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: -DKA
DKA: 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: Sulfonylureas
meglithnides
biguanides
glitazones
insulin
Major complications of type II: Nonketotic hyperosmolar coma

Treat with insulin, fluids, NO GLUCOSE
Badness caused by hyperglycemia in Diabetes Mellitus: -Neuropathy
-nephropathy
-retinopathy
-atherosclerosis
-amputations
Managment of DM: -control hyperglycemia and ketoacidosis
-avoid hypoglycemia
Insulin: 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
(DM-II)
Insulin target tissues: Liver
adipose
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: -Rapid
-intermediate
-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: -Overdose
--hypoglycemia
--coma can result
Treatment of insulin overdose and hypoglycemia: -Give glucose, unless it's NKHO, orally or IV if comatose,

or

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

Lipodystrophy

insulin resistance
Lipodystrophy: 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: Tolbutamide
chlorpropamide
tolazamide
acetohexamide
Second generation sulfonylureases: glyburide
glipizide
glimepiride
Sulfonylureases: Orally active hypoglcemic drugs bound to plasma proteins (90%-99%)
Chlorpropamide: Very long acting first generation oral hypoglycemic sulfonylurease drug
Glipizide: Second generation sulfonylurease with short half-life

-safest
Glimepiride: 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)
-Biguanide
-Glitazones
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: Hypoglycemia
weight gain
Meglitinides mechanism of action: Inhibit ATP-selective K+ channels on beta cells
Types of meglitinides: -Rpaglinide
-Nateglinide
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
Metformin: 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: Rosiglitazone
Pioglitazone
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
Pioglitazones: 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
Rosiglitazon: Well absorbed w/w/o food
plasma level peak w/i 1 hour
->t1/2 3-4 hrs
Metabolized by CYP2C8
ADVERSE EFFECTS Glitazones: -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: Acarbose
Miglitol
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?: HYPOGLYCEMIA
Alcohol plus oral hypoglycemic (like sulfonylureas): HYPOGLYCEMIA
Drugs that cause hypergylemia: glucocorticoids, phenothiazines, benzodiazepines, gatifloxacin
Thiazide diurectis on glucose tolerance: -Reduse glucose tolerance, mainly direct effect on beta cells
Diazoxide: 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)
Glucagon: -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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