GI Pharmacology - Laulima · PDF fileA Beale PHRM 203 - GI Pharmacology 5 GIT Hormones ... A Beale PHRM 203 - GI Pharmacology 22 Lubricant laxatives! Adapted from: Focus on

GI Pharmacology

PHRM 203 Allison Beale

A Beale PHRM 203 - GI Pharmacology 2

Anatomy of the GIT

•  In order of food transport –  Mouth –  Esophagus

• Esophogeal sphincter

–  Stomach •  Pyloric sphincter

–  Small intestine • Duodenum, Jejunum, Ileum

–  Large intestine (cecum, colon & rectum) –  Anus

Accessory Glands Salivary glands

Pancreas Liver/gall bladder


Anatomy of the GIT

•  GIT in four layers –  Mucosa

•  Inner lining = epithelium + connective tissue + smooth muscle

–  Mucosa muscularis •  2 muscle layers

–  Circular, longitudinal

–  Nerve plexus •  Meissner’s (inner) - 1o controls

secretions and blood flow •  Auerbach’s (outer)- 1o controls motor

functions –  Adventitia

•  Outer supportive layer, holds guts in place

•  Hormone/NTs –  ACh –  NE –  ATP –  5-HT –  DA –  Cholecystokinin –  Substance P –  Vasoactive intestinal

peptide (VIP) –  Somatostatin –  Leu-enkephalin –  Met-enkephalin –  Bombesin


GIT secretions

•  Saliva •  Pepsin •  Gastrin •  Somatostatin •  HCl •  Intrinsic Factor •  Secretin •  Cholecystokinin

•  Mucous •  Sodium bicarbonate •  Pancreatic enzymes

–  Chymotrypsin and trypsin, lipase, amylases

•  Bile


GIT Hormones Hormone Release trigger Function (Stimulates:)

Gastrin Peptides, AA, FFA in stomach

Gastric acid secretion

Ghrelin grey-LYN Gastric emptiness? Appetite, GH secretion

Motilin Fasting? Stomach, SI motility

Cholecystokinin koh-leh-siss-toh-KYN-in

HCl, Fatty acids, AA in small intestine (SI)

Pancreas & gall bladder gastric emptying

Secretin Acidic pH in SI Pancreas bicarb & H2O

Gastric inhibitory polypeptide - GIP

Fat, glucose in SI gastric secretion & motility, ⇑insulin release


GI reflexes: 3 basic types •  In gut wall enteric system

– Control GI secretions and motor functions • From gut to autonomic ganglion and back

– E.g., Signal from stomach to colon to empty • From gut to spinal cord or brain and back

– Other reflexes to control motor and secretory activities

–  Pain reflexes – Defecation reflexes


GI reflexes • Gastroenteric reflex

–  Stretching of stomach →↑activity in small intestine

• Gastrocolic reflex –  Stretching of stomach →↑activity in colon to

empty colon to provide space for coming chyme

• Duodenal-colic reflex –  Stretching of duodenum →↑activity in colon


GI reflexes, continued •  Ileogastric reflex

–  Stretch of large intestine →↓stomach activity

•  Intestinal-intestinal reflex –  Irritation to one area of small intestine triggers a ⇓

in activity above the irritation and ⇑ activity below (think, Montezuma’s revenge)

• Peritoneointestinal reflex –  Irritation of the peritoneum (injury or

inflammation) →⊗ of all movement in the GI tract


GI reflexes, continued •  Renointestinal reflex

–  Irritation of the kidney (injury or inflammation to the capsule) → ⊗ of movement in the GI tract

•  Vesicointestinal reflex –  Irritation or overstretching of the bladder → ⊗ of

movement in the GI tract

•  Somatointestinal reflex –  Taut stretching of the skin over the abdomen irritates

the nerve plexus → ⊗ of movement in the GI tract (leading to constipation - tight clothes can have the same effect!)


GI reflexes, continued CNS mediated reflexes

Swallowing

Food bolus shuts off nasal cavity with soft palate, which stops respirations, so the larynx and pharynx close off trachea, causing the pharyngeal muscles to move the food bolus into the esophagus where pairs of muscles contract to move the food to the stomach.

