Benzodiazepines

David Preston Alexa Sardina Brett Feig Ryan Holevinski

Site and Structure of Action

Site of action is the GABAA receptor Structure of GABAA receptor Comprised of 5 subunits o 2 subunits (to which GABA binds) o 2 subunits (to which barbiturates bind) 1 subunit (to which benzodiazepines bind)

Benzodiazepine receptor of GABAA is heterogeneous

o 13 known subunits of the GABAA receptor Benzodiazepine-sensitive 1, 2, 3, 5 Benzodiazepine-insensitive 4 and 6

Properties of GABAA receptor

Myorelaxant, motor-impairing, and anxiolytic-like properties thought to be mediated by 2, 3, and/or 5 subunits2
Benzodiazepines acting on 2, 3, and/or 5 subunits (but NOT 1) have demonstrated nonsedative, nonamnesic anxiolytic properties2

Properties continued
Anticonvulsant activity and amnesic properties are thought to be mediated by 1

receptors2
Benzodiazepines and barbiturates bind more strongly when GABA is also bound to the receptor

Properties Continued
Benzodiazepines increase the affinity of the receptor for GABA, and thus increase Cl- conductance and hyperpolarizing current o Therefore, benzodiazepines are indirect agonists of the GABA receptor

Location(s) and mechanism of action on GABAA receptor:

Appear to act at the limbic, thalamic, and hypothalamic levels of the CNS Neuroanatomically, the amygdala, orbitofrontal cortex, and insula are associated with the production of behavioral responses to fearful stimuli and the central mediation of anxiety and panic PET scans demonstrate increased blood flow to the amygdala concomitant with anxiety responses Patients with panic disorders have shown a global decrease in benzodiazepine binding, largely in the orbitofrontal cortex and insula

Location and mechanism Continued

Increased activity of amygdala function along with concurrent lowered GABAergic inhibition of function produces anxiogenic responses The conclusion is that hypofunctional GABAA- receptor activity may sensitize the amygdala to anxiogenic responses It is thought that the benzodiazepines may reset the threshold of the amygdala to a more normal level of responsiveness

Local and Mechanism Cont.

VTA has been shown as a possible sit for anxiolytic actions of benzodiazepines o We know that dopamine neurons synapse with and are regulated by GABAA Cl- channels in the VTA o Flurazepam injections into the VTA have been shown to block anxious responses

Location and Therapeutic Index

Location of Action Amygdala Orbitofrontal Cortex Insula Cerebral Cortex Alleviate anxiety, agitation, and fear Therapeutic Effect

Hippocampus
Spinal Cord Cerebellum Brain Stem Ventral Tegmental Area Nucleus Accumbens

Mental confusion, amnesia, antiepileptic actions

Mild muscle-relaxing effects

Abuse potential, and psychological dependence

Absorbtion distribution, Metabolism and Excretion

Well absorbed when taken orally, with peak plasma concentrations achieved in approx. 1 hour Several benzos (diazepam, chlordiazepoxide, chlorazepate, halazepam, prazepam, chlorazepate) are first biotransformed to pharmacologically active intermediates These intermediates are then degraded and excreted Thus, long-lasting benzos are so b/c they are first degraded to active intermediates, and both the parent drug and the intermediate are longlasting/acting

Short Acting and the Elderly

o Short-lasting benzos are not converted to active intermediates; they are metabolized directly into inactive products The elderly have a reduced ability to metabolize long-acting benzos (and their active metabolites) Pharmacokinetics are not drastically altered with the short-acting benzos

Pharmacological effects
Those compounds that bind and enhance the inhibitory actions of GABA are complete agonists (Ex) Lorazepam, midazolam, etc. o Those compounds that bind with less than complete agonist action are termed partial agonists (Ex) Ambien (zolpidem) o Those compounds that bind and decrease the inhibitory actions of GABA are inverse agonists

Pharmacological effects cont.

