MODE OF BENZODIAZEPINE ACTION: Benzodiazepines allosterically modulate GABA transmission by potentiating the effects of GABA This occurs by binding to a special BZ site on the GABA-A receptor Hence increasing the ability of endogenous GABA to open chloride channels, "locking" neuronal resting potential Note that BZs can only POTENTIATE the effect of endogenous GABA release Presumably the BZ receptor exists to recognize an endogenous ligand, but none has as yet been discovered Pharmacokinetics: Prolonged half-lives are common, in part because most of the metabolic by-products are also active This accounts for the BZ "hangover" DRUG HALF-LIFE (hrs) Alprazolam (Xanax) 12-15 Chlordiazepoxide(Librium) 5-30 Clonazepam (Klonopin) 18-50 Clorazepate(Tranxene) 30-100 Diazepam(Valium) 20-80 Flurazepam(Dalmane) 2-4 Lorazepam(Ativan) 10-20 Prazepam(Centrax) 30-100 Triazolam(Halcion) 1.5-5.5 Drug Interactions: Benzodiazepines alone have a high therapeutic index Not surprisingly, interact badly with alcohol FUNCTIONAL EFFECTS: BZs are: Anxiolytics: High anxiety is reduced, in humans and in animal models Sedatives/hypnotics: BZs are one of the most common hypnotics, but recall interaction with alcohol! Also recall that Bzs, like alcohol, suppress REM sleep Typically shorter-acting BZs (Dalmane, Xanax, Halcion) are prescribed for insomnia Like so many other compounds, initial BZ exposure is accompanied by sedation, drowsiness, etc, effects which tolerate out in a week to 10 days Muscle relaxants: Work at spinal reflex level Anticonvulsants Amnestics: An approximate 2/3rds reduction in recall of material presented during drug effect Abused! Barbiturates and BZs at high doses clearly cause euphoria Other side effects: Performance deficits: complex motor tasks, including driving, are performed poorly Aggression and violence With time on drug, many patients develop strong dislikes or "hates" May be partly due to anxiolytic effect revealing repressed feelings In rare instances, these can result in aggression REM depression Benzodiazepine Withdrawal: A "rebound" phenomena, involving many of the symptoms inhibited by BZs Not altogether unlike the DTs Due to GABA-A receptor down-regulation Onset is SLOW, may be no effects for first 3 days, then maximal effects after more than a week These effects can fluctuate, and can last for many months Withdrawal symptoms include: Anxiety Vivid dreams, insomnia Convulsions or motor tremor Delirium Weight loss Depression BUSPIRONE: A "NOVEL" ANXIOLYTIC Chemically related to the butyrophenone neuroleptics Agonist at the 5-HT1A site: hence BLOCKS firing of serotonin neurons But may also be active at the D2 and alpha sites Yet also may have antidepressant effects! Lacks the side-effects, abuse potential and withdrawal associated with the benzodiazepines AND like all good neuroleptics and antidepressants, takes weeks for therapeutic efficacy to develop! TREATMENT OF THE ANXIETY DISORDERS: USE OF BENZODIAZEPINES Anxieties of all sorts respond quickly to BZs Hence are the treatment of choice for rapid, acute control of all forms of anxiety BUT anxieties are often life-long disorders, causing real problems with side-effects and withdrawal TREATMENT OF PANIC DISORDERS: SSRIs, Tricyclics and MAOIs are all efficacious in treatment of panic disorders BUT with the usual delayed onset of effect Bupropion is not effective Buspirone is not effective TREATMENT OF GENERAL ANXIETY DISORDER Buspirone is the drug of choice Although benzodiazepines are still prescribed more frequently than buspirone for this disorder SUMMARY: Once again, drugs acting on the serotonin system are most efficacious in the treatment of the anxiety disorders Due in large part to the crippling side-effects of the benzodiazepines Despite the fact that the GABA and NOREPI systems seem more closely linked to fear states! BENZODIAZEPINES: TO PRESCRIBE OR NOT TO PRESCRIBE, THAT IS THE QUESTION! PHARMACOLOGY TYPES ACCUSE MEDIA OF "BENZO BASHING" Point out that BZ is great for treating GAD, and we don't (much anymore) withhold opiates for chronic pain just because of minor problems with addiction and withdrawal! Also point out that: In drug-naive animals and humans, BZs are NOT euphoric, hence extremely low abuse potential Dependency/withdrawal rare without chronic exposure (> 1 yr) to high doses This is the position taken by the text - "The original Pollyana attitude that the drugs can do no harm is no more accurate than irrational fears overstating benzodiazepines as dangerous drugs that do more harm than good" YET THEY ARE ABUSED! Two TYPES of abuse, recreational and iatrogenic Recreational - in 1988, 4.8% of US population reported EVER using tranqs recreationally, with a one-year prevalence of 2.2% and 1-month prevalence of 0.6% (1.3 million users/month) Recreational use is most common among hard- core drug users: + Heroin/methadone users inject BZ, get a heroin-like rush, use to increase effects of methadone + Speed freaks/crack addicts use to come down off a run DOSAGE is extremely high in such cases Iatrogenic dependence - users fear loss of "tranquility"