Transcript Internal Medicine Morning Report

Oral Hypoglycemic Agents
and You
John Kashani DO
St. Josephs Medical Center
New Jersey Poison Center
Objectives
• Outline Insulin physiology, glucose regulation
and hypoglycemia
• Discuss type 2 diabetes and medications
used in it’s treatment
• Outline the management and disposition of
patients exposed to these agents
Physiologic effects of
insulin
• Effects will vary depending on the tissue
involved
– Facilitates the entry of glucose into
muscle, adipocytes and various other
tissues
– Stimulates the production of glycogen
in the liver
Physiologic effects of
insulin
– Activates hexokinase
– Inhibits glucose-6-phosphatase
– Activates phosphofructokinase and
glycogen synthase
– Promotes the synthesis of fatty acids
– Inhibits the breakdown of fat in
adipose tissue
Physiologic effects of
insulin
• Inhibits intracellular lipase
• Stimulates the uptake of amino acids
• Increases the permeability of cells to
potassium, magnesium and phosphate
ions
Glucagon
• Maintains blood glucose levels between
meals and fasting periods
– Initiates glycogenolysis
– Increase the transport of amino acids
in the liver – gluconeogenesis
– Activates adipose cell lipase – makes
fatty acids available for energy
Cathecholamines
• Norepinephrine and epinephrine
– Maintain blood glucose levels during
periods of stress
– Increase lipase activity – increases
the mobilization of fatty acids
–inhibits insulin release
–Promotes glycogenolysis
Growth Hormone
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Increases protein synthesis
Mobilizes fatty acids
Antagonizes the effects of insulin
Decreases the cellular uptake of
glucose
• Initial plasma glucose-lowering effect
Glucocorticoids
• Critical to survival during periods of
fasting and starvation
• Stimulate gluconeogensis
• Decrease tissue use of glucose
• Initial plasma glucose-lowering effect
similar to growth hormone
Glucose Regulation
• Glucose maintained between 70-140
mg/dL by several mechanisms
• Above this range, pancreatic beta cells
secrete insulin
• Below this range, the major acute
defense is glucagon release
Type 2 Diabetes
• Heterogeneous condition describing
hyperglycemia and relative insulin
deficiency
– High, normal or low insulin levels
• No HLA markers or antibodies
• Usually middle aged and overweight
• Symptoms tend to be more gradual than
type 1
Oral Hypoglycemic Agents
• An increasing number of medications
available for the treatment of type 2
diabetes mellitus
• Vary in mechanism of action, adverse
effects and toxicity
• There is little experience with toxicity
and overdose with some of the newer
agents
Common Scenarios
• Accidental ingestion in a child
• Took too much by accident
• Intentional overdose
– Diabetic vs. non-diabetic
Type 2 Agents
• Hypoglycemic agents
– Sulfonylureas
– Benzoic acid derivatives
• Antihyperglycemic agents
– Biguanides
– -glucosidase inhibitors
– Thiazolidinedione derivatives
Sulfonylureas
• Stimulate the beta cells of the pancreas to
produce insulin
• Bind to the sulfonylurea receptor on the
pancreatic beta cell
• Ineffective in type I diabetics who lack the
capacity to produce insulin
• Lower the blood glucose in type 2 diabetic
patients
• Lower the blood glucose in non-diabetic
patients
Sulfonylurea Mechanism
sulfonylurea
Ca
KATP
I
I
I
K+
I
insulin
Pancreatic  cell
Sulfonylurea
receptor
Sulfonylureas
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Decrease hepatic insulin clearance
Increase serum insulin concentrations
Reduce hepatic glucose production
Increase peripheral insulin sensitivity
Sulfonylureas
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Highly protein bound
Metabolized in the liver
Renal excretion
Large Vd (10-15 L/kg)
1st Generation Sulfonylureas
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Acetohexamide
Chlorpropamide
