Drugs used in constipation (laxatives) and diarrhea. Drugs promoting digestion. Pharmacology of liver and biliary tract Flashcards
Laxatives
Laxatives are commonly used in constipation to accelerate the movement of food through the gastrointestinal tract.
Laxatives increase the potential for loss of pharmacologic effect of poorly absorbed, delayed-acting, and extended-release oral preparations by accelerating their transit through the intestines.
May also cause electrolyte imbalances when used chronically.
Classified on the basis of their mechanism of action:
1. Irritants and stimulants:
Sennoside (Senna)
Bisacodyl
- Bulk-forming laxatives:
Plant fiber - Osmotic laxatives:
Magnesium-sulphate Magnesium-citrate Magnesium-hydroxide
Lactulose - Stool softeners:
Docusate
5. Lubricant laxatives: Paraffin oil (mineral oil)
majority of people do not need laxatives
constipation is best prevented with a high-fiber diet, adequate fluid intake, regular exercise
Chronic use of laxatives can lead to failure of their effectiveness - tolerance
- K loss leads to constipation
Sennoside (Senna)
irritant and stimulant
- Active ingredient is a group of sennosides, a natural complex of anthraquinone glycosides (degradation product of senna acts directly as irritant on the colonic wall to induce fluid secretion and colonic motility)
- Taken orally (causes evacuation of the bowels within 8-10 h’) or rectally (effects within minutes)
- May induce darkening of the stool and urine
- Can be used in the treatment of opioid-induced constipation, and in evacuation of the bowel prior to
surgery or invasive rectal/colonic examinations
SE: brown pigmentation of the colon known as melanosis, dark urin and stools, cramps
Bisacodyl
irritant and stimulant
- Potent stimulant of the colon, acts directly on nerve fibers in the colonic mucosa
Diphenylmethane derivative
Bisacodyl is available in tablet and suppository formulations for the treatment of acute and chronic constipation
- Adverse effects include abdominal cramps, potential for atonic colon with prolonged use, and potential
damage to the enteric protective coating - Can be used in treatment of chronic constipation, neurologic bowel dysfunction, and pre-operative
preparation
Plant fiber
Bulk-forming laxatives
- Indigestible parts of fruits and vegetables
- Form gels in the large intestine → causing water retention (absorb water from the colon) → intestinal
distension → increased peristaltic activity
Magnesium-sulphate (Magnesium-citrate)
Magnesium-hydroxide
Osmotic laxatives
Nonabsorbable salts
- Non-absorbable salts that hold water in the intestinal lumen by means of osmosis
- This distends the bowel → increasing intestinal activity → produces defecation in a few hours
Lactulose
Osmotic laxatives
Nonabsorbable sugars
- Semisynthetic disaccharide sugar, cannot be hydrolyzed - by intestinal enzymes
-Lactulose in bowel is converted to lactic acid and acetic acid -> low pH -> decreased NH3 absorption-> use in hepatic encephalopathy
Safe in pregnant women!
- Oral doses are degraded in the colon by colonic bacteria into lactic, formic, and acetic acids
- This increases osmotic pressure, causing fluid accumulation, colon distension, soft stools, and defecation *Lactulose is also used in the management of hepatic encephalopathy (reduces ammonia levels)
SE:
Systemic absorption of salts
oedema (Na), bradycardia (Mg), hyperphosphatemia
Lactulose: bloating, flatus
Docusate
not on the list
Stool softeners
- Surface-active agents that become emulsified with stool, produce softer feces and ease passage
- May take days to become effective; used for prophylaxis rather than acute treatment
Paraffin oil (mineral oil)
Lubricant laxatives
Action after 6-12 h
SE: paraffin decreases the absorbtion of liposoluble vitamins and causes sclerotic changes in mesenterial lymph nodes
Safe in pregnant women and children
- Act by facilitating the passage of hard stools (lubricant activity)
- Should be taken orally in an upright position to avoid aspiration and potential lipoid pneumonia
patients with constipation: treatment
Patients with constipation are treated with laxatives and life-style changes.
If a 3-6 months trial of medical therapy fails, unassociated with obstructed defecation, the patients should be considered for laparoscopic colectomy with ileorectostomy. This should not be undertaken if there is continued evidence of an evacuation disorder or a generalized GI dysmotility.
