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Pharm Endocrine Review Pharm Endocrine Review Oral Hypoglycemic Medications α‐Glucosidase Insulin Secretagouges Insulin Sensitizer Inihibitors Sulfonylureas Meglitinides Phenylalanine Biguanides Thiazolidinediones Acarbose Miglitol Tolbutamide (1) Repaglinide Nateglinide Metformin Rosiglitazone Chloropramide (1) Pioglitazone Glyburide (2) Glipizide (2) Glimepiride (2) INSULIN SECRETAGOUGES The goal of these medications is simply to increase secretion of insulin from the pancreas. Each has its own nuances and proper usage, but essentially, they all regulate potassium efflux in the pancreatic β‐ islets causing an increased release of insulin in a still‐functioning pancreas Sulfonylureas. There are two generations of Sulfonylureas. The first generation (Tolbutamide and Chloropramide) are generally not used anymore because they have a risk of sulfur allergies. The second generation (Glyburide, Glipizide, Glimepiride) have no risk of sulfur allergies and are used much more frequently. Regardless of the generation, these function by blocking potassium efflux leading to depolarization of the pancreatic cells, calcium influx, and the release of insulin. Sulfonylureas can be taken just one time a day and are generally well tolerated. However, they run the risk of hypoglycemia, especially in those with hepatic failure. Meglitanides (Repaglinide). This functions just like a sulfonylurea: blocking potassium channels Æ increased insulin release. This differs from the sulfonylureas in that it has a rapid onset and short duration so is used as a supplement when eating. These are taken just prior to meals. When taken appropriately (i.e. you eat right after you take this) there is a lower risk of hypoglycemia. Of course, these drugs are new, which means expensive, and you must have a diligent diabetic who remembers to take his pill every time he eats. Generally not used as monotherapy. Phenylalanine (Nateglinide). This might as well be a Meglitinide. It has all the same properties, it just happens to be a naturally occurring amino acid. INSULIN SENSITIZERS While the distinction is small, these drugs are antihyperglycemic as opposed to hypoglycemic. That is, these do not drop your sugar, they just prevent your sugar from becoming elevated. 1 | T2 Review Sheets Pharm Endocrine Review Biguanides (Metformin). This is a classic Type 2 diabetes pill, commonly seen on exams. It functions to decrease the liver’s production of glucose. While it has no risk of hypoglycemia, it must be used with caution in patients who have congestive heart failure or kidney/liver disease. These are good because of their safety and their effects on weight and lipids: there is no weight change (unique in oral hypoglycemics) and the lipid profile decreases. It also benefits the LDL HDL ratio. However, it has been known to cause lactic acidosis in some patients (thus its contraindications in conditions that promotes the formation of acidosis such as CHF or Renal Failure). Thiazolidinediones (“‐glitazones”). A problem with type 2 diabetes is phosphorylation and gene modification of the insulin pathway that leads to insulin resistance. A long life of hyperglycemia and obesity lead to the downregulation of the insulin receptor pathways. These bad boys rev that pathway back up. They do this by activating the PPAR‐y part of the steroid receptor in the thyroid superfamily. These basically make insulin work better, getting the glucose into muscle and fat cells. That is good, since it will decrease glucose without risk of hypoglycemia, it can be used once a day, and it well tolerated. Unfortunately, they cause increased weight gain and increased LDL levels. The biggest problem is that at least one (Rosiglitazone) has been shown to cause increased risk of myocardial infarction and heart failure. That is a recent black box warning on a new medication, and sounds like a prime exam question to me. α‐GLUCOSIDASE INHIBITORS α‐Glucosidase Inhibitors (Acarbose, Miglitol). All the drugs above dealt with making insulin work on the sugar that got into the blood. Well, what if we could prevent the absorption altogether? These are drugs that work in the gut, inhibiting the enzymes required to metabolize carbohydrates such as sucrase. These have been found not to work very well. While they do limit the amount of sugar absorbed, they do not alter the HgbA1c significantly, and therefore are not used as monotherapy. What is worse, is that preventing absorption of anything in the GI tract leads to an osmotic diarrhea with gas and bloating (decreasing compliance). COMAPRING BENEFITS AND RISKS OF ORAL DIABETES MEDICATION Sulfonylurea Meglitanides Biguanides Glitazones Glucaronidase Weight ↑ ↑ No Gain ↑ ‐ Lipids ‐ ‐ ↓ ↓↓ ‐ HDL ‐ ‐ ↑ ↓ ‐ LDL ‐ ‐ ↓ ↑ ‐ HbA1c ↓↓ ↓ ↓↓ ↓ ‐ Dosing 1/day Per Meal 1/day 1/day Per meal Onset Long Short Long Really Long Rapid Duration Long Short Long Really Long Rapid Mechanism ↑Insulin ↑Insulin ↓ Glucose ↑ Glucose ↓ Glucose Release Release Production Uptake Absorption Organ Pancreas Pancreas Liver Skeletal Gut Muscle / Fat Side Effect Hypoglycemia Hypoglycemia Lactic acidosis “None” Flatulence 2 | T2 Review Sheets Pharm Endocrine Review Insulin Rapid Acting Insulin Intermediate Insulin Long‐Acting Insulin Lispro Regular Detemir Aspart Inhaled Glargine Glulisine Lente UltraLente There are many ways to do the right thing, and no one regimen is the best. It is important to know how the pancreas works. The pancreas secretes a small amount of insulin all day (basal insulin) in addition to the spikes of insulin every time you eat. In order to get good diabetic control, we have to replace the basal insulin with long‐acting insulin (one a day) and the spikes with short‐acting insulin (postprandial). You have to choose cost, ease of use, number of injections, etc. You do not really have to know which long acting insulin is right for a given patient. Rather, you need to know that you need both long‐acting and short‐acting. Some patients may require only basal insulin if their pancreatic function is maintained enough to give the postprandial burst. The way you determine if someone needs a long‐acting glucose is by looking at their fasting glucose (if its high, you need long‐acting). If your fasting glucose is low, but their postprandial glucose is high, then that patient needs extra prandial help (you need a short‐acting insulin). Knowing the names of the insulins and when they act is the most important thing to do. “LAG, LIRN, DUG.” I had no good mnemonic for this, and it seems to be important only for this exam. So, I remembered (lAg, leern, duhg) said out loud, remembering that Lente means slow in Spanish (so it’s the second L) and Glargine is the really long acting one on the graph above. Crappy, I know, but, much like in biochem, just learn this for the exam and forget it for the shelf. HbA1c is usually 4‐6, target for diabetics is 7 Normal Insulin is a special kind of immediate acting that is given in the hospital 3 | T2 Review Sheets Pharm Endocrine Review Pituitary And Estrogens Estrogens Synthetic Estrogens Anti‐Estrogens Estradiol, Estrone, Estriol Diethylstilbestrol Clomiphene Ethinyl Estradiol Tamoxifen Mestranol Raloxifen Leuprolide ESTROGENS IN GENERAL Most of this lecture was not about the drugs themselves, but rather the general concepts therein. The guy who gives this lecture has an excellent handout to go along with it. Functions and Uses. Estrogen receptors are everywhere in the body. We generally think of estrogens (physiologically 17‐β‐Estradiol) as activating growth, stimulation of secondary sex characteristics, bone growth and involvement in the LH surge/ovulation. They do this by binding nuclear receptors which then bind to estrogen‐response elements on genes that regulate transcription. There are a heap of uses of estrogens that include (take a look at the drug list). Problems. Estrogen replacement therapy in postmenopausal osteoporotic women seemed like a great idea. They had no estrogen, that caused their bone loss, so we might as well give them estrogen. Unfortunately, estrogen is also a growth signal. This is particularly true in the breast and endometrium of the uterus. Administration of exogenous estrogen can and will cause carcinoma in either of these locations. Likewise, while estrogens can be used in abortive preparations, they cannot offer their beneficial side while a woman is pregnant without causing the abortion. You have to realize that estrogen is a steroid hormone and cannot be stored; it simply floats into and through all cell membranes. That means, even if estrogens are in the drinking water, their effects will be seen (such as in gynecomastia in males). SYNTHETIC ESTROGENS Diethylstilbestrol. This is used in the treatment of prostatic carcinoma (estrogens feedback to the pituitary and hypothalamus to decrease the GnRH signal which ultimately produces the growth signal for prostatic growth, DHT) and postcoital contraceptive. Ethinyl Estradiol. This is the most common form of estrogen found in oral contraceptives and is used as one of the morning after pills. This is not THE morning after pill (Mifepristone), but works to prevent blastocyst implantation. It must be taken as a regimen for 5 days. I suppose it is more of the “week after pill.” It must be started within 72 hrs Mestranol. This is a prodrug that gets converted to estrogen that is found in oral contraceptives. Few modern pills contain mestranol. 4 | T2 Review Sheets Pharm Endocrine Review ANTI ESTROGENS Clomiphene. This is a competitive inhibitor of estrogen nuclear receptor. It is designed to block the estrogen receptor in the hypothalamus, acting as a selective estrogen receptor modulator (SERM). The net effect is to activate the ↓the feedback from the periphery to ↑the estrogen “go” signal (↑GnRH, ↑FSH/LH) used to treat infertility. It induces ovulation. Tamoxifen. This is another SERM that targets the breast. In ER+ breast carcinoma, tamoxifen antagonizes the effect of estrogen at the breast to limit the growth of the tumor. It doesn’t cure it, it just slows the growth of breast cancer.
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