A very complex reflex involving >25 pairs of muscles. Assist by: icing tongue.

Vomiting

Emetic zone triggers projectile vomiting. Chemoreceptor trigger zone (CTZ) triggered by: touching the back of the throat, excessive stomach distention, intracranial pressure, stimulation of vestibular receptors in the inner ear, or of stretch receptors in uterus and bladder, intense pain, exposure to certain chemicals (including those from cell death, e.g., during chemotherapy). CTZ receptors: D2, 5HT3, opioid, ACh, sP


Diseases and Drugs that can cause difficulty swallowing

Diseases or conditions Drugs

Spinal cord or head injury, Stroke Nitrates

Cerebral palsy, Myasthenia gravis, Acid reflux disease

Anti-cholinergic antidepressants and anti-allergy medications

Head, neck or esophageal tumor Calcium and iron tablets

Parkinson’s Vitamin C

Multiple sclerosis Anti-psychotics

Huntington’s Tetracycline (acne medication)

Amyotrophic lateral sclerosis Calcium channel blockers


Histamine-2 Antagonists��Adapted from: Focus on Nursing Pharmacology, 4th Ed., by AM Karch. Lippincott, Williams & Wilkins, 2008

Drug Indication/use

Cimetidine (Tagamet)

Duodenal ulcer, benign gastric ulcer, pathological hyper-secretion syndrome, gastro esophageal reflux disease (GERD), prophylaxis of stress ulcers, relief of heartburn symptoms, acid indigestion, sour stomach. These drugs are generally not recommended for use in kids.

Best taken just before bed

Famotidine (Pepcid)

Nizaridine

Ranitidine (Zantac)

Ranitidine may ⇑ the absorption of Glipizide by >30% and Midazolam by >60%

All are PO, IM/IV


Histamine-2 Antagonists Drug Drug Interactions

Cimetidine (Tagamet)

Cimetidine decreases the metabolism of (and therefore increases the circulating levels of): - Warfarin, phenytoin, propranolol, nifedipine, diazepam, TCAs, lidocaine, theophylline and metronidazole - Cimetidine affects the absorption of ketoconazole (↓).

Because of all it’s adverse interactions, cimetidine is not used nearly as much as ranitidine (Zantac) and famotidine (Pepsid).

Drugs that ↓ stomach acidity (↑pH) - H2 antagonists, antacids, proton pump inhibitors, etc. – ↑ diarrhea

The Vestibulocochlear nerve (CN VIII) has lots of mAChR and H1 receptors, so H2 antagonists have no effect on emesis and as anti-emetics, H1 antagonists

are really best at treating nausea caused by motion sickness!


Antacids��Adapted from: Focus on Nursing Pharmacology, 4th Ed., by AM Karch. Lippincott, Williams & Wilkins, 2008

Drug Indication/Use

Aluminum salts GI hyperacidity, hyperphosphatemia, prevention of phosphate urinary stones

Calcium salts GI hyperacidity, calcium deficiency, prevention of hypocalcemia

Magaldrate (Riopan) GI hyperacidity (ulcers)

Magnesium salts GI hyperacidity, prophylaxis of gastric ulcers, constipation, tetany, dialysis, etc.

Sodium bicarbonate GI hyperacidity, ↓uric acid crystalluria, adjunct to treatment for severe diarrhea

Taking antacids too often leads to acid rebound - the neutral pH stimulates gastrin secretion which

triggers gastric acid secretion!


Proton Pump Inhibitors��Adapted from: Focus on Nursing Pharmacology, 4th Ed., by AM Karch. Lippincott, Williams & Wilkins, 2008

Drug Indication/Use Esomeprazole (Nexium)

GERD, severe erosive esophagitis, duodenal ulcers, pathological hypersecretory conditions

Lansoprazole (Prevacid) Gastric ulcer, GERD, pathological hypersecretory

conditions, healing duodenal ulcers or esophagitis, combo therapy to eradicate Helicobacter pylori infection, heartburn, erosive esophagitis

Omeprazole (Prilosec)

Rabeprazole (Aciphex)

Pantoprazole (Protonix)

GERD

OTC &


Proton Pump Inhibitors

Drug Drug Interactions www.drugs.com/pro/omeprazole.html

Omeprazole (Prilosec, Zegerid)

Delayed elimination: phenytoin, warfarin and diazepam Interference with the absorption of drugs where gastric pH is a determinant: ketoconazole, ampicillin esters, iron salts ↓ plasma levels: atazanavir (protease inhibitor) ↑ plasma levels: tacrolimus (Prograf, immunosuppressant)

Amoxicillin/Clarithromycin/lansoprazole (or omeprazole) = triple therapy for Heliobacter pylori caused duodenal ulcers.

