BENZIMIDAZOLES AND PROBENZIMIDAZOLES

Question 1

ANTHELMINTICS /OR ANTIHELMINTHICS/

Answer 1

• Drugs that expel parasitic worms (helminths) from host, by stunning or killing them. - aka vermifuges (stunning) or vermicides (killing).
• Must be selectively toxic to the parasite. - usually achieved either by inhibiting special metabolic processes of worms, or by inherent pharmacokinetic properties that cause the parasite to be exposed to higher ccs of the anthelmintic than the host cells.
• The precise mode of action of many anthelmintics is not clear, the sites of action & biochemical mechanisms of many of them are generally known.

Question 2

Modern anthelmintics generally

Answer 2

• have a wide margin of safety,
• have considerable activity against immature (larval, ovoid) and mature stages of helminths,
• and have a broad spectrum of activity

Question 3

CLASSIFICATION of ANTHELMINTICS 1.

Answer 3

Drugs for roundworms (nematodes) Antinematodals (AN)
• Drugs for tapeworms (cestodes) Anticestodals (AC)
• Drugs for flukes (trematodes) Antitrematodals (AT)

Question 4

CLASSIFICATION of ANTHELMINTICS 2.

Answer 4

Benzimidazoles and probenzimidazoles (AN, AC, some AT) 
Macrocyclic lactones (Avermectins and milbemycins) (AN) 
Imidazothiazoles (AN) 
Isoquinolin and benzazepin derivatives (AC, some AT) Organophosphates (AN) 
Piperazines (AN) 
Tetrahydropyrimidines (AN) 
Salicylanilides and substituted phenols (AT, AC, AN)
Others (unclassified drugs) (AN, or AT, or AC)

Question 5

BENZIMIDAZOLES AND PROBENZIMIDAZOLES SUBSTANCES („BZ-s”)

Answer 5

1. THIAZOLIL BENZIMIDAZOLES Thiabendazole (1961), Cambendazole
2. BENZIMIDAZOLE CARBAMATES (5-keto BZs, Sulphid-BZs) MEBENDAZOLE, OXIBENDAZOLE, Albendazole, Fenbendazole, Oxfendazole (Fenbendazole sulphoxide), Ricobendazole (Albendazole sulphoxide),
   + Halogenated: FLUBENDAZOLE, TRICLABENDAZOLE and Luxabendazole
3. PROBENZIMIDAZOLES (PRO-DRUGS) Febantel=>Fenbendazole=>Oxfendazole Netobimin=>Albendazole=>Ricobendazole Thiophanate=>Lobendazole

Question 6

BENZIMIDAZOLES AND PROBENZIMIDAZOLES MECHANISM OF ACTION

Answer 6

Primary effect:
Inhibition of tubulin polymerization; by binding to the colchicine-sensitive site of tubulin=> inhibiting assembly into microtubules=> degenerative alterations in the tegument & intestinal cells of the worm. (9, 11 or 13 protofilaments).

Secondary effect:
Inhibition of cellular transport and energy metabolism,
- The loss of the cytoplasmic microtubules =>impaired uptake of glucose by the larval and adult stages of the susceptible parasites, and depletes their glycogen stores.
- Degenerative changes in ER, mitochondria of the germinal layer=>release of lysosomes => decreased production of ATP required for the survival of the helminth.
-Albendazole also has been shown to inhibit the enzyme fumarate reductase, which is helminth-specific.

Question 7

BENZIMIDAZOLES AND PROBENZIMIDAZOLES DEWORMING EFFECT - ANTHELMINTIC SPECTRUM

Answer 7

Antinematodal effect (AN) 
- Broad spectrum against roundworms (nematodes).  - Larvicidal and ovicidal (Alb., Fenb., Feban., Oxf., Oxib.) effect. (Triclabendazole has no activity against roundworms.) 

