Download 11/19/2014 Sedative‐Hypnotic and Anxiolytic Medications

11/19/2014
Sedative‐Hypnotic and Anxiolytic Medications
Indications
Anxiety
Panic disorders
Sleep disturbances
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Seizure disorders
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Alcohol withdrawal syndrome
Sedatives for medical procedures, blocking patient’s memory of event
Sedative‐Hypnotic and Anxiolytic Medications
Historical Use
Historical Use
Mid‐1800s
Chloral hydrate, bromide for sleep induction
Early 1900s
Introduction of barbituates (e.g. phenobarbital)
Early 1950s
Alternative sedatives introduced – meprobamate, carisoprodol
1960s
Benzodiazepines first marketed
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Benzodiazepines most commonly prescribed today for anxiety disorders
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Mechanism of Action of Benzodiazepines and Barbiturates
Positive allosteric modulators of GABA receptors
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Binding at sites adjacent to the GABA binding site results in a 3D conformational change in the
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receptor, increasing affinity of GABA for receptor. Gamma‐Aminobutyric Acid (GABA) – Major Inhibitory Neurotransmitter
Binds to GABAA (and sub‐subtypes) and GABAB receptors (ionotropic, fast‐acting)
GABA receptor are chloride ion (Cl‐) channels. When open, Cl‐ can diffuse into neurons with its
concentration gradient (against the electrical gradient) hyperpolarizing membranes,
reducing propensity for action potentials.
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Membrane Potential Across Neurons
Cells polarized:
Outside cell
Outside cell
higher [Na+] higher [Cl‐] Inside cell
higher [K+] higher [A‐]
(charged proteins)
Resting potential
‐70 mV
Ion gradient maintained by active transport (requires energy)
Depolarization of Neuron Can Lead to Action Potential if Threshold Reached
Resting potential
‐70
70 mV
mV
Hyperpolarization
Inside of cell becomes more negative
e.g. ‐70 mV to ‐80 mV
Cl‐ flows into cell – “inhibitory”
Depolarization
Inside of cell becomes more positive
e.g. ‐70 mV to ‐55 mV
Na+ flows into cell – “excitatory”
Neurotransmitter binding to receptor can cause ion channels to open, leading to depolarization or hyperpolarization.
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Actions of Benzodiazepines and Barbiturates
Anxiolytic properties
Activation of GABA neurons at limbic centers – amygdala, orbitofrontal cortex, insula
Sedation, cognitive impairment, amnesia, muscle relaxation, other side effects Activation of GABA neurons in other regions of CNS, including brain stem and cerebral cortex
Barbiturates, Benzodiazepines, Ethanol and Other Sedatives Can Cause Anterograde Amnesia
“Blackout” or “Brain syndrome” – Depressed nerve cell function leads to loss of memory for new events or actions while person is awake and performing such behavioral activities.
Sedative‐hypnotics and anxiolytics have been used as “date rape” drugs
• chloral hydrate
• gamma‐hydroxybutyric acid (GHB)
• flunitrazepam (Rohypnol®) 4
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Barbiturates – Limited Use in Medicine, Largely Replaced by Benzodiazepines Similar chemical structures, classified according to pharmacokinetics (long acting short acting)
pharmacokinetics (long‐acting, short‐acting)
Phenobarbital Treatment of seizures
Occasionally used in alcohol, benzodiazepine detoxification
(sedative, anticonvulsant)
Pentobarbital
Veterinary anesthetic and used in euthanasia in combination with phenytoin
Used in combination with other drugs for executions in US
High doses cause death by respiratory arrest
Barbiturates – Limited Use in Medicine, Largely Replaced by Benzodiazepines 1. Lethal in over‐dose
2. Narrow therapeutic indexes
3. High potential for tolerance, dependence, abuse
4. Drug‐drug interactions
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Non‐Barbiturate, Non‐Benzodiazepine Based Sedative‐Hypnotic
GHB
gamma‐hydroxybutyrate
GABA
gamma‐aminobutyric acid
Endogenous neurotransmitter
Precursor for endogenous synthesis of GHB
Marketed as sodium oxybate
Marketed
as sodium oxybate for narcolepsy
for narcolepsy
(Schedule III – other uses Schedule I)
GHB Precursors Converted In Vivo to Active Drug
Gamma‐butyrolactone (GBL) and 1,4‐butanediol accessed for illicit use
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Benzodiazepines
Widely prescribed – estimated 2.5% of adult population has a benzodiazepine Rx
Indicated only for short‐term use – up to one month, though often used long‐term
12 benzodiazepine derivatives marketed in US
Administration routes and pharmacokinetics differ
Benzodiazepines
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Benzodiazepine Pharmacokinetics
Most are orally bioavailable, with good absorption
Several generate active metabolites in vivo – Valium®, Librium® and thus have longer activities
Half‐lives range from 2 hours to 80 hours
Elderly patients metabolize more slowly – half‐lives may reach 7‐10 days for diazepam (Valium®)
Benzodiazepine Side Effects and Toxicities – Amplified at High Doses or in Combination with Other Depressants, e.g. Alcohol
• Sedation
• Drowsiness
• Mental confusion
• Motor impairment
• Cognitive impairment
• Amnesia
Flumazenil (Romazicon®) – benzodiazepine receptor antagonist for overdose
Limited use ‐ may precipitate seizures
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Benzodiazepine Tolerance and Withdrawal
Rebound and withdrawal symptoms
Tolerance
• Anxiety
Builds more rapidly to the sedative, hypnotic,
• Insomnia
anticonvulsant, and muscle relaxant effects.
• Agitation
• Muscle spasms
Anxiolytic effects can decrease within 4‐6
• Unpleasant dreams
months of use.
• Seizures can occur
Benzodiazepines Versus Alternate Medications
Benzodiazepines indicated for acute use
• Short‐term treatment of debilitating anxiety
Short term treatment of debilitating anxiety
• Medical procedures where anterograde amnesia benefits patient
Injectable lorazepam (Ativan®), midazolam (Versed®)
Antidepressants or atypical antispsychotics preferred for long‐term treatment of: • Insomnia
• Generalized anxiety disorder
• Phobia
• Panic disorder
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