MEDICINAL CHEMISTRY

to the bile acids. Thus due to enterohepatic reabsorptioin of the bile acids further of
cholesterol is suppressed.
Cholestyramine (191) and colestipol (192) are the examples of bile acid-binding resins
which forrti a sort of non-absorbable complex with bile acids due to the presence of
quaternary nitrogen in their structure. Thus these drugs promote their elimination from
the gut and inhibit their reabsorption into the circulation. The fecal excretion of bile
acids in fact, has been shown to increase 30 folds by these drugs.
CH CH2 CH
CH2
H2C CH CH2N(CH3) 3Cl n
Cholestyramine (191)
N
CH
CH 2
CH 2CH 2
OH
N CH 2CH 2
Colestipol (192)
Cholestyramine and colestipol are the examples of anion exchange resins and remain
undigested and nonabsorbable in the GIT. Hence the drugs are considered safest
antilipidemic agents due to the lack of systemic effects. They are used only in the
patients who have elevated LDL levels. In the treatment of familial
hypercholesterolemia, usually a combination of cholestyramine and nicotinic acid gives
better results. Besides bile acids, these resins also bind with other drugs due to their
anionic nature. Thus absorption of thyroxine vitamin C, digitalis glycosides, iron, and
warfarin is reported to be impaired by these resins. Colestipol appears to similar to
cholestyramine in mechanism of action.
Structure-activity Relationships
Cholestyramine is a copolymer consisting primarily of polystyrene with a small amount
of divinylbenzene as the cross-linking agent. These positively charged Cholestyramine
and colestipol are not orally absorbed groups function as binding sites for anions.
Virtually all of and are not metabolized by gastrointestinal enzymes. They these sites are
accessible by bile acids. Increasing the amount of divinylbenzene from 2% to 4% to 8%
increases the cross linkage and reduces the porosity of the resin acids. This prevents
binding of bile acids to interior sites and decreases the efficacy of the compound.
Colstipol is a copolymer of tetraethylenepentamine and epichlorohydrin and is
commercially marked as its hydrochloride salt. The key functional groups on colestipol
are the basic secondary and tertiary amines. Although the total nitrogen content of
colestipol is greater than that of cholestyramine, the functional anion exchange capacity
of the resin depends upon intestinal pH and may be less than cholestyramine.
Quaternization of colestipol with methyl iodide increases the capacity in vitro for
glycocholate
(iv) Inhibition of LDL oxidation: Oxidised LDL is taken by macrophages to convert it
into foam cell. Groups of these foam cells constitute the earliest hallmark of
n
N
N