Dept. Pharmacology & Therapeutic School of MedicineUniversitas Sumatera Utara

Mechanisms for treatment-IAttack a unique enzyme found in parasiteFolate synthesis blocked by sulfonamide (Folate- dihydrofolate reductase - FH2 dihydrofolate reductase FH4 Deoxythymidylic acid Methionine.Allopurinol riboside is phosohorylated and is added to 5-O position in purines and is non functional, all protozoa especially Leishmainaia.

Mechanism IIDrug affect enzyme system found in both host / parasite but is indispensable for parasite.Trypansomebrucic lack krebs cycleSalicyl hyroxamic acid (SHAM) forces parasite into anaerobic condition, glycolysis is blocked by glycerol causing rapid lysis.

Mechanism IIICommon biochemical functions found in host / parasite but have different pharmacological propertiesIvermectin affects synaptic transmission by increasing inhibitory transmitter (GABA) increase inhibition causes flaccid paralysis. does not cross mammalian blood / brain barrier. Drug can act as a GABA agonist causing increased muscular contaction e.g Levamisol

Antiprotozoal drugsChemotherapy of Amebiasis Chloroquine, Dehydroemetine, Diloxanide furoate, Emetine, Metronidazole, Paramomycin.. Chemotherapy of Malaria Chloroquine, Mefloquine, Primaquine, Pyrimethamine, quinine/ quinidine. . Chemotherapy of Tyrpanosomiasis Melarsoprol, Nifurtimox, Pentamidine, Suramin.

Antiprotozoal drugs (contd)Chemotherapy of LeishmaniasisSodium stibogluconateChemotherapy of ToxoplasmosisPyrimethamine.Chemotherapy of GiardiasisQuinacrine

Drugs used in leishmaniasis and trypanosomiasisLeishmaniasis may occur as a skin infection or as an infection of the viscera. Metronidazole is used for the former, and sodium stibogluconate given parenterally for the latter.Trypanosome species cause sleeping sickness in Africa and chagas diseasein south america .Drugs used are suramin given i.v and pentamidine i.m.

Anthelminthic DrugsAn anthelminthic drug may act by causing narcosis or paralysis of the worm, or by damaging the cuticle,leading to partial digestion or to rejection by immune mechanisms. Anthelminthic drugs may also interfere with the metabolism of the worm, and since the metabolic requirements of these parasites vary greatly from one species to another , this may be the reason why drugs that are highly effective against one type of worm are ineffective against others.

Nematoda (roundworms)1st choice2nd choiceAscaris lumbricoides(roundworm)Albendazole/Pyrantel pamoate/MebendazolePiperazineTrichuris trichiura(whipworm)Mebendazole/AlbendazoleOxantel/Pyrantel pamoateNecator americanus(hookworm);Ancylostoma duodenale(hookworm)Pyrantel pamoate/Mebendazole/AlbendazoleStrongyloides stercoralis(threadworm)IvermectinThiabendazole,AlbendazoleEnterobius vermicularis(pinworm)Mebendazole/Pyrantel pamoateAlbendazoleTrichinella spiralis(trichinosis)Mebendazole(+kortikosteroid untuk infeksi berat) Albendazole(+kortikosteroid untuk infeksi berat)Trichostrongylus speciesPyrantel pamoate/MebendazoleAlbendazole

1st choice2nd choiceCutaneous larva migrans (creeping eruption)Albendazole/ IvermectinThiabendazole (topikal)Visceral larva migransAlbendazoleMebendazoleAngiostrongylus cantonensisThiabendazoleAlbendazole/MebendazoleWuchereria bancrofti (filariasis);Brugia malayi (filariasis); tropical eosinophilia;Loa loa (loiasis)DiethylcarbamazineIvermectinOnchocerca volvulus (onchocerciasis)IvermectinSuraminDracunculus medinensis (guinea worm)MetronidazoleThiabendazole/MebendazoleCapillaria philippinensis (intestinal capillariasis)AlbendazoleMebendazole/Thiabendazole

