Drugs Used in Gastrointestinal Disorders
Gastric
A & P
First,
some background physiology….
There
are 3 cells of the gastric gland:
1.
Chief
·
Secretes pepsinogen à pepsin
·
Breaks down proteins in the diet
2.
Mucoid
·
Secretes mucus
·
Provides a protective mucous coat to protect stomach from digestion of
itself from hydrochloric acid (HCl)
3.
Parietal
·
Secretes hydrochloric acid
·
Keeps the pH of the stomach between 1 and 4 so as to properly digest
food
The
wall of the parietal cell has 3 types of receptors: acetylcholine, histamine,
and gastrin.
·
When any one of these receptors is occupied, the parietal cell will
produce and secrete HCl
·
The receptors can also be blocked:
·
Atropine (an anticholinergic) blocks
acetylcholine from binding with the acetylcholine receptor
·
Histamine-2 (H-2) blockers block histamine from the
mast cell from binding with the histamine receptor
When any of these receptors are bound, the parietal cell is stimulated. The cell must now produce HCl, but needs hydrogen ions (H+ ions) to do so. These H+ ions are produced by the proton pump (H+/K+ ATPase pump) of the cell. The proton pump needs energy to function.
So: Energy à activates the H+/K+ ATPase system (proton pump) à proton pump produces H+
ions needed for the production of HCl à HCl is secreted into the stomach
Proton pump inhibitors bind to the H+/K+ ATPase
pump and irreversibly inhibit this enzyme, resulting in a total inhibition of
H+ ion secretion from the parietal cells.
The most common impairment is hyperacidity, or the overproduction of acid.
-
GERD = gastroesophageal reflux disease
The
most harmful is peptic ulcer disease.
Theory of how formed: aggressive (acid + pepsin) and protective
(mucosal layer)
Anti-peptic agents
-
Cheapest
-
Mainstay of antiulcer therapy until the 1970s
-
Neutralize acid, stimulate mucus and bicarbonate secretion, improve
blood flow to area à increase protective layer
-
Problems
-
Mg à diarrhea, Al à constipation
-
Al, Mg, Ca à renal patients unable to eliminate
-
Use caution if the antacid is high in sodium content in patients with
CHF, HTN, sodium restrictions, and other cardiac diseases
-
Best acid neutralizing capacity AND lowest sodium content: Riopan Plus (Al-Mg) and Maalox TC (Mg, Al,
simethicone)
-
There are many drug interactions with antacids because of the effect on
absorption of the medication that is given concurrently with the antacid…check
for interactions before ordering the medication.
-
Best not to administer other
meds within 1-2 hours after an antacid.
-
Especially important to separate by 2 hours: dig, iron, INH, quinolones, tetracyclines
-
Antacids may result in premature dissolving of the enteric coating of
meds, resulting in stomach upset.
-
Increasing the pH of the stomach with an antacid will cause drugs that
are acid salts (HCl salts) to be more ionized and less absorbed and drugs that
are basic salts (sulfate salts) to be less ionized and more readily absorbed
into the bloodstream.
-
The same alteration in absorption in the stomach will affect excretion
of basic and acidic drugs in the urine because the urinary pH will be elevated
and acidic drugs will be more ionized, less absorbed, and more excreted.
-
Began being used in the 1970’s
-
Bind to and block histamine receptors located on parietal cells
-
This blockade renders the parietal cells less responsive to stimuli and
thus acid secretion.
-
Up to 90% inhibition can be achieved with these agents (dose-related)
-
Indications
-
Ulcer (gastric, duodenal)
-
GERD
-
Upper GI bleeding
-
Hypersecretory conditions (Zollinger-Ellison syndrome = non-insulin-secreting
pancreatic tumor; releases large amount of gastrin)
-
Examples (and their equipotent dosages)
-
Cimetidine (Tagamet) 1600 mg.
-
Ranitidine (Zantac) 300 mg.
-
Nizatidine (Axid) 300 mg.
-
Famotidine (Pepcid) 40 mg.
