(Drugs used in A r r e e t t p p a CChh Laxatives and Pharmacodynamics Antidiarrhoeal (Mode of Action of Drugs) Agents 7.1 1.4 LAXATIVES OSMOTIC LAXATIVES These are the drugs which promote the evacuation of bowels and used in constipation These solutes are not absorbed in intestine They retain water osmotically in bowel lumen and distend the bowel thereby increasing peristalsis indirectly These agents should be administered with plenty of water The administration of sodium salts is to be avoided in patients of cardiac failure, renal failure and hepatic failure They are classified as in table 7.1.1 BULK FORMING AGENTS These contain natural or semisynthetic hydrophilic colloidal derivatives of cellulose These drugs act to increase the volume of stool by absorbing water and as a result softening of faeces occurs These are safe drugs (except in patient with strictures when intestinal obstruction may be precipitated) Adequate hydration of the patient is to be maintained The onset of action occurs in 1224 hours after oral intake LACTULOSE It is a semisynthetic disaccharide of fructose and lactose It is not digested or absorbed in small intestine thereby withdrawing water into bowel lumen It breaks down in colon to form more osmotically active products It also causes reduction in ammonia in hepatic coma Table 7.1.1: Classification of laxatives I Bulk forming agents II Osmotic laxatives III Stool softener IV Stimulant laxatives Ispaghula, methylcellulose, psyllium Magnesium salts, (sulphate, hydroxide), sodium salts (sulphate, phosphate), lactulose, glycerol suppositories Liquid paraffin, docusate sodium Bisacodyl, senna, phenolphthalein, danthron, sodium picosulphate, castor oil Section 7/ Drugs Acting on GIT 254 Docusate acts by its detergent action which reduces the surface tension long term use may lead to hypokalemia These drugs are to be avoided in pregnancy and children The onset of action occurs in 612 hours after oral administration LIQUID PARAFFIN BISACODYL It is a petroleum hydrocarbon, an inert viscous liquid It is a faecal softener and causes lubrication of hard scybali by coating them Paraffin lubricates the passage of faeces It is not absorbed and is safe It is stimulant laxative, when administered orally or as a rectal suppository it produces increased peristalsis by direct action on the mucosa of the colon, usually resulting in a soft, formed stool It is indicated in postoperative constipation Dose: CREMAFFIN 10-15 ml/day It is indicated in all forms of constipation, e.g in bedridden patients, due to change of food or environment, illness or digestive disorders; relief of evacuation in painful conditions such as haemorrhoids; pre and postoperatively; pre-paration for barium enema; preparation of colon for proctosigmoidoscopy Dose: DULCOLAX 5-15 mg HS oral and suppository (5-10 mg) STOOL SOFTENER Adverse effects include aspiration pneumonia, perianal pruritus, healing in perianal region may be delayed, unpleasant taste, the absorption of fat soluble vitamins may be affected Long-term administration is not recommended DOCUSATES It is an anionic detergent which softens the stool by water accumulation in intestinal lumen and emulsifies the colon contents It is indicated in obstetric, habitual, geriatric, paediatric constipation or when straining is to be avoided (recent myocardial infarction, severe hypertension, post-operative cases, abdominal hernia), fissures, haemorrhoids and bed ridden patients Dose: 100-200 mg/day Side effects include nausea, cramps and abdominal pain STIMULANT LAXATIVES These drugs exert their laxative action by increasing motility of colon They mainly alter absorptive and secretory activity by inhibiting Na+ K+ ATPase in mucosal cells, leading to water and electrolyte accumulation in lumen Colicky pain may occur and on the SODIUM PICOSULPHATE In the colon, sodium picosulphate is converted in to the active comound bis-(phydroxy diphenyl) pyridyl methane (BHPM) which stimulates propulsive activity of the colon, prevents absorption of water in the colonic lumen and promotes