Trematoda (flukes)1st choice2nd choiceSchistosoma haematobium(bilharziasis)PraziquantelMetrifonateSchistosoma mansoniPraziquantelOxamniquineSchistosoma japonicumPraziquantelClonorchis sinensis (liver fluke);opisthorchis speciesPraziquantelAlbendazoleParagonimus westermani (lung fluke)PraziquantelBithionolFasciola hepatica (sheep liver fluke)Bithionol/ TriclabendazoleFasciolopsis buski (large intestinal fluke)Praziquantel/ NiclosamideHeterophyes heterophyesMetagonimus yokogawai (small intestinal flukes)Praziquantel/ Niclosamide

Cestoda (cacing pita)1st choice2nd choiceTaenia saginata (beef tapeworm)Praziquantel/ NiclosamideMebendazoleTaenia solium (pork tapeworm)Praziquantel/ NiclosamideDiphyllobothrium latum (fish tapeworm)Praziquantel/ NiclosamideCysticercosis (pork tapeworm larval stage)AlbendazolePraziquantelHymenolepis nana (dwarf tapeworm)PraziquantelNiclosamideEchinococcus granulosus (hydatid disease); Echinococcus multilocularisAlbendazole

Mekanisme kerja anthelmentic

ObatMekanisme KerjaEfek SpesifikPiperazineMemparalisisotot cacingMemblokir myoneural junction;agonis gated chloride channels hiperpolarisasi paralisis flasidIvermectinMemparalisisotot cacingMemblokir transmisi sinyal-sinyal sarafdengan berinteraksi dengan glutamategated chloride channelsPyrantelMemparalisisotot cacingAgonis reseptor asetilkolin nikotinik &menghambat kolinesterase depolarisasi & paralisis spastik Metrifonate(Trichlorfon)Memparalisisotot cacingMenginaktivasi asetilkolinesterase &mempotensiasi efek-efek kolinergikinhibitori PraziquantelMemparalisisotot cacingMeningkatkan permeabilitas membranterhadap Ca2+ memaparkan protein-protein membran diserang antibodiBithionolMenghambatproduksi energiMenghambat fosforilasi oksidatif

Mekanisme kerja anthelmentic

ObatMekanisme KerjaEfek SpesifikNiclosamideMenghambatproduksi energi Menghambat fosforilasi oksidatifanaerobik dalam mitokondria cacing sintesa ATPMebendazoleMenghambat produksi energi Berikatan dengan tubulin & menghambat polimerisasiThiabendazoleMenghambat produksi energi & fungsi proteinMenghambat fumarat reduktase & sintesa ATP; berikatan dengan tubulin SuraminMenghambat produksi energi Menghambat enzim-enzim otot yang berkait dengan glikolisis & konsumsi oksigenOxamniquineMengesterifikasi & mengikat DNAMenghambat sintesa asam nukleat & proteinDiethyl-carbamazineMempermudah fagositosis & eliminasiMeningkatkan kesensitifan mikrofilaria, memerangkap mikrofilaria dalam sistem retikuloendotelial

Farmakoterapi

Obat-obat pilihan adalah benzidimazole (BZA): albendazole (dosis tunggal 400 mg, 200 mg: anak-anak 12-24 bulan) / mebendazole (100 mg 2x/hari untuk 3 hari (dewasa & anak >2 tahun) / levamisole (dosis tunggal 2,5 mg/kg) / pyrantel pamoate (dosis tunggal 11 mg/kg, tetapi 1 g)

(WHO 2002) Migrasi larva A. lumbricoides bisa menyebabkan pneumonia hemoragik.

Drugs used in amoebiasisAmoebiases is due to infection with Entamoeba histolytica, which causes dysentery associated with invasion of the intestinal wall and, rarely, of the liver. The organism may be present in motile, invasive form, or as a cyst.Metronidazole: given orally,is active against the invasive form in gut and liver but not the cyst.Unwanted effects, which are rare, include GI upsets and CNS symptoms.Diloxanide: given orally with no serious unwanted effects, active while unabsorbed against the non invasive form.Chloroquine: used for hepatic amoebiasis.

