Lower GI Drugs Katzung (10th ed.) Chapter 63: pg. 1019-1036 Med 5724 Gastrointestinal Hepatobiliary...

Lower GI DrugsKatzung (10th ed.) Chapter 63: pg. 1019-1036

Med 5724 Gastrointestinal Hepatobiliary System

Winter 2009

Dr. Janet Fitzakerley jfitzake@d.umn.edu

http://www.d.umn.edu/~jfitzake/Lectures/Teaching.html

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 KnowIncrease GI Motility

(Prokinetics) Antidiarrheals

CISAPRIDE Propulsid Opiates Absorbants

MACROLIDE ANTIBIOTICS e.g., ERYTHROMYCIN

DIPHENOXYLATE Lomotil

KAOLIN/PECTIN KaoPectate

METOCLOPRAMIDE Reglan

LOPERAMIDE Imodium

Bile Acid Binding Resins

Miscellaneous

CHOLESTYRAMINE Questrin

BISMUTH SUBSALICYLATE Peptobismol

COLESTIPOL Colestid, Colestitabs

OCTREOTIDE Sandostatin

Laxatives and Cathartics

Stool softeners Contact cathartics Osmotic cathartics

DOCUSATE Aqualax, Calube, Colace, Colace Micro-Enema, Correctol Softgel Extra Gentle, DC-240, Dialose, Diocto, Dioctocal, Dioctosoftez, Dioctyn, Dionex, Doc-Q-Lace, Docu Soft, Docucal, Doculax, Docusoft S, DOK, DOS, Doss-Relief, DSS, Dulcolax, Ex-Lax Stool Softener, Fleet Sof-Lax, Genasoft, Kasof, Modane Soft, Octycine-100, Regulax SS, Sulfalax Calcium, Sur-Q-Lax, Surfak Stool Softener and Therevac-SB

ANTHRAQUINONE DERIVATIVES CASACARA SAGRADA, DANTHRON, SENNA

BISACODYL Alophen, Carter's Little Pills, Correctol, Dulcolax, Fleet

CASTOR OIL

LACTULOSE Cephulac

LUBIPROSTONE Amitiza MAGNESIUM HYDROXIDE Milk of Magnesia

Bulk laxatives SODIUM PHOSPHATE

DIETARY FIBER Fleet enema, OsmoPrep, Vicol, Wal-phosphate

METHYLCELLULOSE Celoftel, Citrocel

POLYETHYLENE GLYCOL SOLUTION

PSYLLIUM Metamucil

Miralax, GoLytely, GlycoLax, CoLyte, NuLytely

- also see GI Decontamination handout

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!).

PHARMACOLOGICALLY SIGNIFICANT NEUROTRANSMITTER ACTIONS

GI DRUG and ACTION

ACETYLCHOLINE (M) increases motility

increases water excretion (decreases absorption)

ANTAGONISTS: ATROPINE

SEROTONIN 5HT1 increases water absorption by increasing NANC-

mediated inhibition of water excretion 5HT3 increases distal relaxation by exciting NANC

neurons 5HT4 increases proximal contraction

5HT3 ANTAGONISTS: ALOSETRON, DOLASETRON,

GRANISETRON, ONDANSETRON

5HT4 AGONISTS: CISAPRIDE, TEGASEROD

DOPAMINE (D2) decreases ACh-induced motility

ANTAGONISTS: METOCLOPRAMIDE, Domperidone

ENKEPHALINS μ stimulates 5HT1 increase in water absorption κ and μ inhibit ACh-induced motility

AGONISTS: DIPHENOXYLATE, LOPERAMIDE

NA, VIP,or otherNA, VIP,or other

NANC5HT3

-

NANC5HT3

NANC5HT35HT3

--

ACh

+

ACh

+

-

+

5HT4

++

5HT4

5HT1or2

5-HT

++

+

5-HT

++

5-HT

+

5-HT5-HT5-HT5-HT

++

+

ACh

Enk

+

EnkEnk

+

EnkEnk

,--DA- DADA-D2D2

PERISTALTIC REFLEX

ProximalContraction

DistalRelaxation

WATEREXCRETION

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:o cholinergic transmission o osmolarity of the digestive system contents

o GI 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

+

5HT4

ACh

+

5HT4

++

5HT4

ACh

ACh

+

ACh

+

ACh

+

D2

DA-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

odoses that are subclinical for antibiotic actions will produce significant increases in GI motility

oHOWEVER, 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

NA, VIP,or otherNA, VIP,or other

ACh

+

ACh

+

-

+

5HT4

++

5HT4

5HT1or2

5-HT

+

+

ACh

Enk

+

EnkEnk

+

EnkEnk

,--

1) OPIATES: DIPHENOXYLATE, LOPERAMIDE

Side effects

Functional effects associated withthe main types of opioid receptors

mu delta kappa

Analgesia

Supraspinal +++

Spinal ++

Peripheral ++

Respiratory depression +++

Pupil constriction ++

Reduced GI motility ++

Euphoria +++

Dysophoria -

Sedation ++

Physical dependence +++

-

++

-

++

-

++

-

-

-

-

-

+

++

-

+

+

-

+++

++

+

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:

o softening of feces in anorectal abnormalities o hernia or cardiovascular disease o hemorrhoids o diverticular disease of the colon o radiological 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 ofLaxatives 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