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130 Cards in this Set
- Front
- Back
What are the four types of pancreatic cells?
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Alpha - Produce glucagon
Beta - Produce Insulin, Amylin Delta - Produce somatostatin - inhibitor of secretory cells F - Pancreatic Polypeptides |
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What are the causes of Diabetes Mellitus?
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Impaired insulin secretion, or inappropriate function of glucagon
Inappropriate hepatic gluconeogenesis and glucose release Insulin insensitivity |
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This type of diabetes has selective beta cell destruction. It is subdivided into immune mediated and idiopathic DM. This type of diabetes makes up 5-10% of diabetic population.
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Type 1 Diabetes
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What happens in a severe form of Diabetes Mellitus 1?
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Catabolic state, severe form-ketoacidosis
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What is the Rx for Type I diabetes?
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Insulin Injections, Pancreas Transplant
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What are the details of type II diabetes?
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Tissue resistance to the actions of insulin combined with decreasing insulin secretion.
Insulin is produced by Beta cells but inadequate to overcome resistance resulting in increase of blood glucose and subsequently affecting fat metabolism. Insulin production sufficient to avoid ketoacidosis. |
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Ketoacidosis is not likely in type II diabetes, but it may occur as a resutl of what two things?
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Stress (Infection), or medication that enhances insulin resistance (corticosteroids)
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In type II diabetes, dehydration in untreated people can lead to what?
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Nonketotic hyperosmolar coma = levels of glucose 6-20 times increased in blood.
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What is the Rx for diabetes mellitus type II?
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Treatment escalates over time.
Dietary control, weight loss Monotherapy: 2nd generation sulfonylureas 30% of patients benefit from insulin therapy. Commonly failure within five years, drug combinations (insulin action + insulin release) Oral Agent and Insulin |
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What is considered to be Type 4 Diabetes Mellitus?
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Gestational Diabetes Mellitus
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What are the two risks associated with gestational diabetes, and how is gestational diabetes treated?
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1. Indicates risk for Type II diabetes later in life.
2. 30% increase in fetal abnormalities Rx = Insulin, a-glucosidase inhibitors only. |
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What are the diagnostic criteria for diabetes?
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Two or more of the following more than 24 hours apart.
1. Fasting Blood Sugar >126mg/dL on 2 occasions 2. Symptoms of DM + random glucose > 200mg/dL 3. Blood Glucose > 200mg/dL two hours after ingesting 75mg of oral dextrose. 4. Uriinanalysis positive for glucose and acetone (ketone body), elevated HbA1C |
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Within the insulin chain, what are the numbered designations for the different insulins?
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Insulin Lispro - Lys28, Pro29
Insulin Aspart - Asp28 Insulin Glargine - 31arg, 32arg Procine, and Bovine Insulins - 30Als |
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When is insulin released?
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Released at low basal rate and much higher stimulated rate.
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What are stimulants of glucose?
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Glucose, Mannose, Leu, Arg. hormones (glucagon-like polypeptide-1), vagal activity.
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Where is insulin degraded?
What is the half life of circulating insulin? |
In the liver (60%) and in the kidney (40%)
The half life of circulating insulin is 3-5 minutes. |
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What are the three insulins that act as rapid acting insulins?
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Insulin Lispro
Insulin Aspart Insulin Glulisine |
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What are the benefits of using rapid acting insulin?
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Advantage over human insulin - Low propensity to self associate and form dimers.
Binding to the receptor, circulating half life, and immunogenicity similar to human insulin Lowest variability of absorption, recommended in insulin pumps |
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What are the details of rapid acting insulin?
Onset? Peak? Duration? |
Rapid onset and early peak better mimic physiologic prandial insulin secretion.
Onset = 5 minutes Peak = 1 hour Duration = 3-4 hours, decreased risk of postmeal hypoglycemia |
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What are the short acting insulins?
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Regular Insulin (Humulin, Novolin, Velosulin)
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What are the details of short acting insulin?
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Can be given IV in ketoacidosis, post up when insulin requirement is changing rapidly.
