Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Laxatives
ATC-code: A 06 AB
The active ingredient ispaghula husk consists of the episperm and collapsed adjacent layers removed from the seeds of Plantago ovata Forssk (Plantago ispaghula Roxb.). Ispaghula husk is particularly rich in alimentary fibres and mucilages, its mucilage content being higher than that of other Plantago species. Ispaghula husk is capable of absorbing up to 40 times its own weight in water. Ispaghula husk consists of 85% water-soluble fibre; it is partly fermentable (in vitro 72% unfermentable residue) and acts by hydration in the bowel. Gut motility and transit rate can be modified by ispaghula through mechanical stimulation of the gut wall as a result of the increase in intestinal bulk by water and the decrease in viscosity of the luminal contents or by contact with rough fibre particles. When taken with a sufficient amount of liquid (at least 30 ml per 1 g Agiolax) ispaghula produces an increased volume of intestinal contents due to its highly bulking properties and hence a stretch stimulus, which triggers defaecation; at the same time the swollen mass of mucilage forms a lubricating layer, which makes the transit of intestinal contents easier.
The other active substance, senna pods contain 1,8-dihydroxyanthracene derivatives which possess a laxative effect. The β-O-linked glycosides (sennosides) are not absorbed in the upper gut; they are converted by bacteria of the large intestine into the active metabolite (rhein anthrone).
There are two different mechanisms of action:
1.      stimulation of the motility of the large intestine resulting in accelerated colonic transit.
2.      influence on secretion processes by two concomitant mechanisms viz.
inhibition of absorption of water and electrolytes (Na+, Cl-) into the colonic epithelial cells (antiabsorptive effect) and increase of the leakiness of the tight junctions and stimulation of secretion of water and electrolytes into the lumen of the colon (secretagogue effect) resulting in enhanced concentrations of fluid and electrolytes in the lumen of the colon.
Defaecation takes place after a delay of 8 - 12 hours due to the time taken for transport to the colon and metabolisation into the active compound.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
The active substance ispaghula seed / husk hydrates and swells to form a mucilage because it is only partially solubilised. Polysaccharides, such as those which dietary fibres are made of, must be hydrolysed to monosaccharides before intestinal uptake can occur. Less than 10 % of the mucilage gets hydrolysed in the stomach, with formation of free arabinose.
Intestinal absorption of the free arabinose is approximately 85 % to 93 %.
Aglyca are absorbed in the upper gut. Animal experiments with radio-labeled rhein anthrone administered directly into the caecum demonstrated absorption < 10%.


Biotransformation
The sugar residues of the xylan backbone and the side chains of psyllium are joined by ß-linkages, which cannot be broken by human digestive enzymes.
To varying degrees, dietary fibre is fermented by bacteria in the colon, resulting in production of carbon dioxide, hydrogen, methane, water, and short-chain fatty acids, which are absorbed and brought into the hepatic circulation. In humans, psyllium reaches the large bowel in a highly polymerised form that is fermented to a limited extent, resulting in increased faecal concentration and excretion of short-chain fatty acids. The β-O-linked glycosides (sennosides) of the active substance senna pods are neither absorbed in the upper gut nor split by human digestive enzymes. They are converted by the bacteria of the large intestine into the active metabolite (rhein anthrone). In contact with oxygen, rhein anthrone is oxidised into rhein and sennidins.

Distribution
Rhein and sennidins can be found in the blood, mainly in the form of glucuronides and sulphates. In human pharmacokinetic studies with senna pods powder (20 mg sennosides), administered orally for 7 days, a maximum concentration of 100 ng rhein/ml was found in the blood. An accumulation of rhein was not observed. Active metabolites, e.g. rhein, pass in small amounts into breast milk. Animal experiments demonstrated that placental passage of rhein is low.

Excretion
After oral administration of sennosides, 3 - 6% of the metabolites are excreted in urine; some are excreted in bile. Most of the sennosides (ca. 90%) are excreted in faeces as polymers (polyquinones) together with 2 - 6% of unchanged sennosides, sennidins, rhein anthrone and rhein.