Classification of anti-amoebaTissue Amoebiasis*Both intestinal & extra intestinalNitroimidazoles Metronidazole, Tinidazole, Secnidazole, OrnidazoleAlkaloids Emetine, Hydroemetine* Extra intestinal amoebiasis onlyChloroquineLuminal amoebiasisAmide (Diloxanide furoate)8-Hydroxy quinolones (Quinidochlor)Antibiotics (Tetracycline)

Anti-Amoeba

Anti-amoebaIndication MoAADRChloroquineAmebic liver abscessMetronidazoleIntestinal & extra-intestnalDisruption of DNA synthesis & nucleic acid synthesisMetallic taste, nausea, vomiting, diarrhea, abdominal crampsIodoquinolIntestinalDirectly kills the protozoaN/V, diarrhea, anorexia, agranulocytosisParamomycinIntestinal Inhibiting protein synthesisN/V, diarrhea, stomach cramps, ototoxic, tinnitus

5-nitroimidazolesMetronidazole, tinidazole, ornidazole, nimorazole.Active on anaerobic bacteria and protozoa.Entamoeba (not invariably the cysts) , Trichomonas, Giardia, Blastocystis, ...Disulfiram-like effects, mutagenic in bacteria.Pearson R.D. 2005. Chapter 41, In Mandell G.L. et al.

Metronidazole Prototype drug introduced in 1959 Bactericidal againstGiardia lamblia, anaerobic bacteria,Bacteroides fragilis, Fusobacterium,Clostridium perfringes, Helicobacterpylori, Anaerobic Streptococci

Metronidazole (MoA) Not clearly understood Enters micro-organism by diffusionNitro group reduced DNA damaged CytotoxicityHigh selective anaerobic action interference with electron transportation from NADPH or other reduced substrates Also inhibits cell mediated immunity Induce mutagenesis Cause radio-sensitization

MetronidazoleA nitroimidazole. The nitro group of metronidazole is chemically reduced in anaerobic bacteria and sensitive protozoans. Reactive reduction products appear to be responsible for antimicrobial activity.PharmacokineticsOral metronidazole is readily absorbed and permeates all tissues by simple diffusion.Protein binding is low (

Metronidazole Mechanism of ActionMechanism of actionDisruption of DNA synthesis as well as nucleic acid synthesisBactericidal, amebicidal, trichomonacidalUsed for treatment of trichomoniasis, amebiasis, giardiasis,and antibiotic-associated pseudomembranous colitisAlso has anthelmintic activity

Adverse Effects:Metallic taste, nausea, vomiting, diarrhea, abdominal cramps, many others

MetronidazoleContraindicationsNeurological diseases, blood dyscrasias,First trimester, Chronic alcoholism Drug InteractionsDisulfiram reactionEnzyme inducers - Rifampicin -therapeutic effectCimetidine - metronidazole metabolism - reduce doseMetronidazole renal elimination of Lithium

Emetine Alkaloid from Cephaelis ipecacuanha Potent directly acting amoebicide (trophozoites) Does not kill cysts Cumulative toxicity high Seldom used- Because of major toxicity concerns they have been almost completely replaced by metronidazole.Reserve drug not responding/intolerant to metronidazole Luminal amoebicide follows emetine to eradicate cysts Administered subcutaneously (preferred) or i.m. (but never i.v.) because oral preparations are absorbed erraticallyDihydroemetine =effective but less toxic Preferred over emetine

DiloxanideDiloxanide furoate is a dichoroacetamide derivative.Effective luminal amebicide but is not active against tissue trophozoites.The unabsorbed diloxanide in the gut is the active antiamebic substance.Effective for asymptomatic luminal infections.It is used with a tissue amebicide, usually metronidazole.Adverse Effects: flatulence, nausea, abdominal cramps, rashes, abortion.

Notice !Treatment with tissue amoebicide SHOULD always be followed by Luminal amoebicide to eradicate source of infection

Anti-trichomoniasis DrugsMetronidazoleAcetarsol

Approaches to antimalarial therapyDrugs used to treat the acute attack of malaria (clinical cure) act on the parasites in the blood; they can cure infections with parasites which have no exo-erythrocytic stage.e.g quinine, chloroquineDrugs used for chemoprophylaxis, i.e to prevent malarial attacks when in a malarious area, act on merozoites emerging from liver cells. e.g quinine, chloroquineDrugs used for radical cure are active against parasites in the liver e.g primaquine.Drugs act on gametocytes and prevent transmission by the mosquito e.g primaquine.

