Benzodiazepines.

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Benzodiazepines.

• Florida International University
• Nurse Anesthetist Program
• Pharmacology of Anesthesiology Nursing I
• Linda Wunder MSN,CRNA

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OBJECTIVES

• Discuss the principal pharmacologic effects of
  benzodiazepines.
• Explain mechanism of action associated with
  benzodiazepines and their interaction with the
  CNS.
• Compare the unique chemical structure of
  midazolam and how it differs at various pH
  levels.
• Discuss the pharmacokinetic properties specific
  to benzodiazepines.
• Explain the effects on organ systems of
  benzodiazepines.
• State the clinical indications of midazolam and
  diazepam.
• Discuss the action and dosing regime of
  flumazenil.

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CLINICAL CONSIDERATIONS

• Benzodiazepines exert five principal
  pharmacologic effects
• Sedation
• Anxiolysis
• Anticonvulsant actions
• Spinal cord-mediated skeletal muscle relaxation
• Anterograde amnesia
• Benzodiazepines have replaced barbiturates for
  preoperative medication and production of
  sedation during monitored anesthesia care

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MECHANISM OF ACTION

• Benzodiazepines interact with specific receptors
  in the central nervous system
• Benzodiazepine-receptor binding enhances the
  inhibitory effects of various neurotransmitters
• Facilitates GABA receptor binding which increases
  the membrane conductance of chloride ions
• Causes a change in membrane polarization that
  inhibits normal neuronal function
• Receptor occupancy
• Receptor subtypes

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STRUCTURE-ACTIVITY RELATIONSHIPS

• Benzodiazepines are similar structurally and
  share many active metabolites
• Benzodiazepine refers to the portion of the
  chemical structured composed of a benzene ring
  fused to a seven-membered diazepine ring
• Substitutions at various positions on these rings
  affect potency and biotransformation
• Benzodiazepines differ markedly in speed that
  they are metabolized and eliminated

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CHEMICAL STRUCTUREDIAZEPAM LORAZEPAM
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CHEMICAL STRUCTUREMIDAZOLAM
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PHARMACOKINETICS

• Absorption
• Commonly administered orally, intramuscularly,
  and intravenously
• Diazepam and lorazepam are well absorbed from the
  GI tract, peak plasma levels usually achieved in
  1 and 2 hours
• IM injection of diazepam is painful and
  unreliable
• Oral midazolam popular for pediatric
  premedication
• Intranasal (0.2-0.3 mg/Kg)
• Buccal (0.07 mg/Kg)
• Sublingual (0.1 mg/Kg)
• Premedication IM (0.07-0.15 mg/Kg)
• Sedation IV (0.01-0.1 mg/Kg)

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PHARMACOKINETICS

• Distribution
• Diazepam quite lipid-soluble and rapidly
  penetrates the blood brain barrier
• Midazolam water-soluble at low pH and at
  physiologic pH increase in its lipid solubility
• Moderate lipid solubility of lorazepam
• Redistribution fairly rapid for the
  benzodiazepines
• Benzodiazepines highly protein-bound

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BIOTRANSFORMATION AND EXCRETION

• Rely on the liver for biotransformation into
  water-soluble glucuronide end products
• Phase I metabolites of diazepam are
  pharmacologically active
• Elimination half-life time necessary to
  eliminate 50 of a drug from the body after its
  rapid IV injection
• Long elimination half-life for diazepam
• Lorazepam shorter elimination half-life
• Midazolam shortest elimination half-life
• Metabolites of benzodiazepine biotransformation
  are excreted chiefly in the urine

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EFFECTS ON ORGAN SYSTEMS

• Cardiovascular
• Minimal cardiovascular depressant effects
• Arterial blood pressure, cardiac output, and
  peripheral vascular resistance usually decline
  slightly and heart rate sometimes rises
• Midazolam tends to reduce blood pressure and
  peripheral vascular resistance more than diazepam

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EFFECTS ON ORGAN SYSTEMS

• Respiratory
• Benzodiazepines depress the ventilatory response
  to CO2
• Ventilation must be monitored in all patients
  receiving IV medications
• Cerebral
• Reduce CMRO2, cerebral blood flow, and
  intracranial pressure
• Effective in preventing and controlling grand mal
  seizures
• Provides antianxiety, amnesic, and sedative
  effects
• Possesses mild muscle-relaxant properties
• No direct analgesic properties

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DRUG INTERACTIONS

• Cimetadine binds to cytochrome P-450 and reduces
  the metabolism of diazepam
• Erythromycin inhibits midazolam metabolism and
  causes prolongation and intensification of its
  effects
• Heparin displaces diazepam from protein-binding
  sites and increases free drug concentration
• Combination of opioids and diazepam markedly
  reduces arterial blood pressure and peripheral
  vascular resistance
• MAC of volatile anesthetics reduced as much as
  30
• Ethanol, barbiturates, and other CNS depressants
  potentiate sedative effects

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MIDAZOLAM CLINICAL USES

• Most commonly used benzodiazepine for
  preoperative medication and IV sedation
• Provides amnesia
• Potent anticonvulsant for the treatment of grand
  mal seizures
• Administration
• PO 0.5 mg/Kg
• IV 0.01-0.1 mg/Kg
• IM 0.05-0.10 mg/Kg
• Doses of 1.0-2.5 mg IV effective for sedation
  during regional anesthesia and brief therapeutic
  procedures
• Administered as a supplement for maintenance of
  anesthesia

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DIAZEPAM CLINICAL USES

• Diazepam dissolved in organic solvents and is
  associated with pain on injection and
  thrombophlebitis
• Popular drug for preoperative medication of
  adults, management of delirium tremens, and
  treatment of local anesthetic-induced seizures
• Produces anterograde amnesia
• Skeletal muscle relaxant
• Preoperative PO 10-15 mg
• Extensively bound to plasma protein

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FLUMAZENIL

• An imidazobenzodiazepine, specific and
  competitive antagonist of benzodiazepines at
  benzodiazepine receptors
• Useful in the reversal of sedation and overdose
• Prompt onset (lt 1 minute)
• Slow titration of 0.2 mg doses IV (up to 1 mg)