accumulation of water Following oral administration sodium picosulphate is not absorbed In colon it is converted to the active metabolite BHPM, by the action of arylsulphatases secreted by the colonic bacteria Prolonged use or overdosage can precipitate the onset of an atonic nonfunctioning colon and hypokalemia It is indicated in constipation e.g in patients with cardiovascular disease, hernia and anorectal disorders, the elderly and Laxatives and Antidiarrhoeal Agents 255 postoperatively; bowel clearance before radiography, endoscopy, labour or surgery ANTIDIARRHOEAL AGENTS It is contraindicated in intestinal obstruction, undiagnosed abdominal symptoms Dose: CREMALAX 5-10 mg HS Diarrhoea is defined as frequent passage of liquid faeces with or without blood and mucus It occurs due to various causes, infective or non infective SENNA The antidiarrhoeal agents can be classified as in table 7.1.2 It is an anthraquinone laxative It is not active as such but after oral intake when it reaches colon the bacteria liberate anthrones, which is the active form Active form acts on myenteric plexus to increase peristalsis It also inhibits salt and water absorption in colon It is indicated in intestinal evacuation for radiological examination and atonic constipation Adverse effects include vomiting, nausea, fixed drug eruptions, skin rash It is contraindicated in spastic constipation, electrolyte imbalance, intestinal obstruction, lactation Dose: As powder 0.6-10 gm HS Antidiarrhoeals are given for symptomatic relief of diarrhoea The first step in treatment of acute diarrhoea is replacement of fluid and electrolytes If due to diarrhoea there is severe dehydration, it requires immediate hospitalization for IV fluid and electrolyte replacement Antidiarrhoeal drugs are administered for obtaining symptomatic relief in acute diarrhoea but have untoward effects Alongwith antidiarrhoeal drugs, antispasmodics are administered in those patients who have diarrhoea with abdominal pain Table 7.1.2: Classification of antidiarrhoeal agents I Rehydrating solutions: Containing NaCl, KCl, NaHCO3 (for parenteral administration) and sodium chloride, potassium chloride, sodium citrate and glucose as oral formula (ORS) II Absorbents & bulk forming agents Kaolin Pectin Psyllium Ispaghula Methyl cellulose 2-4 g/day 100-300 mg/day 8-16 g/day 8-16 g/day 4-6 g/day III Antimotility & antisecretory drugs Codeine Loperamide (LOPAMIDE) Diphenoxylate with atropine (LOMOFEN) Sulfasalazine (SALAZOPYRIN) Mesalazine (MESACOL) 30-60 mg TDS 4-16 mg/day mg QID 1-3 g QID 2-4 g/day IV Antimicrobial drugs Details are given in chapter ‘Chemotherapeutic agents’ 256 ABSORBENTS AND BULK FORMING DRUGS They are colloidal bulk forming agents which swell by absorbing water They modify the consistency and frequency of stools They are used for functional bowel disease associated with diarrhoea They are safe substances but their effect occurs slowly ANTIMOTILITY AND ANTISECRETORY DRUGS Antimotility drugs are opioid drugs They increase small bowel smooth muscle tone and segmentation activity They also reduce propulsive movements and decrease intestinal secretions while increasing absorption They mediate these actions through µ receptors LOPERAMIDE It has a direct action on intestinal musculature and having a weak anticholinergic property It is used to treat acute and chronic diarrhoea Adverse effects include addominal cramps and skin rash DIPHENOXYLATE Section 7/ Drugs Acting on GIT may occur leading to abdominal obstruction These are usually not prescribed for bacterial diarrhoea in children because by delaying the passage of liquid faeces there is proliferation of pathogens which is undesirable SULFASALAZINE It is an antisecretory drug It is 5-aminosalicylic acid with linked sulfapyridine through azo bond The drug is poorly absorbed from the intestine and the azo linkage is broken down by the bacterial flora in the distal ileum and colon to release 5-aminosalicylic acid (5-ASA) and sulfapyridine 5-ASA inhibits locally prostaglandin synthesis, decreases mucosal