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Diabetes Pharm-1
Diabetes pharmacology
| Question | Answer |
|---|---|
| Agents used to treat DM-1 | Insulin (insulin replacement therapy) and Amylin analog |
| Types of Insulin | Long-acting, Intermediate-acting, Short/Rapid-acting, Mix of Intermediate- and Short/Rapid-acting (usually used for type-2 patients) |
| Long-acting insulin | Provide basal coverage; Glargine is usually administered daily; Detimer may be given once or twice daily. |
| Intermediate-acting insulin | NPH/Humulin is an example; Often administered twice daily |
| Short/Rapid-acting insulin | Are administered in boluses before meals to curb postprandial blood glucose elevations and to correct pre-meal elevations. |
| Amylin analog | Pramlinitide is an amylin analog that is injected at meal times along with fast-acting insulin. Like amylin it acts on alpha cells to reduce glucagon secretion, which leads to a reduction in hepatic gluconeogenesis and glycogenolyis. Suppresses appetite. |
| Classes of oral agents used to treat DM-Type 2 | Biguanides, Sulfonylureas, Thiazolidenediones, Meglitinides, Alpha-glucose Inhibitors, and Dipeptidyl peptidase (DPP)-IV inhibitors |
| Noninsulin Injectable agents used to treat DM-Type 2 | Exanatide and Pramlintide |
| Agents that reduce insulin resistance | Metformin (a Biguanide), Thiazolidinediones, Pramlintide |
| Metformin MOA | It increases autophosphorylation if IR by stimulating IRK (in the insulin receptor), which phosphorylates IRS-2 (but not IRS-1), which leads to increase in GLUT-1 translocation to membrane (causing increase in Glu uptake) |
| Initial and Delayed Effects of Metformin | Initial: Increased hepatic glucose uptake and utilization. Delayed: Increase glucose uptake in non-hepatic tissues. |
| Outcomes of Metformin Treatment | Decreased HbA1c, modest weight loss, decreased hypoglycemia episodes compared to sulfonylureas |
| Metformin Administration | Administered orally (titrate dose for adequate effect and to reduce severity of ADRs); Administration with meal minimize GI side effects and maintains therapeutic effects. |
| Metformin Pharmocokinetics | Rapidly distributed, not significantly metabolized by the liver, which reduces potential for hepatotoxicity, excreted largely unchanged; |
| Metformin vs. Sulfonyureas when it comes to hypoglycemia | Metformin, unlike Sulfonylureas, rarely causes hypoglycemia since insulin secretion is not stimulated. |
| Names of Thiazolidinediones | Rosiglitazone (Avandia) and Pioglitazone (Actos) |
| MOA of Thiazolidinediones | They activate PPAR-gamma nuclear receptor which leads to increased gene expression of proteins that facilitate insulin-dependent utilization & storage of FAs and glucose. Referred to as insulin sensitizers. |
| Effects of Thiazolidinediones | Oral administration leads to decreased fasting and postprandial blood glucose and FFAs; Decreases insulin resistance in tissues, especially adipose (believed to have highest amount of ppar-gamma; Can lead to weight gain. |
| Common side effects of oral Biguanide: Metformin (Glucophage) | Diarrhea, nausea/vomiting, flatulence |
| Contraindications for Metformin | Renal or hepatic dysfunction (serum creatine levels equal to or greater than 1.5 mg/dL); PMH of metabolic acidosis (DKA). |
| Common side effects of Thiazolidenediones (Rosiglitazone & Pioglitazone) | Weight gain, fatigue, upper respiratory difficulties, headache, fluid retention,etc. |
| Contraindications of Thiazolidenidiones | Patients with CHF and CHD. Will excacerbate exist CVD. (Basically don't use in patients with heart problems). |
| Common side effects of Pramlintide | Nausea, vomiting, headache; Combination Pramlintide and Insulin can increase incidence of hypoglycemia. |
| Agents that promote insulin secretion | Sulfonylureas, Meglintide analogs, Exenatide, Dipeptidyl Peptidase-IV inhibitors |
| What factors affect the efficacy of the agents that promote insulin secretion? | Ability of pancreas to secrete adequate insulin; Extent of insulin resistance; Degree of hypoglycemia |
| Mechanism of Insulin Secretion From Beta Cells | Glucose enters beta cell and is metabolized → ↑ in ATP & ↓ in ADP which causes K-ATP channel (via Kir 6.2) to close → ↑ K+ in cell → depolarization → opening of L-type Ca-channels → ↑ Ca → ↑ insulin vesicles fusing w/ membrane → ↑ insulin release |