Self aggregates - dimers stabilize around Zn and form hexamers resulting in three rates of absorption. |
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What is the onset, peak and duration of short acting insulin?
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Onset = 30 minutes
Peak = 2-3 hours Duration = 5-7 hours |
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Which short acting insulin contains P04 buffers - decreased aggregation - recommended for infusion pumps?
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Velosulin
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What is the Intermediate acting insulins?
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NPH - Neutral Protamine Hagerdorn, or Isophane Insulin
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What do you not use NPH with?
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Rapid acting Insulin
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What are the details of NPH?
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Protamine is a mixture of arginine rich peptides that form complex with insulin
After subcutaneous inejection, proteolytic enzymes degrade protamine allowing insulin absorption |
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What is the onset and duration of intermediate acting insulins?
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Onset = 2-5 hours
Duration = 4-12 NOTE: This is dependent on dose |
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What are the long acting insulins?
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Glargine and Detemir
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What are the details about Glargine?
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It is ultra long acting and "peakless" designed to provide background insulin replacement.
Soluble in acidic: (pH4) but precipitates in neutral pH allowing individual insulin molecules to slowly dissolve. |
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What is the onset, maximum activity and for how long is this maintained in Glargine insulin?
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Onset = 1-1.5 hours
Maximum Activity = 4-6 hours Maintained for = 24 hours |
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What are the details of Detemir?
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Most recently developed - increased self-aggregation and reversible albumin binding - most reproducible effects of all intermediate and long acting insulins with least hypoglycemia.
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What is the onset and duration of Detemir?
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Onset = 1-2 hours
Duration = 24 hours |
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Which insulins give you that initial peak that diabetics are missing?
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Insulin lispro, aspart, glulisine = very rapid insulins
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Insulin therapy provides what?
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Normal basal as well as meal time insulin.
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What are the different mixtures of insulin?
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NPH + lispro, aspart or glulisine = mixed before injection
NPL + Lispro (50/50 and 75/25), and NPA+Aspart (70/30) are all premixed combinations. |
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What two insulins can not be mixed with any other insulin formation?
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Insulin glargine and detemir
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What are the reasons that you would not use intensive insulin Tx in a patient?
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Patients with severe renal disease, the elderly, childern <7 years of age due to high risk of hypoglycemia.
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What are the complications of insulin use?
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Immune response - Formation of anti insulin antibodies.
Hypoglycemia |
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How is Hypoglycemia treated?
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Hypoglycemia can be dangerous and cause brain damage or death.
Rx = Simple sugar or glucose in liquid form. Mild cases = any sugar beverage Serve cases = 20-50ml of 50% glucose IV over 2-3 mins, 1mg of glucagon sc, small amounts of honey in the buccal pouch, call 911. |
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What are physical reactions of hyperglycemia?
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Increased thirst and urination
Large amounts of sugar and ketone in urine Weakness, abdominal pain, generalized aches Loss of appetite, nausea and vomiting |
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What are the physical signs of hypoglycemia?
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Excessive sweating, faintness, headache, pouding of heart, trembling, impaired vision, hunger, not able to awaken, irritability, personality change.
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What are the drugs that are in the insulin secretagogues?
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Sulfonylureas
Meglitinides D-Phenylalanine Derivatives |
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What drugs are members of the Sulfonylureas?
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First Generation - Chlorpropamide
Second Generation - Glyburide, Glipizide, Glimepiride |
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What is the MOA for sulfonylureas?
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Binds to sulfonylurea receptor to close K channel in the B cell membrane resulting in depolarization and subsequent insulin release.
Decrease in glucagon release, indirect inhibition due to enhanced release of insulin and somatostatin. |
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Chlorpropamide has how long of an effect and in what situations is it contraindicated?
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Chlorpropamide is a first generation sulfonylurea.
It is long lasting. Contraindicated in patients who have hepatic or renal disease, it causes prolonged hypoglycemia. |
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Glipizide has what kind of half life and what is its benefit?
