Drugs for Constipation and Diarrhea Fluid and electrolyte balance

DR. GIRISH, REGISTRAR PHARMACOLOGY AND CLINICAL PHARMACOLOGY CHRISTIAN MEDICAL COLLEGE VELLORE

 Constipation: delayed passage of faeces through

intestine with the process remaining normal Evacuation is often associated with straining and is usually incomplete Functional constipation treatment: increase in roughage in the daily diet, increase in daily fluid intake, increase in physical activity, withdraw offending drugs/use alternative drugs to minimize this side effect

 If these fail: laxatives or purgatives can be used

Aperient < Laxative < Emmolient < Evacuant <

Purgative < Cathartic Intensity depends on dose Now only two are used: laxative and purgative (watery evacuation)

Laxatives
Constipation

Avoid undue straining at defaecation in cases having

hernia, hemorrhoids or CV disease Before or after any anorectal surgery or in bed ridden patients They are mild and are usually faecal softeners

 Bulk forming laxatives Eg. Wheat bran, Psyllium

husk, Isaphagula husk. Semisynthetic cellulose such as carboxy-methyl cellulose and polycarbophils (synthetic fibers) Luminally active, hydrophilic, indigestible vegetable fibres They stimulate peristalsis and defaecation reflexes by increasing faecal bulk due to their water absorbing and retaining capacity

 Adequate amount of water must be taken with all

bulk forming laxatives Choice of agent is a matter of personal preference Effect appears within one to three dyas. Bran powder or husk can be sprinkled over stewed food Side effects: Not abosrbed and quite safe. Bacterial digestion of vegetable fibres within the colon may lead to bloating and faltus causing abdominal discomfort

Osmotic laxatives
Lactulose (10g/15ml), Sorbitol

Luminally active, nonabsorbable-indigestibel

disaccharide (sugar). Increases faecal bulk by hydrophilic action and also due to osmotic action Dose: 10g BD/TDS with plenty of water to produce 2 or 3 soft stools per day. Latency period is 1-3 days Non toxic and suitable for long term use. Flatulence is common, cramps may occur in few. Some patients may feel nauseated due to its peculiar sweet taste

 Treatement of hepatic encephalopathy. 20g TDS

orally is needed. Severe hepatocellular damage because of which portal blood is directly shunted to systemic circulation Hence NH3 in particular gets accumulated in blood leading to CNS toxicity. Lactulose is degraded to lactic acid and converts NH4 + salt which is then excreted

Lubricant laxatives
Liquid paraffin Luminally active, pharmacologically inert mineral oil. Faecal lubricant and stool softener as it retards water

absorption from the stool It is given as 15-30 ml per day at bed time. Latency period is 13 days Not palatable but can be given in emulsified form or with juices. Frequent use leads to the deficiency of fat soluble vitamins (A, D, E and K) as they are carried away with stool in emulsified form. Forcible admin can lead to aspiration lipid pneumonia. Delays healing of enteric fistula Though used occasionally it is useful where straining at defaecation is to be avoided

Surfactant Laxatives
Dioctyl sodium sulfosuccinate (docusate sodium)

Luminally active and is an anionic surfactant which

softens the stool by decreasing the surface tension of fluids in the bowel. Wetting agent because by emulsifying the colonic contents it facilitates the mixing of water into fatty substances of the faeces

 100-400 mg per day in divided doses

Mild laxative specially indicated when straining is to

be avoided (latency period 1-3 days) Not absorbed hence not toxic. Bitter in taste. Cramps and abd pain Hepatotoxicity after prolonged use. Dont give liquid parafiin together

Purgatives
Complete colonic cleaning prior to GI endoscopic

procedures May also be needed for post op or post MI bed riddeen patients and to flush out worms after the use of an antihelminthic drug Prepare bowel before surgery or abd X Ray and for neurologically impaired patients. Semifluid stool or watery evacuation Low doses these can be used as laxatives also

Osmotic purgatives
Saline purgatives: Magnesium sulfate, hydroxide (milk of

magnesia), sodium sulfate and sodium phosphate Polyethylene glycol (PEG) Electrolyte osmotic purgative. Osmoteic purgatives lead to watery evacuation All of them act on small as well as large intestine. Saline are inorganic salts which increase faecal bulk by retaining water by osmotic effect, thus increasing peristalsis indirectly. Magnesium salts also release CCk which further helps in inreasing intestinal secretion and peristalsis. Most common is milk of magnesia. 30 ml of it s 8% w/w suspension is given in the morning because it is quite effective. Its effects come within 2-3 hours.