secretion It is used in rheumatoid arthritis and ulcerative colitis Side effects include fever, rashes, blood dyscrasias, nausea, vomiting and headache MESALAZINE 5-ASA is prepared as delayed release preparation by coating with acrylic polymer, which releases 5-ASA in distal ileum and colon It is used in ulcerative colitis to prevent relapses Chemically it is an opioid, related to pethidine It is used in acute and chronic diarrhoea but since it crosses the blood brain barrier it can cause CNS effect similar to opioids Atropine is added with diphenoxylate (LOMOFEN) to discourage abuse Olsalazine and balsalazine are the newer compounds of 5-aminosalicylic acid linked with azo bonds Loperamide and codeine are preferred to diphenoxylate in chronic diarrhoea, because they have less tendency to produce drug dependence Long-term use of these drugs may aggravate irritable bowel syndrome These drugs are used cautiously in attacks of colitis because there is increased risk of toxic megacolon Also all these drugs should be used with caution in elderly because faecal impaction Antimicrobials have a limited role in treatment of diarrhoea because only a small percentage of diarrhoeas are caused by bacterial infection Majority of cases are due to non infective causes, Rota virus and food poisoning in which antimicrobial therapy has no role ANTIMICROBIAL THERAPY Specific antimicrobial drugs are discussed in chapter ‘Chemotherapeutic agents.’ (Drugs used in A r r e e t t p p a CChh 7.2 1.4 Emetics & Antiemetic Pharmacodynamics Agents (Mode of Action of Drugs) EMETICS Vomiting or emesis occurs due to stimulation of vomiting/emetic centre in medulla oblongata The chemoreceptor trigger zone (CTZ) and nucleus tractus solitarius (NTS) are relays for the afferent impulses arising from GIT, throat and other viscera There are different drugs e.g morphine, digitalis glycosides, apomorphine etc which stimulate the CTZ While certain agents e.g chlorpromazine and certain antihistaminics depress it Vomiting due to irritants in the GIT especially upper region does not involve CTZ and is mediated directly by the vomiting centre Histamine (H1), serotonin (5-HT3), dopamine (D2) cholinergic (M) and opioid (µ) receptors on CTZ and NTS are involved in inducing vomiting Impulses from vestibular centre also lead to stimulation of vomiting centre via H1 and M receptors The drugs that produce or evoke vomiting are known as emetics The most common compounds used are apomorphine and ipecacuanha given by subcuta-neous/IM route in the dose of mg and it produces vomiting within 15 minutes Apomorphine induced vomiting can be antagonized by chlorpromazine Side effects include tremors, restlessness and in toxic doses it may cause convulsions and respiratory depression IPECACUANHA It is used as tincture and syrup containing alkaloid emetine obtained from plant Cephaelis ipeca-cuanha It act on both gastric mucosa and CTZ The emetics are used mainly in poisoning when gastric lavage facilities are not available But in certain poisoning e.g kerosene poisoning, corrosive acid or alkali poisoning, emetics are contraindicated They are also not advisable in unconscious patients as they may aspirate vomitus ANTIEMETICS APOMORPHINE These are the drugs which are used to prevent vomiting They are classified in table 7.2.1 It is a semisynthetic opioid and act as dopami-nergic agonist on the CTZ It is The detailed pharmacology of phenothiazines e.g chlorpromazine, triflupro- ... which is the active form Active form acts on myenteric plexus to increase peristalsis It also inhibits salt and water absorption in colon It is indicated in intestinal evacuation for radiological... Containing NaCl, KCl, NaHCO3 (for parenteral administration) and sodium chloride, potassium chloride, sodium citrate and glucose as oral formula (ORS) II Absorbents & bulk forming agents Kaolin Pectin... ABSORBENTS AND BULK FORMING DRUGS They are colloidal bulk forming agents which swell by absorbing water They modify the consistency and frequency of stools They are used for functional bowel