-
All are equally effective in healing ulcers; need to look at
pharmacokinetics and adverse effects
-
Tagamet = shortest ½ life
-
Pepcid = longest ½ life
-
Caution with renal /hepatic dysfunction
-
Problem with Tagamet: inhibits the hepatic enzyme (cytochrome P-450
system) metabolism of the following drugs, thereby increasing their
levels and effects:
-
Theophylline
-
Phenytoin
-
Oral anticoagulants
-
Propranolol
-
Procainamide
-
Quinidine
-
Lidocaine
-
Calcium channel blockers
-
Adverse effects of H2 blockers (worse with patients with multiple
illnesses, elderly, those with hepatic or renal dysfunction)
-
CNS effects (headache, lethargy, confusion, depression, hallucinations
(<1%)
-
Endocrine (impotence, increased prolactin, gynecomastia)
-
GI (diarrhea, abdominal cramps, jaundice, increased LFTs)
-
GU (increased BUN, creatinine)
-
Hematopoietic (agranulocytosis, thrombocytopenia, neutropenia, aplastic
anemia)
-
Integumentary (urticaria, rash, alopecia, sweating, flushing
exfoliative dermatitis)
-
More effective than H2 blockers
-
More expensive than H2 blockers
-
Block the final step in the acid production pathway
-
Blocks all acid secretion
-
Examples:
-
omeprazole (Prilosec) 10, 20 mg
(also available OTC and generic)
-
lansoprazole (Prevacid) 15, 30
mg
-
rabeprazole (AcipHex) 20 mg
-
pantoprazole (Protonix)
-
esomeprazole (Nexium)
-
Adverse effects
-
CNS (headache, dizziness)
-
GI (diarrhea, abdominal pain, N, V, anorexia)
-
GU (proteinuria, hematuria, glycosuria)
-
Hematopoietic (pancytopenia, thrombocytopenia, neutropenia,
leukocytosis, anemia)
-
Integumentary (rash, dry skin, urticaria, pruritis, alopecia)
-
Respiratory (URI, cough)
-
Other (back pain, fever, fatigue)
-
Used for treatment of H. pylori
-
Example: 2 weeks of Prilosec 40
mg once daily plus Biaxin 500 mg 3X/day; follow with 2 week course of Prilosec
20 mg once daily
-
Example: PrevPac: 1 dose bid X 14 days (1 dose = 1 tab of lansoprazole [Prevacid], 2 tabs amoxiciliin, and 1 tab clarithromycin
[Biaxin])
-
A cytoprotective agent for stress ulcerations and PUD (peptic ulcer
disease)
-
Binds to exposed proteins of ulcers and thus limits pepsin’s
proteolytic action
-
Made of sucrose, Al, sulfate
-
Drug effects
-
Sulfate anions bind to positively charged tissue proteins that are
exposed at the tissue surface of an ulcer or an erosion
-
As a weak base, it buffers the acidic pH of the stomach
-
Binds and concentrates epidermal growth factor (EGF), which accelerates
the healing process
-
Simulates gastric mucosal prostaglandin E2 synthesis
-
The aluminum salt stimulates the secretion of mucus and bicarbonate
from the cells of the stomach to counteract the actions of HCl
-
Side effect: constipation
-
Renal patients may have problems with Al
-
Good drug for long-term use
-
Separate drugs by 2 hours; ciprofloxin should not be used at all
-
A synthetic prostaglandin analog
-
Inhibits gastric acid secretion, enhances local production of mucus or
bicarbonate
-
Also helps maintain mucosal blood flow
-
Used in drug induced PUD (from NSAIDs) or for gastric ulcer prophylaxis
during NSAID therapy [Arthrotec = diclofenac + misoprostol]
For
acute ulcer therapy, full dose, and for ulcer prophylaxis, ½
usual dose, given at hs. For
example: for active duodenal ulcer, Axid
150 mg bid or 300 mg @ hs. For
maintenance therapy, Axid 150 mg @ hs
For
drug-induced ulcer prophylaxis, Cytotec, 100-200 mcg qid pc and hs or 200 mcg
bid or tid
-
Maximum plasma concentrations are diminished when taken with food. Because of GI side effects of abdominal pain
and nausea, manufacturer recommends that drug be taken with food.
-
Diarrhea is also a common side effect and is dose-related. It is usually self-limiting (often resolving
in 8 days). The incidence of diarrhea
can be minimized by taking the drug after meals and at bedtime.
NOTE: “Symptomatic response to therapy does not
preclude the presence of gastric malignancy.”
Vomiting, or emesis, is the forcible
emptying or expulsion of gastric and occasionally intestinal contents through
the mouth.
Signals
from 1) the gastrointestinal tract, 2) the labyrinth, and the 3) cortex go to
the 4) chemoreceptor trigger zone (CTZ) which then send the message to the 5)
vomiting center in the medulla.
