Drugs act on GIT motility

AZL & ZRDep. Farmakologi & Terapeutik,

Fakultas KedokteranUniversitas Sumatera Utara

20 Oktober 2009, KBK Block GIS

Gastrointestinal Motility

• Memahami obat-obat yang digunakan untuk mengatasi mual dan muntah

• Memahami farmakologi prokinetik

• Memahami farmakologi antispasmodik• Memahami farmakologi antispasmodik

• Memahami farmakologi antidiare

• Memahami farmakologi pelancar defikasi– Emollient

– Laxantia

– Cathartic/Purgative

Nausea and VomitingPathophysiology

• Vomiting center in brainstem

• Chemoreceptor zone (CTZ) stimulated

• Autonomic nervous system is activated• Autonomic nervous system is activated

– Sympathetic

• Tachycardia

• Diaphoresis

• Parasympathetic

• Relaxation of LES

Vomiting Stimulus

Antiemetics

• Serotonin (5HT) Antagonists

• Dopamine (DA) Antagonists

• Anticholinergics (muscarinic blockers)

• Cannabinoids• Cannabinoids

Medications to Alleviate Nausea/Vomiting

• Antimuscarinics– Scopolamine-patch– Antihistamines

• Promethazine• Benadryl-can be given IV

– Phenothiazines– Phenothiazines• Compazine-given IM

– These classes have anitcholinergic effects– Common contraindications with these classes:

• Do not give to client with glaucoma, BPH (urinary retention), pyloric/bladder neck obstruction, biliary obstruction

• Common side effects: – Dry mouth, constipation, hypotension, sedative

effects

Promethazine

• PO, IM, Rectal, IV

• Inhibits the CTZ in the medulla,

• Give 30-60 minutes ā radiation, chemo, etcetc

• Will cause drowsiness

Medications to Alleviate Nausea/Vomiting

• 5-HT receptors-antagonists to serotonin receptors

– Work peripherally and centrally to reduce

vomitingvomiting

– Used for Chemotherapy/radiation, migraine

induced vomiting

• ondansetron (Zofran),

• granisetron (Kytril),

• dolasetron (Anzemet)

prokinetics

• Metoclopramide and Domperidone

– Antiemetics

– Act on Dopamine receptors

– Enhance release of acetylcholine– Enhance release of acetylcholine

– Increased gastric emptying (prokinetics)

– Side effects of Metoclopramide:

hallucinations, tremors, dyskinesias, anxiety,

restlessness, insomnia

Diarrhea

• Usually self-limitingIndications for treatment• Diarrhea >2-3 d• Severe diarrhea in elderly and children• Chronic inflammatory disease• HIV/AIDS• HIV/AIDS• When specific cause has been determinedContraindications for Antidiarrheals• Diarrhea caused by:

– Toxic materials– Microorganisms (Shigella, Salmonella, E-coli)– Antibiotic associated colitis

Diphenoxylate (Lomotil)

• Opioid derivative (Schedule V)

• Overdose is treated with Naloxone

• Contraindicated in severe liver disease, glaucoma, children (<2 years old)glaucoma, children (<2 years old)

• Decreases GI motility

Teaching: Antidiarrheal

• Drink 2-3 qts of fluid/d

• Avoid spiced foods

• Consult HCP if diarrhea accompanied by

severe abd pain, fever, or blood/mucus appears severe abd pain, fever, or blood/mucus appears

in stool

• May cause Drowsiness!

Anti-spasmodic and anti-diarrhea

• GI anticholinergics and Anti-spasmodics are also known as antimuscarinic agents---muscarinic receptor antagonists– inhibit the actions of acetylcholine at the postganglionic

parasympathetic neuroeffector sites– Larger doses can also block nicotinic sites– Larger doses can also block nicotinic sites– Dose dependant responses– Small doses inhibit salivary and bronchial secretions– Moderate doses dilate the pupil and inhibit accommodation and

increase heart rate– Larger doses decrease GI and urinary tract motility– Very large doses inhibit gastric acid secretion

• primarily used to decrease motility by decreasing smooth muscle tone in the GI, biliary and urinary tracts and provide for anti-secretory effects