Zegerid OTC approved Dec 2009

PO, IV


Antipeptic Agent��Adapted from: Focus on Nursing Pharmacology, 4th Ed., by AM Karch. Lippincott, Williams & Wilkins, 2008

Drug Indication

Sucralfate (Carafate)

Short-term (up to 2 months) treatment of duodenal ulcers, healing ulcers, and oral or esophageal ulcers caused by radiation or chemotherapy

Contraindications: None known!

Mechanism: Unknown - it does form a proteinaceous glob over the ulcer and reduces pepsin activity in gastric juices by 1/3.

PO


Prostaglandin��Adapted from: Focus on Nursing Pharmacology, 4th Ed., by AM Karch. Lippincott, Williams & Wilkins, 2008

Drug Indication

Misoprostol (Cytotec)

Prevention of NSAID-induced ulcers in adults at high risk It is a prostaglandin E analog, used off label as a medical aborticant and to induce labor

www.drugs.com/pro/misoprostol.html

Contraindications: X, allergy to prostaglandins

ADRs: GI - diarrhea; Gynecological - pain and bleeding

¨  May cause abortion, not for pregnant women

PO


Digestive enzymes��Adapted from: Focus on Nursing Pharmacology, 4th Ed., by AM Karch. Lippincott, Williams & Wilkins, 2008

Drug Indication

Pancrelipase (Ultrase)

Digestion and absorption aid for fats, proteins and carbohydrates in conditions resulting in a loss of this enzyme.

Saliva substitute

An aid in conditions that result in dry mouth: stroke, radiation therapy, chemotherapy, various medications (especially anti cholinergics) and diseases

PO


Chemical stimulant��laxatives��

Adapted from: Focus on Nursing Pharmacology, 4th Ed., by AM Karch. Lippincott, Williams & Wilkins, 2008 Drug Indication

Bisacodyl (Dulcolax) Bowel preparation, prevention of constipation after surgery, MI, or obstetrical delivery; acute constipation

Casara Short term constipation therapy, evacuation of bowel for Dx exam

Castor oil (Neoloid)

Senna (Senokot) Short term constipation therapy, treatment of encopresis (inability to retain stools)

Constipation worsened by: Ca++, anti-cholinergics and CCBs, opioids etc.

Prolonged laxative use leads to atonic, dilated colon!

PO


Bulk laxatives��Adapted from: Focus on Nursing Pharmacology, 4th Ed., by AM Karch. Lippincott, Williams & Wilkins, 2008

Drug Indication

Lactulose Short term constipation therapy, especially in patients with CV disorders

Magnesium citrate Evacuation of bowel for Dx exam

Magnesium hydroxide (Milk of Magnesia)

Short term constipation therapy, prevention of straining after surgery, delivery, MI

Polycarbophil Mild laxative; short-term constipation therapy

Psyllium

PO


Lubricant laxatives��Adapted from: Focus on Nursing Pharmacology, 4th Ed., by AM Karch. Lippincott, Williams & Wilkins, 2008

Drug Indication

Docusate Prevention of straining post-op, post-MI, and post-partum

Glycerin Short-term treatment of constipation

Mineral oil

PO


GI Stimulants��Adapted from: Focus on Nursing Pharmacology, 4th Ed., by AM Karch. Lippincott, Williams & Wilkins, 2008

Drug Indication Dexpanthenol Prevention of intestinal atony post-op

Metoclopramide (Reglan, Octamide, Maxolon, etc.)

GERD, chemotherapy or PONV, diabetic gastroparesis, promotion of GI movement during small bowel intubation or promotion of barium movement. Stimulates lactation.

