HYPOGLYCEMICAGENTS

Rama B. Rao, M.D.

Bellevue Hospital Center/NYUMC

New York, N.Y.

Glycemic Control Agents

• Insulin

• Sulfonylureas

• Meglitinides: Repaglinide

• Biguanides: Metformin

• Thiazolidinediones: Pioglitazone Glucosidase inhibitors

Glycogen

Glucose

MUSCLE CELL

Storage

P

Pyruvate

Kreb’s Oxidative ATPPhosphorylation

Cycle

I

I

Glucose

MUSCLE CELLS

P

Pyruvate

I

Kreb’s ATP

Glycogen

EPINEPHRINEGLUCAGON

OxidativePhosphorylation

Glucose

MUSCLE CELLS

P

Pyruvate

I

Kreb’s ATP

KETONES

FFA

PhosphorylationOxidative

P

Glycogen

Glucose

BRAIN

Pyruvate

KrebsOxidativePhosphorylation

ATP

KETONES

HYPOGLYCEMIA

• Hunger/Anxiety

• Focal neurological deficits

• Confusion

• Seizures

• Coma

• Hypothermia

P

Glucose

BRAIN: Anterior Pituitary

ATP

GHEXCITATORY NT

Adrenal medullaCatecholamines

Other Manifestations

• Tachycardia

• Tremor

• Diaphoresis

ALPHA CELL OF PANCREAS

GLUCAGON

DecreasedGlucose

Catecholamines, Amino acids

Glucose

MUSCLE CELLS

P

Pyruvate

I

Kreb’s ATP

Glycogen

EPINEPHRINEGLUCAGON

OxidativePhosphorylation

Glycogen

Glucose

LIVER CELL

Storage

I

P

Pyruvate

Kreb’s ATP

EPINEPHRINEGLUCAGON

Oxidative

CyclePhosphorylation

Ca2+

PANCREAS: BETA ISLET CELL

Insulin

++ +++++

MEMBRANE DEPOLARIZATION

K+

ATP

Ca2+

PANCREAS: BETA ISLET CELL

Insulin

Sulfonylurea, Meglitinides*

+++++

*Repaglinide

SULFONYLUREAS

• Risk of hypoglycemia– Fasting– Elderly: variable data– Chronic renal failure

SULFONYLUREA INDUCED HYPOGLYEMIA

• Administration of glucose for acute correction

• Decontamination

• Nutrition, IV access

• Admission

SULFONYLUREAS

• Monitor potassium, phosphate

• Urinary alkalinization for chlorpropamide

• Octreotide for refractory hypoglycemia

• Observation for at least 12 hours after last dose octreotide

Octreotide Dosing

• Adults: 50 g subcutaneously every 6 hours

• Children: 4-5 g/kg/day subcutaneously divided every 6 hours, with maximum not exceeding the adult dose

K+

ATP

Ca2+

PANCREAS: BETA ISLET CELL

Insulin

DIAZOXIDE

- - - - -- - -

Ca2+

PANCREAS: BETA ISLET CELL

Insulin

OCTREOTIDE

G

SUFONYLUREAS: Other Effects

• Inhibition of aldehyde dehydrogenase

• SIADH

INSULIN

• Oral exposure is benign

• Parenteral Exposures – Unpredictable in overdose– May be dependent upon quantity injection– Formulation

• Treatment: nutrition, supplemental glucose infusion

HYPOGLYCEMICS: MANAGEMENT

• Identify and treat hypoglycemia

• Admission especially if brought to coma or seizure

• Nutrition– Consider enteral infusion of feeds via NG Tube

• Monitor electrolytes

GLUCOSE ADMINISTRATION

• Adults– D50W 1 gram/kg

• Children– D25W 0.5-1 gram/kg

– D10 W 0.5-1 gram/kg in neonates

• Infusion of D10 W at a total of 1 gram/kg/hr

• Monitor potassium

METFORMIN

• Rarely causes true hypoglycemia

• Adverse reaction– Lactic acidosis only in patients with renal

insufficiency or shock states.– Treatment of lactic acidosis: hemodialysis

• Caveat: Co-ingested substances

Glycogen

Glucose

MUSCLE CELL

P

Pyruvate

I

Kreb’s ATPMETFORMIN Oxidative

Phosphorylation

Glycogen

LIVER CELL

P

Pyruvate

ATP

METFORMIN

PhosphorylationOxidative

OTHER AGENTS AFFECTING CARBOHYDRATE METABOLISM

• Ethanol

• Beta adrenergic antagonists

• Unripened ackee fruit

• Valproic acid

• Salicylates

• Pentamidine

• Quinidine

• Disopyramide

Glycogen

Glucose

LIVER CELL

Pyruvate

Oxidative

ATP

Lactate

Phosphorylation

NAD+

NADH+H+

ETHANOL

Acetate

ALPHA CELL OF PANCREAS

GLUCAGON

DecreasedGlucose

Catecholamines, Amino acids

BETA ADRENERGICANTAGONISTS

Glycogen

LIVER CELL

P

Pyruvate

ATPPhosphorylationOxidative

ACKEE

Glucose

LIVER

P

Pyruvate

I

Kreb’s ATP

KETONES

FFA

PhosphorylationOxidative

ACKEEVALPROIC ACID

Glucose

LIVER

P

Pyruvate

I

Kreb’s ATP

PhosphorylationOxidative

Alanine

SALICYLATES

Ca2+

PANCREAS: BETA ISLET CELL

Insulin

++ +++

Membrane depolarization

PENTAMIDINEALLOXAN

STREPTOZOCIN

P

BRAIN

Pyruvate

Kreb’s

OxidativePhosphorylation

ATP

Acetyl Co A

THIAMINE

GLUCOSE

Glycogen

Glucose

MUSCLE CELL

Storage

P

Pyruvate

Kreb’s Oxidative ATPPhosphorylation

Cycle

I

I

Glucose

MUSCLE CELLS

P

Pyruvate

I

Kreb’s ATP

Glycogen

EPINEPHRINEGLUCAGON

OxidativePhosphorylation

Glucose

MUSCLE CELLS

P

Pyruvate

I

Kreb’s ATP

KETONES

FFA

PhosphorylationOxidative

P

Glycogen

Glucose

BRAIN

Pyruvate

KrebsOxidativePhosphorylation

ATP

KETONES

Glycogen

Glucose

LIVER CELL

Storage

I

P

Pyruvate

Kreb’s ATP

EPINEPHRINEGLUCAGON

Oxidative

CyclePhosphorylation