Anti-spasmodic and anti-diarrhea

• Belladonna Alkaloids– readily absorbed orally and cross the BBB

• atropine: stimulant and scopolamine: a depressant

– L-Hyoscyamine Sulfate

– Atropine sulfate

– Scopolamine HydroBromide

– Take 30-60 minutes prior to a meal– Take 30-60 minutes prior to a meal

• Quaternary Anticholinergics– adjunct therapy in the treatment of peptic ulcer

– Methscopolamine Bromide

– Mepenzolate– Clininium bromide

– Glycopyrrolate

– Propantheline – Take 30 minutes before meals and at bedtime

GI Anticholinergics and Antispasmodics

Antispasmodics

ON CH

3

OCH

3

Dicyclomine HCl - Bentyl®, Byclomine®, Di-Spaz®

Indications: Treatment of functional bowel/irritable bowel syndromeIndications: Treatment of functional bowel/irritable bowel syndrome

Drugs for defecation

Classification

• Cathartic/Purgative

• Laxatives

MOA

• Bulk forming

• Surfactants

• Emollient • Stimulants

• Osmotics

Laxatives & Cathartics

Indications• Removal of intestinal parasites• Reduce ammonia• Treating drug-induced constipation

• Post Obstruction• Post Obstruction• Poor physical activity• Bowel preparation

Contraindications• Never give in the presence of undiagnosed abdominal

pain• Obstruction• Fecal Impaction

Irritant/Stimulant Cathartic

• Among the strongest

and most abused

• Irritate the GI mucosa

and pull H2O into the

lumen

• Stimulate peristalsis

• Increases water and

electrolytes secretion

into intestinal lumenlumen

• Can be given PO or

Rect

• Suppository s/b

inserted the length of

the index finger

• Do not chew tablets

into intestinal lumen

• Decreases water and

electrolyte

reabsorption

• Ex:

– Biscodyl (Dulcolax)

– Phenylolpthalein

Fiber/Bulk Forming Laxative

• Largely unabsorbed

• Swell and become gel-like

• Stimulate peristalsis and defecation

• Long term use or for those clients who • Long term use or for those clients who cannot or will not adjust diet

• Ex:– methylcellulose (Citrucel®)

– psyllium (Metamucil®)

– polycarbophil

Teaching: Laxatives & Cathartics

• Fiber and exercise

• Laxative use should be temporary

• No laxatives while abdominal pain or N&V are presentN&V are present

Emollient

• Lowers surface tension

– Facilitates water penetration

• Used to prevent straining at stool

• “stool softener” by incorporating water • “stool softener” by incorporating water into the stool

• Ex:

– Docusate Sodium (Colace)

Mineral Oil - Lubricant• Only lubricant used clinically

• Exact mechanism of action is unknown

• Useful as a retention enema

Lactulose - HyperosmolarLactulose - Hyperosmolar

• Poorly absorbed salts remain in fecal matter, not

absorbed by the GI

• Pulls water from intestine into lumen

• Tx of constipation and encephalopathy

• Reduces the amount of ammonia production in

the intestine (etoh liver disease)

Drugs act on hepato-biliary

system & others

AZL & ZRDep. Farmakologi & Terapeutik,

Fakultas KedokteranUniversitas Sumatera Utara

20 Oktober 2009, KBK Block GIS

ObjectivesBiliary system• Memahami farmakologi sediaan cholekinetic dan

choleretic• Memahami bile acid therapy for gallstoneEnzym Pencernaan• Memahami farmakologi sediaan yang mempengaruhi

enzyme pencernaanenzyme pencernaanIBS• Memahami farmakologi sediaan yang digunakan pada

terapi IBSVarices GIT• Memahami farmakologi sediaan yang digunakan pada

terapi varises saluran cerna– Varices oesophagei– Varices ventriculi– Varices recti (hemorrhoid)

Drugs act on hepatobiliary system

• Choleretic, induces excretion of bile components

• Cholekinetic, stimulates gallbladder contraction

HydrocholereticsHydrocholeretics

• Dehydrocholic acid

• Indications: temporary relief of constipation and

as a adjunctive agent in biliary stasis

• MOA: oxidation product of natural cholic acid---

a bile salt present in bile

Other choleretics( Gallstone Solubilizing Agents)

Ursodeoxycholic acid

• REQUIRES months of therapy to dissolve gall stones of diameter <20 mm primarily in patients that surgery is not an optionin patients that surgery is not an option

• MOA: slowly solubilizes cholesterol gall stones located in the gall bladder

Curcumin (temulawak) & Andrographolid

(sambiloto)