 Should be ingested with enough water , because

being irritants these can induce vomiting. Hyperosmolar agents may lead to intravascular fluid depletion and electrolyte disturbances. Avoid prolonged use in renal insufficiency patients due to risk of hypermagnesaemia, as about 20% of ingested magnesium is normally absorbed

Irritant purgatives
Anthraquinone : Senna, cascara and aloe

Organic irritants: Phenolphthalein, bisacodyl (and

its suppository), sodium picosulfate and Oils: Castor oil. Irritant purgatives provide soft semifluid stools Stimulate peristalsis by irritant action on intestinal mucosa Stimulate colonic electrolyte and fluid secretion by altering the absorptive and secretory activity of mucosal cells.

 Senna is most common Anthraquinone glycosides on reaching colon, the bacteria

degrede them to the active principle anthrol which either acts locally or is absorbed into circulation. After being excreted through bile it then stimulates small intestine Primary site of action of organic irritants is in the colon. Bisacodyl is metabolised in the intestine into an acive deacetylated metabolitte. In the colon sodium picosulfate is also converted to an active metabolite which stimulates peristalsis and promotes water and elecltroltye accumulation

 Castor oil itself is non irritatn. It is hydrolysed in

intesting by pancreatinc lipase to ricinolic acid which increases the intestinal motility Phenolphtalein dose 60 -130 mg at bed tiem Effect within 6 8 hours. Bisacodyl at a dose of 5 10 mg at bed time. Effect within 8 10 hours

 Phenolphthalein : cardiotoxicity and carcinogenicity

Bisacodyl: quite safe except for occ abd cramps and

skin rashes Castor oil not favoured because of its unpalatability, frequent cramping, after constipation and risk for damaging intestinal mucosa. Contraindicated in pregnancy (to avoid pelvic congestion)

Antidiarrhoeal agents
Diarrhea is an abnormal increase in the frequeny

and the liquidity of stools. Increased motility of GIT and the decreased ability of intestine to absorb water from the stool are the major factors in the causation of diarrhoea Treatment of specific infective diarrhea needs proper diagnosis and appropriate drug treatment by selecting proper antibiotic or an antiprotozoal drug or a combination of both

 For symptomatic relief of non-specific diarrheas, foll

drugs are useful: Anitmotility and antisecretory drugs: Opiod agonists Loperamide, diphenoxylate, difenoxin and racecadotril Stimulate peripheral mu as well as delta receptors present on small and large intestine

 Activation of mu receptor decreases motility; while

activation of delta receptors decreases intestinal secretions. Although all opioids such as morphine or codiene have anti-diarrheal effects, their CNS effects and dependence liability limit their usefulness
Loperamide: OTC drum among opioid agonists that

does not cross BBB and has neither analgesic effects nor any addiction liability. As an antidiarrheal agent it is 40 times more potent than morphine

 Usual adult dose is 4 mg followed by 2 mg after each

loose motion to a max of 16mg/day (onset of action is 2 hours; duration of effect is 6 12 hours) However for chronic diarrheas, it si commonly given as 2-4 mg TDS. Diphenoxalate or its active metabolite difenoxin are other agonists that have no analgesic properties. Higher doses have some depr effect More potent than morphine but less than loperamide LOMOTIL contains diphenoxylate 2.5mg with small doses of atropine (0.025mg) to discourage abuse potential

 Atropine prevents possible abuse of diph because of

the undesirable effects would appear prior to pleasurable effects of opioids Dose is 2 tab TDS or QID Effective against travellers diarrhea or to prevent non specific diarrhea but replacement of fluids through ORS is still the mainstay for such therapy Well tolerated, except for some milder side effects like abdominal discomfort and dry mouth

 These drugs should not be used in patients with

colitis in order to avoid development of megacolon. Avoid in patients suffering from acute bacterial diarrheas associated with high fever or blood in stool because of potential of these drugs to decrease the clearance of pathogens and to enhance systemic invasion of these organisms. Not to be used in children below 2 year of age due to danger of paralytic ileus

Racecadotril
New antidiarrheal drug that belongs to this group. Enkephalinase inhibitor that increases local concentration of enkephalins in intestinal mucosa which then stimulates mu and delta opioid receptors

Antisecretory effects are more pronounced compared to its anitmotility effects. Usual adult dose is 100-300 mg TDS. Side effects are mild and include nausea, constipation and headache. It is secreted through breast milk and hence should be avoided in lactating mothers.