⊕ Muscarinic receptors in sm. muscle and 5-HT3&4  DA receptors in CTZ

¨  Not for >12 wks use – risk of tardive dyskinesia

PO, IV, IM


Antidiarrheals��Adapted from: Focus on Nursing Pharmacology, 4th Ed., by AM Karch. Lippincott, Williams & Wilkins, 2008

Drug Indications

Bismuth subsalicylate (Peptobismol, Keopectate)

Traveler’s diarrhea, irritable bowel syndrome, prevention of cramping and distention associated with dietary excess and some viral infections Loperamide

(Imodium)

Diphenoxylate (+atropine) (Lomotil) C-V

Short-term treatment of cramping and diarrhea

PO


Antidiarrheals

Drug Interactions www.drugs.com/pro/loperamide.html

Loperamide (Imodium)

Loperamide is a P-glycoprotein substate; quinidine and ritonavir are both P-glycoprotein inhibitors. Coadministration with either inhibitor can double or triple the plasma levels of loperamide.

Remember: P-GP important in the BBB, liver, kidney and GIT.


Antiemetics •  Anticholinergics •  Antihistamines (H1 receptor antagonists) •  Benzodiazepines •  Cannabinoids •  DA antagonists •  5-HT3 antagonists •  NK1 antagonists •  Steroids •  Others

All anti-emetics may mask the symptoms of ADRs or OD on

other drugs, including anti-neoplastics, and may interfere with Dx of other conditions

including GI obstruction, brain tumors & Reye’s syndrome.

NOTE: post-op nausea & vomiting = PONV. It’s a common acronym


Anti-cholinergic anti-emetics

Drug Uses

Scopolamine hydrobromide (Scopace, Transderm Scop) AKA Hyoscine hydrobromide

Nausea and vomiting associated with motion sickness. Anesthesia adjunct, anti-arrhythmic, anti-cholinergic, anti-dysmenorrheal, anti-emetic, anti-vertigo, antispasmodic for GI and urinary tract.

Precautions Don’t combine with CNS depressants Avoid overheating (reduced ability to sweat) Blurred vision, dry mouth, drowsiness, dizziness & hypotension are possible (anti-muscarinic effects)

Note: Drugs like Droperidol, Diphenhydramine & Prochlorperazine work as anti-emetics because of their anti-cholinergic side effects


Antihistaminic antiemetics��Adapted from: Focus on Nursing Pharmacology, 4th Ed., by AM Karch. Lippincott, Williams & Wilkins, 2008

Drug Indication

Diphenhydramine (Benadryl, Sominex)

Nausea associated with motion sickness; sleeplessness; mild Parkinson’s symptoms & EPS; allergic reactions; cough

Dimenhydrinate (Dramamine)

Nausea and vomiting associated with motion sickness. Off label: Post-op & pregnancy related nausea/vomiting

Hydroxyzine (hydralazine!)

Anxiolytic and sedative with weak antiemetic effects. Prepartum, postpartum and PONV

Meclizine (Bonine, Antivert)

Nausea and vomiting associated with motion sickness ≥12 years old. Antivert Axert (almotriptan for migraines) AKA Dramamine Less Drowsy!!

Used for severe morning sickness, too

All may mask symptoms of ototoxicity, brain tumors or intestinal obstructions


Benzodiazapines

Drug Use as anti-emetic

Midazolam (Versed) C-IV

Off label - Adjuvant for Post-op nausea and vomiting (PONV)

Inadvertent intraarterial injection causes arteriospasm that can lead to gangarene and

amputation!

Lorazepam (Ativan) C-IV

Remember the basic uses of BZDs: sedation, hypnosis, anxiolysis, muscle relaxation,

anticonvulsant, amnesiac and some anesthesia.