These
signals are sent via neurotransmitters:
-
Dopamine (GI tract and CTZ)
-
Histamine 1 (vestibular, vomiting center, and labyrinth pathways)
-
Prostaglandins (GI tract)
-
Serotonin (5 HT3) (GI tract, CTZ, and vomiting center)
-
Acetylcholine (ACh) (vestibular, vomiting center, and labyrinth
pathways)
The
drugs used as antiemetics effect these
neurotransmitters:
-
ACh is blocked by anticholinergic drugs
-
Histamine 1 is blocked by antihistamines (H1 receptor blockers)
-
Dopamine is blocked by neuroleptic agents and prokinetic agents
-
Serotonin is blocked by serotonin blockers (5-HT3 antagonists)
The
drugs used as antiemetics work on each of these areas:
Area |
Types of Drugs Affecting Area |
|
Gastrointestinal
Tract |
-
Prokinetic drugs -
Serotonin blockers |
|
Labyrinth |
-
Anticholinergics -
Antihistamines -
Neuroleptics -
Prokinetic drugs |
|
Cortex |
-
THC (tetrahydrocannabinoid) = the major psychoactive substance in
marijuana |
|
Chemoreceptor
trigger zone |
-
Neuroleptics -
Prokinetic drugs -
Serotonin blockers |
|
Vomiting
center (medulla) |
-
Serotonin blockers |
Let’s
look at each of the categories of antiemetics:
|
Category:
Anticholinergics |
|
|
Examples |
Scopolamine |
|
Mechanism
of Action |
Block
ACh receptors in the vestibular nuclei and reticular formation |
|
Therapeutic
Effects |
Motion
sickness, secretion reduction before surgery, nausea and vomiting |
|
Common
Drug Interactions |
With
antihistamines and antidepressants, additive effect à increased anticholinergic
effects (drying effects) |
|
Adverse
Effects |
Rash,
erythema, difficult urination, dizziness, drowsiness, disorientation, blurred
vision, dilated pupils, dry mouth |
|
Category: Antihistamine (H1 receptor blockers) |
|
|
Examples |
Promethazine
(Phenergan), meclizine (Antivert), diphenhydramine (Dramamine) |
|
Mechanism
of Action |
Block
histamine 1 receptors, thereby preventing ACh from binding to receptors in
the vestibular nuclei |
|
Therapeutic
Effects |
Motion
sickness, nonproductive cough, sedation, rhinitis, allergy symptoms, N &
V |
|
Common
Drug Interactions |
With
barbiturates, narcotics, hypnotics, tricyclic antidepressants, alcohol,
additive effect à increased CNS depression |
|
Adverse
Effects |
Dizziness,
drowsiness, confusion, urinary retention, blurred vision, dilated pupils, dry
mouth |
|
Category: Neuroleptic agents |
|
|
Examples |
Chlorpromazine
(Thorazine), prochlorperazine (Compazine) |
|
Mechanism
of Action |
Block
dopamine in the CTZ and may also block ACh (** Not for use with
Parkinson’s) |
|
Therapeutic
Effects |
Psychotic
disorders (mania, schizophrenia, anxiety), intractable hiccups, N & V |
|
Common
Drug Interactions |
Blocks
levodopa, which may cancel the beneficial effects of levodopa in treatment of
Parkinson’s disease. With quinidine,
additive effect à increased adverse cardiac
effects |
|
Adverse
Effects |
Orthostatics
hypotension, ECG changes, tachycardia, blurred vision, dry eyes, dry mouth, N
& V, anorexia, constipation, urinary retention, extrapyramidal
symptoms, pseudoparkinsonism, akathisia, dystonia, tardive dyskinesia,
headache |
|
Category: Prokinetic Agents |
|
|
Examples |
Metoclopramide
(Reglan), cisapride (Propulsid)** **
Problem with Cytochrome P450 (with Biaxin, emycin,
-azoles à ventricular arrhythmias) |
|
Mechanism
of Action |
Block
dopamine in the CTZ or stimulate ACh receptors |
|
Therapeutic
Effects |
Increases
gastric emptying, GERD, N & V |
|
Common
Drug Interactions |
With
alcohol, additive effect à CNS depression With
anticholinergics and analgesics, block à antagonism of motility
effects of metoclopramide |
|
Adverse
Effects |
Sedation,
fatigue, restlessness, headache, dystonia, dry mouth, N & V, hypotension,
SVT |
|
Category: Serotonin blockers |
|
|
Examples |
Ondansetron
(Zofran), granisetron (Kytril) |
|
Mechanism
of Action |
Block
serotonin receptors in the GI tract, CTZ, and vomiting center |
|
Therapeutic
Effects |
N
& V associated with cancer chemotherapy, postop N & V |
|
Common
Drug Interactions |
|
|
Adverse
Effects |
Headache,
diarrhea, increased AST and ALT levels, rash, bronchospasm |
|
Category: Tetracannabinoids |
|
|
Examples |
Dronabinol
(Marinol) |
|
Mechanism
of Action |
Has
inhibitory effects on the reticular formation, thalamus, and cerebral cortex |
|
Therapeutic
Effects |
N
& V associated with cancer chemotherapy |
|
Common
Drug Interactions |
Additive
effect with other CNS depressants |
|
Adverse
Effects |
Drowsiness,
dizziness, anxiety, confusion, dry mouth, visual disturbances |
NOTE: Antiemetics in general should be given before
any chemotherapy agent is administered, often 1 to 3 hours beforehand.
