Anthelminthic Drugs Vermicide- kill Vermifuge- expell Unlike protozoa, helminths are large and have complex cellular structures
Developing countries Most of the protozoal infections are due to unhygienic conditions. Harm host by depriving him of food, blood loss, injury to organs, toxin, obstruction of intestine or lymphatics Rarely fatal Resistance no big issue Anthelminthic drugs Three major groups of helminths (worms) are Nematodes Trematodes Cestodes
Modes of Transmission Four main mechanisms for parasitic transfer:
Ingestion of eggs from the fecal material of an infected individual Ascaris lumbricoides
The larva of the parasite can burrow into the skin of a person Schistosomes
The larva of the parasite can move from person to person through an insect vector Trypanosomes Plasmodia
Sexual transmission Trichomonas vaginalis Mode of worm infestation A. In the hosts gut: Round worms (nematodes) Tapeworms (cestodes) B. In the tissues of hosts: Schistosomiasis (flukes: bilharzias): S. mansoni, etc. Tissue round worms: filiareae, dranculus medinensis (guinea worm) Anthelminthic drugs Drugs for helminths Nematodes : Albendazole, Mebendazole, Pyrantel pamoate, Diethylcarbamazine, Ivermectin Trematodes : Praziquantel, metrifonate, bithionol, emetine, dehydroemetine Cestodes : Niclosamide, Praziquantel, Albendazole Anti-helminthic drugs Benzimidazole : Thiabendazole, Albendazole & Mebendazole Effective against wide spectrum of nematodes It acts by binding and interfering the assembly of microtubules It also decreases the glucose uptake Inhibits the polymerization of tubulin into microtubules This inhibition prevents cellular division and the absorption of glucose in its intestines Thiobendazole First benzimidazole Effective for all species of nematodes infesting the g.i.t.- roundworm, hookworm, Enterobius, Trichuris, Strongyloides and Trichinella spiralis. It also inhibits development of the eggs of worms and kills larvae. Thiabendazole affords symptomatic relief in cutaneous larva migrans and skeletal muscle symptoms produced by migration of Trichinella spiralis larvae to muscles. Has Antiinflammatory, analgesic and antipyretic actions. These may contribute to its effect in cutaneous larva migrans and other inflammatory conditions produced by larvae or worms in tissues. well absorbed from g.i.t., systemic adverse effects are frequent and often interfere with normal activity Nausea, vomiting, loss of appetite, headache, giddiness are most common. It can impair alertness-driving and operation of machinery should be prohibited. Itching, abdominal pain, diarrhoea and a variety of other symptoms are also produced. Dose - 25 rng/kg/day in two divided doses taken after meals. Tablets must be chewed; Uses Because of frequent side effects and poor patient acceptability, thiabendazole is used only when other better tolerated drugs are ineffective. Strongyloidosis Cutaneous larva migrans Mebendazole congener of thiabendazole it retained the broad-spectrum anthelmintic activity but not the toxicity of its predecessor. It has produced nearly 100% cure rate/ reduction in egg count in roundworm, hookworm (both species), Enterobius and Trichuris infestations, but is much less active on Strongyloides. Upto 75% cure has been reported in tapeworms, but H. nana is relatively insensitive. It expels Trichinella spiralis from intestines, but efficacy in killing larvae that have migrated to muscles is uncertain. Prolonged treatment has been shown to cause regression of hydatid cysts in the liver. Treatment after resection of the cyst may prevent its regrowth Mechanism of action It acts probably by blocking glucose uptake in the parasite and depletion of its glycogen stores. The site of action of mebendazole appears to be the microtubular protein beta-tubulin' of the parasite. It binds to beta-tubulin of susceptible worms with high affinity and inhibits its polymerization. Intracellular microtubules in the cells of the worm are gradually lost. The immobilizing and lethal action of mebendazole on worms is rather slow: takes 2-3 days to develop. p/k- Absorption of mebendazole from intestines is minimal; 75-90% of an oral dose is passed in the faeces. The fraction absorbed is excreted mainly as inactive metabolites in urine/faeces. s/e- Diarrhoea, nausea and abdominal pain. Incidents of expulsion of Ascaris from mouth or nose have occurred, probably due to starvation of the parasite and their slow death. High doses --Allergic reactions, loss of hair and granulocytopenia Pregnancy- C/I
Uses of mebendazole The dose and duration of treatment is the same for children above 2 years as for adults; 1/2 dose for 1-2 yr age. Roundworm, Hookworm, Whipworm 100 mg twice a day for 3 consecutive days. No fasting, purging or any other preparation of the patients is needed. Enterobius 100 mg single dose. Strict hygienic measures and simultaneous treatment of all children in the family or class Trichinella spiralis: 200 mg BD for 4 days; less effective than albendazole. Hydatid disease: 200-400 mg BD or TDS for 3-4 weeks; less effective than albendazole. Albendazole congener of mebendazole: retains the broad-spectrum activity and excellent tolerability of its predecessor, and has the advantage of single dose administration One dose treatment has produced cure rates in ascariasis, hookworm (both species) and enterobiasis which are comparable to 3 day treatment with mebendazole. Results in trichuriasis have been inferior to mebendazole. In strongyloidosis, more effective than mebendazole: a 3 day course has achieved nearly 50% cure, and a second course repeated after 3 weeks cured practically all patients. Three day treatment has been found necessary for tapeworms including H. nana.
