Benzodiazepines

1. Benzodiazepines David Preston Alexa Sardina Brett Feig Ryan Holevinski

2. 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)

3.  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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. Location of Action Therapeutic Effect Amygdala Alleviate anxiety, agitation, and fear Orbitofrontal Cortex Insula Cerebral Cortex Mental confusion, amnesia, antiepileptic actions Hippocampus Spinal Cord Mild muscle-relaxing effects Cerebellum Brain Stem Ventral Tegmental Area Abuse potential, and psychological dependence Nucleus Accumbens Location and Therapeutic Index

11. 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

12. 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

13. 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

14. 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

15. Receptor Ligands

16. 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

17. 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

18. Benzodiazepine Therapy

19. 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

20. 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. 

21. 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

22. 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)

23. 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

24. 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

25. Partial Agonists • 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”