• Rapid onset, unknown MOA

Drugs act on digestive enzymesLipase Inhibitors, Orlistat (Xenical)• Indications: obesity management• Dosage is a function of body mass index and the

presence of other risk factors such as hypertension, diabetes and dyslipidemia

• MOA: A reversible inhibitor by covalent reaction with the serine active site group of gastric and pancreatic lipases serine active site group of gastric and pancreatic lipases in the intestinal tract----prevents the breakdown and absorption of fats since undigested triglycerides are not absorded

• Highly plasma protein bound (>99%), metabolism included beta-lactone hydrolysis including ester hydrolysis and hepatic deformylation---fecal elimination

• Will prevent the absorption of fat-soluble substances such as vitamins and drugs---take vitamin supplements if you use this drug

• Side effects: gas, greasy stools, fecal urgency

Two Types of Movement

• Peristaltic

– moves food forward

• Segmental• Segmental

– mixing

Bloating/

distention

Abdominal

pain/

discomfort

enhancedvisceral sensitivity

anti-serotonin

Irritable Bowel SyndromeIrritable Bowel Syndrome

TEGASEROD

Altered

bowel

function

discomfort

constipation diarrheadisturbancesin GI motility

anti-spasmodic

serotoninagonistsTEGASEROD

Some possible mediators of motilityand visceral hypersensitivity

�Motility:� Serotonin� ACh� CCK� Motilin� Nitric oxide� Nitric oxide� Somatostatin� Substance P� Vasoactive intestinal polypeptide (VIP)

�Visceral hypersensitivity:� Serotonin� Bradykinin� Tachykinins� Calcitonin gene-related peptide (CGRP)� Neurotrophins GriderGrider JR, et al. Gastroenterology. 115:370JR, et al. Gastroenterology. 115:370--380,1998380,1998

Kim D, Kim D, CamilleriCamilleri M. Am J M. Am J GastroenterolGastroenterol. 95:2698. 95:2698--709,2000709,2000GriderGrider JR, et al. Gastroenterology. 115:370JR, et al. Gastroenterology. 115:370--380,1998380,1998

Kim D, Kim D, CamilleriCamilleri M. Am J M. Am J GastroenterolGastroenterol. 95:2698. 95:2698--709,2000709,2000

Physiologic distribution of serotoninand its Brain-Gut Connection in IBS

5% CNS

Psychosocialfactors

Vagal nuclei

95% GI tract• 90% ECs• 5% neurons

Adapted from Coulie B, Camilleri M. Clin Perspect Gastroenterol. 2:329338,1999

Alteredmotility

Viseralhypersensitivity

Sympathetic

S2,3,4S2,3,45-HT

Inhibition

Dorsal Root Ganglion

Serotonin Signaling Pathways

CNS

SerosaLongitudinal muscle

Myenteric plexus

INHIBITION

Extrinsic primary

afferent neurons

ECs

Inhibitorymotor neuron

Excitatorymotor neuron

5-HT

5-HT4 receptor

ECs = enterochromaffin cells

Circular muscle

Submucosal plexus

Muscularis mucosae

Lamina propria

Epithelium

EnterocytesECs

ACTIVATIONIntrinsic primaryafferent neurons

Serotonin and enterochromaffin cells in altered GI motility

Hypomotility

Bowel

Hypermotility

Increased number of EC cellsIncreased circulating 5-HT

decreased number of EC cellsdecreased circulating 5-HT

Alternating

DiarrheaDiarrheaConstipationConstipation

Bowel movements

C-IBS D-IBS

Bearcroft CP et al. Gut. 42:42-6,1998

Spiller RC et al. Gut. 47:804-11,2000

El-Salhy M et al. Scand J Gastroenterol. 34:1007-11,1999

NH2

OH

N

O

NH

NHNH

Structure activity relationship

NH NH

Serotonin = 5-HT5-hydroxytripthamine Tegaserod

� Tegaserod is a selective 5-HT4 receptor agonist

� A new class of compound: aminoguanidine indoles

� Structure similar to serotonin

Differences Between Tegaserod and Cisapride

� Tegaserod� Selective 5-HT4 receptor

agonist

� Alleviates multiple symptoms of IBS (abdominal pain, bloating,

� Cisapride� Combined 5-HT3

antagonist and 5-HT4

agonist� Prokinetic agent with no

proven benefit in IBS(abdominal pain, bloating, and constipation)