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Glipizide is a second generation sulfonylurea. It has a shorter half life 2-4 hours, and it is less likely to cause severe hypoglycemia.
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Which of the second generation sulfonylureas has a long half life and only requires a once daily dosing leading to better compliance?
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Glimepiride
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What is the drug member of the meglitinide class?
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Repaglinide
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What is the MOA for Repaglinide?
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It modulates insulin release by regulating K channel efflux.
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What are the details of Repaglinide?
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Taken just before the meals, short acting drug, hypoglycemia is a risk if meal is skipped, monotherapy or in combination with metformin. Caution in patients with liver disease.
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What insulin secretagogue is specifically good for patients with a sulfur allergy?
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Repaglinide - a Meglitinide
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What drug is a member of the D-Phenylalanine class?
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Nateglinide
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What is the MOA of Nateglinide?
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Very rapid and transient rlease via closure of K channel
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What are the details of Nateglinide?
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It restores initial insulin release in response to an IV glucose tolerance test. Diminished effect in the presence of normoglycemia. Given alone or in combination with metformin.
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What are the details of D-Phenylalanine Derivatives?
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Lowest incidence of hypoglycemia.
Duration of action less than four hours, completely reabsorbed within 20 minutes. Safe in patients with reduced renal function. Dose titration not required Use to control postprandial hyperglycemia. |
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What drug is a member of the Biguanide class?
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Metformin
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What is the proposed MOA of Metformin?
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Decreased hepatic gluconeogenesis AMPK activation.
Stimulation of peripheral glycolysis. Reduced GI glucose absorption. Reduced plasma glucagon. |
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What are the details of Metformin?
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Reduces postprandial and lasting glucose levels in Type 2 patients via unknown mechanism not dependent on living beta cells.
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Biguanides have no?
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Hypoglycemia - euglycemic agents.
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Metformin can be use as monotherapy or given in combination with what other drugs?
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Insulin Secretagogues or Thiazolidinediones.
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What is the toxicity of metformin?
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GI distress - contraindicated in patients with renal disease, hepatic disease, or conditions predisposing to tissue anoxia (chronic cardiopulmonary dysfunction), Also inhibition of B12 absorption. Also can very rarely cause lactic acidosis because it uses a pyruvate dehydrogenase to start making lactic acidosis.
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What drugs are members of the Thiazolidinediones class?
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Rosiglitazone, Pioglitazone
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What is the MOA for the Rosiglitazone and Pioglitazone?
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Incompletely Understood - Increase target tissue sensitivity to insulin such reducing insulin resistance. PPABy agonist - Orphan receptor, transcription factor, controls genes of carbohydrate and lipid metabolism.
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What are the effects of Thiazolidinediones?
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Major site of action adipose tissue promoting glucose uptake, modulation of processes involved in energy regulation, regulation of adipocyte apoptosis and differentiation. Increase muscle uptake of glucose, inhibit hepatic gluconeogenesis, reduce fasting and post prandial hyperglycemia, effects on vascular endothelium, immune system and tumor cells. Use alone or in combination. Euglycemic and efficacious in about 70% of users.
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What drug classes are showing a benefit int he prevention of Type 2 diabetes?
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Metformin and the Thizolidinediones.
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What is the toxicity of the Thiazolidinediones?
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Hypoglycemia but rare in monotherapy
Hypoglycemia with sulfonylureas Edema, mild anemia Pioglitazone is a CYP3A4 iducer - DDIs |
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What drugs are in the alpha glucosidase inhibitor class?
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Acarbose and Miglitol
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What is the MOA for Acarbose and Miglitol?
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Act in intestine by inhibiting the enzyme that converts di- to mono- saccharides.
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What are the effects of the alpha glucosidase inhibitors?
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Slowed absorption - lower postprandial glucose
Use in monotherapy or in combination |
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What is the toxicity of the alpha-glucosidase inhibitors?
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GI tract - abdominal pain, diarrhea. Hypoglycemia only when combined with sulfonylurea - in case of hypoglycemia oral glucose not sucrose should be given
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What drug has been used since the 1920's for the treatment of type one diabetes?
