Gastrointestinal Drugs, Endocrine Drugs - Lecture 12
I. Gastrointestinal Drugs
Many of the drugs discussed to this point have applications in GI disorders;
such as -
Specific Applications:
1) Drugs used to treat Peptic Ulcers
Ulcers are due to increased gastric acid secretion (HCl) and pepsin production
may also have decreased epithelial mucus production (no protection) or decreased bicarbonate production
recent studies indicate that a bacterium (Helicobacter pylori) is involved
Treatment can involve remedying any of the above
recurrent ulcers are treated with antimicrobial drugs to eradicate H pylori
A) Antacids
weak bases that react with gastric acid to form water and salt - (bicarbonate to carbonic acid)
NaCO3 + H+ è H2CO3 + Na+ è H20 + CO2 + Na+
Systemic Antacids -- Sodium Bicarbonate (NaCO3) is very effective
however, it is absorbed into the circulation and thus can alter pH (alkalosis)
also the CO2 that is released can cause belching and flatulence
Nonsystemic Antacids -- not a lot absorbed systemically (there may be some) -- Calcium Carbonate (CaCO3), Aluminum Hydroxide (Al(OH(3), Magnesium Hydroxide (Mg(OH2) -- see textbook for different preparations
Calcium - available over the counter (Tums) - the calcium can be absorbed to give hypercalcemia - used if person needs extra calcium for bones
Aluminum - found in numerous liquid antacids (Maalox, Mylanta) - can cause constipation
Magnesium - the salts produced attracts water and results in diarrhea
Most Antacids combine the Aluminum and the Magnesium to counteract the constipation and the diarrhea
B) Inhibitors of Gastric Acid Production (chief cells produce pepsinogen, mucous neck cells produce mucous, parietal cells produce HCl and intrinsic factor (needed for Vit B12 absorption), G cells produce Gastrin)
gastric acids secretion is controlled by 4 different receptors -
Ach, Histamine and Gastrin increase acid -- Prostaglandin decreases acid
1) Histamine H2 blockers -- cimetidine (Tagamet), famotidine (Pepcid), rantidine (Zantac- was #1 prescription drug world wide - 3 billion in sales), etc
these drugs are taken orally and 90% of patients are healed in 3-4 weeks
minimal side effects
smoking can complicate disease -- if healing does not occur -- antibiotics are administered with bismuth
2) Anti-muscarinic - pirenzepine -
often used in combination with histamine blockers
pirenzepine is quite specific for M1 (not just CNS) receptors and has little effect on glands and smooth muscle (M3)
3) Proton Pump Inhibitors
Omeprazole (Prilosec) - irreversibly inhibits the H/K pump
it is a prodrug that is activated in the acid environment
the drug suppresses 100% of acid secretion but has no effect on pepsin
not combined with antacids
4) Mucosal Protective Agents
a) Sulcralfate - is a sulfated disaccharide (aluminum sucrose sulfate)
it selectively binds to necrotic ulcer tissue
it acts as a barrier to acid and pepsin
the drug is activated in acid and is not absorbed systematically
b) Bismuth (Pepto-Bismol) - coats and binds ulcer tissue protecting against acid
it also may:
inhibit pepsin activity
stimulate mucus production
increase PG production
and has antimicrobial activity against H pylori
c) Prostaglandins
a synthetic PG - Misoprostol is used to prevent ulcers produced by NSAIDs
the NSAIDs prevent cyclooxygenase (COX I) from producing PGs - the decreased PG in the stomach leads to increased acid production
2) Laxatives
used to increase movement of food along GI tract
1) Bulk Laxatives
hydrophilic colloids (made from plants and seeds) and fibers from fruits and vegetables, psyllium, bran -- these agents distend the intestine and stimulate peristaltic movement
also saline cathartics -- salts that hold water into the intestine and distend intestine
2) Irritants and Stimulants
