Constipation 2 - Pharmacology Flashcards
Treatment of Constipation
•Usually effectively treated with dietary modification (increasing fibre, hydration, exercise)
•Only if this fails should laxatives be used. Therapy Classes: 1. Bulk-forming laxatives 2. Osmotic laxatives 3. Stimulant laxatives 4. Stool softeners 5. Other agents
- Bulk-forming laxatives
increase volume of matter in GI tract
bulk forming laxative - increases volume of substance in colon by doing that they activate stretch receptor and tactile receptor in wall of colon and that acts to increase colonic activity and peristalsis
- Osmotic laxatives
increase the volume of liquid in GI tract
has a dual purpose - by increasing fluid content it makes the stools softer and by increasing volume in the colon it activates stretch receptors and the tactile receptors then increases activity
- Stimulant laxatives
increase activity of colon
direct stimulants increase activity of muscles in the colon wall and increase peristalsis
- Stool softeners
act to allow the colon to do its job more efficiently
- Other agents
viewed as separate due to their mechanism of action
Laxatives: Broad Mechanisms of Action
- fibre increases bulk of stools
- faecal softener lubricates the stool
- stimulant increases peristalsis
- stimulant increases peristalsis
- osmotic laxative increases fluid content of stool
General Contraindications to Use
- Broadly, laxatives should not be used in the presence of undiagnosed abdominal pain
- The danger is that the drugs may cause an inflamed organ (eg, the appendix) to rupture and spill GI contents into the abdominal cavity with subsequent peritonitis, a life-threatening condition.
- Oral drugs also are contraindicated when a diagnosed GI disturbance is likely to be worsened by increased motility (e.g. with intestinal obstruction and fecal impaction or inflammatory bowel diseases)
Bulk Laxatives
- Insoluble Non digestible and non-absorbable (pass into the colon whole and unaffected)
- Increase in bowel content volume triggers stretch receptors in the intestinal wall
- Causes reflex contraction (peristalsis) that propels the bowel content forward
- May take several days – 2 weeks to have full effect
Classes of Bulk Laxatives
- Isphagula (Psyllium)
- Methylcellulose
- Sterculia
Bulk laxatives
• ADR’s
– Bloating and flatulence; GI obstruction & impaction
Bulk laxatives
• Cautions
– Adequate fluid intake should be maintained to avoid obstruction
• May need management in elderly & debilitated patients
Bulk laxatives
• Contraindications
- Colonic atony – colon will not be stimulated by activation of stretch receptors
- Faecal impaction & intestinal obstruction – increased motility will not lead to defecation
Atony definition
muscles in colon are not activated
Osmotic Laxatives
-work more rapidly than bulk forming laxative
• Effective in 1-3 hours
• Used to purge intestine (e.g. prior to surgery, poisoning)
• Fluid is drawn into or retained in the bowel by osmotic force, increasing volume and triggering peristalsis (makes stools wetter and softer)
Osmotic Laxatives classes
• Nondigestible sugars and alcohols
- Lactulose (broken down by bacteria to acetic
and lactic acid, which causes the osmotic effect)
• Macrogol 3350– polymer of ethylene glycol (acts to retain water in colon)
• Salts
• Magnesium hydroxide (Mg(OH)2) (Milk of Magnesia)
• Sodium Phosphates (used as enema)
• (Epsom Salt (MgSO4)) - very strong and causes very rapid evacuation of colon - not recommended anymore
Two main issues associated with osmotic laxatives
– Increased GI activity
– Electrolyte & osmotic imbalances (in danger of dehydration)
Osmotic Laxatives
• ADR’s
–abdominal discomfort; diarrhoea
Osmotic Laxatives
• Cautions
– Broadly those at danger of dehydration (elderly, debilitated); and those at risk of electrolyte imbalance (cardiac diseases)
Osmotic Laxatives
Contraindications
Acute GI conditions; intestinal obstruction & inflammation
Stimulant Laxatives
- Irritate the GI mucosa and Increases intestinal motility
- Indicated for severe constipation where more rapid effect is required (6-8 hours) or where bulk forming laxatives haven’t had the required effect
Stimulant Laxatives classes
- Bisacodyl
- Anthraquinones – Co-danthramer, Co-danthrusate, Senna
- (Cascara, Castor Oil - From the Castor Bean – obsolete) NOT RECOMMENDED
Pharmacology of Stimulant Laxatives
draw chart
Galenic form
- Bisacodyl -> activated by colonic hydrolases -> activated by bis-(p-hydroxyphenyl)-pyridyl-2-methane
