Download Pharmacology Objectives 18 - U

Pharmacology
Lecture 18 Pharmacology of the Hypothalamus and Pituitary
1) What drug tests are used to diagnose hypopituitarism?
Insulin IV, arginine IV, or oral L-dopa (after estrogen sensitization for several days) failure to respond with an increase in plasma growth hormone indicates deficiency.
Thyrotropin releasing hormone - failure to illicit a rise in TSH indicates deficiency.
2) How does bromocriptine reduce glactorrhea (abnormal lactation)?
Bromocriptine is an ergot derivative and a dopamine agonist, with a high affinity for
dopamine D2 receptors in the pituitary. Stimulation of these receptors inhibit
prolactin release from the anterior pituitary thus lowering circulating prolactin levels.
3) In addition to giving vasopressin replacement therapy what other drugs can be
used to treat diabetes insipidus? Diabetes insipidus is the consequence of
inadequate secretion of the posterior pituitary hormone, anti-diuretic hormone
(ADH). Vasopressin was the first preparation of ADH it became available.
1-desamino-8-D-arginine-vasopressin (DDAVP), an ADH analog, was
subsequently developed. DDAVP has less oxytocic activity that vasopressin thus is
the drug of choice during pregnancy.
Thiazide diuretics decrease polyuria by decreasing the ability of the kidney to
excrete dilute urine and thereby decreasing urine volume in patients with diabetes
insipidus.
Chlorpropamide, a sulfonylurea drug, decreases urine volume by stimulating
secretion of ADH in sensitizing the kidney to the actions of ADH.
Clofibrate, a lipid lowering agent, is also effective in decreasing urine volume in
diabetes insipidus.
4) How are androgens used as drugs? Androgens are used as replacement therapy for
primary or secondary gonadal failure in men. They are also used to produce anabolic
effects in debilitated patients. In particular, the stimulation of erythropoiesis is used
to treat various kinds of aplastic anemia. There are also effective in the treatment of
postmenopausal metastatic carcinoma of the breast.
5) In addition to oral contraceptives, how are progestins used as drugs? Progestin
alone is used in the treatment of functional uterine hemorrhage in cancer
chemotherapy of endometrial cancer. Oral contraceptive preparations are also used to
treat endometriosis, severe acne, hirsutism, and dysmenorrhea.
6) What are the contraindications for use of estrogens in post-menopausal women?
The major complication of postmenopausal estrogen therapy is the increase in
incidence of endometrial cancer (minimized by the addition of other cyclic or
continuous administration of a progestin). Other side effects of estrogen include
hypertension, exacerbation of uterine fibroids or polycystic disease of the breast, and
breakthrough bleeding. There is also an increased risk of breast cancer, stroke, heart
attacks, and thrombophlebitis in women taking estrogen replacement therapy.
7) What are the advantages of using more potent glucocorticoids as drugs instead
of hydrocortisone? Adrenocorticoid analogues, like prednisone and
methylprednisolone, have more potent glucocorticoid effects but less
mineralocorticoid effects than hydrocortisone. This reduces the incidence and
severity of such undesirable mineralocorticoid effects such as hypertension,
hypokalemia, and edema in comparison with the natural substances.
8) What test is used to diagnose adrenal insufficiency? Adrenocorticotropic hormone
(ACTH) is administered and failure to elicit a rise in cortisol levels may indicate a
primary or secondary adrenal insufficiency. If secondary, due to adrenal atrophy in
hypopituitarism, plasma ACTH levels would be decreased.
9) How is metyrapone used as a diagnostic agent? Metyrapone reduces
hydrocortisone production by inhibiting 11-B-hydroxylation in the adrenocortical
cells. It is used as a diagnostic test of the pituitary, eliciting a compensatory increase
in ACTH release, which is reflected by in increased secretion of 11-deoxycortisol in
the plasma and urine.
10) Name some diseases where glucocorticoids are used. Diseases include: primary or
secondary adrenal insufficiency, congenital adrenal hyperplasia, rheumatoid arthritis,
lupus erythematous, nephrotic syndrome, allergic diseases, asthma, ulcerative colitis,
lymphomas, sarcoidosis, idiopathic thrombocytopenic purpura, hemolytic anemia,
and organ transplantation.
11) Describe compounds that decrease adrenal steroid secretion. Aminoglutethimide
decreases steroidogenesis from cholesterol and has been used to treat patients with
adrenal tumors. The systemic antifungal agent ketoconazole inhibits adrenal and
gonadal steroidogenesis and has been used to treat patients with glucocorticoid
excess. O,p’-DDD, a toxic agent that destroys adrenocortical cells, is employed in the
treatment of patients with nonresectable adrenal tumors.
12) How is 9-alpha-flurohyrocortisone used? 9-alpha-flurohyrocortisone, an
adrenocorticoid analog, has 125 times the mineralocorticoid activity of
hydrocortisone and is used for its potent salt-retaining activity in the treatment of
adrenocortical insufficiency associated with mineralocorticoid deficiency.
13) How do the bile sequestering resins decrease serum cholesterol? Cholestyramine
and colestipol are ion exchange resins of high molecular weight that bind bile acids in
the intestine. This interferes with the normal recycling of bile acids through the
enterohepatic circulation. The liver converts more cholesterol to bile acid to
compensate leading to a fall in total plasma cholesterol concentration (lower LDL,
HDL unchanged).
14) What are the adverse side effects of gemfibrozil? Side effects include rashes,
gastrointestinal symptoms, myopathy, arrhythmias, hypokalemia, high blood levels of
aminotransferases or alkaline phosphatase.
15) What drugs are used to treat hypertriglyceridemia?
Clofibrate - (mechanism unknown) lowers plasma VLDL, but carries increased risk
of cholelithiasis and colorectal carcinoma. Albumin bound displaces Coumadin.
Nicotinic acid (niacin) - (mechanism also unknown) reduces hepatic synthesis of
triglycerides, augments fecal excretion of neutral sterols (end products of cholesterol),
and diminishes lipolysis in adipose tissue while increasing lipoprotein lipase activity.
This leads to reductions in plasma VLDL and LDL lipoproteins while HDL levels
usually rise.
16) What is the main mechanism of action of the HMG-CoA reductase inhibitors?
HMG-CoA reductase inhibitors inhibit HMG coenzyme a reductase, the first
committed enzymatic reaction in cholesterol biosynthesis. The main mechanism of
action in these compounds appears to be an increase in the synthesis of LDL
receptors, particularly in the liver, allowing LDL particles to be cleared more rapidly
from the circulation. Current preparations include lovastatin, pravastatin, simvastatin,
fluvastatin, atorvastatin, and rosuvastatin.