During medical evaluation and investigation for constipation, consider warning signs for colorectal cancer:
- Constipation alternating with diarrhea
- Blood in the stool
- Anemia (newly-diagnosed)
- Fatigue, weakness
- Weight loss (involuntary)
Antidiarrheal agents
obsipants
Loperamide
Diphenoxylate
Activated charcoal
*all antidiarrheal agents are contraindicated in the management of bloody-diarrhea (ex. infectious colitis, erosive colitis); the underlying cause must be diagnosed and treated
Always consider: rehydration, glucose, NaCl, KCl
Loperamide
Antidiarrheal agents
- Synthetic opioid derivatives
- Activate μ receptors in the enteric nervous system →
inhibit Ach release →
decrease motility - Minimal analgesic effects
inhibit motility and activity of secretomotoric neurons
kinetics:
- Oral
- Hepatic P450 metabolism
- Does not cross the blood-brain-barrier
indications:
- Non-specific, non-infectious diarrhea
Side effects: - Abdominal cramps opioid dependence, analgesic, constipation
Diphenoxylate
Antidiarrheal agents
- Synthetic opioid derivatives
- Activate μ receptors in the enteric nervous system →
inhibit Ach release →
decrease motility - Minimal analgesic effects
inhibit motility and activity of secretomotoric neurons
kinetics:
- Oral
- Hepatic P450 metabolism
- Crosses the blood-brain-barrier at high doses
- Formulated with muscarinic antagonist (atropine) to reduce abuse liability
Indications:
- Non-specific, non-infectious diarrhea
Side effects: - Abdominal cramps - CNS effects and toxicity with higher doses opioid dependence, analgesic, constipation
Activated charcoal
Antidiarrheal agents
Attract and expel ingested toxins from the gastrointestinal tract
- Oral
- Non-specific, non-infectious diarrhea
drugs of liver and biliary tract
- N-Acetylcysteine
- Ursodeoxycholic- acid
(Ursodiol) - Silymarin
- Resins - bile acid sequestrants:
- Colesevelam
- Colestipol
- Cholestyramine
N-Acetylcysteine
Provides -SH groups
- Oral, IV, inhaled
- T1/2 5-6 h’
- Hepatic P450 metabolism
toxic N-acetyl-p-benzoquinone imine (NAPQI) is synthesized
contributes to synthsis of antioxidant glutathione, glutathione is conjugated with NAPQI and inactivated
Indications:
- Acetaminophen toxicity
(best given within 8-10 h’ of overdose)
- Mucolytic agent - Reduces disulfide bonds in the mucus matrix → mucus viscosity ↓ (used in COPD and CF, bronchitis)
Side effects:
- Nausea, vomiting
- Anaphylaxis-like allergic reaction
Ursodeoxycholic- acid
Ursodiol
- Reduces cholesterol absorption
- Potential anti-inflammatory effects in the GI
- Oral
Contraindications: - Acute hepatitis
- Biliary obstruction
- Cholelithiasis (patients unfit for cholecystectomy)
- Used to dissolve cholesterol gallstones
- Prophylaxis (patients undergoing rapid weight loss or bariatric surgery – biliary cholesterol oversaturation)
- Primary biliary cirrhosis (PBC)
Indication:
Better digestion
Dissolving small bile stones – chenodiol or ursodeoxycholic acid suitable, if cholecystectomy is contraindicated
biliary cirrhosis – ursodeoxycholic acid decreases the cholestasis, improve symptoms, but do not improve prognosis.
Side effects (generally well-tolerated)
- Diarrhea
liver failure
Contraindications:
acute hepatitis,
bile duct obstruction
Silymarin
- Milk thistle extract derived from the fruit and seeds of ‘Silybum marianum’
- Support liver function
Several effects: reduce ROS level, inhibition of lipid peroxidation, increased protein biosynthesis
Ind.: Acut toxic liver failure (CCl4, amanita phalloides), chronic inflammatory liver diseases and adjuvant therapy of liver cirrhosis
- Oral
- Potentially protects against liver injury caused by alcohol, acetaminophen, and Amanita mushrooms
- Antidote to Amanita phalloides mushroom poisoning
Resins - bile acid sequestrants
- Colesevelam!!
