Lower GI Drugs Katzung (10th ed.) Chapter 63: pg Med 5724 Gastrointestinal Hepatobiliary System Winter 2009 Dr. Janet Fitzakerley

Critical Facts 1.Many of the drugs that affect lower GI function work by modulating the actions of the enteric nervous system. The neurotransmitters acetylcholine (ACh), serotonin (5HT3), dopamine and the enkephalins are the important regulators of motility and water absorption (from a pharmacologist’s perspective!). 2.METOCLOPRAMIDE and CISAPRIDE act as cholinomimetics to increase GI motility. CISAPRIDE has severe side effects (fatal arrhythmias) that restrict its use. 3.The opiates LOPERAMIDE and DIPHENOXYLATE decrease both GI motility and water excretion, and are the most effective antidiarrheal drugs. They can be distinguished by the degree of their CNS penetration. LOPERAMIDE is available OTC because it has very little potential for addiction. 4.Several antidiarrheal agents have very limited uses: BILE ACID BINDING RESINS for diseases of the terminal ileum or surgical resection resulting in decreased bile salt reabsorption; OCTREOTIDE for dumping syndrome, short bowel disease, etc. and BISMUTH SUBSALICYLATE for traveler’s diarrhea. 5.MINERAL OIL (a stool softener) can cause severe lipid pneumonitis if aspirated; long term use may result in decreased absorption of fat soluble vitamins. 6.BISACODYL and ANTHRAQUINONES act on the large intestine and are less potent. CASTOR OIL acts on both the small and large intestine  short latency and extremely potent effects --- as well as more significant side effects. 7.Osmotic laxatives (LACTULOSE, MAGNESIUM HYDROXIDE) can cause intravascular volume depletion and electrolyte imbalances, esp. reduced potassium concentrations (therefore contraindicated in patients who are frail, elderly, have renal insufficiency or have significant cardiac disease). 8.Prescription of laxatives should be secondary to dietary modifications, increasing fluid intake and physical activity. Patients can become reliant on a daily laxative dose (cathartic colon).

Learning Objectives 1.Describe the neurotransmitters of the enteric nervous system that are key to understanding pharmaceutical treatment of diarrhea and constipation (paying particular attention to the role of serotonin). Be able to 1) name agonists and antagonists that act on each neurotransmitter system, and 2) differentiate among the specific therapeutic uses for those drugs. 2.Describe the mechanism of action and side effects of drugs that increase GI motility. Differentiate between prokinetics and laxative/cathartics. Identify the reason that CISAPRIDE is restricted in its availability. 3.Describe the mechanisms of action of antidiarrheal agents and relate these to their side effects. Be able to identify the specific types of diarrhea that BILE ACID BINDING RESINS, OCTREOTIDE, and BISMUTH SUBSALICYLATE are used to treat. 4.Be able to differentiate among laxatives and cathartics with respect to mechanisms of action, potency, latency and side effects.

Important Material from Other Lectures 1.Physiology of GI motility and defecation, function of the enteric nervous system and mechanism of water and electrolyte transport in the GI tract (Dr. Heller, GIHBS) 2.Macrolide antibiotics (Dr. Regal, Principles) 3.Opiates and dopamine antagonists (Dr. Eisenberg, Nervous System) 4.Drugs affecting the autonomic nervous system (Dr. Trachte, CV and Nervous systems) 5.Bile Acid Binding Resins (Dr. Trachte, CV)

Drugs You Need to Know

Review of Large Intestine Physiology motility and water absorption are often treated as separate processes, but they are interrelated (e.g., increasing transit time increases water absorption) - many drugs affect both processes the enteric nervous system can regulate GI motility and secretion independent of extrinsic sympathetic and parasympathetic input Many of the drugs that affect lower GI function work by modulating the actions of the enteric nervous system. The neurotransmitters acetylcholine (ACh), serotonin, dopamine and the enkephalins are the important regulators of motility and water absorption (from a pharmacologist’s perspective!).