Those compounds that bind and have no effect on GABA inhibition are antagonists o Prevent enhancement of GABA effects, but do NOT reduce the basal conductance of Clo Prevent gating of Cl- channels in spite of the presence of benzodiazepines o Flumazenil (a benzodiazepine) binds with high affinity to the GABAA complex, but illicits no response Rapidly metabolized in the liver, and therefore has a very short half-life

Receptor Ligands

Uses
Major indication is for use in treatment of severely debilitating anxiety (because of their anxiolytic properties) Effective as hypnotics, as they possess many of the same sedative qualities as barbiturates o Therefore useful in treatment of insomnia Effective muscle relaxants Generate anterograde amnesia o Lorazepam long-lasting amnesia Midazolam short-lasting amnesia

Uses Cont.
Useful for panic attacks and phobias Efficacy may be less than that achieved with SSRIs Treatment of alcohol withdrawal Effective anticonvulsant useful in treatment of epilepsy Advantages: Rapid onset Anxiolysis Low-level side effects Disadvantages: Impaired psychomotor performance and alertness

Potential for dependence and abuse

Benzodiazepine Therapy

Side Effects and Toxicity

At low doses symptoms can include sedation, drowsiness, ataxia, lethargy, mental confusion, motor and cognitive impairments, disorientation, slurred speech, amnesia, dementia, etc. At high doses mental and psychomotor dysfunction can progress to hypnosis (i.e., pass out) o Respiration is not seriously depressed, unless benzo is taken concurrently with another CNS depressant (i.e., alcohol) o Short-acting agents taken at bedtime can result in both earlymorning wakening and rebound insomnia the following night o Long-acting agents taken at bedtime can result in daytime sedation the following day Cognitive impacts are considerable: o Inhibition of learning behaviors, academic performance, and psychomotor functioning common These symptoms can persist long after treatment is discontinued
-

Tolerance and Dependence

Reputation for causing only a low incidence of abuse and dependence, however, when taken for prolonged periods of time, dependence can develop and result in withdrawal Withdrawal symptoms include: Return (and possible intensification) of anxiety state, increases in rebound insomnia, restlessness, agitation, irritability, etc.

Effects on Pregnancy
Benzodiazepines (and their metabolites) can freely cross the placental barrier and accumulate in fetal circulation o Administration during the first trimester can result in fetal abnormalities o Administration in third trimester (close to the time of birth) can result in fetal dependence, or floppy-infant syndrome Benzodiazepines are also excreted in the breast milk

Second-Generation Anxiolytics
Zolpidem (Ambien) General: Nonbenzodiazepine Structurally unrelated to benzos, but acts in much the same manner Binds to (subtype 1) GABAA1 receptors Useful for the short-term treatment of insomnia Primarily a sedative (rather than an anxiolytic)

Pharmacokinetics and Dynamics and Adverse Effects

Pharmacokinetics Rapidly absorbed in the GI tract following oral administration (75% reaches plasma) Only approx. 20% is metabolized in first-pass metabolism o Metabolized in the liver and excreted by the kidneys Peak plasma levels reached in approx. 1 hour Pharmacodynamics Produces sedation and promotes good sleep (w/o anxiolytic, anticonvulsant, or muscle-relaxant effects) Memory is affected Flumazenil reported to reverse memory impairments and overdoses o Flumazenil also reported to improve memory and learning, thus suggesting a possible role of endogenous benzos in memory function Adverse Effects Drowsiness, dizziness, and nausea at therapeutic doses o Severe nausea and vomiting greatly limit overdoses

Agonists of Benzo Receptors

Zaleplon & Zopiclone Nonbenzodiazepine agonist that acts at the GABAA1 receptors to exert actions similar to benzos Short half-life Only approx. 30% of an orally administered dose reaches the plasma, and most of that undergoes first-pass elimination o Half as potent as zolpidem
Improves sleep quality w/o rebound insomnia, and little chance of developing dependency

Partial Agonists
o
o o o o o o

Full GABA agonists (i.e., benzodiazepines) are effective anxiolytics use is limited though by their potential for rebound anxiety, physical dependence, abuse potential, and side effects (i.e., ataxia, sedation, memory impairment, etc.) Partial agonists provide effective anxiolytics without the limiting side effects Alpidem Partial agonist of GABA1 and GABA3 receptors More anxiolytic than full agonists, with less sedation and no interaction with EtOH May induce hepatitis though Etizolam Potent anxiolytic lower incidence of side effects at comparable efficacy