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ADA/PDR: Medications for the Treatment of Diabetes, Ch. 18, Pt. 2

Diabetic Neuropathic Disorders, Part 2

ADA/PDR_Medications_for_the_Treatment_of_Diabetes

John R. White, Jr., PharmD, PA
R. Keith Campbell, PharmB, MBA, CDE
Travis E. Sonnett, PharmD

Adaptation by Matthew Szabo, PharmD (candidate)

Diabetic Gastroparesis Treatment Options

This week we continue our exploration of diabetic neuropathic disorders with analyses of two drugs used to treat diabetic gastroparesis….

Metoclopramide

  • First approved for use in 1979 and is FDA approved for treatment of diabetic gastroparesis
Pharmacology
  • Acts on many neurotransmitters: is a 5HT4 agonist, a 5HT3 antagonist, a central and peripheral dopamine D2 antagonist, as well as a cholinesterase inhibitor
  • 5HT4 receptor agonism and peripheral dopamine D2 receptor antagonism causes a decrease in fundal relaxation and increased antral contractions, resulting in improved gastric emptying
  • Acts as an anti-emetic via antagonism of central D2 receptors in the area postrema and antagonism of 5HT3 receptors
Kinetics
  • Available in oral (onset of action 10-15 mins) and parenteral (onset 10-15 mins for IM, 1-3 mins for IV) forms
  • 30% protein bound
  • Crosses the blood brain barrier
  • Half life is 2.5-6 hours, allowing for dosing multiple times a day with meals
  • Metabolism occurs via conjugation, and is excreted mainly via the urine (85%)

Clinical Advantages

  • Acts as both an antiemetic and prokinetic agent
  • QT prolongation is a nonissue when compared to other agents

Therapeutic Considerations

  • Due to its multiple dosage forms, it is available in all patient settings
  • After one month of therapy, it was not shown to improve gastric emptying of liquids, whereas erythromycin was shown to maintain improvement of liquids and solids
  • Side effects target mainly the central nervous system, and include: dizziness, drowsiness, motor and coordination impairment, and extrapyramidal symptoms
  • Due to effects on dopamine, it may also cause neuroendocrine effects such as lactation, gynecomastia, and impotence
  • Its effects on gastric emptying may increase or decrease the absorption of simultaneously administered medications (such as lithium and digoxin), and thus plasma levels should be monitored initially for drugs with a narrow therapeutic window
  • Use in Parkinson’s disease may lead to symptom exacerbation and/or complications due to effects on dopamine antagonism
  • Due to its renal clearance, dose adjustment may be necessary in renally impaired patients, as accumulation and toxicity may occur
  • Classified pregnancy category B and crosses into breast milk; caution is suggested in breastfeeding
Erythromycin
  • Introduced as a macrolide anti-infective agent in 1952, clinical trials later demonstrated its use for treating diabetic gastroparesis, gastritis, and bowel preparation for colonoscopy
  • Not FDA approved for gastroparesis, but it is frequently used off-label
Pharmacology
  • Mechanism of action is via motilin receptors in the gastric antrum and proximal duodenum, mimicking the effect of the polypeptide motilin, which causes an increase in both motility and improves gastric emptying of both liquids and solids
Kinetics
  • Available in both oral and parenteral forms (oral bioavailability is very low)
  • Peak concentrations of the oral form is reached in 1-4 hours, and can be influenced by food, gastric emptying rate, and the salt form administered
  • Metabolism occurs primarily in the liver, and excretion is via the feces
  • Hepatic impairment may result in increased plasma concentrations and half-life

Clinical Advantages

  • The most potent agent available for the treatment of diabetic gastroparesis when given intravenously
  • The oral suspension has been shown to be more effective than the tablets in studies
  • Absorption and efficacy are impaired by the presence of hyperglycemia, and thus control of blood glucose is essential to obtain therapeutic effectiveness

Therapeutic Considerations

  • Can be used successfully for long term therapy,
  • Long-term exposure to antibiotic therapy is a concern, and needs to be monitored especially in the presence of infection
  • Common side effects include: nausea, vomiting, diarrhea, abdominal pain, headache, rash, and QT interval prolongation
  • Inhibits CYP450 3A4, and thus interactions with drugs metabolized by this enzyme should be monitored
  • Recommend avoidance of grapefruit juice due to increase in serum concentrations
  • Caution in simultaneous use with antiarrhythmic medications as it increases risk of cardiovascular complications
  • Classified pregnancy category B, and is considered safe for use in breastfeeding patients
Next Week: Diabetic Neuropathic Disorders — Erectile Dysfunction (ED)
 
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