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A. Gama-Aminobutyric Acid (GABA) [1]navigator

  1. Glutamate from Krebs Cycle is converted to GABA by glutamate decarboxylase (GAD)
  2. GABA is released at the axonal synapses and can be transported back into the cell
    1. Four types of carrier proteins for GABA reuptake are known
    2. These carriers are found on neurons as well as glial cells
    3. These carriers are labelled GAT-1 through GAT-4
  3. GABA transaminase converts GABA to succinate, which re-enters the Krebs Cycle
  4. GABA binds to specific receptors on the post-synaptic neuron
    1. The GABA-A receptors are chloride channels (reduce cAMP)
    2. GABA-A-R consist of 5 polypeptide chains: 1 alpha, 2 beta, 1 gamma and 1 delta
    3. GABA-B-R is a G-coupled protein receptor, increases Ca2+ and K+ conductance
    4. GABA-C-R is a ligand gated ion channel as well
  5. Isoforms
    1. Six different alpha subunits identified
    2. Three different beta subnits identified
  6. Multiple subtypes of GABA-A-R exist in the brain

B. Functions of GABA [14]navigator

  1. Major inhibitory neurotransmitter in brain
  2. Nearly 70% of mammallian brain neurons are believed to be GABAergic
  3. Maintains "normal" brain activity, involved in vision, motor neurons, others
  4. Low brain concentrations of GABA associated with resistance to anti-seizure drugs [2]
  5. Generalized anxiety, phobia, fear, and associated disorders [12]
  6. Detected on skeletal muscle

C. Utility of GABA Agonistsnavigator

  1. Seizure therapy
  2. Muscle relaxation
  3. Pain - chronic pain may be treated with some of these agents
  4. Sleep induction
  5. Stiff man syndrome [8]

D. GABA Potentiating Drugs [3]navigator

  1. Barbiturates
    1. Bind ß-subunit of GABA-A-R
    2. Syndergistic with alcohol
  2. Sedative Hypnotics (see below)
    1. Benzodiazepines
    2. Other Hypnotic Agents
    3. All bind alpha subnit of GABA-A-R
  3. Alcohol
  4. Antiepileptic Agents
  5. Baclofen
    1. GABA-B receptor agonist
    2. Used as a muscle relaxant usually for acute or chronic back pain
    3. Also good for centrally mediated muscle spasms
    4. Suppresses alcohol withdrawal symptoms including in cirrhotic patients [19,20]
    5. Maintains alcohol abstinence in alcoholics with cirrhosis [20]
    6. Intrathecal dosing inhibits sensory input neurons of spinal cord
    7. Dosing: initial 5mg po tid x 3 days, up to 40-80mg/d (20mg qid)
    8. Dosing for alcohol abstinence is 5mg po tid x 3 days, then 10mg po tid [20]
  6. Gabapentin (Neurontin®) [4]
    1. GABA analog but unclear mechanism of action
    2. Does not bind any known GABA recpetor, or affect specific GABA metabolism in any way
    3. Appears to affect transport of amino acids (such as glutamate) in the CNS
    4. Also Inhibits sodium channels in CNS
    5. Very safe; non-protein bound, excreted in urine
    6. Seizure control (add on) and neuropathic pain efficacy
    7. Also reduces postmenopausal and chemotherapy induced hot-flashes [25,26]
  7. Pregabalin (Lyrica®) [27]
    1. Structural analog of GABA and gabapentin
    2. Approved for postherpetic neuralgia and diabetic peripheral neuropathic pain
    3. Also approved for epilepsy and fibromyalgia
    4. Initial dose is 150mg per day divided 2-3 times (bid or tid)
    5. May increase to maximum of 300mg per day for neuropathic pain, 600mg/d for epilepsy
    6. Adverse effects are dose related: dizziness, somnolence, blurred vision
    7. Associated with euphoria and Schedule V controlled substance by FDA

