PHARMACOLOGY Antihelminthics Notes Lecturer: Laura M. Aguirre-Aguinaldo, M.D.

, DPPS
Antihelminthics Drugs that act locally to expel worms from the GIT or systemically to eradicate adult helminths or developmental forms that invade organs or tissues OBJECTIVES To discuss the antihelminthic drug prototypes To discuss the PK/PD properties of each drug To discuss their adverse effects To cite some medications used as alternative drugs of choice Eradication Programs WHO World Bank Partnership for Child Development (PCD)

Transcriber: Joshua Arcaira Editor: Number of pages: 4

metabolites and a little of its unchanged form; the parent form has antihelminthic action Albendazole : absorption is enhanced with a fatty meal, rapidly metabolized in the liver and possibly the intestine to albendazole sulfoxide which has potent antihelminthic property THERAPEUTIC USES: THIABENDAZOLE: As therapy for creeping eruption (cutaneous larvae migrans) and Strongyloides stercoralis infection. Topically applied as a 15% water soluble cream 23x/day X 5 days MEBENDAZOLE: highly effective against GIT nematodes especially useful in treating mixed infections. Dose in adults and children 2 years: for enterobiasis 100mg tab once repeated after 2 weeks. For control of ascariasis, trichuriasis or hookworms 100mg BID X 3days or a single 500mg tab once, may be repeated after 2 weeks ALBENDAZOLE: DOC for treating cystic hydatid disease due to Echinococcus granulosus, should be used in combination with surgical removal of cysts for higher cure rates. Dose 400mg BID, in children 15mg/kg/day BID (not to exceed 800mg), duration will depend on the target organism Preferred treatment for neurocysticercosis caused by larval forms of Taenia solium Glucocorticoids are usually given as pre treatment before initiating therapy to reduce incidence of inflammatory reactions to dead and dying cysterci and causes increase in plasma levels of albendazole sulfoxide TOXICITIES, PRECAUTIONS & CONTRAINDICATIONS THIABENDAZOLE: Potential for hepatotoxicity Anorexia, nausea, vomiting and dizzines. Less common are diarrhea, fatigue, drowsiness, giddiness, headache. Others: fever, rashes, erythema multiforme, hallucinations, sensory disturbances, SJS. Rare: angioedema, shock, tinnitus, convulsions,intrahepatic cholestasis No known absolute contraindications to its use Avoid activities requiring mental alertness during tx In Pregnancy, category C drug: benefit vs risk MEBENDAZOLE: Does not cause systemic toxicity in routine clinical use probably due to its low systemic bioavailability. PHARMACOLOGY: Antihelminthics | 1

Recognized the impact of helminth infections on the health and education of school-aged children Promotes periodic and frequent use of antihelminthics as a means to control soiltransmitted helminths (STH) and schistosomes

ANTIHELMINTHICS

BENZIMIDAZOLES (BZAs)
MOA: Inhibition of microtubule polymerization by binding to -tubulin Inhibition of mitochondrial fumarate reductase Reduced glucose transport Uncoupling of oxidative phosphorylation Three compounds Thiabendazole Mebendazole: prototype Albendazole ALBENDAZOLE/MEBENDAZOLE/THIABENDAZOLE ADME Thiabendazole: rapidly absorbed orally, reaches peak plasma concentrations after 1 hour; mostly excreted in the urine Mebendazole: poor and erratic oral absorption, low drug plasma levels (extensive first-pass effect), extensively bound to plasma proteins; excretion via bile and urine as

Transient abdominal pain, distention and diarrhea. Rare are allergic reactions, alopecia, reversible neutropenia, agranulocytosis and hypospermia A potent embryotoxin and teratogen in laboratory animals hence not generally recommended for pregnant women and children less than 2 years old

Not recommended for use in pregnant women and children < 2 years Should not be used with piperazine because of their mutually antagonistic effects with respect to neuromuscular blockade of parasites

IVERMECTIN
ALBENDAZOLE: Mild adverse effects, usually transient GI symptoms Most common side effect noted is transient elevation of liver enzymes Should not be given in pregnant women (embryotoxic and teratogenic) Use in children < 2 years has not been extensively studied. MOA: A semisynthetic macrocyclic lactone derived from Streptomyces avermitilis causes immobilization of affected organisms by inducing a flaccid paralysis of the musculature probably by binding to glutamate-activated Cl channels found in nematode nerve or muscle cells Causes paralysis of nematodes and arthropods by intensifying GABA mediated transmission of signals in peripheral nerves