Serotonin Here is what I hope is a simplified --- and understandable --- explanation for the effects of 5HT3 antagonists and 5HT4 agonists. It is becoming increasingly clear that serotonin plays a critical role in the pathophysiology of the lower GI tract (particularly in IBS). 5HT acts by altering sensory afferent activity, as well as by altering cholinergic and non-adrenergic, non-cholinergic (NANC) nerve activity, both directly and via reflex loops. One of the major roles for serotonin in the gut is thought to be regulation of the peristaltic reflex, which consists of both PROXIMAL CONTRACTION and DISTAL RELAXATION. In both cases, 5HT primarily acts on vagal afferents, which subsequently invoke a complicated reflex loop (which I simplified considerably by having the 5HT “neuron” act directly on the ACh and NANC neurons in your diagram). It’s also important to consider that the phrases “smooth muscle contraction” and “GI motility” (i.e., co- coordinated muscle contractions) are not necessarily synonymous.

Serotonin (cont’d) First, the easier to understand stuff. PROXIMALLY, stimulation of 5HT4 receptors  stimulation of vagal afferents  activation of interneurons containing ACh and/or CGRP  stimulation of ACh motoneurons  increased contractility. Therefore, administration of 5HT4 agonists (like CISAPRIDE and TEGASEROD) promote gastric emptying and speed up intestinal transit by stimulating ACh-containing motor neurons (  good things for the treatment of constipation-predominant IBS).

Serotonin (cont’d) Now for the tough stuff. DISTALLY, stimulation of 5HT3 receptors  stimulation of vagal afferents  activation of interneurons containing nitric oxide or VIP  inhibition of ACh motoneurons  decreased contractility  passage of food bolus. This means that administration of 5HT3 antagonists (like ONDANSETRON and ALSOETRON) increase distal contraction, which interferes with the timing of the peristaltic reflex. The net result of this is a decrease in the “effectiveness” of colonic motility and an increase in total transit time (  benefits for the treatment of diarrhea-predominant IBS). During vomiting, interference with reverse peristalsis is thought to be due to a similar interruption in effective segmentation.

Serotonin Bottom Line ABSOLUTE BOTTOM LINE: 5HT4 agonists increase GI motility (decrease transit time) 5HT3 antagonists increase contractility but decrease co-ordination (increase transit time)

Drugs Causing Constipation or Diarrhea many drugs produce diarrhea, constipation or both as adverse side effects drugs produce adverse lower GI effects by altering: ocholinergic transmission oosmolarity of the digestive system contents oGI motility obviously, these mechanisms can overlap

Drugs affecting cholingergic transmission Inhibiting transmission (contstipating): anticholinergics, antihistamines, antiParkinonian drugs, clonidine, ganglionic blocking agents, phenothiazines, tricyclic antidepressants Facilitating transmission (producing diarrhea): adrenergic ganglionic blocking agents, cholinergic agonists and cholinesterase inhibitors, prostaglandins, quinidine

Drugs affecting water reabsorption Increasing reabsorption (contstipating): aluminum hydroxide Decreasing reabsorption (producing diarrhea): magnesium hydroxide, diuretics that cause hypokalemia, heavy metals (esp. lead), iron, antidiarrheals

Drugs affecting GI motility Decreasing motility (contstipating): monoamine oxidase inhibitors, muscle relaxants, opioids, verapamil Increasing motility (producing diarrhea): macrolide antibiotics, osmotic and contact cathartics, prokinetic agents

DRUGS THAT INCREASE GI MOTILITY (PROKINETICS) METOCLOPRAMIDE, CISAPRIDE, MACROLIDE ANTIBIOTICS

CHOLINOMIMETICS: METOCLOPRAMIDE, CISAPRIDE METOCLOPRAMIDE and CISAPRIDE act as cholinomimetics to increase GI motility. CISAPRIDE has severe side effects (fatal arrhythmias) that restrict its use.

CHOLINOMIMETICS: METOCLOPRAMIDE, CISAPRIDE Mechanisms of action ACh + D2D2 DADA - X

CHOLINOMIMETICS: METOCLOPRAMIDE, CISAPRIDE Therapeutic Uses

CHOLINOMIMETICS: METOCLOPRAMIDE, CISAPRIDE Side Effects

MACROLIDE ANTIBIOTICS (e.g., erythromycin) stimulate motilin receptors on GI smooth muscle  initiation of migrating motor complex o doses that are subclinical for antibiotic actions will produce significant increases in GI motility o HOWEVER, these lower doses are sufficient to produce resistance; therefore, use of MACROLIDES solely for GI effects is controversial

ANTIDIARRHEALS all are safely used in patients with mild to moderate acute diarrhea should not be used in patients with bloody diarrhea, high fever or systemic toxicity because of the risk of exacerbating the underlying condition - should be discontinued if the diarrhea is worsening despite therapy

Types

1) OPIATES: DIPHENOXYLATE, LOPERAMIDE The opiates LOPERAMIDE and DIPHENOXYLATE decrease both GI motility and water excretion, and are the most effective antidiarrheal drugs. They can be distinguished by the degree of their CNS penetration. LOPERAMIDE is available OTC because it has very little potential for addiction.