Anti malarial drugsChloroquine: Drug of choice for both chemoprophylaxis and treating the acute attack . It is given orally; it is concentrated in the parasite. Unwanted effects include GI tract upsets, dizziness, urticaria; given i.v. it can cause dysrhythmias.Quinine: Drugsfor treating the acute attack are quinine, given orally; it can be given i/v in emergency. Unwanted effects include GI tract upsets, tinnitus, blurred vision and with large doses,dysrhythmias and CNS disturbances.

Anti malarial drugsPrimaquine: It is effective against the liver hypnozoites, and is also active against gametocytes. Given orally . Unwanted effects are mainly GI tract upsets and, with large doses, methaemoglobinaemia. Haemolysis is produced in individuals with genetic deficiency of erythrocyte glucose 6 phosphate dehydrogenase.

Classification of anti-malariaClassified by their selective actions on different phases of the parasite life cycle:Tissue schizonticides: eliminate developing or dormant liver forms.Blood schizonticides: act on erythrocytic parasites.Gametocides: kill sexual stages and prevent transmission to mosquitoes.No one available agent can reliably effect a radical cures.

ChloroquineA synthetic 4-aminoquinoline formulated as the phosphate salt for oral use.PharmacokineticsRapidly and almost completely absorbed from the gastrointestinal tract.Very large apparent volume of distribution of 100-1000 L/kg.Necessitate the use of a loading dose to rapidly achieve effective serum concentrations.Slowly released from tissues and metabolized.Principally excreted in the urine.Control symptoms

Pharmacological EffectsAntimalarial action: highly effective blood schizonticide. Moderately effective against gametocytes of P vivax, P ovale, and P malariae but not against those of P falciparum not active against liver stage parasites.Mechanism: plasmodium aggregates chloroquine. chloroquine incorporated into DNA chain of plasmodium inhibit proliferation. chloroquine prevents the polymerization of the hemoglobin breakdown product, heme, into hemozoin and thus eliciting parasite toxicity due to the buildup of free heme. pH plasmodium protease activityResistance: very common among strains of P falciparum and uncommon but increasing for P vivax. The mechanism of resisitance to chloroquine is resistant strains excretes drug more rapidly. Killing Amibic trophozoites : chloroquine reaches high liver concentrations.Immunosuppression action:Schizonticide gametocyteNot active against liver stage

Adverse Effects and CautionsUsually very well tolerated, even with prolonged use.Pruritus is common.Nausea, vomiting, abdominal pain, headache, anorexia, malaise, blurring of vision, and urticaria are uncommon.Dosing after meals may reduce some adverse effects.Rare reactions include hemolysis in G6PD-deficient persons, impaired hearing, confusion, psychosis, seizures, hypotension, ECG changes.teratogenesis

QuinineQuinine and quinidine remain first-line therapies for falciparum malariaespecially severe disease.Quinine is an alkaloid derived from the bark of the cinchona tree, a traditional remedy for intermittent fevers from South America.Quinine is the levorotatory stereoisomer of quinidine.Rapidly absorbed after oral administration.Metabolized in the liver and excreted in the urine.Control symptoms

Pharmacological EffectsHighly effective blood schizonticide against the four species of human malaria paresites.Gametocidal against P vivax and P ovale but not P falciparum.Not active against liver stage parasites.Depressing cardiac contractility and conduction, lengthening refractory period, exciting uterine smooth muscle, depressing central nervous system, little antipyretic-analgesic effect.

Clinical Uses: mainly for chloroquine-resistant falciparum malaria, especially for cerebral malaria.Parenteral treatment of severe falciparum malariaOral treatment of falciparum malariaMalarial chemoprophylaxisBabesiosisQuinine

Adverse Effects and CautionsCinchonism: tinnitus, headache, nausea, dizziness, flushing, visual disturbancesCardiovascular effects: severe hypotension and arrhythmia can follow too-rapid intravenous infusion.Idiosyncrasy: hemolysis with G6PD deficiency.Others: hypoglycemia through stimulation of insulin release, stimulate uterine contractions

Mefloquine A synthetic 4-quinoline methanol that is chemically related to quinine.PharmacokineticsOnly be given orally because severe local irritation occurs with parenteral use.Well absorbed.Highly protein-bound, extensively distributed in tissues, and eliminated slowly. t1/2 is 20 days.Pharmacological Effects: Strong blood schizonticidal activity against P falciparum and P vivax, but not active against hepatic stages or gametocytes.Control symptoms

Clinical UsesChemoprophylaxis: Treatment: mainly for chloroquine-resistant falciparum malaria.Adverse Effects and CautionsNausea, vomiting, diarrhea, abdominal paindose-dependentNeuropsychiatric toxicities: dizziness, headache, behavioral disturbances, psychosis, seizures.

