Tutorial 2

Antihelmintics and drugs used against ectoparasitic infections

Antihelmintics : drugs against worms (helminths) infections Ectoparasite : surface parasites

Learning outcomes

• Know the classification of anthelmentic drugs

• Know the structures, mode of action and metabolism of benzimidazoles

• Understand how the anthelmentic Oxamniquine can act in way similar to alkylating agents

• Correlate the solubility characteristic of some anthelmentics and their site of actions

• Understand the impact of metabolism on safety profile of some insecticides

Antihelmintics

3

Drugs against worms (helminths) infections

One of the most serious public health problems, especially in developing coutries,

¼ of the world population may be infected

Platyhelminths

(flatworms) Nematodes

(roundworms)

Helminths

Cestodes (tapeworms)

Intestinal infections

Trematodes (flukes) : Intestinal/

systemic

Hook worm (ancylostomiasis)

Pinworm (enterobiasis)

Whipworm (trichuriasis)

Ascaris

Intestinal infections (but can be systemic)

Wuchereria bancrofti and Brugia malayi

(filariasis)

River blindness (onchocerciasis)

Tissue Nematodes

General drug modes of action,:

1. Worm killing

2. Worm paralysis (easier

expulsion or phagocytosis)

4

Antihelmintics

Benzimidazoles

Thiabendazole

Mebendazole

Albendazole

Piperazines

Piperazine citrate

Diethylcarbamazine

Others

Niclosamide

Pyrantel pamoate

Ivermectin

Praziquantel

Oxamniquine

Benzimidazole Thiazole

1) a) Draw the general structure of benzimidazoles. Draw structure of thiabendazole and give the names of the heterocyclic ring systems included in its structure. Which of the two heterocycles is also present in many other antihelmintics?

1

2

3 4

5

6

7

1

2 3

4

5 present in

many other

antihelmintics

Thiabendazole

General structure of benzimidazoles:

b) Assess the basicity of the benzimidazole nitrogen with respect to the thiazole nitrogen in thiabendazole structure. Explain!

pKa= 4.7

pKa= 2.5

The basicity of the nitrogen in thiazole is reduced by the presence of sulphur.

Compared to N1 of imidazole, sulphur has a weaker electron-releasing

resonance effect. So, in imidazole resonance stabilization is more possible

after protonation making imidazole more basic.

Thiabendazole

c) Draw the structures of mebendazole (methyl 5-benzoyl-2-benzimidazole carbamate) and albendazole (methyl 5-(propylthio)-2-benzimidazole carbamate).

Mebendazole

Albendazole

d) Is the poor water solubility of benzimidazoles beneficial for the pharmacological action? Explain your answer!

Beneficial because the primary indications are

intestinal helminthes.

e) Give three side effects of the most toxic benzimidazole from the ones mentioned above. Which side effect is the most severe one? Which benzimidazoles shoud not be given during pregnancy?

Most toxic benzimidazole: thiabendazole

Side effects: hepatotoxicity and crystallurea less used

than the other benzimidazoles

Most toxic side effect: Steven-Johnson syndrome

Benzimidazoles should not be given during pregnancy:

mebendazole and albendazole (teratogenic in rats)

Stevens–Johnson syndrome is a life-threatening case affecting the skin and mucous membrane. The syndrome is a hypersensitivity complex.

Disintegration Dissolution

……..

……… absorption

GIT

Blood

Dissolution may be rate limiting factor for absorption

2) a) Draw the structure of the antihelmintic drug piperazine citrate indicating the right stoichiometry of the salt.

Piperazine Citrate

b) Give its indication and mechanism of action.

Treatment of pinworm and roundworm infections

Mechanism of action: paralysis of the worm by

blocking neuromuscular transmission

Highly soluble in water and rapidly absorbed.

3) Explain the role of the pamoate anion in the antihelmintic drug pyrantel pamoate (embonate).

Pamoate causes reduced water solubility reduced

absorption and longer residence time in GI tract, the drug

is mainly acting against intestinal nematodes

pamoate pyrantel

Drug of choice against tapeworm infections ( not

effective against pinworms and round worms

4) Give the name of the following drug and indicate its major therapeutic application.

Niclosamide

Cl

OH

NH

O

Cl

N

O

O

Salicylanilide analog

5)a) Give the name of the following drug and indicate its major therapeutic application and metabolism.