Tolazamide
Tolbutamide
1st Generation
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Reduce hepatic clearance of insulin
Produce active hepatic metabolites
Long half life and duration of action
Dependent on urinary excretion to
maintain euglycemia
Chlorpropamide
• Half-life may be >24 hours with up to
60 hours duration of action
• Can cause hyponatremia (SIADH)
• Disulfuram reaction
• Cholestatic jaundice
• Agranulocytosis, thrombocytopenia,
anemia
• Elimination enhanced by urinary
alkalinization
2nd Generation Sulfonylureas
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Glimeperide
Glipizide
Glyburide
100x more potent than first generation
Improved safety profile
2nd Generation
• Half lives approach 24 hours
• Associated with substantial fecal
excretion of the parent drug
• More lipid soluble than first generation
Sulfonylureas
Agent
Onset (h)
Peak (h)
Duration (h)
Acetohexamide
2
4
12-24
Chlorpropamide
1
5
24-72
2.5
24
Glimepride
Glipizide
0.5
1
< 24
Glyburide
0.5
4
24
Tolazamide
1
5
18
Tolbutamide
1
6
6-12
Sulfonylureas
• Chlorpropamide, Glyburide, and
Glipizide are the most likely to cause
prolonged hypoglycemia
• Duration of action prolonged in
presence of renal and hepatic disease
Pediatric Ingestion
• 5 year retrospective review (Clin Tox
34(3)1996)
– 93 cases, 25 patients (27%)
developed hypoglycemia
– 79% onset within 4 hours
– Remainder up to 16 hours
Biguanides
• Active component of Galega officinalis,
the French lilac
• Lower the blood glucose in diabetic
patients
• Does not lower blood glucose in normal
patients
• Improves insulin sensitivity
Galega officinalis
Everything Spectatularis
Biguanides
• Phenformin
– Withdrawn from the US market in
1976
– 1/4000 patients develop lactic
acidosis
• Metformin (Glucophage)
– Introduced in the US in 1995
Metformin
• Inhibits gluconeogenesis and reduces
hepatic glucose output
– Reduces fasting plasma glucose
– Increases glycogen formation
• Causes increase in glucose uptake and
utilization in peripheral tissues
• Reduction of serum insulin concentrations
• Inhibits lipolysis
Metformin
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Orally absorbed within six hours
Peak serum levels 2-3 hours
Minimally bound to plasma proteins
Not metabolized by the liver
Half life 4 - 8.7 hours
Excreted by the kidney
Metformin
• Lactic acidosis
– 1/40000-80000 patients
– Majority have renal insufficiency
– Has been found in association with
levels above 5 ug/ml
– Generally assumed to be type B
Mechanism of Lactic Acidosis
• Inhibit gluconeogenesis - accumulation of
pyruvate
• Fat catabolism - oxidation of fatty acids depletes NAD+ - increases NADH
• Increased ratio inhibits pyruvate
dehydrogenase and the entry of pyruvate
into the Kreb’s cycle
Mechanism of Lactic Acidosis
• Fatty acid oxidation increases acetyl
CoA/CoA ratio - further decreases entry
of pyruvate into the Kreb’s cycle
• With pyruvate dehydrogenase inhibited
and gluconeogenesis blocked, the
accumulated pyruvate is metabolized to
lactate
-glucosidase Inhibitors
• Acarbose
• Miglitol
• Do not cause hypoglycemia but may
potentiate the action of the
sulfonylureas
Acarbose
• Results in competitive inhibition of the glucosidase on the brush border of the
small bowel
– Reduces intestinal starch and
disaccharide absorption
• Delayed carbohydrate absorption and
redistribution throughout the intestines
yields a decreased, constant insulin
production due to lowered postprandial
glucose concentrations
Acarbose
• Only 1-2% is absorbed by the gut
• Does not cause hypoglycemia
• Toxicity:
– Abdominal discomfort
– Mild GI effects
– Flatulence, abdominal bloating
• Hepatic toxicity has been reported
Thiazolidinediones
• Troglitazone (Rezulin)
– Withdrawn from the market in the US
in 2000 due to cases of fatal liver
toxicity
• Rosiglitazone (Avandia)
• Pioglitazone (Actos)
