Laxatives

LAXATIVES

(Aperients, Purgatives, Cathartics)

These are drugs that promote evacuation of bowels. A distinction is sometimes made according to the intensity of action.

a) Laxative or Aperient: milder action, elimination of soft but formed stools.

a)  Purgative or Cathartic: stronger action resulting in more fluid evacuation.

Many drugs in low doses act as laxative and in larger doses as purgative.

Classification

1. Bulk Forming

Dietary fibre: Bran, Psyllium (Plantago)

Ispaghula, Methylcellulose

2. Stool Softener

Docusates (DOSS), Liquid paraffin

3. Stimulant Purgatives

a) Diphenylmethanes: Phenolphthalein, Bisacodyl, Sodium picosulfate

b) Anthraquinones (Emodins): Senna, Cascara sagrada

c) 5HT₄ Agonist: Tegaserod

d) Fixed Oil: Castor oil

4. Osmotic purgatives

Magnesium Salts: sulfate, hydroxide

Sodium Salts: sulfate, phosphate Sod. pot. tartrate Lactulose

Mechanism Of Action

All purgatives increase the water content of faeces by:

a)     A hydrophilic or osmotic action, retaining water and electrolytes in the intestinal lumen—increase volume of colonic content and make it easily propelled.

b)     Acting on intestinal mucosa, decrease net absorption of water and electrolyte; intestinal transit is enhanced indirectly by the fluid bulk.

c)    Increasing propulsive activity as primary action—allowing less time for absorption of salt and water as a secondary effect.

For some of the drugs, controversy continues as to whether they increase water content of stools as the primary action or it is a consequence of increased motility. However, certain purgatives do increase motility through an action on the myenteric plexuses. Laxatives modify the fluid dynamics of the mucosal cell and may cause fluid accumulation in gut lumen by one or more of following mechanisms:

a)     Inhibiting Na+K+ATPase of villous cells— impairing electrolyte and water absorption.

b)    Stimulating adenylyl cyclase in crypt cells— increasing water and electrolyte secretion.

c)    Enhancing PG synthesis in mucosa which increases secretion.

d)    Structural injury to the absorbing intestinal mucosal cells.

BULK PURGATIVES

Dietary Fibre: Bran

Dietary fibre consists of unabsorbable cell wall and other constituents of vegetable food—cellulose, pectins, glycoproteins and other polysaccharides. Bran is a byproduct of flour industry—consists of ~40% dietary fibre. It absorbs water in the intestines, swells, increases water content of faeces—softens it and facilitates colonic transit. Osmotically active products may be formed in the colon by bacterial degradation of pectins, etc. which act to retain water. Dietary fibre supports bacterial growth in colon which contribute to the faecal mass. Certain dietary fibres (gums, lignins, pectins) bind bile acids and promote their excretion in faeces → degradation of cholesterol in liver is enhanced → plasma LDL-CHolesterol is lowered.

Increased intake of dietary fibres is the most appropriate method for prevention of functional constipation. It is the first line approach for most patients of simple constipation. Prolonged intake of bran and other bulk forming agents reduces rectosigmoid intraluminal pressure—relieves symptoms of irritable bowel syndrome (IBS) including pain, constipation as well as diarrhoea, and of colonic diverticulosis. It is also useful when straining at stools has to be avoided.

Drawbacks: Bran is generally safe, but it is unpalatable, large quantity (20–40 g/day) needs to be ingested. It has been included in some breakfast cereals. Full effect requires daily intake for at least 3–4 days. It does not soften faeces already present in colon or rectum. As such, bran is useful for prevention of constipation, but not for treating already constipated subjects. Flatulence may occur.

It should not be used in patients with gut ulcerations, adhesions, stenosis and when faecal impaction is a possibility.

Psyllium (Plantago) and Ispaghula

They contain natural colloidal mucilage which forms a gelatinous mass by absorbing water; 3–12 g of refined husk freshly mixed with water or milk and taken daily—acts in 1–3 days. It should not be swallowed dry (may cause esophageal impaction).