Diarrhea:
-
Leading cause of morbidity and mortality in third world countries
-
5-8 million deaths per year in infants and children
-
Loss of time and productivity at work has an enormous financial impact
with an estimated cost of $23 billion per year or $108 per person per year in
the
-
Most acute diarrhea is self-limiting, subsiding in 3 days to 2 weeks
-
Fluid and electrolyte replacement is vital
-
Causes of acute diarrhea:
o
Bacterial
o
Drug-induced
o
Viral
o
Nutritional
o
Protozoal
o
Other
-
Causes of chronic diarrhea:
o
Tumors
o
Diabetes mellitus
o
Hyperthyroidism
o
Addison’s disease
o
Irritable bowel syndrome
o
Other
Constipation: Causes
-
Metabolic and endocrine disorders (DM, hypothyroidism, pregnancy,
hypercalcemia, hypokalemia)
-
Neurogenic disorders (autonomic neuropathy, intestinal
pseudo-obstruction, multiple sclerosis, spinal cord lesions, Parkinson’s
disease, CVA)
-
Adverse drug effects (analgesics, anticholinergics, iron supplements,
aluminum antacids, calcium antacids, opiates, calcium channel blockers, Vinca
alkaloids)
-
Lifestyle
o
Poor bowel movement habits (voluntary refusal to defecate resulting in
constipation)
o
Diet (poor fluid intake and/or low-residue (roughage) diets or
excessive consumption of dairy products)
o
Physical inactivity (lack of proper exercise, especially in elderly
individuals)
o
Psychologic (anxiety, stress, hypochondria)
Drugs
therapy for diarrhea includes:
-
Adsorbents
-
Anticholinergics
-
Opiates
-
Intestinal flora modifiers
|
Category: Adsorbents |
|
|
Examples |
Bismuth
subsalicylate (Pepto Bismol), attapulgite (Kaopectate) |
|
Mechanism
of Action |
Coat
walls of GI tract, absorbing bacteria or toxins causing diarrhea, and
eliminating them with stool |
|
Adverse
Effects |
With
bismuth subsalicylate: increased
bleeding time, constipation, dark stools, confusion, twitching, hearing loss,
tinnitus, metallic taste, blue gums |
|
Drug
Interactions |
With
digoxin, clindamycin, quinidine:
decreased absorption With
oral anticoagulants: increased
bleeding time, bruising With
methotrexate: increased toxicity With
probenecid: decreased probenecid
effects With
hypoglycemia agents: decreased
hypoglycemic effects |
|
Category: Anticholinergics |
|
|
Examples |
Atropine |
|
Mechanism
of Action |
Decreased
intestinal muscle tone and peristalsis, thereby slowing the movement of fecal
matter through the GI tract. Often
combined with other antidiarrheals to increase their effectiveness |
|
Adverse
Effects |
Urinary
retention and hesitancy, impotence, headache, dizziness, confusion, anxiety,
drowsiness, hypotension, HTN, Bradycardia, tachycardia, dry skin, rash,
flushing, blurred vision, photophobia, increased pressure in the eye |
|
Drug
Interactions |
With
antacids, decreased anticholinergic effects With
amantadine, tricyclic antidepressants, MAOIs, antihistamines à increased anticholinergic
effects |
|
Category: Opiates |
|
|
Examples |
Opium
tincture, paregoric, codeine diphenoxylate (Lomotil), loperamide (Imodium) |
|
Mechanism
of Action |
Cause
constipation by lowering the motility of the bowel and relieving rectal
spasms. By slowing the time it takes
to pass food through the intestines, water and electrolytes have a greater
chance of being absorbed, with reduces tool frequency and volume |
|
Adverse
Effects |
Drowsiness,
sedation, dizziness, lethargy, N & V, anorexia, constipation, respiratory
depression, bradycardia, palpitations, hypotension, urinary retention,
flushing, rash, urticaria |
|
Drug
Interactions |
Increased
CNS depressant effects with CNS depressants, alcohol, narcotics, sedative
hypnotics, antipsychotics, skeletal muscle relaxants |
|
Category: Intestinal Flora
Modifiers |
|
|
Examples |
Lactobacillus acidophilus |
|
Mechanism
of Action |
Suppress
the growth of diarrhea-causing bacteria and help reestablish the normal
intestinal flora that has been depleted by the diarrhea |