Artemisinin Extracted from yellow flower mugwort.Kill trophozoites of erythrocytes.quick and effective. maybe kill earlier period trophozoites.Through blood-brain barrie, treatment for cerebral malaria.recurrence rate is high.Resistence.Interaction with others antimalarial drugs:Control symptoms

Artemether and ArtesunateDihydroartemisininControl symptoms

Primaquine Synthetic 8-aminoquinoline.Pharmacological EffectsAgainst hepatic stages of malaria parasites. The only available agent active against the dormant hypnozoite stages of P vivax and P ovale. Also gametocidal against the four human malaria species.Control relapse and transmission

Clinical UsesTherapy (Radical Cure) of Acute Vivax and Ovale Malaria: chloroquine + primaquineTerminal Prophylaxis of Vivax and Ovale Malaria: prevent a relapseChemoprophylaxis of Malaria: protection against falciparum and vivax malaria. But potential toxicities of long-term use limited its routinely administration.Gametocidal Action: A single dose of primaquine (45 mg base) can be used as a control measure to render P falciparum gametocytes noninfective to mosquitoes. This therapy is of no clinical benefit to the patient but will disrupt transmissionPneumocystis carinii infection: clindamycin+primaquine mild to moderate pneumocystosis

Adverse Effects and CautionsNausea, epigastric pain, abdominal cramps, headache.Hemolysis or methemoglobinemia, especially in persons with G6PD deficiency or other hereditary metabolic defects.Primaquine

Pyrimethamine PharmacokineticsSlowly but adequately absorbed from the gastrointestinal tract.Slowly eliminated and excreted from urine.Pharmacological EffectsKill schizonts of primary exoerythrocytic stage.Act slowly against premature schizonts of erythrocytic stage.No action against gametocytes, but can inhibit development of plasmodium in mosquito.Inhibit plasmodial dihydrofolate reductase inhibiting breeding of plasmodium.Etiological factor prophylaxis

Adverse Effects and CautionsGastrointestinal symptoms, skin rashes.Interfering folic acid metabolism in human megalocyte anemia, granulocytopenia.Acute intoxicationTeratogenesis Pyrimethamine

Sulfonamides and Sulfone Competing dihydropteroatesye synthase with PABA inhibiting to form dihydrofolic acid inhibiting production of purines and synthesis of nucleic acids.Only inhibiting plasmodial of exoerythrocytic stageNot used as single agents for the treatment. Combination with other agents.Etiological factor prophylaxis

Rational Use of Antimalarial DrugsChoice of Antimalarial Drugs:Control symptoms: chloroquineCerebral malaria: chloroquine phosphate, quinine bimuriate, artemisinin injectionChloroquine-resistant falciparum malaria: quinine, mefloquine, artemisininDormant hypnozoite stages : pyrimethamine + primaquineProphylaxis: pyrimethamine, chloroquineCombination therapy: chloroquine + primaquine: symptom stagespyrimethamine + primaquine: dormant hypnozoite stages Combination of drugs with different mechanisms: therapeutic effect, resistance

Antimalarial DrugsAttack the parasite during the asexual phase, when it is vulnerableErythrocytic phase drugs: chloroquine, hydroxychloroquine, quinine, mefloquinePrimaquine: kills parasite in both phases

May be used together for synergistic or additive killing power

Antimalarials: Mechanism of Action4-Aminoquinoline derivatives: chloroquine and hydroxychloroquine

Bind to parasite nucleoproteins and interfere with protein synthesis; also alter pH within the parasite

Interfere with parasites ability to metabolize and use erythrocyte hemoglobin

Effective only during the erythrocytic phase

Antimalarials: Mechanism of Action 4-Aminoquinoline derivatives: quinine and Mefloquine (Lariam)