| MOA of Sulfonylureas & Meglitinide Analogs | They increase the time K-ATP channels are closed (by interacting with SUR-1 receptor), which results in more insulin being released from beta cells. |
| Mutation in kir 6.2 subunit on K-ATP channel | Can cause K-ATP channel to be unresponsive to increased ATP, thus leading to decreased insulin secretion (this occurs in rare forms of DM-1). |
| How Sulfonylureas & Meglitinide Analogs overcome mutation in K-ATP Kir 6.2 subunit | They don't bind directly to the Kir 6.2 subunit on K-ATP receptor but they bind to SUR-1 receptor, which increases the time of closure of Kir 6.2 subunits of K-ATP receptor. |
| Administration of Sulfonylureas & Meglitinide Analogs | Intiate with smallest effective oral dose, then increase dosage weekly until there is a decrease in hyperglycemia and no hypoglycemia. |
| Advantage of Meglitinide analogs over Sulfonylureas | Their rapid onset and rapid metabolism and exrection lead to short duration of action and decreased side effects; Allows stimulation of normal prandial insulin profiles; Used in adjunct management of prandial hyperglycemia. |
| Names of Meglitinide Analogs | Repeglinide & Nateglinide |
| Names of Sulfonyyureas | 1st Generation: Tolbutamide & Chlorpropamide. 2nd Generation: Glyburide, Glimepinide, & Glipizide |
| What is Exenatide (Byetta) an analog of? | Glucagon-like peptide-1 (GLP-1), thus its called a GLP-1 Mimetic (meaning it mimics GLP-1) |
| When and from where is GLP-1 released? | It is a circulation incretin-class peptide that is released when eating from enteroendocrine L-cells in the proximal gut. |
| MOA of Exanatide (Byetta) and GLP-1 | Bind to Gs-linked receptors on beta cells → ↑ in cAMP→ ↑ Glut-2 in membrane→ ↑ Glu uptake→ ↑ ATP→ ↑ depolarization→ ↑ calcium→ ↑ Ca-dependent fusion of insulin granules→ ↑ insulin secretion |
| Administration of Exanatide (Byetta) | Subcutaneous injections |
| GLP-1 mimetics and Sulfonylureas | GLP-mimetics (Exanatide/Byetta) can be used in people with sulfonylurea insensitivity due to different MOA. Exanatide can be used as monotherapy or as adjunct therapy with sulfonylureas. |
| Dipeptidyl peptidase-IV inhibitors | They antagonize GLP-1 breakdown, thus increasing GLP-1 duration of action and bioavailability. It can be used as monotherapy (to maintain endogenous GLP-1) or with Exenatide or sulfonylureas. |
| Common side effects of Sulfonylureas and Meglitinide analogs | Hypoglycemia & nausea (8%) |
| Common side effects of Exenatide | Hypoglycemia, nausea (8%). But if in combination with Metformin, nausea (44%), dyspepsia or vomiting (13%), etc; combination with Thiazolidinediones, nausea (40%), dispepsia and vomiting (13%) |
| Contraindication of Exenatide | PMH of pancreatitis |
| Glucovance | The first drug used as combination therapy for DM. It has Glyburide (Sulfonylurea) and Metformin (Biguanide)in it. It decreases insulin resistance. Can use much less dose of each drug if used alone. |
| Goal of combination therapy | Use drugs that act by different mechanisms to decrease insulin resistance OR increase insulin secretion. (Initially they tried to do both but found it easier to do either or). |
| Names of Alpha Glucosidase Inhibitors | Acarabose, Migitol, Vogilbose |
| MOA of Alpha Glucosidase Inhibitors | They antagonize intestinal uptake of carbohydrates into blood by inhibiting intestinal mucosal alpha-glucosidase. Leads to decrease in postprandial rise in blood glucose. |
| Treating hypoglycemia caused by exogenous insulin (given for DM-1 treatment),DM-2 agents that cause increased insulin secretion, or insulin resistance | Parentaral glucagon, Ocreotide, Diazoxide (Proglycem), and Alpha-Glucosidase Inhibitors |
| Parenteral glucagon | Increase hepatic glucose release; Administered I.V, I.M, or S.C.; Onset 15-30 mins; Half-life 45-60 mins |
| Ocreotide | Is a long-acting somatostatin analog. It directly decreases insulin secretion from beta cells or insulinoma; Administered I.V. or S.C.; Onset 1 hr; Half-life 6-8 hours |
| Diazoxide (Progylcem) | It increases membrane permeability to K+ which causes decrease in Ca2+ uptake, which leads to decreased Ca-mediated insulin secretion; Admin. oral or any route; Onset 1 hr; Half-life 6-8 hrs |
| Non-pharmacological management of Type 2 DM | Excercise (increases glucose use and decreases insulin resisitance), weight reduction (decrease obesity induced insulin resistance), and dietary management (low glycemic index) |
Created by:
MarcoB78
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