- Sodium picosulfate -> activated by colonic flora -> activated by bis-(p-hydroxyphenyl)-pyridyl-2-methane
- Senna -> activated by colonic flora -> activated by rhein anthrone
Pharmacology of Stimulant Laxatives - what is galenic form
is the formulated form which patients take the medicine in
Pharmacology of Stimulant Laxatives: bisacodyl
has to be formulated so it reaches the colon before the active ingredient becomes available
Pharmacology of Stimulant Laxatives: sodium picosulfate
almost a pro drug of bisacodyl
Pharmacology of Stimulant Laxatives: colonic hydrolases
in the gut wall
Pharmacology of Stimulant Laxatives: colonic flora
only bacteria found in the colon
Pharmacology of Stimulant Laxatives: bis-(p-hydroxyphenyl)-pyridyl-2-methane
irritates and activates wall of GI tract
Stimulant Laxatives
- main issues
• Do what they say on the tin…
– ADR’s, cautions & contraindications similar to osmotic laxatives
Two main issues
– Increased GI activity
– Electrolyte & osmotic imbalances
Stimulant Laxatives
• Cautions
– Those at risk of dehydration or hypokalaemia
Stimulant Laxatives
• CI’s
– Inflamed & obstructed intestines; undiagnosed abdominal pain
Co-danthrusate and Co- danthramer
-very effective laxative
• Evidence of carcinogenicity & genotoxicity in animal studies
• Use limited to patients with terminal illnesses
genotoxicity
destructive effect on a cell’s genetic material (DNA, RNA) affecting its integrity.
carcinogenicity
Ability of a carcinogen to produce invasive cancer cells from normal cells.
Stool Softners - Emollients (types)
• Docusate sodium (surfactant and stimulant) main one used
• Arachis oil (enema) help with fecal impaction
- Peanut oil (allergies)
• Liquid Paraffin (oral solution)
- Extemporaneous preparation
Docusate sodium
Surfactant and bulking agent (stimulates wall of GI tract)
• Oral: up to 500mg daily in divided doses
– Acts within 1-2 days
• Rectal (enema): 120 mg for 1 dose
– Acts within 20 minutes
• ADRs: Abdominal pain, diarrhoea; hypokalaemia
• Cautions: Patients where hypokalaemia to be avoided; Rectal preparation not indicated with haemorrhoids
• Contraindications :Intestinal blockage
Opioid Antagonists for Opioid-Induced constipation - draw diagram and explain
draw diagram
- Endogenous opioids act at opioid receptors in brain and periphery.
- In the brain activation of central u opioid receptors can provide analgesia (pain relieve).
- Exogenous opioids such codeine and morphine are used as analgesics for patients in palliative care or patients with cancer.
- u opioid receptors in GI tract activation leads to changes in muscle tone and sensitivity.
- Opioid antagonists can be given to block u opioid receptors in GI tract but not all opioid antagonists will be suitable as they may cross the BBB and block action of opioid agonist in the brain aswell.
- Instead we want Peripheral opioid antagonist to act at gut only and not brain.
Methylnaltrexone
- Peripherally acting opioid antagonist
- Subcutaneous injection; 8-12 mg 4-7 doses/week
- Tmax: 0.5hr; T1⁄2 8hrs (rapid t max but long half life - leads to well above therapeutic threshold)
- ADRs: Abdominal pain, diarrhoea; flatulence
- Cautions: Patients with damaged GI tract
- Contraindications:Acute surgical abdominal conditions; Intestinal blockage
Prucalopride
- Selective 5HT-4 agonist with prokinetic properties (increase activity, decrease GI transit time)
- 2mg once daily, review after 4 weeks
- ADRs - wide range of abdominal side effects associated with action
- Cautions – arrythmias & ischaemic heart disease (hERG) affects QT interval
- Contraindications – Crohn’s disease, abdominal obstruction and other serious GI conditions
Lubiprostone (trade name - Amitiza)
- Chloride channel blocker – acts locally to increase fluid secretion and motility
- 24 μg (micrograms) twice daily for 2-4 weeks
- PK – low oral bioavailability – actions in GI tract (limits the ADR to abdominal ADRs)
- ADR’s – wide range of abdominal side effects associated with action
- Contraindications – GI obstruction
• ALWAYS bear in mind potential for damage
– when a diagnosed GI disturbance is likely to be worsened by increased motility
– When undiagnosed abdominal pain is present
What does peripheral opioid antagonist do?
Peripheral opioid antagonist dislodges opioid from u-opioid receptors in GI tact and this leads to reduction in adverse gastrointestinal effects of exogenous opioid analgesics