Alter pH within the parasite

Interfere with parasites ability to metabolize and use erythrocyte hemoglobin

Effective only during the erythrocytic phase

Antimalarials: Mechanism of Action Diaminopyrimidines (pyrimethamine & trimethoprim)

Inhibit protein synthesis essential for growth and survival

Only effective during the erythrocytic phase

These drugs may be used with sulfadoxine or dapsone or synergistic effects

Antimalarials: Mechanism of Action PrimaquineOnly exoerythrocytic drug (works in both phases)Binds and alters parasitic DNA

Sulfonamides, tetracyclines, clindamycin

Used in combination with antimalarials to increase protozoacidal effects

Antimalarials Drug EffectsKill parasitic organismsChloroquine and hydroxychloroquine also have antiinflammatory effects

IndicationsKills Plasmodium organisms, the parasites that cause malariaThe drugs have varying effectiveness on the different malaria organismsSome drugs are used for prophylaxis against malaria2 weeks prior and 8 weeks after returnChloroquine is also used for rheumatoid arthritis and systemic lupus erythematosus

AntimalarialsAdverse EffectsMany adverse effects for the various drugs

Primarily gastrointestinal: nausea, vomiting, diarrhea, anorexia, and abdominal pain

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MebendazoleA synthetic benzimidazole that has a wide spectrum of anthelmintic activity and a low incidence of adverse effects.PharmacokineticsOral absorption 10, Absorption increases with fatty mealFirst pass elimination is high.Protein-binding 90Excreted mostly in the urine, a portion of absored drug and its derivatives are excreted in the bile. It is converted to inactive metabolites rapidly in liver.It has half life of 2-6 hours

Pharmacologic Effects Inhibits microtubule synthesis in nematodes, thus irreversibly impairing glucose uptake. Intestinal parasites are immobilized or die slowly.Kills hookworm, ascaris, and trichuris eggs.Clinical UsesPinworm infectionAscaris lumbricoides, Trichuris trichiura, Hookworm, and TrichostrongylusOther infections: intestinal capillariasis, trichinosis, taeniasis, strongyloidiasis, dracontiasis, et al.

Adverse Effects and CautionsLow-dose: nearly free adverse effects.Diarrhea, abdominal pain is infrequent.High-dose: pruritus, rash, eosinophilia, reversible neutropenia, musculoskeletal pain, fever, transient liver function abnormalities, alopecia, glomerulonephritis, agranulocytosisused with caution under 2ys of age may cause convulsion in this group.enzyme inducers and inhibitors affect plasma level of the drug.hepatic parenchymal disease

AlbendazoleA benzimidazole carbamateA broad-spectrum oral anthelmintic for treatment of hydatid disease and cysticercosis, pinworm infection, ascariasis, trichuriasis, strongyloidiasis, and infections with both hookworm species.Effect better than Mebendazole.

*Albendazole con;dMechanism of action: It inhibits microtubule synthesis in nematodes(intestinal round worms) that irreversibly impairs glucose uptake, intestinal parasites are immobilized and die slowly.

It is larvicidal in hydatid, cysticercosis, ascariasis and hook worm infection.

Also ovicidal in ascariasis, ancyclostomiasis (hookworm), tricurasis

*Pharmacokinetics (Albendazole) it is adminstered orally , and absorbed erratically (unpredictable) , absorption can be increased with fatty meal It is metabolized in the liver rapidly to active metabolite albendazole sulphoxideIt has a plasma half life of 8-12 hours Sulphoxide is mostly protein bound , distributes well to tissues and enters bile, CSF, hydated cyst Metabolites are excreted in urine

Clinical UsesAdministered on an empty stomach when used against intraluminal parasites but with a fatty meal when used against tissue parasites.Ascariasis, Trichuriasis, and Hookworm and Pinworm infections.StrongyloidiasisHydatid DiseaseNeurocysticercosisOther infections: cutaneous larva migrans, gnathostomiasis

*Albendazole condAdverse effects: In short term: use no significant adverse effects. In long term use : as used in hydatid cyst and cysticercosis, abdominal distress, headache ,fever , fatigue, alopecia , increased liver enzymes , pancytopenia. Blood counts and LFT should be followed.Not given during pregnancy and in hypersensitive people.