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Pramlintide - synthetic analog of amylin
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What are the details of pramlintide?
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Modulates postprandial glucose - Suppresses glucagon release via unknown mechanism. Delays gastric emptying thus slowing the absoprtion of glucose - lowers body weight.
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What drug is a DPP-4 inhibitor?
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Sitagliptin
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Sitagliptin's MOA is what?
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GIP and GLP-1 are degraded by dipeptidyl-peptidase 4. Sitagliptin prolongs the action of normal GLP and GLP-1. It is given once a day alone or in combination with metformin, TZDs, Glitazone, Sulfonylureas.
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Exenatide is?
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A synthetic analog of GLP1
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What are the details of Exenatide?
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Peak at 2 hours, duration of action is 10 hours. It was the first incretin therapy. Approved as injectable, adjunctive therapy with metformin or sulfonylureas. Shown to potentiate glucose mediated insulin secretion, suppress postprandial glucagon release, slow gastric emptying.
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Glucagon is synthesized by?
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A-Cells
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Glucagon is a ?
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Peptide with a very short half life, given IV or IM
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What does glucagon due to gut smooth muscle?
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Relaxes it
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What are the clinical uses of Glucagon?
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Diagnostic - give to relax GI tract so it can be viewed easier.
Rx for severe B-blocker overdose - can stimulate heart without access to cardiac b-receptors Rx for severe hypoglycemia, especially when patient is unable to swallow, requires intact hepatic glycogen stores. |
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What are the drugs used to treat Alzheimers disease?
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CNS acting cholinesterase inhibitors
NMDA receptor blocker NSAIDS Others for multiple symptoms |
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AchE inhibitors are effective for approximately how long?
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For about 6 months they can delay institutionalization.
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What are the problems with using cholinesterase inhibitors?
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Only modest improvement, lasts only six months.
Only effective in about 30% of patients Does not stop underlying disease Effects disappear six weeks after the drug is discontinued |
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What are the CNS acting cholinesterase inhibitors?
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Tacrine
Donepezil Galantamine Rivastigmine |
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This cholinesterase inhibitor is the first of the centrally active AchEIs, rarely used now due to hepatotoxicity. If you use this drug you have to monitor LFTs.
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Tacrine
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This drug is a reversible AchEI. It is uses for mild or moderate alzheimer's disease.
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Donepezil
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What are the Contraindications for Donepazil?
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Hypersensitivity to piperidines. Cl in liver disease (OK/Renal Disease). Succinylcholine - Prolonged Action. Bradycardia, GI Sx (N, V, D)
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How is Donepezil metabolized, and what do you have to monitor?
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Its metabolism is with 2D6 and 3A4, you have to also monitor LFTs if giving this drug.
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What are the DDIs for Donepezil?
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Cholinomimetics - additive effects
NSAIDS - Monitor GI for bleeding Succinylcholine Ketoconazole - a 3A4 inhibitor Quinidine - a 2D6 inhibitor |
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How is rivastigmine administered?
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PO or Patch
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What is rivastigmine used for?
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Mild-Moderate Alzheimer's Disease
It is a slowly reversible AchEI |
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Rivastigmine is contraindicated when?
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Hypersensitivity to Carbamates
Succinylcholine Hx of bradycardia |
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What is a benefit of Rivastigmine metabolism?
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It is a plasma esterase, so it has only a small amount of P450 metabolism. This makes it a good choice because it avoids other drugs using this system. The only drawback is that you have to give it twice daily.
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What are the ADRs for Rivastigmine?
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N, V, and D. Headache, and dizziness.
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What are the DDI's of Rivastigmine?
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Possibly none, although nicotine will increase the clearance of rivastigmine
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Galantamine is a ?
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Reversible AchEI
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What are the contraindications for Galantamine?
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Same as others, its metabolism is also CYP2D6 and 3A4.
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What are the ADRs for galantamine?
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GI effects, bradycardia
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What is a dosing notice for all of these drugs?