E. Benzodiazepines [3] navigator

  1. Bind alpha subunit of GABA-A-R
  2. Synergistic with alcohol
  3. Utility
    1. Generally reserved for short-term chronic use or for acute use
    2. Rapid acting (midazolam) useful for anesthesia and pre-procedure anxiety
    3. Short term combination with antidepressants very effective for depression [13]
    4. Moderate half-life agents are good anxiolytics for prn use or <2 weeks
    5. Useful for panic disorder or agorophobia, initially in combination with other agents
    6. Chlordiazepoxide or oxazepam are often used for alcohol withdrawal
    7. Standard benzodiazepines should no longer be used for sleep disorders
    8. Daily or maximally bid doses are used for elderly and patients with hepatic impairment
  4. Specific Benzodiazepines
    1. Midazolam (Versed®): only for rapid anesthesia, caution with hypotension
    2. Lorazepam (Ativan®): 0.5-2mg q6-12 hours prn
    3. Oxazepam (Serax®): 15-30mg po q6-8 hours prn
    4. Alprazolam (Xanax®): 0.25-0.50 mg po tid to max 4mg daily divided
    5. Clonazepam (Klonopin®): 0.25mg bid slowly titrate up; max 4mg daily divided
    6. Diazepam (Valium®): 2-10mg po tid-qid
    7. Chlordiazepoxide (Librium®): 25-50mg q6-8 hours prn
    8. Flurazepam (Dalmane®): 15-30mg po qhs
    9. Triazolam (Halcion®): 0.25mg qhs; max 0.5mg po qhs
    10. Temazepam (Restoril®): 7.5mg qhs initially; max 30mg po qhs
    11. Estazolam (Prosom®): 1mg qhs; max 2mg po qhs
    12. Clorazepate (Tranxene-SD®): 15mg po qhs, then 15mg bid, to max 60mg daily divided
  5. Related Agents [21]
    1. Several GABA potentiating agents used as party drugs and implicated in date rate
    2. Flunitrazepam (Rohypnol®) is a rapid acting (15-20 minutes) benzodiazepine implicated in "date-rape" [11]
    3. Gamma-hydroxybutyrate (GHB; see below) [22]
    4. Gamma-butyrolactone (GBL)
    5. 1,4-butanediol
  6. Flumazenil (Romazicon®) [18]
    1. Benzodiazepine receptor antagonist
    2. Reverses effects of benzodiazepines
    3. Can be useful in benzodiazepine overdose; may cause vomiting
    4. Can precipitate acute withdrawal in patients dependent on benzodiazepines
    5. MMay cause seizures in patients who take cocaine or other pro-epileptic agents
    6. Flumazenil should be used only with caution in comatose patients where identity of ingested drug(s) is not certain
  7. Withdrawal from benzodiazepine dependence is similar to alcohol withdrawal [21]

F. Other Hypnotic Agents [14]navigator

  1. Zolpidem (Ambien®) [15,16] (Schedule 4 Controlled Substance)
    1. Non-benzodiazapine, binds alpha subnit GABA-A-R
    2. Rapid onset of action, 4-6 hour duration, does not affect REM sleep
    3. Non-habit forming without apparent tolerance generation (no tachyphylaxis)
    4. Dose 5-10mg po qhs
    5. Drug interactions minimal and no impairment of mental functions on day after use
    6. As effective as benzodiazepines from sleep induction [7]
    7. Highly recommended in most patients, particularly for long term use
  2. Zaleplon (Sonata®) [17] (Schedule 4 Controlled Substance)
    1. Pyrazolopyridimine hypnotic for short term treatment of insomnia
    2. Binds selectively to alpha2 and alpha3 subunits of GABA-A-R
    3. Rapid onset of action with duration ~4 hours
    4. Increased frequency of early awakening compared with zolpidem
    5. Usual dose is 10mg po qhs (reduce dose by 50% for elderly or hepatic impairment)
    6. Dose may be increased to 20mg qhs, but increased risk of transient visual halucinations
    7. Metabolized in part by CYP3A4 so caution with drugs that inhibit this enzyme
  3. S-Zopiclone (eszopiclone, Lunesta®) [14,23]
    1. Nonbenzoziazepine pyrrolopyrazine hypnotic with long (6 hour) half-life
    2. Approved for acute and long term insomnia
    3. Initial dose 2mg qhs, maximum dose 3mg qhs; reduce dose in elderly
    4. Headache, unpleasant taste, dry mouth, dizziness side effects
    5. Metabolized by CYP3A4 and CYP2E1 so caution with drugs that inhibit these enzymes
    6. Is labelled for chronic use and probably maintains sleep longer than other agents
  4. GHB (sodium oxybate, Xyrem®) [22]
    1. Rapidly acting hypnotic acts through GHB and GABA-B receptors
    2. Approved for narcolepsy patients with moderate to severe cataplexy
    3. Does not interact with the GABA-A or GABA-C (ligand activated ion channel) receptors
    4. GHB normally present in micromolar levels in mammalian brain, activate GHB receptors
    5. GHB required at millimolar concentrations to activate GABA-B receptor
    6. GHB intoxication (direct or through 1,4 butanediol ingestion) can cause intoxication
    7. GHB intoxication: bradycardia, hypothermia, delirium, myoclonus, seizures, transient coma, amnesia and has been implicated in "date rape" [24]
    8. Flumazenil or naloxone do not reverse GHB induced coma
    9. GHB withdrawal symptoms can be severe or life-threatening in highly dependent persons
    10. Withdrawal symptoms usually begin within 6 hours but not in usual narcolepsy doses