Results in hydatid disease and hookworm have been superior to mebendazole. Albendazole has weak microfilaricidal action, kills cysticerci, hydatid larvae, ova of ascaris/hookworm and is also effective in cutaneous larva migrans. The mechanism of action is similar to that of mebendazole. Absorption of albendazole after oral administration is moderate, but inconsistent. It is enhanced when the drug is taken with fatty meal (may help in treating neurocysticercosis and hydatid disease). Active metabolite albendazole exert antihelmintic activity in tissues as well. Albendazole is well tolerated; only gastrointestinal side effects have been noted. Few patients have felt dizziness. Prolonged use, as in hydatid or in cysticercosis, has caused headache, fever, alopecia, jaundice and neutropenia No preparation or postdrug fasting/ purging is required. For intestinal worms it should be given on empty stomach, while for cysticercosis, hydatid and cutaneous larva migrans it should be given with a fatty meal. Ascaris, hookworm, Enterobius and Trichuris: single dose of 400 mg (for adults and children above 2 yrs, 200 mg for 1-2 yr age). Tapeworms and strongyloidosis: 400 mg daily for 3 consecutive days. Trichinosis: Three day treatment expels the adult worm from intestine, but has limited effect on larvae that have migrated to muscles. Neurocysticercosis: Albendazole is the anthelmintic of choice for the treatment of neurocysticercosis. Usually 8-15 days course of 400 mg BD (15 mg/kg/ day) is employed. Cysticercosis of other tissues (muscles, subcutaneous area) also responds, but no drug should be given for ocular cysticercosis-blindness can occur due to the reaction. Cutaneous larva migrans: Albendazole 400 mg daily for 3 days is the drug of choice; kills larvae and relieves symptoms. Hydatid disease: 400 mg BD for 4 weeks, repeat after 2 weeks (if required), up to 3 courses. It is the preferred treatment given before and after surgery as well as to inoperable cases. Filariasis: Added to diethylcarbamazine (DEC) or ivermectin, albendazole has adjuvant value C/I pregnancy
Benzimidazole : Albendazole and Mebendazole are poorly absorbed from GIT whereas thiabendazole is well absorbed. Albendazole and Mebendazole are well tolerated , thiabendazole causes hallucinations Mebendazole and Albendazole are used to treat intestinal nematode infections Thiabendazole is preferred drug of choice in cutaneous larva migrans. Contraindicated in pregnancy Pyrantel Pamoate : It acts as a depolarizing neuromuscular agent persistent activation of nicotinic receptors -resulting in persistent depolarizatio-- slowly developing contracture and spastic paralysis. Worms are then expelled. An anticholinesterase action. Because piperazine causes hyperpolarization and flaccid paralysis, it antagonizes the action of pyrantel. Cholinergic receptors in mammalian skeletal muscle have very low affinity for pyrantel. Only 10-15% of an oral dose of pyrantel pamoate is absorbed: this is partly metabolized and excreted in urine Used to treat round worm, hook worm and pin worm. Efficacy comparable to mebendazole. Lower cure rates (about 60%) have been obtained in case of Necator infestation. It is less active against Strongyloides and inactive against Trichuris and other worms. g.i. symptoms,headache and dizziness is reported. It is tasteless, nonirritant; abnormal migration of worms is not provoked. Its safety in pregnant women and in children below 2 years has not been established. For Ascaris, Ancylostoma and Enterobius: a single dose of 10 mg/kg No fasting, purging or other preparation needed. Piperazine highly active drug against Ascaris and Enterobius now considered a second choice drug Piperazine causes hyperpolarization of Ascaris muscle by a GABA agonistic action -- opening Cl- channels that causes relaxation and depresses responsiveness to contractile action of ACh. Flaccid paralysis worms are expelled alive often a purgative (senna) is given with it, but is not necessary. No fasting or patient preparation is required. Piperazine does not excite Ascaris to abnormal migration. It does not affect neuromuscular transmission in man. safe and well tolerated. Nausea, vomiting, abdominal discomfort and urticaria. Dizziness and excitement occur at high doses; toxic doses produce convulsions; death is due to respiratory failure. It is contraindicated in renal insufficiency and in epileptics, but is safe in the pregnant. 