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82 Cards in this Set
- Front
- Back
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Features of Type I (IDDM)
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-Autoimmune destruction of pancreatic beta cells destroys insulin secretian
-Absolute requirement for Insulin replacement |
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Major complications of type I
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-DKA
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DKA
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Due overproduction of ketoacids with hyperglycemia
-Treat with insulin and fluid replacement |
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Features of Type II
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Reduced Beta cell function and reduced tissue responses to insulin
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Non-medicine treatment of Type II
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Diet, weight loss, exercise
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Medicines to treat type II
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Sulfonylureas
meglithnides biguanides glitazones insulin |
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Major complications of type II
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Nonketotic hyperosmolar coma
Treat with insulin, fluids, NO GLUCOSE |
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Badness caused by hyperglycemia in Diabetes Mellitus
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-Neuropathy
-nephropathy -retinopathy -atherosclerosis -amputations |
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Managment of DM
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-control hyperglycemia and ketoacidosis
-avoid hypoglycemia |
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Insulin
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only hormone that can cause hypoglycemia
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Hormones that counteract insulin and INCREASE blood glucose
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Glucagon, epinephrine, cortisal, growth hormone
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How is insulin made?
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-a 2 chain, disulfide-linked polypeptide produced by cleavage of a "c-peptide" from PRO-INSULIN
(the snakey thing) |
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How is insulin stored?
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-Proinsulin is packaged into cytosolic secretory granules during maturation
--Coordinated with Zn Ion --Equimolar amounts of C-peptide also packaged and produced |
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Process of insulin secretion
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-Increased blood glucose level
->glucose taken into beta cell through GLUT-2 transporter ->glocose metabolized to glucokinase and ATP produced ->ATP blocks ATP Sensitive K+ channel (ASKC) ->Causes K+ to accumulate in the cell and depolarization of the cell membrane ->Depolarization opens Voltage Dependent Calcuim channels ->Calcium enters cells ->Calcium is essential for secretion and exocytosis of insulin |
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Factors controlling Insulin secretion
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-Blood Glucose
-Autonomic Activity -Physiological potentiation |
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How blood glucose controls insulin release
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Uptake of glucose via glut-2 transporter, then metabolism of glucose, causing release of insulin
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Bisaphic release of insulin means?
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Two phases of release (duh)
-Acute phase-releasing already packaged insulin -Delayed phase-synthesis and packaging of new insulin for release |
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How Autonomics control insulin release
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-Beta-2 and M2 increase insulin secretion
Alpha-2 decreases insulin secretion |
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PHow does physiological potentiation control insulin release?
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Amino acids (lys, leu), FFA, ketones
GIP, Gastrin, CCK, VIP, enteroglucagon i have no idea |
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Drugs that stimulate insulin release
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-alpha-2 blockers, beta 2 agonists, theophyline
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Drugs that inhibit insulin release
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-diazoxide, thiazides, ethacrnic acid, furosemide, phenytoin
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How does insulin act?
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-Binds to insulin receptor
->initiaets internalization of ligand:receptor complex ->Evokes intrinsic protein tyrosine kinase activity and gene activation ->Genes activated by tyrosine kinase are IRS1-4 |
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Mutations in IRS1-4
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Decrease gene activation in response to insulin
can cause insulin resistance (DM-II) |
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Insulin target tissues
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Liver
adipose skeletal muscle |
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Insulin effect on liver
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decreases hepatic glucose prodcution
->decreases gluconeogenisis ->decreases glycogenolysis ->decreases ketogenesis ->Increases glycogen synthesis |
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eInsulin effects on Skeletal muscle
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Increases glut-4 glucose uptake, glucose oxidation, glycogen synthesis, amino acid uptake, protein synthesis
Decreases glycogenolysis and amino acid release |
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Insulin effects on Adipocytes
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Increase glucose uptake, triglyceride synthesis, decreases FFA and glycerol release
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Net effect of insulin on metabolism
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Cause hypoglycemia and increase fuel storage in muscle, fat, liver
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Insulin as a drug
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-Ineffective orally
-Plasma t1/2 <9min -Inactivated by liver and kidney |
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Sources of commercial insulin
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-Animal (beef, pork)
-Human (E. coli recombinant or semisynthetic porcine (same primary structure as human insulin) |
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Classifications of commercial insulin
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-Rapid
-intermediate -slow acting |
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Rapid acting insulin
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-Regular, insulin lispro, insulin aspart
15 min to 1 hr onset |
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Intermediat acting insulin
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NPH, lents
1-2 hour onset |
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Slow acting Insulin
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ultralent, glargine
4-6 hour onset |
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Diagnostic use of Insulin
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Insulin tolerance test of GH secretion
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Therapeutic use of insulin
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Treatment of DM I and II
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Goal of insulin use as a drug
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-control blood glucose and normalize metabolism
-->self administered -->Regimens revolve around meals, excersize, sleep, |
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"split mix" insulin
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Regimin with longer acting insulin to handle basal glucose level and shortor acting insulin before meals
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Toxicities of insulin use
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-Overdose
--hypoglycemia --coma can result |
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Treatment of insulin overdose and hypoglycemia
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-Give glucose, unless it's NKHO, orally or IV if comatose,
or give glucagon, then glucose |
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Adverse effects of insulin use
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allergic reactions
Lipodystrophy insulin resistance |
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Lipodystrophy
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changes in subcutaneous fat at repeated injection site
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Insulin resistence as side effect ofinsulin use
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-activating antibodies
-abnormal gulocorticoids -tissue unresponsiveness d/t excess insulin |
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First generation sulfonylureases
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Tolbutamide
chlorpropamide tolazamide acetohexamide |
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Second generation sulfonylureases
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glyburide
glipizide glimepiride |
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Sulfonylureases
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Orally active hypoglcemic drugs bound to plasma proteins (90%-99%)
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Chlorpropamide
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Very long acting first generation oral hypoglycemic sulfonylurease drug
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Glipizide
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Second generation sulfonylurease with short half-life
-safest |
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Glimepiride
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Second generatin sulfonylurease oral hypoglycemic drug
-New drug, long acting, approved for use with insulin |
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How sulfonylurease drugs work
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-Primary mechanism
-->stimulates edogenous insulin release by binding to ATP-sensitive K Channel (ASKC) ->inhibits this like ATP does Other mechanisms->may reduce hepatic clearance of insulin |
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Clinical uses of sulfonylureases
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-Treatment for DM-2 only
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Best patients for sulfonylureases
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-over 40yrs old
-less then 10 yrs with DM -daily insulin less than 40 units |
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Sulfonylureas contraindicated in ?