Castor oil - is broken down to ricinoleic acid in the small intestine which irritates wall and stimulates peristalsis (mineral oil is a stool softener)
Phenolphthalein (ex-Lax), Cascara and Senna (Senokot) - stimulates peristalsis in colon
3) Antidiarrheal Drugs
diphenoxylate (a weak derivative of the narcotic meperidine) plus atropine (prevents SLUD) is called Lomotil
loperamide (called Imodium) - this is a narcotic related to haloperidol (antipsychotic) -- blocks muscarinic receptors and results in constipation
kaolin (dirt - a fine white clay) and pectin (Kaopectate) -- absorb toxins from the material in the intestine
Pepto-Bismol - absorbs bacterial toxins
4) Diet Drugs
Orlistat (Xenical) - blocks absorption of about 30% of dietary fat resulting in approximately 200 calories/day
this non-systemic drug works by targeting all GI lipases (pancreatic lipase, gastric lipase colipase, carboxylipase, etc) - inhibits the lipases so that fat can not be broken down and absorbed
adverse effects - diarrhea and abdominal cramps
Sibutramine (Meridia) - serotonin and epinephrine uptake inhibitor - enhances satiety and and raises metabolic rate - this drug was initially an antidepressant
dexfenfluramine (redux) - serotonin reuptake inhibitor - the increased serotonin reduces appetite
fenfluramine + phenmetrazine (fenphen) - phenmetrazine is a stimulant - reduces appetite but severe heart valve problems
Endocrine Pharmacology:
I. Hormones of Hypothalamus, Pituitary and Thyroid
Endocrine system releases hormones (chemical messengers) into the blood stream - response takes seconds, hours, days, weeks or months
this is different than the nervous system -- response in less than seconds
the endocrine and nervous system are closely interrelated
Hypothalamus is nervous tissue
Pituitary is nervous tisssue (posterious pit.) and glandular tissue (anterior pit.)
The pituitary is the Master Endorcine Gland
A. The hormones secreted by the Hypothalamus and Pituitary are all peptides (proteins) that bind to specific receptors at tissue sites-
the hormones (or drugs) can be administered IM or SC but not orally (broken down in GI system)
Most of the hormones listed here have little therapeutic use
ACTH (Adrenocorticotrophic Hormone) - ACTH is not used except to diagnose Addison’s disease (primary adrenal insufficiency) from secondary adrenal insufficiency (inadequate ACTH production) - a synthetic version of ACTH (Cosyntropin) is used
Growth Hormone (somatotropin) - now produced by recombinant DNA technology - used to treated GH deficiency in children
Oxytocin - used to stimulate labor (uterine contraction)
Vasopressin (ADH) - treat pituitary diabetes insipidus (lack of ADH)
Thyroid Hormones - not necessary for life but lack of hormones results in bradycardia, mental and physical slowing, cold intolerance, constipation -- an excess results in tachycardia, arrhythmias, nervousness, body wasting, excess heat production (heat intolerance)
Excess thyroid hormone (hyperthyroidism) - diseases include-Graves’s disease (bulging eyeballs), goiters (enlarged thyroid), etc
drugs are given orally - they have short half life
iodide also inhibits release of the thyroid hormones (not known exactly)
given orally - can only be used short time because thyroid adapts
II. Hypoglycemic Drugs - Insulin
Pancrease produces insulin (b cells) and glucagon (a cells) - they play a role in control of metabolic activity
insulin stimulates - glucose to glycogen (drives glucose into cells)
glucagon stimulates - glycogen, triglyceride or protein breakdown to sugar, fat, or amino acids
Diabetes Mellitus - elevation of blood glucose due to deficiency in insulin
often excess glucagon
Type I - insulin deficiency - loss of b cells (due to viruses, chemicals, auto-immune)