G. Antiepileptic Agents navigator

  1. Valproate Sodium [10]
    1. Increases presynaptic concentrations of GABA
    2. Effective for treatment of all types of seizures
    3. Also effective for treatment of manic episodes associated with bipolar disorder
  2. Vigabatrin [7]
    1. Inhibits catabolism of GABA by GABA transaminase
    2. Increases CNS levels of GABA
    3. Non-protein bound; excreted in urine
  3. Topiramate [5,10]
    1. Antiseizure medication as add-on therapy
    2. Has been used as a mood-stabilizing drug
    3. Does not cause weight-gain
    4. Cognitive impairment and renal stone formation may occur
  4. Tiagabine [1,6]
    1. Inhibits reuptake of GABA by both neurons and glial cells
    2. Selectively blocks GAT-1 > GAT-3
    3. Generally well tolerated - dizziness, headache, somnolence most common side effects

References navigator

  1. Leach JP and Brodie MJ. 1998. Lancet. 351(9097):203 abstract
  2. Petroff OAC, Rothman DL, Behar KL, Mattson RH. 1996. Ann Neurol. 40:908 abstract
  3. Drugs for Epilepsy. 1995. Med Let. 37(947):37 abstract
  4. Gabapentin. 1994. Med Let. 36(921):39 abstract
  5. Topiramate. 1997. Med Let. 39(1001):51 abstract
  6. Tiagabine. 1998. Med Let. 39(1024):45
  7. Chadwick D, et al. 1999. Lancet. 354(9172):13 abstract
  8. Levy LM, Dalakas MC, Floter MK. 1999. Ann Intern Med. 131(7):522 abstract
  9. van Hilten BJ, van de Beek WJT, Hoff JI, et al. 2000. NEJM. 343(9):625 abstract
  10. Valproate for Psychiatric Illness. 2000. Med Let. 42(1094):114 abstract
  11. Schneider RK, Levenson JL, Schnoll SH. 2001. Ann Intern Med. 134(5):387 abstract
  12. Weinberger DR. 2001. NEJM. 344(16):1247 abstract
  13. Furukawa T, Streiner DL, Young LT. 2001. J Affective Disorders. 65:173 abstract
  14. George CFP. 2001. Lancet. 358(9293):1623 abstract
  15. Zolpidem. 1993. Med Let. 35:35
  16. Nowell PD, Mazumdar S, Buysse DJ, et al. 1997. JAMA. 278(24):2170 abstract
  17. Zaleplon. 1999. Med Let. 41(1063):93 abstract
  18. Acute Reactions to Drugs of Abuse. 2002. Med Let. 44(1125):21 abstract
  19. Addolorato G, Caputo F, capristo E, et al. 2002. Am J Med. 112(3):226 abstract
  20. Addolorato G, Leggio L, Ferrulli A, et al. 2007. Lancet. 370(9603):1915 abstract
  21. Kosten TR and O'Connor PG. 2003. NEJM. 348(18):1786 abstract
  22. Sneed OC III and Gibson KM. 2005. NEJM. 352(26):2721 abstract
  23. Eszopiclone. 2005. Med Let. 47(1203):17 abstract
  24. Tancredi DN and Shannon MW. 2003. NEJM. 349(13):1267 (Case Record) abstract
  25. Pandya KJ, Morrow GR, Roscoe JA, et al. 2005. Lancet. 366(9488):818 abstract
  26. Shanafelt TD, Barton DL, Adjei AA, Loprinzi CL. 2002. Mayo Clin Proc. 77:1207 abstract
  27. Pregabalin. 2005. Med Let. 47(1217):75 abstract