Anticestodal effect (AC) 
Febantel, Fenbendazole, Netobimin, Albendazole, Ricobendazole, Mebendazole, Oxfendazole, Flubendazole, Luxabendazole 

Antitrematodal effect (AT) (for flukes, Fasciola, Dicrocoelium, Paramphistomum spp.)
Netobimin, Albendazole (only for older larval & adult stages of liver + other flukes).
Triclabendazole – only liver fluke (Fasciola hepatica) effective against both immature & adult flukes.

Question 8

BENZIMIDAZOLES AND PROBENZIMIDAZOLES
OTHER EFFECTS
RESISTANCE

Answer 8

OTHER EFFECTS Antitumor Antifungal / fungicide Antiviral Ion-pump inhibition (Omeprazol) Antiparasitic effect (giardia /FEN/, ear mite /THIA/)

RESISTANCE
Ruminants GI-roundworms, frequently as multiple resistance against BZs, endectocides and Levamisole Swine Oesophagostomum spp. (Germany, Denmark) Horse large strongyles

Question 9

BENZIMIDAZOLES AND PROBENZIMIDAZOLES PHARMACOKINETIC FEATURES

Answer 9

• Limited absorption from the GI of the host (except e.g. Alb., Oxf., and Triclab. F<0.3).
• Absorption lasts for 6-30 h after dosing (Flub. 2-7 h).
• Rate of passage is slowed by the rumen/caecum (eq)
• Reduced feed intake may increase the activity of BZs. - The rumen acts as a drug reservoir from which plasma concentrations can be sustained for long periods.

Metabolism of the benzimidazoles is variable & may alter their activity, e.g. Albendazole is rapidly and reversibly oxidized to its sulphoxide.

• Benzimidazole sulphoxides i.e. Oxfendazole & Albendazole sulphoxide bind poorly to parasite β-tubulin & act like prodrugs for Fenbendazole + Albendazole.
• The sulphoxide may be irreversibly oxidized to its sulphone, which is significantly less active than the sulphoxide. Excretion: The biliary route=most important pathway for secretion & (enterohepatic) recycling of BZs to the GI tract.
• Parent drugs & their metabolites are eliminated with faeces.

SIDE-EFFECTS PO relatively safe, non-toxic agents (TI≥20)
• Teratogenicity /Oxfendazole, Albendazole, and Febantel/ (e.g. Albendazole during the early pregnancy in ewes, infertility may occur in cows).
• Hepatotoxicity, hair/ feather-loss (using larger doses or according to prolonged application).
• Neurotoxicity (according to mega doses or „parenteral use”).

Question 10

APPLICATION

Caps= not food producers

Answer 10

• BZs are sparingly soluble in water
• PO as a suspension, paste, bolus or premix, (except Netobimin, which can be injected).
• Thiabendazole - topically too (as fungicide/ against ear mites & cutaneous larva migrans).
• Withholding periods 8-14 days before slaughtering for meat, and 3-5 days before milking, longer for bolus .
• Ruminants (Netob., Alb., Ricob., Feban., Fenb., Oxf., Meb (MEB. not in cattle)., and Triclab.)
• Systemic anthelmintic activity of most BZs is greater in Ov than in Bo (faster metabolism)=>Bo doses often higher.

Special drug delivery systems: (only sheep and goat)
- Pulse-release bolus /Oxfendazole (750 or 1,250 mg/tablet) are released app. every3 wk in rumen
- Sustained-release bolus /Fenbendazole 12 g, release profile of 140 d./,
- Slow-release capsule /Albendazole 3,85 g, release profile of 105 d./.
Widespread resistance among GI nematodes!

• Horses (Fenb., Febant., Oxf., MEB., TRICLAB.) High levels and repeated administration may be necessary for extraintestinal migrating stages of large strongyles (widespread resistance).
• Swine (Fenb., Flub., OXIB., MEB.) BZs show high efficacy against both adult & immature stages of Ascaris suum. Highly effective against most other Sus nematodes. (resistance Oesophagostomum spp.)
• Cats and Dogs (Febant., Fenb., Flub., Meb., Oxib.) Treatment of roundworms, hookworms & tapeworms. However, treatment must be given bid for 3 days.
• Birds, Poultry (Flub., FENB., MEB.) Against GI and respiratory nematodes.