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DM-I, Secondary diabetes, unstable, ketosis prone diabetics, gestational diabetes
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Sulfonylureas can be used with which other drugs?
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-insulin (glipizide)
-Biguanide -Glitazones |
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Adverse effects of first generation sulfonylureas
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-low in first generation drugs
hypoglycemi of overdose** hep toxicity disulfiram-like reaction with alcohol (inhibits alcohol dehydrogenase and causes n/v) hematological reactions allergic reactions weight gain |
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adverse effets of second generation sulfonylureas
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Hypoglycemia
weight gain |
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Meglitinides mechanism of action
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Inhibit ATP-selective K+ channels on beta cells
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Types of meglitinides
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-Rpaglinide
-Nateglinide |
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Meglitinides factoids
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-rapid onset, short acting
-T1/2 1-11/2 hours -Less effective than sulfonylureas as monotherapy -can be used with metformin to improve Blood glucose control |
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Biguanide drugs
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-oral antihypeglycemic
-do not stimulate insulin release or cause hypoglycemia -Increase glucose uptake in muscle and decrease glucose production by liver |
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Metformin
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only biguanide in US
Orally active does not bind plasma proteins excreted unchanged in urine t1/2 1.3-4.5 hours often combined with sulfonylurea drug also used for polycistic ovary syndrome |
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Adverse effects of biguanides (metformin)
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-produces lactic acidemia (rare, but more common in pts with renal impairment
-N/v/d, abd pain, anorexia -decreased b12, folate absorption |
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Metformin and MI or Septicemia
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-stop immediatly
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Metform contraindications
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-hepatic disease
-past history of lactic acidosis -cardiac failure -chronic hypoxic lung disease -->causes metabolic acidosis |
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Glitazones (Thiazolidinediones)
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Bind to peroxisome proliferator-activatedreceptor-gamma (PPARgamma) involved in transpription of insulin-responsive genes and regulation of adipocyte lipid metabolism
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Approved Glitazones
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Rosiglitazone
Pioglitazone |
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What do glitazones do?
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-in presence of insulin (indogenous or exogenous), these drugs
->dec gluconeogenisis, glucose output and triglyceride production in the liver ->increas glucose uptake, and utilization in liver ->increase glucose uptake and decrease fatty acid output in adipose tissue |
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How to use glitazones?
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Monotherapy or with metformin/sulfonylureas
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Pioglitazones
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Taken orally w/w/o food
->peak plasma level w/i 3hrs ->T1/2 3-7hrs ->Liver metabolism by CYP2C8 and CYP3A4 and excreted in feces2/3 and urine 1/3 |
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Rosiglitazon
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Well absorbed w/w/o food
plasma level peak w/i 1 hour ->t1/2 3-4 hrs Metabolized by CYP2C8 |
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ADVERSE EFFECTS
Glitazones |
-fluid retention->edema, anemia
-dose-related weight gain -safety in preg/lact not determined -does NOT cause lactic acidosis |
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adverse effects of pioglitazone
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-subject to interactions due to CYP3A4 metabolisme
-can lower oral contraceptive level containing ethinyl estradiol and norethindrone -may interact with many other CYP3A4 metabolized drugs |
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Alpha Glucosidase inhibitors
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Acarbose
Miglitol |
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Alpha glucosidase inhibitor MOA
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-taken orally to act on gut
-delay and prolong gi absorption of glucose -small reductions in blood glucose swill not cause hypoglycemia in monotherapy -competitive inhibitors(take before meals) -causes GI disturbances or hepatic toxicity |
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Alcohol plus insulin causes?
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HYPOGLYCEMIA
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Alcohol plus oral hypoglycemic (like sulfonylureas)
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HYPOGLYCEMIA
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Drugs that cause hypergylemia
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glucocorticoids, phenothiazines, benzodiazepines, gatifloxacin
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Thiazide diurectis on glucose tolerance
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-Reduse glucose tolerance, mainly direct effect on beta cells
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Diazoxide
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used to treat hypoglycemia (insulinomas)
->inhibits insulin release ->stimulates catecholamin release ->increases hepatic glucose production |
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Propanolol in diabetes
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-Blocks compensatory effect of epinephrine (don't recognize signs of hypoglycemia)
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Glucagon
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-single chain peptide (29AA)
-Stored in secretory granules in pancreatic Alpha cells |
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Glucagon secretion
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increased with glucose, somatostatin, FFA
decreased with aa, gut hormones, beta-2, M2 agonists |
