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Anti-Diabetic Drugs


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Features of Type I (IDDM)
-Autoimmune destruction of pancreatic beta cells destroys insulin secretian
-Absolute requirement for Insulin replacement
Major complications of type I
Due overproduction of ketoacids with hyperglycemia

-Treat with insulin and fluid replacement
Features of Type II
Reduced Beta cell function and reduced tissue responses to insulin
Non-medicine treatment of Type II
Diet, weight loss, exercise
Medicines to treat type II
Major complications of type II
Nonketotic hyperosmolar coma

Treat with insulin, fluids, NO GLUCOSE
Badness caused by hyperglycemia in Diabetes Mellitus
Managment of DM
-control hyperglycemia and ketoacidosis
-avoid hypoglycemia
only hormone that can cause hypoglycemia
Hormones that counteract insulin and INCREASE blood glucose
Glucagon, epinephrine, cortisal, growth hormone
How is insulin made?
-a 2 chain, disulfide-linked polypeptide produced by cleavage of a "c-peptide" from PRO-INSULIN

(the snakey thing)
How is insulin stored?
-Proinsulin is packaged into cytosolic secretory granules during maturation
--Coordinated with Zn Ion
--Equimolar amounts of C-peptide also packaged and produced
Process of insulin secretion
-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
Factors controlling Insulin secretion
-Blood Glucose
-Autonomic Activity
-Physiological potentiation
How blood glucose controls insulin release
Uptake of glucose via glut-2 transporter, then metabolism of glucose, causing release of insulin
Bisaphic release of insulin means?
Two phases of release (duh)

-Acute phase-releasing already packaged insulin
-Delayed phase-synthesis and packaging of new insulin for release
How Autonomics control insulin release
-Beta-2 and M2 increase insulin secretion

Alpha-2 decreases insulin secretion
PHow does physiological potentiation control insulin release?
Amino acids (lys, leu), FFA, ketones

GIP, Gastrin, CCK, VIP, enteroglucagon

i have no idea
Drugs that stimulate insulin release
-alpha-2 blockers, beta 2 agonists, theophyline
Drugs that inhibit insulin release
-diazoxide, thiazides, ethacrnic acid, furosemide, phenytoin
How does insulin act?
-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
Mutations in IRS1-4
Decrease gene activation in response to insulin

can cause insulin resistance
Insulin target tissues
skeletal muscle
Insulin effect on liver
decreases hepatic glucose prodcution

->decreases gluconeogenisis
->decreases glycogenolysis
->decreases ketogenesis
->Increases glycogen synthesis
eInsulin effects on Skeletal muscle
Increases glut-4 glucose uptake, glucose oxidation, glycogen synthesis, amino acid uptake, protein synthesis

Decreases glycogenolysis and amino acid release
Insulin effects on Adipocytes
Increase glucose uptake, triglyceride synthesis, decreases FFA and glycerol release
Net effect of insulin on metabolism
Cause hypoglycemia and increase fuel storage in muscle, fat, liver
Insulin as a drug
-Ineffective orally
-Plasma t1/2 <9min
-Inactivated by liver and kidney
Sources of commercial insulin
-Animal (beef, pork)
-Human (E. coli recombinant or semisynthetic porcine (same primary structure as human insulin)
Classifications of commercial insulin
-slow acting
Rapid acting insulin
-Regular, insulin lispro, insulin aspart

15 min to 1 hr onset
Intermediat acting insulin
NPH, lents

1-2 hour onset
Slow acting Insulin
ultralent, glargine

4-6 hour onset
Diagnostic use of Insulin
Insulin tolerance test of GH secretion
Therapeutic use of insulin
Treatment of DM I and II
Goal of insulin use as a drug
-control blood glucose and normalize metabolism

-->self administered
-->Regimens revolve around meals, excersize, sleep,
"split mix" insulin
Regimin with longer acting insulin to handle basal glucose level and shortor acting insulin before meals
Toxicities of insulin use
--coma can result
Treatment of insulin overdose and hypoglycemia
-Give glucose, unless it's NKHO, orally or IV if comatose,


give glucagon, then glucose
Adverse effects of insulin use
allergic reactions


insulin resistance
changes in subcutaneous fat at repeated injection site
Insulin resistence as side effect ofinsulin use
-activating antibodies
-abnormal gulocorticoids
-tissue unresponsiveness d/t excess insulin
First generation sulfonylureases
Second generation sulfonylureases
Orally active hypoglcemic drugs bound to plasma proteins (90%-99%)
Very long acting first generation oral hypoglycemic sulfonylurease drug
Second generation sulfonylurease with short half-life

Second generatin sulfonylurease oral hypoglycemic drug

-New drug, long acting, approved for use with insulin
How sulfonylurease drugs work
-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
Clinical uses of sulfonylureases
-Treatment for DM-2 only
Best patients for sulfonylureases
-over 40yrs old
-less then 10 yrs with DM
-daily insulin less than 40 units
Sulfonylureas contraindicated in ?
DM-I, Secondary diabetes, unstable, ketosis prone diabetics, gestational diabetes
Sulfonylureas can be used with which other drugs?
-insulin (glipizide)
Adverse effects of first generation sulfonylureas
-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
adverse effets of second generation sulfonylureas
weight gain
Meglitinides mechanism of action
Inhibit ATP-selective K+ channels on beta cells
Types of meglitinides
Meglitinides factoids
-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
Biguanide drugs
-oral antihypeglycemic
-do not stimulate insulin release or cause hypoglycemia

-Increase glucose uptake in muscle and decrease glucose production by liver
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
Adverse effects of biguanides (metformin)
-produces lactic acidemia (rare, but more common in pts with renal impairment
-N/v/d, abd pain, anorexia
-decreased b12, folate absorption
Metformin and MI or Septicemia
-stop immediatly
Metform contraindications
-hepatic disease
-past history of lactic acidosis
-cardiac failure
-chronic hypoxic lung disease
-->causes metabolic acidosis
Glitazones (Thiazolidinediones)
Bind to peroxisome proliferator-activatedreceptor-gamma (PPARgamma) involved in transpription of insulin-responsive genes and regulation of adipocyte lipid metabolism
Approved Glitazones
What do glitazones do?
-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
How to use glitazones?
Monotherapy or with metformin/sulfonylureas
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
Well absorbed w/w/o food
plasma level peak w/i 1 hour
->t1/2 3-4 hrs
Metabolized by CYP2C8
-fluid retention->edema, anemia
-dose-related weight gain
-safety in preg/lact not determined
-does NOT cause lactic acidosis
adverse effects of pioglitazone
-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
Alpha Glucosidase inhibitors
Alpha glucosidase inhibitor MOA
-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
Alcohol plus insulin causes?
Alcohol plus oral hypoglycemic (like sulfonylureas)
Drugs that cause hypergylemia
glucocorticoids, phenothiazines, benzodiazepines, gatifloxacin
Thiazide diurectis on glucose tolerance
-Reduse glucose tolerance, mainly direct effect on beta cells
used to treat hypoglycemia (insulinomas)
->inhibits insulin release
->stimulates catecholamin release
->increases hepatic glucose production
Propanolol in diabetes
-Blocks compensatory effect of epinephrine (don't recognize signs of hypoglycemia)
-single chain peptide (29AA)
-Stored in secretory granules in pancreatic Alpha cells
Glucagon secretion
increased with glucose, somatostatin, FFA

decreased with aa, gut hormones, beta-2, M2 agonists

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