BENZODIAZEPINES and BUSPIRONE – Flashcards
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Alprazolam (Xanax)
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MOA: GABA-A receptor allosteric agonist t 1/2= 6-12 TU: anxiety, panic attacks
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Diazepam (Valium)
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MOA: GABA-A receptor allosteric agonist t 1/2= 20-100 hrs [36-200 metabolites] TU: anxiety, panic attacks, preanesthetic medication, skeletal muscle relaxant, status epilepticus
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Flurazepam (Dalmane)
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MOA: GABA-A receptor allosteric agonist t1/2= [40-250 metabolites] TU: insomnia (long duration)
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Lorazepam (Ativan, Alzapam)
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MOA: GABA-A receptor allosteric agonist t1/2= 10-20 hrs TU: anxiety, sedative hypnotic, treat withdrawal from alcohol and sedative hypnotics
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Midazolam (Versed)
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MOA: GABA-A receptor allosteric agonist t1/2= 2 hrs TU: preanesthetic med
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Temazepam (Restoril)
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MOA: GABA-A receptor allosteric agonist t1/2= 8-22 hrs TU: insomnia (medium duration)
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Triazolam (Halcion)
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MOA: GABA-A receptor allosteric agonist t1/2=2 hrs. TU- insomnia- short duration
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Flumazenil (Romazicon)
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MOA: Benzodiazepine Receptor Antagonist. binds to the benzo site on the GABA receptor (preventing benzo from binding) TU: reverse the sedative effect of benzodiazepine overdose PK: given IV
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Buspirone (BuSpar)
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TU: really good for generalized anxiety (not effective for other types) MOA: not totally clear: partial agonist at 5-HT1A (serotonin) receptor Advantages over benzos: little sedative or euphoric effects, no rebound anxiety or withdrawal signs on abrupt discontinuation, does not potentiate effects of CNS depressants, Little abuse potential, Pregnancy Cat B Disadvantages: Antianxiety effect takes 1-2 weks to work SE: only seen in 5% (dizziness, lightheaded, tachycardia, palpitations, nervous, restless, GI, paresthesias)
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What is sedation?
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decreased responsiveness to external stimuli but not asleep. anti-anxiety effect. Calm the patient
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what is Hyponosis
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sleep-like state from which the patient can be easily awakened (NOT being hypnotized)
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what is Unconsciousness?
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unresponsive to external stimuli (can't wake you up) but responsive to pain with muscle movement
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What is anesthesia?
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A state of unconsciousness in which patient is amnestic and unresponsive to pain or external stimuli
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What is the progression from sedation to death from CNS depressants?
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sedation-->sleep (hypnosis)--> unconscious (can't wake you up) ---> anesthesia (don't respond to pain)--> death
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will benzodiazepines produce a true anesthetic state or death?
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no, benzodiazepines by themselves will not depress the respiratory center enough to lead to true anesthesia or death if given orally.
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what is GABA?
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gamma-aminobutyric acid= a major inhibitory neurotransmitter in the CNS. Acts at both Presynaptic and post synaptic receptors
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what is the GABA-A receptor
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ligand gated Cl- ion channel. site of action of benzodiazepines, barbiturates, alcohol, and general anesthetics. regulates chloride flux, hyperpolarizing cells, decreasing excitatory neurotransmitter release. Net result is neuronal inhibitions.
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what is the structure of the GABA-A receptor?
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5 subunits most receptors contain alpha, beta, gamma sununits
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where is the benzodiazepine binding site?
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allosteric site (intersection of the alpha and gamma subunits)
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which of the 6 possible alpha subunits do benzodiazepines bind to?
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alpha 1, 2,3, and 5 (no effect on alpha 4 and 6)
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what are the different effects of the alpha 1, 2, 3, and 5 subunits of the GABA-A receptor?
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alpha1 subunit- sedative and amnestic effects alpha 2,3 sunuits- anxiolytic properties (cortex, amygdala) alpha 5 subunit-memory and learning (hippocampus) alpha4 and 6 have no benzodiazepine effects
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What is the MOA of benzodiazepines?
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bind GABA-A receptors at an allosteric site , increasing the affinity of GABA-A receptor for GABA. This increases the neuronal hyperpolarization more than the normal amount of GABA alone (increased GABA potency)
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What principle governs the onset of action of CNS drugs?
