Pharmacology: Benzodiazepines

Benzodiazepines

• Classified as “sedative-hypnotics” or “minor tranquilizers”

• Midazolam, diazepam, zolazepam (1/2 of telazol)

• Alprazolam, clonazepam — will cover with behavior drugs

Common clinical uses of Benzodiazepines

• Sedation

• Injectable anticonvulsant

• Anesthesia adjunct

• Muscle relaxation

• Anti-anxiety

• Appetite stimulant

What is the mechanism of action for Benzodiazepines?

• GABA receptor agonist

• Secreted by neurons in brain and spinal cord

• facilitate GABA binding to the GABA receptor

• No analgesia

GABA

• gamma-aminobutyric acid

• Major INHIBITOR neurotransmitter

• results in sedation/sleep

What are the goal effects of Benzodiazepines?

• Sedation + muscle relaxation (will never produce general anesthesia)

• Anxiolysis

• Amnesia

• Reversibly

How does the reliability of sedation for Benzodiazepines differ with species, dosage, clinical state, age?

• Best effects in “very, young, very old, very sick” animals

• Sedation in pigs and rabbits > dogs

• Pharmacokinetics

What are the side effects of Benzodiazepines?

• Minimal effects to CV function

• Minimal effect to ventilation

• Can see paradoxical excitation in young, healthy dogs/cats/horses (decreases inhibitions)

• Can see loss of learned behaviors (following commands)

Metabolism of Benzodiazepines

• Rapid metabolism (<1 hr) in most species, expect horses (> 4 hrs)

• Under liver metabolism (prolonged effects in patients with decreased liver function)

Diazepam (Valium)

• Highly lipid soluble drug (caution with soft plastics PVC - adsorption)

• Vehicle = propylene glycol (pain, erratic absorption, hemolysis)

• Hepatic metabolism with active metabolites (liver disease can decrease metabolism)

What is the route of administration of Diazepam (Valium)?

• IV, PO, rectal

• IM — erratic absorption (due to propylene glycol)

• DON’T administer to cats orally

What happens if you give a cat Diazepam ORALLY?

Idiosyncratic hepatotoxicity

What has largely replaced diazepam in the US (for injection)?

Midazolam

Medazolam (Versed)

• Water-soluble — imidazole ring (pH change after administration alters imidazole ring to make the molecule lipid soluble)

How is Midazolam administered?

• Water soluble at administration makes for better absorption from extravascular sites and makes transport to CNS faster

• IM/SQ/intranasal

What are the effects of Midazolam?

• Clinical effects comparable to diazepam

• Minimal CV and/or respiratory side effects

• Liver metabolism

• Short duration of action (except in horses)

• No propylene glycol so less pain on injection/no hemolysis

Flumazenil

Competitive antagonist specific for benzodiazepine site on GABA receptor

How is Flumazenil administered?

• typically administered IV

• IM, transmucosal work but less reliable

• Not used orally (1st pass effect decreases effectiveness)

What is Flumazenil clinically used for?

• Used clinically to reverse

• Sedation/prolonged recovery for anesthesia

• Excessive muscle weakness

What is the mechanism of action of Guaifenesin (GG)?

• central skeletal muscle relaxant (vs peripheral muscle effects)

• No analgesic effects

• Muscle weakness vs. sedation

What are the clinical used of Guaifenesin (GG)?

• Part of induction and maintenace of anesthesia in horses and ruminants

• “Triple drip” for field anesthesia (Guaifenesin, xylazine, and ketamine)

What are the storage conditions for Guaifenesin (GG)?

• will crystalize in cool temperatures so keep warm

• Not very convenient for ambulatory veterinarians / expensive

What are the adverse effects of Guaifenesin?

• Caution in awake horses/weakness

• Does not deepen anesthetic plane (not anesthetic)

• Avoid highly concentrated formulations (use ~5% solutions)

• Accidental overdose in horses = ataxia, poor recovery