Benzodiazepines

1.       Pharmacology (refer Table 11)

2.       Five basic effects

a.       Anxiolytic

b.       Sedative/Hypnotic

c.       Anticonvulsant

d.       Muscle Relaxant

e.       Amnesic

3.       Mechanism of action (non-selective)

a.       Through enhancement of GABA activity

b.       GABA, a major inhibitory neurotransmitter in CNS binds to GABA-A receptor (refer Table 11), causes inhibitory effects throughout the brain on:

                                                              i.      cerebral cortex - drowsiness and cognitive impairment

                                                            ii.      mesolimbic dopamine system - dampened mood

                                                          iii.      hippocampus - memory impairment and anticonvulsant actions

                                                          iv.      cerebellum and other motor areas - impairment of balance, coordination, motor control and muscle tone

4.       Duration of action

a.       Rapidly redistributed into fatty tissue after absorption

b.       With repeated dosing, more accumulation within the fatty tissue occurs and a steady state of blood concentration can be reached in approximately five half-lives

c.       Usually half-life is significantly longer than the duration of clinical action (wears off after few hours)

d.       May continue to exert subtle effects

5.       Tolerance

a.       Steady state occurs in about 5 half-lives (few days to two weeks)

b.       Within days of reaching steady state, tolerance may start to appear

c.       Tolerance develops at different rates and to certain degrees:

                                                              i.      Tolerance to anticonvulsant effect for patients with epilepsy, and muscle relaxant effect for those with spasticity disorders à mostly within a few weeks

                                                            ii.      Tolerance to hypnotic effect à less clear

                                                          iii.      Tolerance to anxiolytic and amnesic effects àmay not occur at all

d.        Also differs between patients

6.       On side-effects (list is not exhaustive)

More common:

·       Drowsiness - affect ability to drive or use machinery

·       Confusion

·       Ataxia & risk of falls

·       Dysarthria

·       GI upset

·       Anterograde amnesia

Less common:

·       Paradoxical excitement

·       Disinhibition

·       Respiratory depression

On long-term use:

·       Abuse and dependence

·       Tolerance

·       Withdrawal

7.       High degree of cross-tolerance between BDZ and other sedative/hypnotic drugs and alcohol.

8.       The “Z’ drugs enhance GABA activity by binding at same locations as BDZ. However, these drugs are marketed for insomnia due to kinetic profile. Higher doses are required to produce other actions. Evidence shows that “Z” drugs may have same risks as BDZ.