- Colestipol
- Cholestyramine
Non-absorbable polymers that bind bile acids in the intestine and prevent their absorption – decreased enterohepatic recirculation
They bind bile acids – increased bile acid synthesis in the liver from cholesterol
Ind.: hypercholesterolemia, bile acid induced diarrhea (following small intestine resection), in case of liver diseases (cholestasis) to reduce pruritus
SE.:
gastrointestinal (obstipation)
Could interfere with absorption of other drugs
kinetics:
- Oral, taken with meals
- Not absorbed
- Interfere with absorption of drugs (warfarin, thiazides, digoxin, aspirin, statin), administer 4 h’ apart
Indications:
- Dyslipidemia (in combination with statins)
- Reduce pruritus in patients with cholestasis and bile
acid accumulation
Side effects:
- Elevated VLDL and triglycerides
- GI disturbances (bloating, constipation, diarrhea)
- Malabsorption of lipid-soluble vitamins (‘DEAK vitamins’)
- Hyperglycemia
Management of hepatic encephalopathy
Address the underlying precipitating factor
Hypokalemia, hypoglycemia, dehydration, infection, GI bleeding
- lactulose
- Lactulose (acidic disaccharide) passes through the small bowel completely undigested (unlike glucose, sucrose, and lactose, which are easily fermented in the small bowel) → once in the colon, lactulose is fermented by anaerobic bacteria → fermentation yields weak acids (lactic, acetic, butyric) and gases (hydrogen) → this leads to the acidification of ammonia into ammonium which is poorly absorbed - Rifaximin
- 1st-line lumen-active antibiotic
(rifaximin kills deaminating enteric bacteria → decreased production of nitrogenous compounds) - Neomycin/ Metronidazole
- 2nd -line lumen active antibiotic - zinc supplement
Appetizing and prodigestive drugs
Tinctura amara, Tinctura aromatica
Reflex mechanism of action: they increase apetit and digestion (better peristalsis and secretion of digetive enzymes)
Ind.: problems with digestion, inapettence
cannabinoids
Liver toxic drugs
Dose-dependent, predictable liver toxicity - paracetamol, Fe, CCl4.
Dose-dependent, predictable cholestasis (indirect liver failure) –sex hormones, rifampicin.
Non-dose-dependent, direct liver toxicity - halothan, indomethacin.
Non-dose-dependent, cholestasis - chlorpromazin.
others: cirrhosis (alcohol), benign liver tumors (sex hormones)
IBS classification
Based on clinical pattern of the most dominant symptoms.
IBS‑D → diarrhea is the predominant symptom
IBS‑C → constipation is the predominant symptom
IBS‑M → mixed diarrhea and constipation
IBS‑A → alternating diarrhea and constipation
Proposed pathomechanism
Altered intestinal motility/secretion in response to environmental or luminal stimuli
Enhanced pain perception (‘visceral hypersensitivity’)
Dysregulation of the brain-gut axis
Immune activation and mucosal inflammation
Altered gut flora
Psychological factors (stress, anxiety, depression)
Post-infectious IBS
Since the mechanism behind the disease is not yet entirely clear, most treatment modalities currently used concentrate on symptomatic relief.
1. Patient counseling and education
2. Dietary modification
Increase: fluid intake, fiber intake Decrease: short-chain carbohydrate, irritative foods, lactose, gluten
3. Life style changes and preventive means
4. Symptomatic treatment of constipation
Osmotic laxatives (psyllium, PEG)Lubiprostone (locally-active Cl- channel activator)
5. Symptomatic treatment of diarrhea
Antidiarrheal agents – Loperamide is 1st-line, bile-acid sequestrants are considered 2nd-line.
- Symptomatic treatment of abdominal pain,
spasm, and severe bloating
Antispasmodics on an ‘as-needed basis’Direct acting → mebeverine, pinaverineIndirect-acting → dicyclomine, hyoscyamine - Antidepressant drugs
In addition to their mood-elevating effects, antidepressants have several physiologic effects that suggest they may be beneficial in IBS.
TCA → anticholinergic effects, slow intestinal transient time, may alter visceral afferent neural function. - Antibiotics
Not routinely recommended in all patients with IBS !
2-week trial of Rifaximin (lumen-active Abx.) should be considered in patients with moderate to severe IBS without constipation, particularly those with bloating, who have failed to respond to other therapies (diet, life-style, TCA, antispasmodic). Beneficial effect is via modulation of gut flora. - Others
Serotonin modulators (modulate pain pathways)
Chloride channel activators (ex. Lubiprostone)
Guanylate Cyclase-C agonist (ex. Linaclotide)