4 gm OD for 2 days. Intestinal obstruction due to roundworm. Levamisole, Tetramisole use is restricted to ascariasis and ancylostomiasis, because action on other worms is poor. The ganglia in worms are stimulated causing tonic paralysis and expulsion of live worms. Interference with carbohydrate metabolism (inhibition of fumarate reductase) may also be contributing. Single dose of 50, 100, 150 mg according to weight. Immunomodulator Diethylcarbamazine : It acts by immobilizing the microfilaria and render them susceptible to host defense Well absorbed orally Used mainly in the drug of choice for Filariasis and Visceral larva migrans Diethylcarbamazine : Piperazine derivative. Diethylcarbamazine has a highly selective effect on microfilariae (Mf). A dose of 2 mg/kg TDS clears Mf of W. bancrofti and B. malayi from peripheral blood in 7 days. However, Mf present in nodules and transudates (hydrocoele) are not killed. Mechanism of action- alteration of Mf membranes so that they are readily phagocytosed by tissue fixed monocytes, but not by circulating phagocytes. Muscular activity of the Mf and adult worms is also affected causing hyperpolarization due to the piperazine moiety, active against Mf of Loa loa and onchocerca volvulus Filariasis: 2 mg/kg TDS produces rapid smptomatic relief. However, the adult worm survives in the lymphatics and gives rise to intermittent microfilaraemia and symptoms. Elephantiasis due to chronic lymphatic obstruction is not affected by DEC, because fibrosis of lymphatics is irreversible. Yearly treatment with a combination of DEC and albendazole on mass scale has brought down transmission of filariasis by reducing microfilaraemia. Tropical eosinophilia: 2 mg/kg TDS for 2-3 weeks Mazzoti reaction Onchocerciasis t/t with DEC Fever, urticaria, swollen tender LN, tachycardia, hypotension, arthralgia, oedema. Anti-helminthic drugs Ivermectin : obtained from Streptomyces avermitilis Ivermectin is the drug of choice for single dose treatment of onchocerciasis and strongyloidosis, and is comparable to DEC for bancroftian and brugian filaria. It is also highly effective in cutaneous larva migrans and ascariasis, while efficacy against Enterobius and Trichuris is moderate. Certain insects, notably scabies and head lice are killed by ivermectin. Acts by acting on parasites GABA chloride channel receptors chloride influx in enhanced hyperpolarisation and paralysis of the worm. It acts through a special type of glutamate gated Cl- channel found only in invertebrates. Such channels are not involved in the motor control of flukes and tapeworms which are unaffected by ivermectin. Potentiation of GABAergic transmission in the worm has also been observed. The lack of GABA-related actions in man could be due to its low affinity for mammalian GABA receptors and its exclusion from the brain, probably by P-glycoprotein mediated efflux at the blood brain-barrier. Anti-helminthic drugs Ivermectin : Well absorbed orally, metabolized in liver and excreted in feces. Contraindicated in pregnancy does not cross mammalian blood / brain barrier Drug can act as a GABA agonist causing increased muscular contaction e.g Levamisol Used for Onchocerca volvulus, strongyloides and cutaneous larva migrans.
Ivermectin has replaced DEC for onchocerciasis and has been used in the 'river blindness' control programme of WHO in Africa and Latin America. Ivermectin is the only drug effective orally in scabies and pediculosis. Single 0.2 mg/kg dose cures most patients. Anti-helminthic drugs Praziquantel : It acts by increasing the permeability of tegument to calcium paralysis of the parasite. Well absorbed orally Good tissue distribution CNS. Metabolites are excreted in bile and urine Anti-helminthic drugs Praziquantel : Active against trematodes like Chinese liver fluke Clonorchis sinesis Lung fluke ---- Paragonimus westermani Schistosomiasis Schistosoma sp Also active against Cestodes Anti-helminthic drugs Praziquantel : Not advised for ocular cysticercosis because of destruction of the organism in the eye may damage eye. Anti-helminthic drugs Bithionol used for the treatment of fasciola hepatica sheep liver fluke.
Anti-helminthic drugs Niclosamide Acts by inhibition of parasite mitochondrial phosphorylation of ADP to ATP. The drug is lethal for Cestodes scolex and segments but not for ova. Laxative is used to purge all the dead segments of the intestine ova liberation and absorption can lead to cysticercosis. It is used for most Cestodes infections.
Niclosamide blocks glucose uptake by intestinal tapeworms. It may cause some mild gastrointestinal symptoms.
Piperazine may cause hypersensitivity reactions, neurological symptoms (including worm wobble) and may precipitate epilepsy.