PYRANTEL PAMOATE
A tetrahydropyrimidine derivative MOA: Depolarizing neuromuscular agents which open nonselective cation channels and induce marked, persistent activation of nicotinic acetylcholine receptors which result in spastic paralysis of the worm. Acts mainly on luminal organisms, both immature and mature forms ADME: Poorly absorbed from the GIT which contributes to its selective action on gastrointestinal nematodes Excreted mainly in the feces and about 15% in the urine as the parent drug THERAPEUTIC USES: An alternative drug to mebendazole in the treatment of ascariasis and enterobiasis. Also for effective for hookworms Ancylostoma duodenale and Necator americanus High cure rates with a single standard oral dose of 11 mg/kg to a maximum of 1 gm though may be repeated after two weeks. For pinworms: dose may be repeated after 2 weeks, with 95% cure rate For ascariasis: SD yields cure rates of 85-100%, retreat if eggs are found 2 weeks after treatment For hookworm: SD for light infections. For heavy intestinal burdens 3 day course of treatment and may be repeated after 2 weeks

ADME: Used only orally in humans Peak plasma levels are achieved after 4-5 hours of oral ingestion Has a terminal half-life of 57 hours due to low systemic clearance ( 1-2 L/hr) and a large Vd, 93% protein-bound Extensively metabolized by hepatic CYP3A4 mostly to hydroxylated and demethylated derivatives. Excreted in the feces Little CNS penetration despite being lipid soluble, animal studies suggest the presence of a Pglycoprotein (P-gp) efflux pump in the BBB THERAPEUTIC USE: DOC for onchocerciasis and strongyloidiasis Given as a single oral in adults and children aged 5 years or older Dose 150 g/kg with water given on an empty stomach Treatment regimens vary from monthly to less frequent ( every 6-12 months) intervals, after acute treatment, doses are repeated yearly until adult worms die sometimes 10 years or longer. Corticosteroids may be given on the first course of treatment only in patients with microfilariae in the cornea or anterior chamber to avoid inflammatory eye reactions. TOXICITIES, ADVERSE EFFECTS, CONTRAINDICATIONS/PRECAUTIONS Mazzoti reaction Itching, swollen lymph nodes lasting for several days usually relieved by aspirin and antihistamines High fever, arthralgia, tachycardia, hypotension, prostration, dizzines, headache, myalgia, diarrhea, facial and peripheral edema which may respond to glucocorticoids.

ADVERSE EFFECTS, CONTRAINDICATIONS/PRECAUTIONS Can produce neuromuscular blockade in animals when given parenterally. Transient mild GI symptoms: diarrhea,N/V, abdominal cramps; fever, rash, headache, dizziness Used with caution in patients with liver dysfunction

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Treatment may be associated with Loa encepalopathy in individuals with high microfilariae levels in the blood ( 30,000 microfilariae/mm) Little evidence for carcinogenicity or teratogenicity CI in conditions with impaired BBB because of its effect on the GABA Rcs

DIETHYLCARBAMAZINE
MOA: A synthetic piperazine derivative Not well understood but appears to be due to its direct effect on W. bancrofti microfilariae causing organelle damage and apoptosis Immobilizes microfilariae and alters their cell structure which displaces them from tissues which makes them more susceptible to host defense mechanisms DOC for: Wuchereria bancrofti, Brugia malayi, Brugia timori and Loa loa, tropical eosinophilia Affects intracellular processing and transport of macromolecules to the plasma membrane May affect specific inflammatory and immune host response

TOXICITIES, SIDE EFFECTS, PRECAUTIONS, CONTRAINDICATIONS: Mazzoti reaction : occurs within a few hours after the first dose and includes intense itching, enlargement and tenderness of lymph nodes, which may be accompanied by a papular rash, headache, fever, tachycardia and arthralgias. Persists for 3-7 days then gradually subsides. Ocular complications: limbitis, punctate keratitis, uveitis, and atrophy of retinal pigment epithelium. Delayed reactions to mature dying filarial forms include lymphangitis, swelling and lymphoid abscess in bancroftian and brugian filariasis and small skin wheals in loiasis. Appears to be safe for use in pregnancy Use with caution in patients with HPN or renal disease

PRAZIQUANTEL
MOA: A synthetic isoquinoline-pyrazine derivative ++ causes Ca influx across the tegument causing damage. At the lowest effective dose: increased muscular activity followed by contraction and spastic paralysis.