1) OPIATES: DIPHENOXYLATE, LOPERAMIDE Mechanism of Action

1) OPIATES: DIPHENOXYLATE, LOPERAMIDE Side effects

2) BABRS: CHOLESTYRAMINE, COLESTIPOL Mechanism and Uses

2) BABRS: CHOLESTYRAMINE, COLESTIPOL Side effects

3) OCTREOTIDE Mechanism of action

3) OCTREOTIDE Therapeutic Uses

3) OCTREOTIDE Side effects

4) BISMUTH SUBSALICYLATE Mechanism of action

4) BISMUTH SUBSALICYLATE Therapeutic Uses

4) BISMUTH SUBSALICYLATE Side effects

5) ABSORBANTS: KAOLIN, PECTIN Mechanism and Side Effects

LAXATIVES and CATHARTICS

Categories

1) STOOL SOFTENERS: DOCUSATE, MINERAL OIL Mechanism of action

1) STOOL SOFTENERS: DOCUSATE, MINERAL OIL Therapeutic Uses despite widespread use, have marginal efficacy in most cases of constipation are used clinically for: osoftening of feces in anorectal abnormalities ohernia or cardiovascular disease ohemorrhoids odiverticular disease of the colon oradiological examination of the bowel

1) STOOL SOFTENERS: DOCUSATE, MINERAL OIL Contraindications

1) STOOL SOFTENERS: DOCUSATE, MINERAL OIL Side effects MINERAL OIL may result in severe lipid pneumonitis if aspirated; long term use can cause decreased absorption of fat soluble vitamins.

2) STOOL SOFTENERS: DIETARY FIBRE, METHYLCELLULOSE, PSYLLIUM Mechanism of action

2) STOOL SOFTENERS: DIETARY FIBRE, METHYLCELLULOSE, PSYLLIUM Side effects

3) CONTACT CATHARTICS: ANTHRAQUINONE DERIVATIVES (Cascara sagrada*, Danthron, Senna), BISACODYL, CASTOR OIL Mechanisms of action BISACODYL and ANTHRAQUINONES act on the large intestine and are less potent. CASTOR OIL acts on both the small and large intestine  short latency and extremely potent effects --- as well as more significant side effects.

3) CONTACT CATHARTICS: ANTHRAQUINONE DERIVATIVES (Cascara sagrada*, Danthron, Senna), BISACODYL, CASTOR OIL Side effects

4) OSMOTIC (SALINE) CATHARTICS: LACTULOSE, LUBIPROSTONE, MAGNESIUM HYDROXIDE, SODIUM PHOSPHATE, POLYETHYLENE GLYCOL (see GI decontamination handout) Mechanisms of Action

4) OSMOTIC (SALINE) CATHARTICS: LACTULOSE, LUBIPROSTONE, MAGNESIUM HYDROXIDE, SODIUM PHOSPHATE, POLYETHYLENE GLYCOL (see GI decontamination handout) Therapeutic Uses

4) OSMOTIC (SALINE) CATHARTICS: LACTULOSE, LUBIPROSTONE, MAGNESIUM HYDROXIDE, SODIUM PHOSPHATE, POLYETHYLENE GLYCOL (see GI decontamination handout) Mechanisms of Action All osmotic laxatives can cause intravascular volume depletion and electrolyte imbalances, esp.reduced potassium concentrations (therefore contraindicated in patients who are frail, elderly, have renal insufficiency or have significant cardiac disease).

Use and Abuse of Laxatives and Cathartics the overwhelming majority of people do not need laxatives, yet they are self-prescribed by a large portion of the general population prescription of laxatives should be secondary to fiber-rich diet, adequate fluid intake, physical activity, with milder laxatives (such as bulk- forming laxatives) being the first choice use lowest effective dosage, as infrequently as possible, and discontinue as soon as possible patients can become totally reliant on a daily dose (cathartic colon), although recent research suggests that this is quite rare