PONV = post op- CINV = chemo-

RINV = radiation- Induced nausea and vomiting

PO, IV, IM


Cannabinoids

Drug Indication

Cannabis C-I - anti-emetic for CINV and AIDs patients

Dronabinol (Marinol)

C-III - anti-emetic for CINV and AIDs patients, anorexia in Alzheimer’s patients

Nabilone (Cesamet)

C-II - synthetic used to treat severe CINV

Used for cachexia, cytotoxic nausea and or vomiting that is unresponsive

to other drugs

Has sympathomimetic effects on HR

Use with caution in CV, substance abuse, psych, elderly, pregnant patients

PO


Phenothiazine antiemetics (DA antagonists)��Adapted from: Focus on Nursing Pharmacology, 4th Ed., by AM Karch. Lippincott, Williams & Wilkins, 2008

Drug Indication

Chlorpromazine Nausea and vomiting, including that associated with anesthesia. Severe vomiting, intractable hiccoughs Perphenazine

Prochlorperazine (Compazine) Severe nausea and vomiting, including that associated with

anesthesia and chemotherapy. OTC & I

Promethazine (antihistamine)

Nausea, vomiting & pain associated with motion sickness and surgery, allergies, used to induce a light sleep

EPS, NMS, sedation & other ADRs limit usefulness, but DA antagonists are used for radiation sickness, drug-induced nausea/vomiting & neoplasms.

PO, PR, IM, IV


Nonphenothiazine DA antagonist antiemetics��Adapted from: Focus on Nursing Pharmacology, 4th Ed., by AM Karch. Lippincott, Williams & Wilkins, 2008

Drug Indication

Metoclopramide (Reglan, etc.) (like moclobemide an MAOI)

Nausea and vomiting, especially if due to CTZ stimulation

Droperidol (Inapsine) A butyrophenone, antipsychotic, sedative, tranquilizer, anti emetic for PONV.

Metoclopramide ADRs: suicidal ideation, EPS, NMS, seizures, arrhythmias, neutropenia, ↑ prolactin. May trigger catecholamine release, hypertensive crisis may be controlled with phentolamine. Adults only; use for <12 weeks.

¨  Not for >12 wks use – risk of tardive dyskinesia


5-HT3 Receptor Blockers��

Adapted from: Focus on Nursing Pharmacology, 4th Ed., by AM Karch. Lippincott, Williams & Wilkins, 2008 Drug Indication Dolasetron

CINV, RINV, PONV Granisetron

Ondansetron (Zofran)

Palonosetron Acute and delayed CINV

5-HT3 receptors on vagal nerve terminals in GIT mucosa and in the CTZ (medulla) sense irritants (chemical, radioactive and bacterial/viral (etc.)

May mask ileus &/or gastric distension

PO, IV, IM Ondansetron = 1st choice for PONV


Substance P/Neurokinin 1 Receptor Antagonist antiemetic��

Adapted from: Focus on Nursing Pharmacology, 4th Ed., by AM Karch. Lippincott, Williams & Wilkins, 2008 Drug Indication

Aprepitant (Emend)

Acute and delayed CINV or PONV

Aprepitant antagonizes Substance P and neurokinin-1 receptors in the CNS (including CTZ).

It is not used alone and shouldn’t be taken with grapefruit in the diet. Use in combination with 5-HT3 antagonist and a corticosteroid.

Serious ADRs include constipation and hiccups. Rarely neutropenia, bradycardia

CYP3A4↓ CYP2C9↑

PO, IV


Steroids Drug Indication/use as anti-emetic

Dexamethasone PONV

Dexamethasone has an EXTENSIVE list of indications including allergic, dermatologic, endocrine, GI, hematologic, neoplastic, neurologic (e.g., MS), eye,

kidney, lung and rheumatic conditions or disorders. To see a full listing, go to http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=2934#nlm34067-9 or

Google “dexamethasone dailymed”

As with other corticosteroids, it is contraindicated in fungal infections.

PO, IM, IV, Topical

Dexamethasone = 1st choice for PONV due to low cost and few ADRs


Miscellaneous antiemetics

Drug Indication

Trimethobenzamide Nonsedating antiemetic

Ginger Herbal used to prevent/treat motion-related, PONV, pregnancy (morning sickness), and CINV

Propofol (Diprivan)

IV rescue for severe emesis (Ultra-short acting anesthetic)

Peppermint Herbal used to treat nausea (usually as a tea)

Documents

GI Pharmacology - Laulima · PDF fileA Beale PHRM 203 - GI Pharmacology 5 GIT Hormones ... A Beale PHRM 203 - GI Pharmacology 22 Lubricant laxatives! Adapted from: Focus on