� Tegaserod and placebo have a similar effect on QT interval

proven benefit in IBS� Removed from the US

market in July 2000 because of its effects on the QT interval and the potential development of fatal cardiac arrhythmias

Talley. Aliment Pharmacol Ther. 6:273,1992Talley. Aliment Pharmacol Ther. 6:273,1992Schutz, et al. Aliment Pharmacol Ther. 11:387,1997Schutz, et al. Aliment Pharmacol Ther. 11:387,1997Farup, et al. Scand J Gastroenterol. 33:128,1998Farup, et al. Scand J Gastroenterol. 33:128,1998

Talley. Aliment Pharmacol Ther. 6:273,1992Talley. Aliment Pharmacol Ther. 6:273,1992Schutz, et al. Aliment Pharmacol Ther. 11:387,1997Schutz, et al. Aliment Pharmacol Ther. 11:387,1997Farup, et al. Scand J Gastroenterol. 33:128,1998Farup, et al. Scand J Gastroenterol. 33:128,1998

Differences Between Tegaserod and Alosetron

� Tegaserod�Selective 5-HT4 receptor

agonist

�Stimulates peristaltic reflex, triggers stimulatory activity in GI tract,

� Alosetron� 5-HT3 receptor

antagonist

� Delays colonic transit, increases colonic compliance and activity in GI tract,

reduces firing of rectal afferents in animals, increases chloride secretion and reduces rectal sensitivity

�Adverse events:

• Diarrhea (T=8.8%; PI=3.8%)

• Headache (T=15%; PI=12.3%)

compliance and increases water and electrolyte absorption

� Adverse events:

• Constipation (A=~30%; PI=3%)

• Acute ischemic colitis (0.001 - 0.01%)

Talley, et al. Lancet. 358:2061,2001

Lotronex. Product Information. Feb 2000

Lucy, et al. J Clin Gastroenterol. 34(1):27,2001

Camilleri. Aliment Pharmacol Ther. 15:277,2001

Muller-Lissner, et al. Aliment Pharmacol Ther. 15:1655,2001

Talley, et al. Lancet. 358:2061,2001

Lotronex. Product Information. Feb 2000

Lucy, et al. J Clin Gastroenterol. 34(1):27,2001

Camilleri. Aliment Pharmacol Ther. 15:277,2001

Muller-Lissner, et al. Aliment Pharmacol Ther. 15:1655,2001

Esophageal Varices

• Esophageal varices are damaged veins due to portal hypertension

• Bleeding varices are the most serious complication of portal hypertensioncomplication of portal hypertension

• Other causes of bleeding must be excluded

• Mortality ranges from 30-50%

• Manifestations of portal hypertension can be seen throughout the body

Medical Management of Bleeding Esophageal Varices

• Endocopy� Variceal band ligation

�Sclerotherapy

• Direct tamponade with Sangstoken-Blakemore • Direct tamponade with Sangstoken-Blakemore tube or Minnesota tube

• Initiation of drug therapy�Pitressin

�Somatostatin

�B-Blockers

• Transjugular Intrahepatic Porto-systemic Shunt

Pitressin

• Exogenous form of vasopressin

• When given intravenously causes arterial vasoconstrictionand bowel wall contraction– Decreases blood through intestinal arterial bed

causing decreased venous outflowcausing decreased venous outflow

• Successfully controls bleeding in 36-100% of cases however re-bleeding occurs in 22-71%

• Has significant side effects however the risk is decreased when administered intra-arterial

• Depending upon patient history nitroglycerin may used for prophylaxis of angina

• Dose ranges from 0.5-1.0 unit/min

Pitressin

• Side effects which require the infusion to be

stopped include:

� Mesenteric ischemia

�Coronary ischemia

�Arrhythmias

• Side effects which require the dose to be

decreased or stopped include:

� Volume overload/CHF

�Hyponatremia

Somatostatin

• Hormone that inhibits GI motility, small bowel and pancreatic secretion

• Drug of choice for variceal bleeding

• Reduces splanchnic blood flow with out • Reduces splanchnic blood flow with out systemic side effects

• Cessation of bleeding and reduction in rebleeding rate is similar to vasopressin

Beta-blockers

• Propanolol and Nadolol are the only B-blockers shown to reduce portal pressure

• Works by decreasing inotropy and chronotropy of heartchronotropy of heart

• Heart rate must be reduced below 60 beats/min