ANTI HELMINTHICS-INTRODUCTION, CLASSIFICATION, MOA

This introduces Helminthic infestations and classification of anthelmintics with MOA and synthesis

1. ANTI HELMINTHIC AGENTS

2. Introduction Anti helmintics are the drugs to treat parasitic infestations due to worms<or> used to expel the worms from the GIT <or> drugs having capability to rid off the body of the parasitic worms or helminths Helminthes infestations are the major problem among the third world nations. These infestations include Nematode infections Ancyclostomiasis or Hook worm infection Enterobiasis or Pin worm infection Ascariasis or Round worm infection Trichuriasis or Whip worm infection Trichinosis or Trichina infection Filariasis Cestode or Trematode Cysticercosis or Tape worm infection Schistosomiasis or Blood flukes

3. Ancyclostomiasis or Hook worm infection: Infestations cause pulmonary lesions, skin reactions, intestinal ulceration and anemia. Enterobiasis or Pin worm infection: perianal pruritus Ascariasis or Round worm infection: abdominal discomfort and Pain Trichuriasis or Whip worm infection: irritation and inflammation of the colonic mucosa, abdominal pain, diarrhea, and distention. Trichinosis or Trichina infection: both intestinal and systemic forms: diarrhea, abdominal pain, and nausea & muscle pain and tenderness, edema, conjunctivitis, and weakness. Filariasis : Elephantiasis is the most common disease associated with filariasis Cysticercosis or Tape worm infection: beef, pork, dwarf and fish tape worms: They especially absorb vitamin B12 and folic acid. Depletion of these critical nutrients, especially vitamin B12, can lead to pernicious anemia. Schistosomiasis or Blood flukes: The patients might experience headache, fatigue, fever, and GI disturbances during the early stages of the disease. Hepatic fibrosis and ascites occur during later stages.

4. Chemical classification Benzimidazoles : Thiabendazole , mebendazole , albendazole Quinolines and isoquinolines : Oxamniquine , praziquantel Piperazine derivatives: Piperazine , diethylcarbamazepine citrate Vinyl pyrimidines : Pyrantel pamoate , oxantel Amides: Niclosamide Natural compounds: Avermectin Organo phosphorus compounds: Metrifonate Imidazothiaoles : Levamisole Nitro derivatives: Niridazole

5. Niclosamide oxamniquine Thiabendazole Albendazole

6. Diethylcarbamazepine (DEC): a piperazine derivative discovered in 1940s. MOA: is anti filaricidal agent to show action activation of a cellular component is necessary. “Blood platelets” were excited by the released filarial excretory proteins. Morphological changes occur leading to loss of cellular sheath, exposing antigenic determinants to immune mechanisms, damage of organelles. Inhibition of microtubule formation and destruction of preformed microtubules Interferes with arachidonic acid metabolism: Cyclooxygenase and LTA 4 synthase: which leads to vascular and cellular adhesiveness and cellular activation. ADVERSE REACTIONS: anaphylactic reaction, intense pruritis and ocular complications. Mazzotti reaction: severe anaphylactic reactions

7. BENZIMIDAZOLES Broad spectrum antihelmintics discovered in 1960s by Townsend and Wise. MOA: I Fumarate reductase Fumarate Malate NADH NAD + energy Benzimidazoles Oxidative Phosphorylation MOA: II Tubulin + Tubulin Tubulin dimer Microtubules Benzimidazoles polymerization Dissociation By capping

8. Also inhibit glucose transportation into the worm and depletes the glycogen stores of the intracellular microtubules. Has poor oral absorption but can be enhanced with a fatty meal Metabolised by oxidation, hydroxylation and conjugation. (CYP3A4 &CYP1A2) Metabolites of albendazole i.e., albendazole sulfoxide is an active metabolite and the intermediate metabolite is active against hydatid cyst of echinococciasis (tape worm disease). General adverse effects are GIT disturbances with Albendazole and mebendazole . Thiabendazole can cause Steve- Jhonson’s Syndrome, hepatotoxicity and crystalluria . Benzimidazoles are effective on ascaris , enterbius , trichuris and hook worm infestations.

9. Praziquantel (PZQ) An isoquinoline derivative where levo enantiomer is active Broad spectrum agent, highly effective on cestodes and trematodes . MOA :I:helminths of lumen of host Either direct or indirect Ca 2+ redistribution by altering the permeability of membrane Muscle contraction and paralysis(inhibition of phosphoinositide metabolism) Worm expulsion MOA :II: intravascular-dwelling helminths Drug induced damage to tegument of the worm Recognition by immune antibodies Antigen-antibody complex engulfed by phagocytes and the worm die

10. IVERMECTIN Extracted from the soil actinomycete Streptomyces avermitilis , the natural avermectins are 16-membered macrocyclic lactones that are an 80:20 mixture of avermectin B1a and B1b , respectively degeneration of microfilariae in utero . Rapidly absorbed, bound to plasma protein and excreted in the urine or feces either unchanged or 3′- O-demethyl-22,23- dihydroavermectin B1a or as the dihydroavermectin B1a monosaccharide. The absorption of IVM is significantly affected by the presence of alcohol.

11. USES: Diethylcarbamazepine (DEC): effective against filariasis (Bancroft & onchocerciasis ), microfilaria, ascariasis . Albendazole : single dose for treating ascariasis , New and old hookworm infestation and trichuriasis . Mebendazole : drug of first choice for hookworm, pin worm, round worm, whip worm, guinea worm, filariasis , alternative for visceral larva migrans , an adjunct of steroid in trichinosis. Thiabendazole : broad spectrum antihelmintic for treatment of enterobiosis , strongylodiasis , ascariasis , uncinariasis , trichuriasis , cutaneous larva migrans , invasive phase of trichinosis. Praziquantel : drug of choice for Strongylodiasis , effective for treatment of intestinal, chinese liver, sheep liver, liver and lung flukes. Ivermectin : Wuchereria bancrofti , Brugia malayi , Loa loa , and Mansonella ozzardi , as well as activity against Strongyloides stercoralis , the drug is used primarily in the treatment of onchocerciasis (African river blindness ) caused by Onchocerca volvulus .