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If restarting the drug, start at lowest dose and then re-escalate
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What is the name of the NMDA receptor blocker?
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Memantine
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Memantine is used with what for the treatment of moderate to severe Alzheimer's Disease?
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AchEI
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What is a major benefit of Memantine?
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It appears to make the patients rest easier. Although there is no evidence that it prevents or slows disease progression.
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What drug is used to treat ALS?
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Riluzole
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What are the functions of Riluzole?
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Decreases glutamate release
Neuroprotective Interferes with glutaminergic signaling events. |
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What is the metabolism for Riluzole?
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CYP1A2, then glucoronidation. Watch for DDIs.
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What is the toxicity of Riluzole?
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Muscle weakness, N, V, and D, anorexia. Decreased lung function, Neutropenia (rare but caution), elevated liver enzymes. YOU MUST monitor LFTs.
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How do you treat the acute attacks of MS?
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Glucocorticoids and Plasmapheresis
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What are the disease modifying therapies that are used for the treatment of MS?
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IFNB-1b
IFNB-1a Glatiramer acetate Natalizumab |
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What interferon will make MS worse?
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IFNy
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What is an effective treatment for RR-MS
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IFNB
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What will IFNa do if you try to use it for Tx of RR-MS
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It is ineffective, or it will cause exacerbations.
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What is the supposed MOA of IFNb?
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Enters CNS secondary BBB disruption. Reduces levels of TNFa and IFNy, Increases the number of suppressor T cells - Fewer autoreactive T cells.
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What are the ARs for IFNb-1b?
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Injection site reactions (SC only)
Flu-Like Symptoms - Chills, headache, myalgias, nausea, vomiting, diarrhea, fatigue. Mildly elevated liver enzymes Leukopenia, anemia Photosensitivity Spontaneous Abortion |
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What are the Contraindications for IFNb-1b?
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Hypersensitivity to IFNB or human albumin.
Depression - Suicide precautions Seizure History Cardiac, Hepatic Disease Monitor CBC, LFTs |
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What are the DDIs for IFNb-1b?
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Suppression of CYP450?
Zidovudine = 2/3 decrease clearance possible decreased glucorinidation. |
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IFNB-1a is doses how?
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Avonex = IM weekly
Ribef = SC 3X week There are fewer injection site reactions for the IM form |
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What drug is an amino acid copolymer?
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Glatiramer Acetate
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Glatiramer acetate is a copolymer of what four things?
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L-ala, L-glu, L-lys, L-tyr
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What is the MOA for glatiramer acetate?
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Unknown, but it is an MBP mimic, it stimulates suppressor T cells, and inhibits MBP specific effector T cells leading to a decrease in T cell proliferation, and a decrease in secretion of IL-2 and IFNy
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What is the efficacy of Glatiramer acetate?
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32% decrease in relapse rate.
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What are the ADRs for Glatiramer Acetate?
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It is given SC daily, so injection site RXNs are common. Transient systemic effects following injection include chest tightening, flushing and anxiety.
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What drug for MS is a monoclonal antibody?
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Natalizumab
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When was Natalizumab first used?
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Crohn's disease
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How is Natalizumab useful in RR-MS?
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It helps to decrease new CNS lesions, and it decreases cerebral inflammation.
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What is the MOA for Natalizumab?
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It is an anti-glycoprotein a4-integrin. It is approved for Crohn's disease and MS. The A4-integrin is on surface of lymphocytes, and monocytes. The drug prevents transmigration of leukocytes across endothelium.
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How does Natalizumab work in comparison to the IFN's?
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It is at least as effective, or more effective than IFNs, there are fewer relapses BUT there are some rare serious ADRs.
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What drug is approved to treat CP-MS?
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Mitoxantrone and Cyclophosphamide
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What are the details of Mitoxantrone?
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It is FDA approved, immunosuppressant, anticancer drug
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What are the ADRs of Mitoxantrone?
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Cardiotoxic, so monitor LV function before starting
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Cyclophosphamide is what kind of drug?
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Anticancer drug for off label use.
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