|
Adverse
Effects |
N/A |
|
Drug
Interactions |
N/A |
NOTE: alosetron HCl tablets (Lotronex) –
Drugs for constipation include 5 types:
-
Bulk-forming
-
Emollient
-
Hyperosmotic
-
Saline
-
Stimulant/Irritant
|
Category: Bulk-forming |
|
|
Examples |
Psyllium,
methylcellulose (Metamucil) |
|
Mechanism
of Action |
Absorbs
water to increase bulk, distending bowel to initiate reflex bowel activity
(onset of action 12 hours to 3 days) |
|
Therapeutic
Effects |
Acute
constipation, IBS, diverticulosis |
|
Adverse
Effects |
Impaction
above strictures, fluid overload |
|
Drug
Interactions |
Increased
absorption of antibiotics, digoxin, nitrofurantoin, salicylates,
tetracyclines, oral anticoagulants |
Note: Bulk-forming agents: Drug of Choice
Note: Psyllium contains sugar: give cautiously in DM
|
Category: Emollient/Surfactants |
|
|
Examples |
Docusate
salts (Surfak, Colace), mineral oil |
|
Mechanism
of Action |
Wetting
agent used to soften fecal mass (onset of action 1-3 days) |
|
Therapeutic
Effects |
Acute
constipation, softens fecal impacts, facilitates bowel movements in anorectal
conditions |
|
Adverse
Effects |
Skin
rashes, decreased absorption of vitamins, lipid pneumonia |
|
Drug
Interactions |
With
mineral oil, increased effect of oral anticoagulants, decreased absorption of
fat-soluble vitamins (A, D, E, K) |
Note: Lipid pneumonia – especially in elderly
(inhale the mineral oil)
Leakage
of oil can cause pruritis ani; disturbs normal defecation reflex
|
Category: Hyperosmotic |
|
|
Examples |
Lactulose,
sorbitol, glycerine |
|
Mechanism
of Action |
Osmotic
molecules (like excess sugar) pulls water into GI tract (onset of action
24-48 hours) |
|
Therapeutic
Effects |
Chronic
constipation, diagnostic and surgical preparations |
|
Adverse
Effects |
Caution
with diabetics, galactose or lactose intolerance Abdominal
bloating, rectal irritation |
|
Drug
Interactions |
With
oral antibiotics, decreased effects of lactulose |
|
Category: Saline |
|
|
Examples |
Magnesium
sulfate, magnesium phosphate, magnesium citrate, MOM |
|
Mechanism
of Action |
Increases
water content of feces, resulting in distention, peristalsis, and evacuation
(onset of action 1-3 hours) |
|
Therapeutic
Effects |
Constipation,
removal of anthelmintics and parasites, diagnostic and surgical preparations |
|
Adverse
Effects |
Magnesium
toxicity (with renal insufficiency) |
|
Drug
Interactions |
With
barbiturates, general anesthetics, narcotics, and antipsychotics à increased CNS depression With
neuromuscular blockers, increased effects |
Caution: MOM contains high concentration of sodium à Watch
renal disease!
|
Category: Simulant/Irritant |
|
|
Examples |
Castor
oil, bisacodyl (Dulcolax) |
|
Mechanism
of Action |
Direct
action on intestinal mucosa (onset of action 6-10 hours) |
|
Therapeutic
Effects |
Acute
constipation, diagnostic and surgical bowel preparations |
|
Adverse
Effects |
Nutrient
malabsorption, skin rashes, gastric irritation, rectal stimulation |
|
Drug
Interactions |
With
antacids and H2 blockers à gastric irritation With
antibiotics, digoxin, nitrofurantoin, salicylates, tetracyclines, oral
anticoagulants à decreased absorption |
Stimulant/Irritant
Laxatives: Most commonly abused by teens
and elderly
NOTE: Long-term use may lead to laxative
dependence.
Zelnorm (tegaserod maleate):
·
New medication (2004) for constipation-dominant IBS
·
A serotonin 5-HT4 receptor partial agonist
·
For short-term treatment of women who have IBS with constipation as
their main bowel problem
·
FDA warning in May 2004: Zelnorm associated with serious consequences of diarrhea
and ischemic colitis
For chronic idiopathic constipation (24 mcg bid) and constipation-predominant IBS (8 mcg bid)
Activates chloride channels, increasing intestinal fluid secretion and motility
Cost: 8 mcg (60 ea) $220; 24 mcg (30 ea) $114
Drugs
for chronic inflammatory bowel: