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 α subunits (to which GABA binds)• o       2 β subunits (to which barbiturates

bind)

• 1 γ subunit (to which benzodiazepines bind)

 Benzodiazepine receptor of GABAA is heterogeneous

• o       13 known subunits of the GABAAγ

receptor

•       Benzodiazepine-sensitive        α1, α2, α3, α5

•       Benzodiazepine-insensitive        α4 and α6

Properties of GABAA receptor

• Myorelaxant, motor-impairing, and anxiolytic-like properties thought to be mediated by α2, α3, and/or α5 subunits2

• Benzodiazepines acting on α2, α3, and/or α5 subunits (but NOT α1) have demonstrated nonsedative, nonamnesic anxiolytic properties2

-        

Properties continued

     Anticonvulsant activity and amnesic properties are thought to be mediated by α1 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 GABA A 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 Therapeutic Effect

Amygdala

Alleviate anxiety, agitation, and fearOrbitofrontal Cortex

Insula

Cerebral Cortex

Mental confusion, amnesia, antiepileptic actionsHippocampus

Spinal Cord

Mild muscle-relaxing effectsCerebellum

Brain Stem

Ventral Tegmental Area

Abuse potential, and psychological dependenceNucleus Accumbens

Absorbtion distribution, Metabolism and Excretion

• Well absorbed when taken orally, with peak plasma concentrations achieved in approx. 1 hour

• Several benzo’s (diazepam, chlordiazepoxide, chlorazepate, halazepam, prazepam, chlorazepate) are first biotransformed to pharmacologically active intermediates

• These intermediates are then degraded and excreted • -         Thus, long-lasting benzo’s are so b/c they are

first degraded to active intermediates, and both the parent drug and the intermediate are long-lasting/acting

Short Acting and the Elderly

• o       Short-lasting benzo’s are not converted to active intermediates; they are metabolized directly into inactive products

• -         The elderly have a reduced ability to metabolize long-acting benzo’s (and their active metabolites)

• Pharmacokinetics are not drastically altered with the short-acting benzo’s

Pharmacological effects

• -         Those compounds that bind and enhance the inhibitory actions of GABA are complete agonists

• o       (Ex) Lorazepam, midazolam, etc.• -         Those compounds that bind with “less than

complete agonist action” are termed partial agonists

• o       (Ex) Ambien (zolpidem)• -         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 Cl-

• o       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 SSRI’s         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 early-morning 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 benzo’s, 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 Dynamicsand 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 kidney’s         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 benzo’s 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 benzo’s

        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

• Full GABA agonists (i.e., benzodiazepines) are effective anxiolyticso 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 effectso Alpidemo Partial agonist of GABA1 and GABA3 receptorso More anxiolytic than full agonists, with less sedation and no interaction with

EtOHo May induce hepatitis thougho Etizolamo Potent anxiolytic• “lower incidence of side effects at comparable efficacy”