Anticholinergics and alpha agonists

motility which results in an increase of fluid absorption, back from the intestinal tract and a decrease in abdominal cramps. However these drugs are not used as a sole anitdiarrheal drug but are used in combination with adsorbents or opiates
Clonidine (0.1 mg BD) oral facilitates absorption,

inhibits secretion of fluids and electrolytes as well as increases the intestinal transit time

 Special role in the treatment of diabetic diarrhea and

in diarrhea caused by opiate withdrawal Blood pressure lowering effects are major factors for its use as a routine agent

Octreotide
Semisynthetic octapeptide with actions similar to

somatostatin. Longer half life (1.5 2hr) compared to somatostain (3 min). It is even more potent than somatostain in inhibiting the secretion of growth hormone, glucagon, insulin and VIP. Release of 5 HT, gastrin, secretin, CCk, motilin and pancreatic polypeptide. Reduces GI motility, intestinal fluid and electrolyte secretion, pancreatic secretion and gall bladder contractions

 Hence mainly used to treat secretory diarrheas

associated with carcinoid tumours and VIP secreting tumours as well as to treat acromegaly and to prevent variceal bleeding (as it decreases hepatic blood flow). It may be given sub cu in a dose of 100 ug BD or TDS. In half dose, it rather stimulates GI motility. Short term therapy leads to slight nausea, abd discomfort and pain at site of injection

 Long term therapy leads to gall stone formation and

hypothyroidism Imapired pancreatic secretion may cause steatorrhea which can lead to fat soluble vitamin deficiency

 Adsorbent drugs

Kaolin and pectin or combination

liquidity in acute diarrheas due to inhibition of PG synthesis and CL- secretion by it s salicylate counterpart. Bismuth has some antimicrobial effects, binds to enterotoxins and also provided protective coating over inflamed gastric mucosa.

 Given in a dose of 524 mg (or 30 60 ml) every six

hours daily to control travelers diarrhea It causes blackening of stool mistaken for malena and darkening of tongue because of a reaction between bismuth and the sulfide produced by bacteria to form a black bismuth sulfide No adsorbent drug should be taken within 2 hours of other medication, because it may decrease the absorption of other orally administered drugs

Misc agens
Lactobacillus sporogenes: are intended to replace the

normal bacterial flora that is lost during acute diarrhea or due to the use of anitbiotics Used as adjuvant therapy for apthous stomatitis and diarrhoea Lacatse is indicated for individuals who have insufficient amount of lactase in the small intestine Lactase is an enzyme responsible for disgesting lactose, a common disachharide present in the diary products.

 In the absensce of lacase, lacose draws water into the

GI tract and causes diarrhea. The dose is 1-2 capsules of lacase taken with milk

ORS
During diarrhea, a glucose coupled sodium transport

continues in the intestines which causes water and electrolyte losses through stools. Hence, glucose-electrolyte solutions are simple, effective and cheaper oral therapy to treat a vast majority of watery diarrhea If fluid loss is severe and severe vomiting persists, IV fluids must be pursued

 Glucose based ORS as per WHO standard formula

Sodium chloride
Potassium chloride Sodium citrate

3.5g 1.5g
2.9g

Glucose

20g Water 1L Total osmolarity is 311 mmol/L

 The higher sodium content of WHO formulation is

baseed on approx sodium loss in adult diarrhea. However, low sodium glucosee based formulations may be preferred in infants and children whose faecal losses of sodium are less. WHO has recommended the replacement of standard 311 mmol/L formula by the new 245 mmol/L formula

 Sodium chloride

Potassium chloride
Sodium citrate Glucose

2.6g 1.5g 2.9g

13.5g Water 1L Total osmolarity is 245 mmol/L

 Cereal based ORS has the advantage of controlling

diarrhea much more than glucose based ORS.

 Thanks