ENDO EXAM 1_ DM PHARM.pdf

Pathophysiology of Diabetes Endocrinology ❖ Studies the physiology of hormones Biosynthesis Sites of production Sites of action MOAs and interaction ❖ Major hormone functions Regulation of energy storage, production and utilization Maturation and function of the reproductive system Facilitation of g...

Pathophysiology of Diabetes Endocrinology ❖ Studies the physiology of hormones Biosynthesis Sites of production Sites of action MOAs and interaction ❖ Major hormone functions Regulation of energy storage, production and utilization Maturation and function of the reproductive system Facilitation of growth and development Adaptation to new environments or conditions of stress ❖ Two classes of hormones Hormones mostly acting via nuclear receptors to modulate gene transcription in target cells ○ Steroid hormones ○ Thyroid hormones ○ Vitamin D Hormones mostly acting via membrane receptors to exert rapid effects on signal transduction pathways ○ Peptide and amino acid hormones → insulin Pancreas ❖ The endocrine pancreas consists of 4 different cell types that produce several hormones: Alpha cells (20%) ○ Beta cells (75%) ○ Produce insulin and proinsulin, C-peptide and amylin Delta cells (5%) ○ Produce glucagon and pro-glucagon Produce somatostatin → endogenous inhibitor of secretory cells Epsilon cells ( PPARa) Rosiglitazone → selective PPARy agonist 2. Alter glucose homeostasis other than via insulin a. Reduce glucose production Drug Class MOA Biguanide Metformin is transported into the liver by OCT1 where it inhibits the mitochondrial respiration chain → decreases ATP and increases AMP ○ Activation of AMPK → decreases gluconeogenesis and increases insulin sensitivity Effects Lowers hyperglycemia Does not affect BG in normoglycemic states + does not induce insulin release → low hypoglycemic risk ADRs Mainly GI Lowers vitamin B12 levels b. Increase glucose excretion Drug Class MOA SGLT2 Inhibitors The kidney contributes to the regulation of the glucose balance ○ Filters and then reabsorbs glucose back into circulation using transporters ○ Reabsorption is 100% in non-diabetics ○ Hyperglycemia → saturation of the transporters → glycosuria (+ hyperglycemia) SGLT2 is a high-affinity, low capacity transporter ○ Main transporter for renal glucose reabsorption against gradient using the Na+ flux as energy → excretion threshold is 180 mg/dL Effects Decrease excretion threshold to 50 mg/dL Increase glucose excretion (glycosuria) Reduce glucose reabsorption in the proximal tubule Lower BG and promote diuresis d/t osmotic effect of glucose ADRs Increased risk for infections of the lower urinary tract and genital mycoplasma Mild diuresis Do not affect CV diseases → some even reduce risk Canagliflozin + Bexagliflozin → increased risk of lower extremity amputation c. Reduce glucose absorption Drug Class A-glucosidase inhibitors Amylin analog Bromocriptine Info A-glucosidase ○ Enzyme expressed in the intestinal brush border ○ Breaks down complex carbohydrates into monomers to allow intestinal absorption Acarbose + Miglitol ○ Decrease intestinal carbohydrate absorption by reducing the conversion to monomers ○ Increase release of the incretin GLP1 into the circulation ○ Decrease BG levels Amylin ○ Glucoregulatory peptide produced by beta-cells ○ Stored and secreted with insulin ○ Binds to amylin receptors (AMY) in the brain ○ Secretion is altered in DM → absent in T1DM and reduced in T2DM → postprandial hyperglycemia + weight gain ○ Induces feeling of satiety → lowers appetite ○ Reduces GER ○ Reduces glucagon secretion Pramlintide ○ Synthetic analog of human amylin ○ Activates AMY ○ Used as an adjunctive agent to insulin → administered SQ immediately before eating (rapid onset) ○ Main ADR → risk for insulin-induced hypoglycemia (black box warning for T1DM) Centrally acting agonist for the dopamine D2 receptor Decreased hypothalamic D2 activation may contribute to insulin resistance Quick release → resets hypothalamus to reverse increased plasma glucose, TG and free fatty acid levels in fasting and postprandial states in insulin-resistant pts Hypoglycemia ❖ Causes (Inappropriate) use of anti-diabetic agents Increased insulin secretion (ex: bc of disease) ❖ Effects Dizziness, confusion, weakness, falls Tachycardia Headaches, seizures, loss of conscience Coma and death ❖ Treatment options Glucagon Diazoxide ❖ Glucagon Pancreatic peptide released by alpha-cells Secretion of glucagon ○ Stimulated by low BG, NE/EPI and several AAs ○ Inhibited by high BG, insulin + somatostatin Activates Gs-coupled glucagon receptors → increases cAMP Has catabolic actions and opposes the effect of insulin ○ Promote glycogenolysis in liver → production of glucose from stored glycogen ○ Promote gluconeogenesis in liver → production of glucose Administered IV, IM or SC when oral glucose is not an option and IV glucose is not available Other actions ○ Increase HR and cardiac contraction d/t increase in cAMP ○ Relaxation of smooth muscle ❖ Diazoxide Anti-HTN, anti-diuretic with strong hyperglycemic action Keeps the K+ ATP-channel on beta-cells open → increased K+ efflux → hyperpolarization → inhibition of Ca++ influx → suppression of insulin secretion Bile acid sequestrants Colesevelam ○ T2DM pts have abnormal bile acid metabolism ○ Lowers BG via an unknown mechanism