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the more lipid soluble the drug the faster the onset of action, but the shorter its duration of action
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what is the primary factor limiting the duration of action of a lipid soluble CNS drug?
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-redistribution. muscle and fat larger volume than brain and it takes longer for them to reach equilibrium with drug conc in blood. They act as a reservoir for the drug
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Which benzodiazepine used for anxiety has the shortest half life?
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alprazolam (6-12 hrs)
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which benzodiazepine for anxiety has the longest half life?
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Diazepam (Valium) (20-100 hrs) [metabolites 36-200 hrs]
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which benzodiazepinenes are used for insomnia?
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Flurazepam, Temazepam, Triazolam
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Which benzodiazepines are used for anxiety?
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Alprazolam, Diazepam, Lorazepam
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which benzodiazepines are primary ones used as preanesthetic medication?
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Midazolam (Versed), Diazepam
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which benzodiazepine is used as a skeletal muscle relaxant and for status epilepticus?
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Diazepam- to decrease spasticity and muscle spasm (GABA-A in spinal cord)
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what is the difference between duration of the benzodiazepines for insomnia? (FLurazepam, Temazepam, Triazolam)
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short duration- Triazolam medium duration- Temazepam long duration- flurazepam
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what types of anxiety can be treated by the benzodiazepines?
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Generalized anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, post traumatic stress disorder
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which benzodiazepine is used to treat alcohol and sedative-hypnotic withdrawal?
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Lorazepam Diazepam
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can benzodiazepines be used interchangably?
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yes, the approved uses are based primarily on marketing and half-life of the drug but they can be used interchangeably
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what are some of the CNS effects of benzodiazepines?
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a. decrease anxiety b. sedation and hypnosis c. anticonvulsant activity d. muscle relaxation e. anterograde amnesia f. interfere with learning and memory g. additive or greater than additive CNS depressive effects with other CNS depressants like alcohol
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how do benzos affect respiration?
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a. no effect on respiration in normal ppl b. may suppress respiration in patients with sleep apnea or chronic lung disease
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benzo effect on heart?
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-effect generally minor
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what is phase 1 metabolism? what is phase 2 metabolism?
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phase 1= cytochrome p450 enzymes phase II= conjugation reactions
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which long acting benzos undergo both phase 1 and phase II metabolism?
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Diazepam Flurazepam
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which short acting benzos use both phase 1 and II reactions for metabolic elimination?
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Alprazolam Midazolam Triazolam
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Which short acting benzos only use phase II metabolism?
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Lorazepam Temazepam
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what other drugs/compounds may interfere with the metabolism of benzos (by CYP inhibition?)
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Cimetidine Oral contraceptives Isoniazid Grapefruit juice
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which phase reactions are less affected by old age or liver disease?
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phase II glucuronide conjugation reactions are less affected by old age or liver disease than oxidative phase 1 CYP metabolism. so phase II drugs safer in elderly and liver disease
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adverse effects of benzodiazepines?
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most common SE: drowsiness, sedation, impaired motor coordination, weakness, dizziness, confusion, memory loss Tolerance often develops to these effects, though.
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less common side effects of benzos?
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less common SE: blurred vision, hallucinations, paradoxial rage reactions consisting of excitement, stimulation, and hyperactivity
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Toxicity of benzodiazepines?
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drowsiness, ataxia (orally do not produce fatal toxicity) but may have additive effect with other depressants
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Can you use benzos during pregnancy?
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NO- Category X for hypnotics and Cat D for anxiolytics
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for which uses of benzodiazopenes does tolerance develop?
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tolerance to the anti-convulsant and hypnotic effects so don't generally prescribe long term for epilepsy and sleep disorders
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for which use are benzodiazopenes good drugs long term?
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anti-anxiety effects -tolerance does not develop
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can patients develop dependence on benzos?
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yes- psychological dependence is more common than physical dependence but discontinuation of long term use can result in symptom recurrence, rebound, or withdrawal reactions -long acting drugs can be used to prevent the withdrawal symptoms of shorter-acting depressant drugs such as alcohol
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Withdrawal symptoms of benzodiazepines
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may result in increased seizures. other S/S: anxiety, autonomic signs, flu-like , sensory disturbances. intensity of withdrawal less severe with long acting drugs
