PROKINETICS ANTISPASMODICS (SPASMOLYTICS) PURGATIVES (LAXATIVES) ANTIDIARRHOEAL AGENTS

1. PROKINETICS • ANTISPASMODICS (SPASMOLYTICS) • PURGATIVES (LAXATIVES) • ANTIDIARRHOEAL AGENTS Martin Štěrba, MSc. 2006/7

2. PROKINETICSdrugs increasing GIT motility • These drugs increase: • Tonus of the lower oesophageal sphincter (inhibition of gastro-intestinal reflux) • Gastric emptying (improve gastroparesis and functional dyspepsia) • intestinal motility (increased peristalsis) • Mechanisms of Action • Antagonism at D2 receptors – desinhibition of myenteric motor neurons leads to the increased ACh release • Modulation of 5-HT receptors (5-HT4, 5-HT1) – complex effects resulting in increased ACh release (among others)

3. Prokinetics • Domperidon Mechanism of action: predominantly a D2-antagonist • It does not cross the blood-brain barrier (hence no extrapyramidal adverse effects) ! But it affects those CNS areas which lack the barrier - area postrema (antiemetic action ) - hypophysis (prolactin secretion ) Adverse reaction: galactorrhea, gynecomastia, amenorrhea • Metoclopramide Mechanism of action is more complex: D2-antagonism, 5HT4 receptor agonism, sensitisation of M receptors - antiemetic action - CNS adverse effects: extrapyramidal (parkinsonian-like symptomes) • Itopride - D2-antagonist/Acetylcholinesterase inhibitor

4. Prokinetics • (Cisaprid)Just for your information: Mechanism of action: an agonist on 5-HT4 receptors It was quite potent and often used drug! It was recently withdrawn in number of countries due to the increased risk of arrhythmias - „torsades de pointes“ The name means „twisting of the points“ in French, referring to the characteristic appearance of the electrocardiogram during the rhythm abnormality. - It is uncommon polymorphous ventricular tachyarrhythmia with potentially fatal outcomes (associated with long QT-interval)

5. ANTISPASMODICS (SPASMOLYTICS) • Drugs used to relieve spasms of smooth muscle in the GIT • Two main groups of drugs: A) drugs affecting autonomic innervations – (anticholinergics and parasympatolytics) B) Drugs directly affecting smooth muscle function • Combination of drugs from the both groups  synergism • Combination with analgesics (pethidine, codeine, tramadol, metamizol) = analgo-spasmolytic preparations • Indications and therapeutical use: • Irritable bowel syndrome, flatulent distension of the abdomen (meteorism), smooth muscle spasms • Analgo-spasmolytics: in painful smooth muscle spasms like – biliary, renal and intestinal colics (also in spastic dysmenorrhoea etc.)

6. Antispasmodicsaffecting autonomic innervations • Parasympatolytics (antimuscarinics) • Antagonists on M – receptors • Spasmolytic effect on smooth muscle but they tend to have rather opposite effects on sphincters (e.g. Oddi) • Drugs: atropine, trospium, tolterodine • Adverse effects (relatively frequent): xerostomia, mydriasis, cycloplegia, increased ocular pressure, urinary retention and • Anticholinergics • Antagonists on both M and N types of cholinergic receptors • Spasmolytic effects on both smooth muscle and sphincters • Often in combination with other drugs • Quarternary amines – low/slow absorption (low adverse effects on the CNS) Drugs: otilonium, fenpiverine

7. Antispasmodicsdirectly affecting smooth muscle • Different mechanisms of action are involved: inhibition of Ca2+ channels, activation of K+ channels, stimulation of NOsynthesis • Drugs: papaverine (opiate) and drotaverine, mebeverine, alverine

8. PURGATIVES (LAXATIVES) • Drugs used for treatment of acute constipation (drugs accelerating the passage of food through the intestine). Normal stool frequency  3/week • Asymptomatic therapy which should not be used chronically • Constipation is defined as a decreased stool frequency and is usually associated with changes in stool consistency, difficulty of defecation and abdominal discomfort • Living habit factors: diet (fibber content, fluid intake), exercise… • Higher frequency in pregnancy • constipation - a symptom of the disease (e.g. GIT obstruction due to malignancies! Laxatives may mask the disease and induce complications!) • Constipation - an adverse effect of drug treatment - consider substitution if possible – anticholinergics, antidepressants, antihistamines Opioids (no tolerance – severe constipation may develop). • Non-pharmacological approach (recommended) – improvement of diet and life-style • Laxatives are contraindicated in the „ileus“ disease

9. PURGATIVES (LAXATIVES) • Classification of purgatives due to the mechanisms • Bulk laxatives • Osmotic laxatives • Stimulant laxatives • Emollient laxatives

10. Bulk laxatives • The treatment is based on ingestion of semi-synthetic drugs/natural materials rich with indigestiblepolysaccharides • Bulk laxatives retain water, increase the volume of feces and stimulate natural peristalsis • Remind patient of adequate fluid intake necessity! • Methylcellulose and etulose (semi-synthetic) • Agar, Psyllium, Sterculia and other natural products • Adverse reactions are weak and infrequent (safe) • Bulk laxatives can be recommended for longer treatment in contrast to most of other drugs in this group

11. Osmotic laxatives • The mechanism of action is based on administration of poorly absorbed osmotically active agents. It results in increased volume of fluid in the lumen of the bowel due to the osmosis  it accelerates the transfer of the gut content and induce purgation (abdominal cramps can occur) Inorganic salts: magnesium sulfate.magnesium hydroxide - Mg absorption is usually very low, however it can be a problem in small children or in patients with decreased renal functions Lactulose– semisynthetic disaccharide which is converted into fructose and galactose. These are poorly absorbed and fermented to the lactic and acetic acids which acts as an osmotic laxative and lowers pH,  modified microbial flora (decreased ammonium production). Indication: hepatoencephalopathy Glycerin – suppositories working osmotically in the rectum - is used as a safe laxative recalling natural defecation reflex Sorbitol – rectally as suppositories is given before endoscopic examination

12. Stimulant purgatives • The mechanism of action is based on stimulation of intestinal motility and mucosal electrolyte secretion (stimulation of enteric nerves?!) • Natural plants: Senna (Cassia senna), Rheum palmatum, Aloe sp. active compounds – antraquinones (e.g. emodin). These are formed in the gut due to the activity of bacterial flora and are supposed to have direct stimulant effects in themyenteric plexus The active compounds are found in mother's milk (caution!) • Synthetic compound: bisacodyl, sodium picosulfate, phenolphtalein • Adverse reactions: abdominal cramps, pain, electrolytical imbalances, chronic treament may cause profound GIT toxicity • Contraindication: pregnancy, lactation, apendicitis etc.

13. Emollient laxatives • Agents which makethe stool more soft and allow its easier passage • Docusate sodium – surface active compound (oral or rectal administration) • Mineral oils (liquid paraffin) – coating stool, increasing stool weight and decreasing transit time. It may be administered both orally or rectally. Adverse reactions: decreasedabsorption of fat-soluble vitamins (A,D, E, K) hypovitaminosis

14. ANTIDIARRHOEAL AGENTS • Diarrhoea is a state characterised by a frequent passage of liquid faeces • Different aetiology: infections, toxins, drugs (laxatives, antacids containing Mg, antineoplastics, several antibiotics – especially broad spectrum ones, cholinergics – e.g. neostigmine, digoxin…. • Can be associated with various complications – from discomfort to even medical emergency (due to the electrolyte imbalances and hypovolemia, etc) • Classification of antidiarrheal agents • Adsorbents • Anti-infective agents • Antimotility agents • Other drugs

15. Adsorbents • Agents adsorbing toxins and other xenobiotics and/or microorganisms • with enormous surface area: Carbo adsorbens (charcoal), kaolin, chalk, attapulgit (diosmectit = magnesium aluminium silicate) • action is not selective – they also adsorb drugs and some nutrients (the absorption is decreased) • widely used (mostly OTC) • Indications – problems arising from inappropriate diet, dysmicrobial condition, intoxications due to drugs and chemicals

16. Anti-infective agents • Drugs with antibacterial, antimycotic and antiprotozal effects • cloroxin, • nifuroxazid • Indication: in diarrhoea with suspected infective etiology, traveller's diarrhoea They can be useful even in moderate diarrhoeas arising from changes in natural bacterial mircoflora

17. Antimotility agents • Drugs significantly decreasing intestinal motility – opioids and antimuscarinics (the latter mainly in combination) • Opiates and opioids • Acting on opioid receptors (mainly  type) on enteric nerves, epithelial cells and smooth muscle • Tinctura opii (made up from opium, it contains mainly morphine, codeine and spasmolytic papaverin) • Difenoxylate – in normal doses does not have remarkable morphine-like effects; however in large doses it is well feasible and it may be abused (atropine is added to support the antidiarrhoeal effect and to prevent abuse) • Loperamide – low bioavailability and CNS penetration, highly effective in the bowel  it is a safe drug (OTC) with low adverse reactions used in the treatment of traveller's diarrhoea, acute and chronic diarrhoea etc.

18. Other drugs • Octreotide – a somatostatine analogue inhibiting intestinal motility and secretion • Bacterial replacement – Lactobacillus sp. • Bismuth susalicylate