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.