Oxamniquine

Tetrahydroquinoline analog

Indicated for the treatment of intestinal schistosomiasis caused by S. mansoni. Good oral bioavailability.

Metabolism: inactive metabolites

HN

O2N

CH2OH

HN

HN

O2N

CH2OH

NH2

O

+

HN

O2N

CH2OH

CHO

NH3

+

HN

O2N

CH2OH

COOH

1 2 3

1) Oxidative N-dealkylation

2) Deamination

3) Aldehyde oxidation

H N

O 2N

C H 2O H

HN

H N

O 2N

C H O

HN

H N

O 2N

C O O H

HN

a lc ox id a tion a ld eh yde o x ida tio n

5)b) Oxamniquine has a unique mechanism of action involving its esterification to phosphate or sulfate followed by the formation of a reactive carbocation that alkylates DNA. Write a reaction sequence illustrating this unique mechanism of action.

electrophile

the helminth DNA is destroyed

Oxamniquine

17

Drugs against ectoparasitic infections

Pyrethrines

Benzyl Benzoate

Lindane

Crotamiton

Scabies

Lice (pediculosis) Treatment

Benzyl benzoate Crotamiton

6) Draw the structures of benzyl benzoate , crotamiton is (N-ethyl amide of o-toluidine and crotonic acid) explain and give their major indications.

Indicated for the topical treatment of scabies

Natural product from

Perubalsam

trans

o-toluidine crotonic acid

ϒ-1,2,3,4,5,6-hexachlorocyclohexane

b) why is lindane only a second-line antiscabious and antipedicular agent?

It is readily absorbed through skin (especially the

scalp) causing neurotoxic side effects (convulsions,

dizziness)

7) a) Draw the structure of the insecticide lindane indicating the right stereochemistry.

d) Why has lindane been banned from the agricultural use?

1) It is not metabolized

2) Highly lipophilic drug accumulating in the body

So considered as an environment pollutant

c) what precautions should be taken while using it?

Application should avoid longer contact with skin

8) a) Explain the expressions pyrethrines and pyrethroides.

Pyrethrines: natural active ingredients extracted from from dried

flower heads of Chrysanthemum plants and used as insecticide.

Pyrethrines are expensive and undergo easy hydrolysis and oxidation.

Pyrethroides: synthetic analogs of pyrethrins.

Pyrethroids are cheaper and more stable.

b) Indicate whether the following structures belong to pyrethrines or pyrethroides. Which one has a generic name permethrin?

Pyrethrine

Pyrethrine

Pyrethroide

Permethrin

c) Give the structures of metabolites of Pyrethrin I and Permethrin. Which one is the most effective insecticide?

Oxidation

Epoxidation

Oxidation

Oxidation Hydrolysis

Permethrin (a pyrethroid) is less extensively metabolised than the natural

pyrethrines. However it still can be metabolized to remain safe for human.

d) Pyrethrines are used in a combination with piperonyl butoxide. Explain the role of the coadministrated piperonyl butoxide .

e) Explain in short the mechanism of action of permethrin.

They act on the nerve cell membranes disturbing the

sodium channel conductance

Pyrethrines high cost, rapid degradation

So they are used in combination with piperonyl butoxide

(inhibits the P450 enzyme preventing the oxidative

inactivation of the drug by the insect)

NB. piperonyl butoxide is also combined with some

pyrethroids which show high metabolic liability (check

LICID ®)

Study Guide (tut 2) The lecture slides describing different types of parasites and their

characteristics are background preparatory slides to understand the

treatment but no to memorize. Only read them. (slides 3-11in the

lecture).

Structures to be memorized : thiabendazole, mebendazole albendazole, piperazine citrate, benzyl benzoate and lindane.

All the other structures in the tut and the lecture slides are to be

identified

The metabolic reactions and synthetic pathways outlined should be

well-understood so that you are able to predict and complete them

yourself.

For the uses of all Antihelmintics whether in lecture or tutorial slides

you can depend on the table uploaded on PBT website as

supplementary material for lec 2 (enough to study the uses from this table) :http://pbt.guc.edu.eg/Courses/Material.aspx?crsEdId=123

http://pbt.guc.edu.eg/Courses/Material.aspx?crsEdId=123