Ispaghula husk (refined): ISOGEL (27 g/ 30 g), NATURE CURE (49 g/100 g), FYBOGEL (3.5 g/5.4 g) powder FIBRIL (3.4 g/11 g) powder;

Psyllium hydrophilic mucilloid: ISOVAC (65 g/100 g) granules.

Methylcellulose

A semisynthetic, colloidal, hydrophilic derivative of cellulose; 4–6 g/day is satisfactory in most individuals.

Generous amounts of water must be taken with all bulk forming agents. The choice among different bulking agents is a matter of personal preferences.

STOOL SOFTENER

Docusates (Dioctyl sodium sulfosuccinate: DOSS)

It is an anionic detergent, softens the stools by net water accumulation in the lumen by an action on the intestinal mucosa. It emulsifies the colonic contents and increases penetration of water into faeces. By a detergent action, it can disrupt the mucosal barrier and enhance absorption of many nonabsorbable drugs, e.g. liquid paraffin—should not be combined with it. It is a mild laxative; especially indicated when straining at stools must be avoided.

Dose: 100–400 mg/day; acts in 1–3 days.

CELLUBRIL 100 mg cap; LAXICON 100 mg tab, DOSLAX 150 mg cap.

As enema 50–150 mg in 50–100 ml; LAXICON 125 mg in 50 ml enema.

Cramps and abdominal pain can occur. It is bitter; liquid preparations may cause nausea. Hepatotoxicity is feared on prolonged use.

Liquid Paraffin

It is a viscous liquid; a mixture of petroleum hydrocarbons, that was introduced as a laxative at the turn of 19th century. Millions of gallons have passed through the intestinal pipeline since then. It is pharmacologically inert. Taken for 2–3 days, it softens stools and is said to lubricate hard scybali by coating them.

Dose: 15–30 ml/day—oil as such or in emulsified form.

Disadvantages

a)      It is bland but very unpleasant to swallow because of oily consistency.

b)      Small amount passes into the intestinal mucosa—is carried into the lymph → may produce foreign body granulomas in the intestinal submucosa, mesenteric lymph nodes, liver and spleen.

c)       While swallowing it may trickle into lungs—cause lipid pneumonia.

d)      Carries away fat soluble vitamins with it into the stools: deficiency may occur on chronic use.

e)       Leakage of the oil past anal sphincter may embarrass.

f)        May interfere with healing in the anorectal region. Thus, it should be used only occasionally.

STIMULANT PURGATIVES

They are powerful purgatives: often produce griping. They were thought to irritate the intestinal mucosa and thus stimulate motor activity. Though some of them do primarily increase motility by acting on myenteric plexuses, the more important mechanism of action is accumulation of water and electrolytes in the lumen by altering absorptive and secretory activity of the mucosal cell. They inhibit Na+K+ATPase at the basolateral membrane of villous cells—transport of Na+ and accompanying water into the interstitium is reduced. Secretion is enhanced by activation of cAMP in crypt cells and by increased PG synthesis.

Larger doses of stimulant purgatives can cause excess purgation → fluid and electrolyte imbalance. Hypokalaemia can occur on regular use. Routine and long-term use must be discouraged; produces colonic atony. They can reflexly stimulate gravid uterus—contraindicated during pregnancy. Subacute or chronic intestinal obstruction is another contraindication.

Diphenylmethanes

Phenolphthalein is an indicator and is in use as purgative from the beginning of the 20th century. It turns urine pink if alkaline.

Bisacodyl is a later addition and is more popular. They are partly absorbed and re-excreted in bile: enterohepatic circulation is more important in phenolphthalein which can produce protracted action. Bisacodyl is activated in the intestine by deacetylation. Their primary site of action is in the colon: irritate the mucosa, produce mild inflammation and secretion. One or  two semiformed motions occur after 6–8 hours. Optimum doses vary considerably among individuals. Average doses are:

Phenolphthalein 60–130 mg: LAXIL 130 mg tab. To be taken at bedtime (tab. not to be chewed).

