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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
A Beale PHRM 203 - GI Pharmacology 3
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
A Beale PHRM 203 - GI Pharmacology 4
GIT secretions
• Saliva • Pepsin • Gastrin • Somatostatin • HCl • Intrinsic Factor • Secretin • Cholecystokinin
• Mucous • Sodium bicarbonate • Pancreatic enzymes
– Chymotrypsin and trypsin, lipase, amylases
• Bile
A Beale PHRM 203 - GI Pharmacology 5
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
A Beale PHRM 203 - GI Pharmacology 6
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
A Beale PHRM 203 - GI Pharmacology 7
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
A Beale PHRM 203 - GI Pharmacology 8
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
A Beale PHRM 203 - GI Pharmacology 9
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!)
A Beale PHRM 203 - GI Pharmacology 10
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
A Beale PHRM 203 - GI Pharmacology 11
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
A Beale PHRM 203 - GI Pharmacology 12
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
A Beale PHRM 203 - GI Pharmacology 13
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!
A Beale PHRM 203 - GI Pharmacology 14
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!
A Beale PHRM 203 - GI Pharmacology 15
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 &
A Beale PHRM 203 - GI Pharmacology 16
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
A Beale PHRM 203 - GI Pharmacology 17
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
A Beale PHRM 203 - GI Pharmacology 18
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
A Beale PHRM 203 - GI Pharmacology 19
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
A Beale PHRM 203 - GI Pharmacology 20
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
A Beale PHRM 203 - GI Pharmacology 21
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
A Beale PHRM 203 - GI Pharmacology 22
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
A Beale PHRM 203 - GI Pharmacology 23
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
A Beale PHRM 203 - GI Pharmacology 24
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
A Beale PHRM 203 - GI Pharmacology 25
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.
A Beale PHRM 203 - GI Pharmacology 26
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
A Beale PHRM 203 - GI Pharmacology 27
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
A Beale PHRM 203 - GI Pharmacology 28
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
A Beale PHRM 203 - GI Pharmacology 29
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
A Beale PHRM 203 - GI Pharmacology 30
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
A Beale PHRM 203 - GI Pharmacology 31
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
A Beale PHRM 203 - GI Pharmacology 32
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
A Beale PHRM 203 - GI Pharmacology 33
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
A Beale PHRM 203 - GI Pharmacology 34
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
A Beale PHRM 203 - GI Pharmacology 35
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
A Beale PHRM 203 - GI Pharmacology 36
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)