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Martin Šterba, MSc.
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
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. (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It was recently withdrawn in number of countries due to the increased risk of arrhythmias - „torsades de pointes“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) Prokinetics
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. Antispasmodics affecting 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
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. 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
Antispasmodics directly affecting smooth muscle
8. 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
9. PURGATIVES (LAXATIVES) Classification of purgatives due to the mechanisms
10. 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
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).
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 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.
13. 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
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
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
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.