Bisacodyl 5–15 mg: DULCOLAX 5 mg tab; 10 mg (adult), 5 mg (child) suppository: CONLAX 5 mg, 10 mg suppository, BIDLAX5 5 mg tab.

These doses may be ineffective in some individuals, but produce fluid evacuations and cramps in others. Morphological alterations in the colonic mucosa have been observed—mucosa becomes more leaky.

Allergic reactions—skin rashes, fixed drug eruption and Stevens Johnson Syndrome have been reported.

Phenolphthalein has been found to produce tumours in mice and genetic damage. The USFDA has ordered its withdrawal from the market.

Bisacodyl is also available as 5 mg (infant) and 10 mg (adult) suppository—acts by irritating the anal and rectal mucosa → reflex increase in motility → evacuation occurs in 20–40 min. It can cause inflammation and mucosal damage.

Sodium picosulfate: Another diphenylmethane related to bisacodyl. Like others, it is hydrolysed by colonic bacteria to the active form, which then acts locally to irritate the mucosa and activate myenteric neurones. Bowel movement generally occurs after 6–12 hours of oral dose. Along with mag. citrate solution, it has been used to evacuate the colon for colonoscopy or surgery.

Dose: 5–10 mg at bed time. Indications and side effects are similar to bisacodyl.

CREMALAX, LAXICARE 10 mg tab; PICOFIT 5 mg/5 ml syr.

Anthraquinones

Senna is obtained from leaves and pod of certain Cassia sp., while Cascara sagrada is the powdered bark of the buckthorn tree. These and a number of other plant purgatives contain anthraquinone glycosides, also called emodins. Senna is most popularly used. The glycosides are not active as suCh. No. Unabsorbed in the small intestine, they are passed to the colon where bacteria liberate the active anthrol form, which either acts locally or is absorbed into circulation—excreted in bile to act on small intestine. Thus, they take 6–8 hours to produce action. Amount secreted in milk is sufficient to cause purgation in the suckling infant.

The purgative action and uses of anthraquinones are quite similar to diphenylmethanes. Taken at bed time—a single, soft but formed evacuation generally occurs in the morning. Cramps and excessive purging occur in some cases. The active principle acts on the myenteric plexus to increase peristalsis and decrease segmentation. They also promote secretion and inhibit salt and water absorption in the colon. Senna anthraquinone has been found to stimulate PGE₂ production in rat intestine—this is blocked by indomethacin and the purgative action is reduced.

Skin rashes, fixed drug eruption are seen occasionally.

Regular use for 4–12 months causes colonic atony and mucosal pigmentation (melanosis).

Sennosides (Cal. salt): GLAXENNA 11.5 mg tab; PURSENNID 18 mg tab; SOFSENA 12 mg tab.

Tegaserod

It is a new selective 5HT₄ receptor partial agonist with no action on other receptors. By activating prejunctional 5HT₄ receptors on intrinsic enteric afferents (see Fig. 47.2), tegaserod enhances release of excitatory transmitters ACh and calcitonin gene related peptide (CGRP) which promote peristalitic reflex and colonic secretion (by enhancing cAMP mediated Cl– efflux). Propulsive activity is increased in the stomach, ileum and most prominently in colon.

The primary indication of tegaserod is constipation-predominant irritable bowel syndrome (IBS), in which modest increase in stool frequency and some relief of abdominal pain and bloating have been noted. It is also approved for treatment of chronic constipation: frequency of satisfactory bowel movement is moderately increased and hardness of stools/straining are reduced. However, efficacy in IBS as well as chronic constipation is not superior to conventional laxatives.

Only a small fraction of tegaserod is absorbed. It is mainly excreted unchanged in faeces. The elimination t½ of absorbed drug is 11 hr. Side effects reported are loose motions, flatulence and headache.