10-20% of 6 million with diabetes (occurs mostly in juveniles)
treatment is exogenous insulin
Type II - non insulin dependent - insulin levels are high but insufficient to control glucose levels -- these people are usually obese (glucose converted to fats) - problem may be due to decreased insulin receptors or a defect in the events after binding to receptor (target organs are insulin resistant)
80-90% of patients (due to genetics)
treatment is insulin or hypoglycemic agents (Sulfonylurea drugs)
Agents:
1) Insulin - small protein - isolated from animal sources (beef and pork) or produced synthetically (recombinant DNA technology)
Insulin must be injected
IV -- half life of 9 minutes
SC -- longer half life
A. Different Preparations - see textbook for examples
1. Rapid Acting/Short Lasting - effect appears in 15 minutes and lasts 5-7 hours
Regular Insulin - purified from beef or pork or synthetic - SC or IV in emergency
2. Intermediate - effect in 1 hour and lasts 24 hours
Lente Insulin - most widely used - (a combination of 70% ultralente (long-beef primarily) and 30% semilente (short) insulin) - SC - often combined with regular insulin
3. Long acting
Untoward Effects of Insulin - Hypoglycemia - tachycardia, confusion, dizziness, sweating, etc
2) Oral Hypoglycemic Agents - Sulfonylureas
for patients with non-insulin dependent diabetes that can not by managed by diet
-- drugs are given orally
A. Agents (see text) - tolbutamide, acetohexamide, tolazamide, chlorpromide, glipizide, glyburide, glimepiride
Effects-
1) stimulate insulin release , 2) decrease serum glucagon, 3) increase binding of insulin to receptor
B. Alternatives: 1995 release from FDA -
Biguanides - Metformin (Glucophage) -
decreases glucose release from liver, increases insulin binding (increases sensitivity)
Troglitazone (Rezulin) - increases target sensitivity - very controversial - many deaths - liver failure - banned by FDA in spring of 2000
good alternative - Rosiglitazone (Avandia) - advertized as an alternative to Rezulin
Acarbose - decreases the rate of glucose absorption by GI track by blocking enzyme
II. Steroid Hormones -
Steroid Sex Hormones - produced by gonads and adrenals - controlled by LH and FSH
important in conception, development, and sexual characteristics
Adrenal Cortex Steroids - controlled by ACTH
Adrenocorticoids - glucocorticoids and mineralcorticoids
Adrenal androgens
A. Sex Hormones -
1. Estrogen - estradiol, estrone, estriol
Produced by ovaries, liver, adrenal, other tissues (fat, hair follicles, skeletal muscle - can convert testosterone into estrogen) - true for men and women - men produce estrogen via adrenals
natural estrogens have a large first pass and can not be given orally - they are given IM synthetic versions such as ethinyl estradiol and mestranol can be given orally or SC
Action - bind with intracellular receptors and stimulate RNA synthesis
A) Uses - replacement therapy
1) Postmenopausal hormone therapy - protective against CV disease, prevents osteoporosis, prevents hot-flashes, etc
2) Primary hypogonadism - stimulates secondary sex characteristics
3) Contraception - suppresses ovulation - no eggs released - they degenerate in ovary
Usually combined with progestin
B) The Anti-estrogens - such as Tamoxifen (competitive partial agonist) - is used to treat breast cancer
Estrogens - stimulate normal breast growth
2. Progestins -progesterone - produced by corpus luteum, the placenta and adrenal cortex - and in males the adrenal cortex and testes
Important in maintaining pregnancy - preparation of endometrium
Action - same as all steroids - stimulates RNA synthesis
A) Uses -
1) Contraception - combined with estrogren
synthetic progestins are used because natural progesterone is rapidly metabolized
medroxyprogesterone, norethindrone, norgestrel, etc.