PiperazineOnly recommended for the treatment of ascariasis.No longer recommended for treatment of pinworm infection, because a 7-day course of treatment is required.Not useful in hookworm infection, trichuriasis, or strongyloidiasis.Causes flaccid paralysis of ascaris by blocking acetylcholine at the myoneural junction.Neurotoxic adverse effects.

*Piperazine cond pharmacokinetics :it is readily absorbed orally and excreted unchanged in urine.75 mg /kg/day for 2 days once dailytreatment is continued for 3-4 days or repeated after one week in case of heavy infections.Adverse effects:GI disturbance, Neurotoxicity ,allergic reactions serum sickness like syndromeContraindications Epilepsy, Impaired liver or kidney functions, pregnancy, Malnutrition

LevamizoleA synthetic imidazothiazole derivative and the L isomer of D,L-tetramisole.Highly effective in eradicating ascaris and trichostrongylus and moderately effective against both species of hookworm.Inhibiting succinic dehydrogenase energy flaccid paralysisImmunomodulating effect.

*PYRANTEL PAMOATEA tetrahydropyrimidine derivative.A broad-spectrum anthelmintic, but it is not effective against tricuriasis (whip worms), and trichostrongylus orientalis infections. Oxantel pamoate is more effectivePharmacokinetics:It is poorly absorbed orally , Half of the drug is excreted unchanged in the feces.Mechanism of action:It is a depolrazing neuromuscular blocking agent that causes release of acetylcholine and inhibition of cholinestrase leads to spastic paralysis of worms.

*Pyrental pamoate cond Adverse Effects . Infrequent mild transient GI disturbance drowsiness , headache ,insomnia. Rash ,feverContraindciations Should not be used in liver diseases. Pregnancy and child under 2 years of age

Pyrvinium EmbonateA dye.Not absorb orally.treatment of pinwormSelectively interfering energy metabolism enzymatic systemInhibiting glucose-transporting enzymatic systemRed feces

Niclosamide A salicylamide derivativeTreatment of most tapeworm infection.Pharmacologic Effects Scoleces and segments of cestodes but not ova are rapidly killed on contact with nicolsamide due to the drugs inhibition of oxidative phosphorylation or to its ATPase-stimulating property.With the death of the parasite, digestion of scoleces and segments begins.

Clinical UsesGiven in the morning on an empty stomach.The tablets must be chewed thoroughly and are then swallowed with water.Niclosamide can be used as an alternative drug for the treatment of intestinal fluke infections.Adverse Effects and CautionsInfrequent, mild and transitory.Nausea, vomiting, diarrhea, and abdominal discomfort.

PraziquantelEffective in the treatment of schistosome infections of all species and most other trematode and cestode infections, including cysticercosis.A first choice in the treatment cestodiasis.

BenzimidazolesAlbendazole, mebendazole, thiabendazole Inhibit glucose absorption Poorly absorbed (PO).Active against nematodes (drugs of choice).

Leder K. & Weller P. 2003. In ASM Manual of CM.

Write the pharmacological action and side effects of the following drugsChloroquineMetronidazoleMelarsoprolPrimaquineMebendazolePraziquantelNiclosamidePyrantel pamoateThiabendazole

Books & sitesBasic and clinical Pharmacology by B.G. KatzungPharmacological basis of therapeutics by Goodman and gillman Pharmacology by Rang and Dalewww.pharmacology2000.comwww. medicalstudents.com

Tubulins polymerize to form microtubules. Microtubules are a dynamic portion of the cytoskeleton, involved in molecular motors for transport vesicles, organelles (eg secretory granules), and mitochondria from one pt of the cell to another.Fumarate reductase= fumarase (in Krebs cycle)Cholinergic= parasympathetic

**There is evidence that when ivermectin resistance occurs in nematodes, there may be selection on some, but not all of the genes that code for ligand-gated chloride channel subunit proteins as well as on some ABC-transporter genes, whose products may be involved in regulating macrocyclic lactone drug concentrations at receptors, and on some structural protein genes of amphidial neurones. Although ivermectin resistance has not been reported in filarial nematodes, there have recently been reports of suboptimal responses to ivermectin in Onchocerca volvulus. Evidence has been found of ivermectin selection on at least ABC-transporter genes and some neuronal structural protein genes in O. volvulus. **