Dose: 2–6 mg BD before meals.

TEGIBIS, IBSINORM 2, 6 mg tabs; TAGON, TEGOD 6 mg tab.

Castor oil

It is one of the oldest purgatives. Castor oil is a bland vegetable oil obtained from the seeds of Ricinus communis; has been used on the skin as emollient. It mainly contains triglyceride of ricinoleic acid which is a polar long chain fatty acid. Castor oil is hydrolysed in the ileum by lipase to ricinoleic acid and glycerol. Ricinoleic acid, being polar, is poorly absorbed. It was believed to irritate the mucosa and stimulate intestinal contractions. The primary action has now been shown to be decreased intestinal absorption of water and electrolytes, and enhanced secretion by a detergent like action on the mucosa. Structural damage to the villous tips (expected of a detergent) has also been observed. Peristalsis is increased secondarily.

Dose: 15–25 ml (adults) 5–15 ml (children) is generally taken in the morning. Because the site of action is small intestine, purgation occurs in 2–3 hours—motion is semifluid and often accompanied by griping.

Due to its unpalatability, frequent cramping, a rather violent action, possibility of dehydration and afterconstipation (due to complete evacuation of colon), it is no longer a favoured purgative. Regular use is particularly to be avoided—may damage intestinal mucosa.

OSMOTIC PURGATIVES

Solutes that are not absorbed in the intestine retain water osmotically and distend the bowel—increasing peristalsis indirectly. Magnesium ions release cholecystokinin which may aid purgative action of Mag. salts. All inorganic salts used as osmotic (saline) purgatives have similar action—differ only in dose, palatability and risk of systemic toxicity.

·          Mag. sulfate (Epsom salt): 5–15 g; bitter in taste.

·      Mag. hydroxide (as 8% W/W suspension— milk of magnesia) 30 ml; bland in taste, also used as antacid.

·          Sod. sulfate (Glauber’s salt): 10–15 g; bad in taste.

·          Sod. phosphate: 6–12 g, taste not unpleasant.

·          Sod. pot. tartrate (Rochelle salt): 8–15 g, relatively pleasant tasting.

The salts in above mentioned doses, dissolved in 150–200 ml of water, produce 1–2 fluid evacuations within 1–3 hours with mild cramping; cause nearly complete emptying of bowels. Smaller doses may have a milder laxative action.

Mag. salts are contraindicated in renal insufficiency, while Sod. salts should not be given to patients of CHF and other Sod. retaining states. Repeated use of saline purgatives can cause fluid and electrolyte imbalance.

They are practically not used for the treatment of constipation, because after-constipation is quite common. However, they may be preferred for preparation of bowel before surgery and colonoscopy; in food/drug poisoning and as after-purge in treatment of tapeworm infestation.

Lactulose

It is a semisynthetic disaccharide of fructose and lactose which is neither digested nor absorbed in the small intestine—retains water. Further, it is broken down in the colon by bacteria to osmotically more active products. In a dose of 10 g BD taken with plenty of water, it produces soft formed stools in 1–3 days. Flatulence and flatus is common, cramps occur in few. Some patients feel nauseated by its peculiar sweet taste.

Lactulose causes reduction of blood NH₃ concentration by 25–50% in patients with hepatic encephalopathy. The breakdown products of lactulose are acidic—reduce the pH of stools.

Ammonia produced by bacteria in colon is converted to ionized NH⁺₄ salts and is not absorbed. For this purpose 20 g TDS or more may be needed.

LACSAN, MTLAC 10 g/15 ml liq. DUPHALAC, LIVOLUK 6.67 g/10 ml liq.

Other drugs used to reduce blood NH₃ in hepatic coma are sod. benzoate and sod. phenyl acetate. They combine with NH₃ in blood to form hippuric acid or phenyl acetic glutamine respectively: these are rapidly excreted in urine.