ADME: Rapidly absorbed from the GIT, peak plasma levels reached after 1-2 hours of administration, with plasma half-lives from 2-20 hours depending on urine pH Rapidly and extensively metabolized; its metabolite diethylcarbamazine-N-oxide is also biologically active Renally excreted (alkaline urine decreases excretion), extrarenal excretion also occurs THERAPEUTIC USES: A first line agent for control and treatment of lymphatic filariasis and for therapy of tropical Wuchereria bancrofti and Brugia malayi Remains to be the best drug available for Loiasis despite its toxicity W. bancrofti, B. malayi, and B. timori: Drug of choice; rapidly kills microfilariae but adults may require retreatment Treat for 2-3 weeks as follows : Day 1- 50 mg (1mg/kg in children), Day 2- 50mg x three doses, Day 3- 100mg x 3 doses (2mg/kg in children) then 2mg/kg 3x/day to complete the rest of the course. Antihistamines may be given for the first few days to limit allergic reactions , in cases of severe reactions, corticosteroids should be started and diethylcarbamazine doses lowered. As chemoprophylaxis 300mg weekly or 300mg on 3 successive days each month for loiasis, 50 mg monthly for bancroftian and Malayan filariasis Contraindicated for the treatment of onchocerciasis because it causes severe reactions related to microfilarial destruction

ADME: Readily absorbed orally reaching peak plasma concentration after 1-2 hours, half life is 0.8- 3 hours, 80% bioavailability Undergoes extensive first pass metabolism limiting its bioavailability 80% protein-bound Excreted in the kidneys (60-80%), bile (15-35%) Inc plasma conc with high CHO meal and cimetidine, while antiepileptics and corticosteroids limits its bioavailability THERAPEUTIC USE: In the U.S. approved for use only fof Schistosomiasis and liver flukes, elsewhere also for other trematodes and nematodes. DOC for all schistosoma species that infect humans Regimens vary but may be given as a single oral dose of 40mg/kg or three doses of 20mg/kg each 4-6 hours apart. TOXICITIES, ADVERSE EFFECTS, CONTRAINDICATIONS/PRECAUTIONS Abdominal discomfort, diarrhea, headache, dizziness and drowsiness. These effects are transient and may be dose-related. Others: fever, urticaria, pruritus, rashes, arthralgia,myalgia In neurocystercosis: delayed onset of meningismus, seizures, mental changes, CSF pleocytosis may occur, lasts 2-3 days, treated with appropriate symptomatic therapy PHARMACOLOGY: Antihelminthics | 3

Safe in children 4 years or older, use in pregnant women Cat. C CI: ocular cysticercosis because the host response can irreversibly damage the eye

Causes dizziness and drowsiness CI in pregnancy, use with caution in pxs with epilepsy

PIPERAZINE
An alternative for the treatment of ascariasis, causing paralysis by blocking acetylcholine at the neuromuscular junction. Not recommended for other helminth infections Dose is 75 mg/kg ( max 3.5g) orally OD X 2 days for heavy infections, continued for 2-3 days or repeated after 1 week Readily absorbed with peak plasma levels reached in 2-4 hours Should not be given in pregnant women, in patients with deranged renal or hepatic function or those with epilepsy or history of chronic neurological disease.

OTHERS

METRIFONATE (Trichlorfon)
A safe, low-cost alternative drug for the treatment of Schistosoma heamatobium. Not active against S mansoni or S japonicum An organophosphate compound whose MOA may be related to cholinesterase inhibition S. haematobium : 7.5-10 mg/kg P.O. TID x 14 days AR: transient cholinergic symptoms Contraindicated in pregnancy A salicylamide derivative A second-line drug for treatment of most tapeworm infections. Kills adult worms but not ova presumably by inhibition of oxidative phosphorylation or stimulation of ATPase activity Adult dose is 2g once, in the morning taken on an empty stomach, chewed thoroughly then swallowed with water Safety is not established for use in pregnancy or in those less than 2 years

NICLOSAMIDE

DOXYCYCLINE
has been shown to have significant macrofilaricidal activity vs. W. bancrofti and also onchocerciasis. It acts indirectly by killing Wolbachia an intracellular bacterial symbiont of filarial parasites Alternative drug to triclabendazole for treatment of fascioliasis (sheep liver fluke) and also an alternative drug for treatment of pulmonary paragonimiasis Peak levels are reached after 4-8 hours and renally excreted. Dose paragonimiasis and fascioliasis 30-50 mg/kg in 2-3 divided doses given after meals on alternate days for 10 -15 doses Limited info for its use in children <8 years -ENDJust how Dra. Aguinaldo explained it. PURELY PPT. HAHA. Grab somebody sexy tell em, Hey! Give me everything tonight.

BITHIONOL

OXAMNIQUINE
A semi-synthetic tetrahydroquinoline Readily absorbed orally and should be taken with food An alternative to Praziquantel for the treatment of S mansoni infections (Katayama syndrome) especially in cases of resistance. It has also been extensively used for mass treatment . It is not effective in S haematobium or S japonicum MOA is unknown but it is active vs both mature and immature stages of S mansoni but appears to be not cercaricidal. Causes contraction and paralysis of the organism

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