These drugs prevent implantation and make the cervial mucus impermeable to sperm
2) Other uses - treatment for uterine bleeding, postpartum lactation, endometriosis
Anti-progestins - such as Mifepristone (RU 486) - blocks progestin receptor and results in abortion of fetus - morning after pill - uterine bleeding may result
3. Androgens - testoterone - anabolic and/or masculinizing effects in males and females
testosterone is produced in Leydig’s cells of testes and in the ovary and adrenal cortex
important in development of secondary sex characteristics in males
spermatogenesis
anabolic growth - muscle growth, bone growth
sex drive in males and females
Action -
Testosterone binds to intracellular receptors and increases RNA synthesis
testosterone is converted to DHT (dihydrotestosterone) to effect reproductive tissue
A) Uses -
1) Hypogonadism - problem with testes or with pituitary
2) Anabolic effects - treatment of osteoporosis, severe burns, speed recovery from surgery, etc
3) Growth - treat pituitary dwarfism - combined with other growth hormones
4) Increase lean body mass and muscle strength -- body builders - not approved or advised
Pharmacology -
Testosterone can not be given orally - given IM
Derivatives such as fluoxymesterone and stanozolol - are given orally
Untoward effects - masculinization in women, impotence, excess androgen leads to decreased spermatogenesis, coronary heart disease, edema, liver problems, closure of bone growth, aggression (‘roid rage’)
B. Adrenal Corticosteroids - controlled by ACTH
Adrenal cortex produces mineralcorticoids (aldosterone), glucocorticoids (naturally produced is cortisol which is the same as hydrocortisone), adrenal androgens
Mechanism - binds to intracellular receptors and increases RNA synthesis
- the agents in this category have varying degrees of anti-inflammatory and salt retaining capabilities (ie. cortisone has equal anti-inflam. and salt retaining)
1) Glucocorticoid Actions - hydrocortisone, methylprednisolone, dexamethasone - see text for a list of agents
a) Promotes normal metablism - stimulate gluconeogenesis - protein catabolism and fat lipolysis (these increase glucose levels for energy use)
-- Increased resistance to Stress - increase glucose needed for energy - increase blood pressure (enhance vasocontriction produced by NE - fight, flight)
b) Alter blood cell levels - decrease lymphocytes and monocytes but increase PMNs and RBCs - decreased lym. and mono. decreases the ability of the body to fight infection
-- Anti-inflammatory - decrease lymphocyte numbers - inhibits phospholipase A2 which decreases PG and leukotriene production - inhbits PMNs from adhereing to vessel wall (block adhesion receptors)
c) Alters endocrine system - negative feedback of ACTH which inhibits glucocorticoid production - also decreased TSH - but increased GH
2) Mineralcorticoids
a) Water and electrolyte homeostasis
Aldosterone controls Na reabsorption, K secretion and water reabsorption
3) Theraperutic Uses for Glucocorticoids and Mineralcorticoids
a) Replacement therapy for primary adrenocortical insufficiency (Addison’s disease - the adrenal cortex does not work)
- give hydrocortisone (short acting - identical to natural cortisol) and fludrocortisone (synthetic mineralcorticoid)
b) Replacement for secondary (no ACTH) or tertiary (no CRF) adrenocortical insufficiency
c) Diagnosis Cushing’s syndrome - hypersecretion of glucocorticoids - is hypersecretion due to adrenal tumor or excess ACTH?
- tested by giving dexamethasone (long acting) - this provides negative feedback in pituitary dependent Cushing’s - no effect in adrenal tumor Cushing's
d) Relief of Inflammatory Symptoms - reduces inflammation - ie. rheumatoid and osteoarthritis, etc
e) Treat allergies -- treat bronchial asthma
beclomethasone as an aerosol - anti-inflammatory and reverses mucosal edema
fluticasone (Flovent) - aerosol - 2 times a day - anti-inflammatory and reverses mucosal edema
4) Pharmacology -
-readily absorbed from GI tract, others can be given IV, IM, topically
-90% bound to plasma proteins
alternate day therapy is used to prevent suppression of the hypothalamic-pituitary-adrenal axis (HPA)
5) Untoward Effects -
Osteoporosis, edema and hypertension due to salt retention, euphoria that can lead to psychological dependency, peptic ulcers, Cushing’s syndrome (puffy face, acne, increased body hair, increased appetite), HPA suppression
6) Inhibitors of Adrenocorticoid biosynthesis -
metyrapone - blocks corticosteroid production - used to treat Cushing’s
aminoglutethimide - blocks production of all steroids - breast cancer, etc
ketoconazole (used as antifungal agent- steroids are important in fungal membranes) - inhibits production of all steroids - treat Cushing’s syndrome
Return to Pharmacology
Syllabus
House's Home | Biology Department | Elon University (sdh) 1/01
Copyright © 2001 [sdh]. All rights reserved.