PROKINETICS

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

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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)

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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

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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• It was recently withdrawn in number of countries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)

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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.)

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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

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Antispasmodics directly affecting smooth muscle

• Different mechanisms of action are involved
  inhibition of Ca2 channels, activation of K
  channels, stimulation of NO synthesis
• Drugs papaverine (opiate) and drotaverine,
  mebeverine, alverine

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PURGATIVES (LAXATIVES)

• Drugs used for treatment of acute constipation
  (drugs accelerating the passage of food through
  the intestine). Normal stool frequency ? 3/week
• A symptomatic 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

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PURGATIVES (LAXATIVES)

• Classification of purgatives due to the
  mechanisms
• Bulk laxatives
• Osmotic laxatives
• Stimulant laxatives
• Emollient laxatives

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Bulk laxatives

• The treatment is based on ingestion of
  semi-synthetic drugs/natural materials rich with
  indigestible polysaccharides
• 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

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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

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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 the myenteric 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.

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Emollient laxatives

• Agents which make the 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 decreased absorption of
  fat-soluble vitamins (A,D, E, K) ?
  hypovitaminosis

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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

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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

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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

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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.

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Other drugs

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