Praziquantel paralyses both adult worms and larvae. It is extensively metabolised. Praziquantel may cause nausea, headache, dizziness and drowsiness; it cures with a single dose (or divided doses in one day). Mebendazole blocks glucose uptake by nematodes. Mild GI distarbunces may be caused, and it should not be used in preg- nancy or in children under the age of 2. Albendazole is similar to mebendazole.
Levamisole paralyses the musculature of sensitive nematodes which, unable to maintain their anchorage, are expelled by normal peristalsis. It is may cause abdominal pain, nausea, vomiting, headache and dizziness.
Thiabendazole inhibits cellular enzymes of susceptible helminths. Gastrointestinal, neurological and hypersensitivity reactions, liver damage and crystalluria may be induced.
Pyrantel depolarises neuromuscular junctions of susceptible nematodes which are expelled in the faeces. It cures with a single dose. It may induce GI disturbance, headache, dizziness, drowsiness and insomnia. Diethylcarbamazine kills both microfilariae and adult worms. Fever, headache, anorexia, malaise, urticaria, vomiting and asthmatic attacks following the first dose are due to products of destruction of the parasite, and reactions are minimised by slow increase in dosage over the first 3 days.
Ivermectin may cause immediate reactions due to the death of the microfilaria. It can be effective in a single dose, but is best repeated at 612-month intervals.
Anthelminths Drugs that are active against roundworms and flatworms Benzimidazoles
Macrocyclic lactones
Symptoms of a round or flatworm infection: Loss of appetite, distended abdomen, painful abdomen, coughing, fever, vomiting, diarrhoea, listlessness and generally feeling unwell Can lead to malnutrition and anemia, with a small chance of more severe problems due to wandering worms
Niclosamide Active against T. saginata, D. latum, H. nana (6 days), D. caninum, T. solium (risk of autoinfection due to disintegration; prefer praziquantel). Molluscicide used in snail control programs (Bayluscide WP 70).
Pearson R.D. 2005. Chapter 41, In Mandell G.L. et al. Praziquantel Works by: Disrupting the membrane of the schistosome that coats the parasite with host molecules Causing the rapid influx of calcium ions into the parasite, resulting in muscular tetany Paralysis of adult worms, ... Over 80% is absorbed after an oral dose. Adverse effects are mild but common (in over 30% of patients): dizziness, lethargy, headache, nausea, abdominal pain, ... Active against almost all trematodes (including all schistosomes, but not Fasciola hepatica) and cestodes.
Ivermectin I Related to avermectin, also produced by Streptomyces avermitilis. By interfering with the target animal's nervous system. These drugs kill by interfering with the target animal's nervous system Drugs bind to glutamate-gated Cl ion channels in the musculature of the worm This binding causes an unregulated ion flux through the cells membranes Paralysis of the parasite Active on most common intestinal worms (except tapeworms), most mites, and some lice. Used for Strongyloides stercoralis, onchocerciasis, body lice, and scabies. Common for animal use (e.g. heartworm prophylaxis). Ivermectin II Category IV, or very low toxicity. Occasional Mazzoti-type (anaphylactoid) reactions seen in onchocerciasis. Available for human use in the US, Canada, France, The Netherlands ...
Mectizan Donation Program (MDP) by Merck & Co., Inc., in collaboration with the WHO, Elimination of lymphatic filariasis (LF) in areas that are co-endemic for onchocerciasis and lymphatic filariasis. Mectizan is co-administered with albendazole, which is donated by GlaxoSmithKline, in these settings.
schistosomiasis Drugs that are active against schistosomiasis Currently, praziquantel is the most common drug used for the treatment of all species of schistosomes The drug artemisinin, an antimalarial, is also effective against schistosomes Symptoms of schistosomiasis: May develop a rash or itchy skin, fever, chills, cough, and muscle aches during the early phases of infection Most people have no symptoms at this early phase of infection The eggs of the parasite can damage the liver, intestines, lungs, and bladder Schistosomes are very difficult to kill because they disguise themselves within the host by coating their outer membrane with the hosts own molecules The immune system will not respond to an infection, because it will not recognize the invading schistosomes as a threat
Worms (helminths) Drug of choice Tapeworms (cestodes) Niclosamide or Praziquantel or Albendazole Roundworms (nematodes) Enterobius vermicularis (pinworm) Ascaris lumbricoides Trichuris trichiura (whipworm) Trichinella spiralis (trichinellosis)
Strongyloides stercoralis Necator americanus (hookworm) Ancylostoma duodenale
Mebendazole or Pyrantel Mebendazole or Pyrantel Mebendazole or Albendazole Mebendazole and Thiabendazole Thiabendazole Mebendazole or Pyrantel Mebendazole, Pyrantel or Albendazole Ivermectin Diethylcarbamazine Flukes (trematodes) Schistzoma (Schistozomes)