Oral Hypoglycemic Agents and You

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Oral Hypoglycemic Agents and You

• John Kashani DO
• St. Josephs Medical Center
• New Jersey Poison Center

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Objectives

• Outline Insulin physiology, glucose regulation
  and hypoglycemia
• Discuss type 2 diabetes and medications used in
  its treatment
• Outline the management and disposition of
  patients exposed to these agents

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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

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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

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Physiologic effects of insulin

• Inhibits intracellular lipase
• Stimulates the uptake of amino acids
• Increases the permeability of cells to potassium,
  magnesium and phosphate ions

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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

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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

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Growth Hormone

• Increases protein synthesis
• Mobilizes fatty acids
• Antagonizes the effects of insulin
• Decreases the cellular uptake of glucose
• Initial plasma glucose-lowering effect

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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

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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

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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

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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

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Common Scenarios

• Accidental ingestion in a child
• Took too much by accident
• Intentional overdose
• Diabetic vs. non-diabetic

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Type 2 Agents

• Hypoglycemic agents
• Sulfonylureas
• Benzoic acid derivatives
• Antihyperglycemic agents
• Biguanides
• ?-glucosidase inhibitors
• Thiazolidinedione derivatives

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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

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Sulfonylurea Mechanism
sulfonylurea
Ca
KATP
Sulfonylurea receptor
I
K
I
I
I
Pancreatic ? cell
insulin
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Sulfonylureas

• Decrease hepatic insulin clearance
• Increase serum insulin concentrations
• Reduce hepatic glucose production
• Increase peripheral insulin sensitivity

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Sulfonylureas

• Highly protein bound
• Metabolized in the liver
• Renal excretion
• Large Vd (10-15 L/kg)

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1st Generation Sulfonylureas

• Acetohexamide
• Chlorpropamide
• Tolazamide
• Tolbutamide

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1st Generation

• Reduce hepatic clearance of insulin
• Produce active hepatic metabolites
• Long half life and duration of action
• Dependent on urinary excretion to maintain
  euglycemia

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Chlorpropamide

• Half-life may be gt24 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

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2nd Generation Sulfonylureas

• Glimeperide
• Glipizide
• Glyburide
• 100x more potent than first generation
• Improved safety profile

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2nd Generation

• Half lives approach 24 hours
• Associated with substantial fecal excretion of
  the parent drug
• More lipid soluble than first generation

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Sulfonylureas
Agent Onset (h) Peak (h) Duration (h)
Acetohexamide 2 4 12-24
Chlorpropamide 1 5 24-72
Glimepride 2.5 24
Glipizide 0.5 1 lt 24
Glyburide 0.5 4 24
Tolazamide 1 5 18
Tolbutamide 1 6 6-12
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Sulfonylureas

• Chlorpropamide, Glyburide, and Glipizide are the
  most likely to cause prolonged hypoglycemia
• Duration of action prolonged in presence of renal
  and hepatic disease

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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

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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

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Galega officinalis
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Everything Spectatularis
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Biguanides

• Phenformin
• Withdrawn from the US market in 1976
• 1/4000 patients develop lactic acidosis
• Metformin (Glucophage)
• Introduced in the US in 1995

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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

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Metformin

• 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

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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

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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 Krebs cycle

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Mechanism of Lactic Acidosis

• Fatty acid oxidation increases acetyl CoA/CoA
  ratio - further decreases entry of pyruvate into
  the Krebs cycle
• With pyruvate dehydrogenase inhibited and
  gluconeogenesis blocked, the accumulated pyruvate
  is metabolized to lactate

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?-glucosidase Inhibitors

• Acarbose
• Miglitol
• Do not cause hypoglycemia but may potentiate the
  action of the sulfonylureas

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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

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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

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Thiazolidinediones

• Troglitazone (Rezulin)
• Withdrawn from the market in the US in 2000 due
  to cases of fatal liver toxicity
• Rosiglitazone (Avandia)
• Pioglitazone (Actos)

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Thiazolidinediones

• Increase insulin sensitivity
• Decrease hepatic glucose output
• Mechanism
• Bind to nuclear peroxisome proliferator-activated
  receptors involved in transcription of
  insulin-responsive genes and in regulation of
  adipocyte differentiation and lipid metabolism

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Thiazolidinediones

• Rapidly absorbed
• Highly (gt99) 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

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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

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Repaglinide

• Rapidly absorbed
• Metabolized by the 3A4
• Short half-life (1 hr)
• Excreted primarily in the bile
• Highly protein bound (gt98)
• Hypoglycemia is expected in overdose, no cases
  reported to date

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Repaglinide

• Severe hypoglycemia from clarithromycin-repaglinid
  e drug interaction
• Khamaisi M, Leitersdorf E
• Pharmacotherapy. 2008 May28(5)682-4

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Repaglinide

• Serious hypoglycemia associated with misuse of
  repaglinide
• Flood TM
• Endocr Pract. 1999 May-Jun5(3)137-8

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Repaglinide

• Hypoglycemia probably due to accidental intake of
  repaglinide
• Lee IT, Sheu WH, Lin SY
• Chang Gung Med J. 2002 Nov25(11)783-6

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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

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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

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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

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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

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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

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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)

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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

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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

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Other Management Points

• Treat lactic acidosis early and intensively
• Sodium bicarbonate for pH lt 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

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Who Needs Admission?

• Hypoglycemia in the setting of an oral
  Sulfonylurea
• Pediatric exposures (potential) to a sulfonylurea
  
• Hypoglycemic Repaglinide exposures

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Salient Points

• Dont 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