Thiazolidinediones
• Increase insulin sensitivity
• Decrease hepatic glucose output
• Mechanism:
– Bind to nuclear peroxisome
proliferator-activated receptors
involved in transcription of insulinresponsive genes and in regulation of
adipocyte differentiation and lipid
metabolism
Thiazolidinediones
• Rapidly absorbed
• Highly (>99%) protein bound
• Metabolized by CYP3A4
– Loss of contraceptive effect reported
with ethinyl estradiol/norethindrone
• Half-life 16 - 34 hours
• 2 reports of hepatotoxicity with
rosiglitazone
Benzoic Acid Derivatives
• Repaglinide
• Limited experience with this agent
• Binds to the KATP channel on the beta
cell at a different receptor from the
sulfonylureas
– Extrapancreatic effect leading to
increased insulin sensitivity
postulated
Repaglinide
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Rapidly absorbed
Metabolized by the 3A4
Short half-life (1 hr)
Excreted primarily in the bile
Highly protein bound (>98%)
Hypoglycemia is expected in overdose,
no cases reported to date
Repaglinide
• Severe hypoglycemia from
clarithromycin-repaglinide drug
interaction
– Khamaisi M, Leitersdorf E
– Pharmacotherapy. 2008
May;28(5):682-4
Repaglinide
• Serious hypoglycemia associated with
misuse of repaglinide
– Flood TM
– Endocr Pract. 1999 MayJun;5(3):137-8
Repaglinide
• Hypoglycemia probably due to
accidental intake of repaglinide
• Lee IT, Sheu WH, Lin SY
• Chang Gung Med J. 2002
Nov;25(11):783-6
Management
• Patient asymptomatic with normal glucose,
but agent known to produce hypoglycemia
– Activated charcoal
– Prophylactic glucose not recommended
– Observe 8 hours, if hypoglycemia
develops admit
Management
• Patient already hypoglycemic: IV
dextrose
– Adult initially 1g/kg of D50W
– Children .5 to 1 g/kg D25W
– Neonates .5 to 1 g/kg D10W
IV Glucose
• D10 maintenance infusion
• Rate of infusion adjusted to keep the
patient euglycemic
• Central venous line when D20 is
required
• As the patient begins to eat and glucose
rises, taper the infusion
• Switch to D5W
Octreotide
• Semisynthetic long-acting analog of
somatostatin
• IV half life of 72 minutes
• Inhibits the secretion of insulin,
glucagon, growth hormone, gastrin and
other hormones
Octreotide
• 50 - 100 g subcutaneously every 8 -12
hours
• Has been shown to reduce the glucose
infusion requirements to maintain
euglycemia following sulfonylurea
overdose
• Most frequent side effect is mild
steatorrhea
Diazoxide
• A vasodilator
• Effective for refractory hypoglycemia
• Directly inhibits insulin secretion by opening
KATP channels
• Increases hepatic glucose production
• Decreases cellular glucose utilization
• Slow IV infusion (300 mg IV over 30
minutes every 4 hours)
Glucagon
• Recruits hepatic glycogen stores and
induces gluconeogenesis
• Partially dependent on the adequacy of
glycogen stores
• Reserve for temporizing treatment in
patients in whom IV access cannot be
rapidly established
Dialysis
• Not effective for most oral hypoglycemic
agents because of their high protein
binding
• May be needed for severe lactic
acidosis from biguanides
– Corrects metabolic acidosis
– Removes lactate, ketones, and
metformin
Other Management Points
• Treat lactic acidosis early and
intensively
– Sodium bicarbonate for pH < 7.1
• Urinary alkalinization effective only for
chlorpropamide
– A pH of 7-8 can reduce the half-life
from 49 to 13 hours
– Check Potassium frequently
Who Needs Admission?
• Hypoglycemia in the setting of an oral
Sulfonylurea
• Pediatric exposures (potential) to a
sulfonylurea
• Hypoglycemic Repaglinide exposures
Salient Points
• Don’t F%$# with hypoglycemia
• Chlorpropamide excretion may be
increased by urinary alkanilization
• 1st generation oral Suffonylurease are
sulfonamide based
• GI upset is expected with -glucosidase
Inhibitors
• Hepatic toxicity may occur with
Thiazolidinediones