, t1/2-3-10hrs Dose: Oral & IM-80 mg BD on day 1 (3.2 mg/kg) 80 mg OD (1.6 mg/kg) for 7 days ARTEETHER Ethyl ether of dihydroartemisinin Therapeutically equivalent to quinine in cerebral malaria A longer t1/2 & more lipophilic than artemether favoring accumulation in brain Given IM only T1/2-23hrs Dose:3.2 mg/kg on day1 followed by 1.6 mg/kg daily for next 4 days ARTEROLANE-available for oral use only in combination
DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES
Adverse reactions Leucopenia Hypersensitivity: Drug fever, itching GIT: nausea, vomiting, abdominal pain (common) ECG changes: ST-T changes, QT prolongation Abnormal bleeding, dark urine Reticulocytopenia D/I-concurrent administration with astemizole, antiarrhythmics, tricyclic antidepressants and phenothiazines increase the risk of cardiac conduction defects DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES Artemisinin based combination therapy (ACT) Artemisinin compounds are shorter acting drugs Monotherapy needs to be extended beyond disappearance of parasite to prevent recrudescence This can be prevented by combining 3-5 day regimen of Artemisinin compounds with one long acting drug like mefloquine 15 mg/kg single dose Indicated by WHO in acute uncomplicated resistant falciparum malaria Rapid clinical & parasitological cure High cure rates & low relapse rates DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES Choice of ACT Combinations which have been evaluated: Artemisinin + piperaquine mefloquine Artesunate + dihydroartemisinin + piperaquine mefloquine artemether + lumefantrine mefloquine naphthoquine chloroquine amodiaquine sulfadoxinepyrimaethaminine mefloquine proguanil-dapsone chlorproguanil-dapsone atovaquone-proguanil clindamycin tetracycline Doxycycline There are now more trials involving Artemisinin & its derivatives than other antimalarial drugs, so although there are still gaps in our knowledge, there is a reasonable evidence base on safety & efficacy from which to base recommendations
DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES
Prophylaxis of malaria Indication: Duration :1-2 weeks before to 4 weeks after returning from endemic area Drug regimens: Chloroquine sensitive malaria: 300 mg / week Chloroquine resistant malaria: Mefloquine 250 mg once a week , Doxycycline 100 mg daily , Atovaquone + Proguanil daily
DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES
Drugs not allowed for prophylaxis Quinine , Artemisinin compounds Pyrimethamine sulfadoxine Amodiaquine Drugs used in chloroquine resistant malaria Mefloquine Quinine Sulfadoxine pyrimethamine Artemisinin compounds
DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES
Lumefantrine+artemether Lumefantrine is highly effective, long acting oral erythrocytic schizonticide related to mefloquine MOA- similar to chloroquine -also affects nucleic acid & protein synthesis of parasite Fatty food increases absorption Highly lipophilic onset delayed , peak 6 hrs Available as fixed dose combination 80 mg artemether bd with 480 mg lumefantrine bd for 3 days DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES Tetracyclines Tetracyclines & doxycycline Slow but potent action on erythrocytic stage of all MP & Pre-erythrocytic stage of falciparum Always used in combination with quinine or S-P for treatment of chloroquine resistant malaria CLINDAMYCIN Bacteriostatic antibiotic, erythrocytic schizontocide Potentiates the action of quinine & artemisinin DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES Chloroquine sensitive malaria Tab. Chloroquine phosphate 250 mg Contains 150 mg of base Give 4 tablets stat , 2 tablets after 8 hours & , 1 tablet BD for 2 days Patients who cannot take orally 3.5 mg/kg IM every 6 hrs for 3 days Tab primaquine 15 mg OD for 14 days in Plasmodium vivax, ovale Primaquine 45 mg single dose for falciparum after chloroquine (gametocidal) DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES Chloroquine resistant malaria Pts who can take orally: 3 tablets of (Pyrimethamine + sulfadoxine) single dose followed by quinine 600 mg TDS for 2 days or Tab Quinine 600 mg TDS X 3 days with Cap doxycycline 100 mg BD for 7 days or Quinine 3 days with mefloquine or (Atovaquone 250 mg + Proguanil 100 mg) 4 tab(Single dose ) for 3 days or Artesunate 100 mg BD x 3 days with Sulfadoxine- Pyrimethamine or mefloquine
DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES
Chloroquine resistant malaria Pts who cannot take orally Inj Quinine Hcl 20 mg/kg in 500 ml dextrose saline over 4 hrs then 10 mg/kg in dextrose saline over 2 hrs every 8 hrly till patient is able to swallow Then quinine 600 mg TDS for 7 days & tetracycline/ doxycycline Or Artemether / Arteether injection Chloroquine resistant malaria DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES Complicated Falciparum malaria Artesunate 2.4 mg/kg IV/IM, BD on day1 then 2.4 mg/kg daily for 7 days OR Artemether 3.2 mg/kg IM on day 1 then 1.6 mg/kg daily for 7 days OR Arteether 3.2 mg/kg IM on day1, followed by 1.6 mg/kg daily for next 4 days Switchover to 3 Day oral ACT in between whenever patient can take oral medication
DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES
Complicated Falciparum malaria Quinine: 20 mg quinine salt/kg on admission (i.v. infusion in 5% dextrose/dextrose saline over a period of 4 hours) followed by maintenance dose of 10 mg/kg body weight 8 hourly. When ever patient can swallow orally switch over to oral quinine 10 mg/kg 8 hrly & complete 7 days course
DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES
Malaria in children Quinine parenteral high toxicity / oral well tolerated Primaquine avoided in neonates Mefloquine not used in children below 15 kg weight Acute malaria in pregnant women Chloroquine in usual doses Mefloquine C/I in first trimester Primaquine/ tetracycline avoided Anemia: folic acid & iron DEPARTMENT OF PHARMACOLOGY KEMPEGOWDA INSTITUTE OF MEDICAL SCIENCES