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Barbiturates, General Anesthetics, and Antiepileptic Drugs

Barbiturates, General Anesthetics, and Antiepileptic Drugs. Laureen Trail Spring 2003. History. Humans have always sought ways to induce sleep, relieve stress and anxiety Natural CNS depressants Alcohol Morphine (opium alkaloid) Manufactured CNS depressants

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Barbiturates, General Anesthetics, and Antiepileptic Drugs

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  1. Barbiturates, General Anesthetics, and Antiepileptic Drugs Laureen Trail Spring 2003

  2. History Humans have always sought ways to induce sleep, relieve stress and anxiety Natural CNS depressants Alcohol Morphine (opium alkaloid) Manufactured CNS depressants Phenobarbital (1912) – 1stbarbiturate 1912-50 many tested/marketed Dominated market until 1960

  3. Action Sites and Mechanisms Early understanding - “Depressed” neuronal pathways in brain stem/cerebral cortex Severe depression = DEATH Present day – Reduced metabolic and brain electrical activity

  4. Neurotransmitters & Receptor Sites Glutamate (excitatory) Reduce excitatory activity GABA (inhibitory) Augment inhibitory activity Barbiturates/benzodiazepines bind here

  5. GABA Site

  6. GABAA Site Action Binding to GABAA receptors Facilitates GABAA-induced neurotransmission Channel opens, influx of Cl- ions, hyperpolarization Reason for sedative-hypnotic & anesthetic effects of barbiturates, benzodiazepines, anesthetics, other “depressants”

  7. Barbiturate Problem Barbiturates can open Cl- channel without GABA Possibility of extreme toxicity in overdose!

  8. Uses of Barbiturates Only 10% of depressant prescriptions Lethal in overdose Narrow therapeutic-to-toxic range High potential for tolerance, dependence, abuse Dangerous interaction with other drugs Still used as anticonvulsant, intravenous anesthetics, death inducing, “brain protection” (head injury), psychiatric sedation

  9. Sedation-Induced Brain Dysfunction “Blackout” is antegrade amnesia All sedatives can produce Alzheimer-like amnesia Dementias produce characteristic patterns

  10. Mental Status Exam Used to evaluate mental functioning Five areas affected in dementia SENSORY – clouded; disorientation to time/place MEMORY – forgetfulness, loss of ST INTELLECT – depressed reasoning JUDGMENT – altered insight AFFECT – wide mood swings Severe in elderly – STOP MEDS!

  11. Specific CNS Depressants

  12. Barbiturates Primary prescription for anxiety, insomnia from 1912-1960 Associated with suicides, accidental overdose, dependence/abuse, dangerous drug interactions Still prototype for drug comparison

  13. Pharmacokinetics Wide range of half-life – 3 min to 120 hrs Redistribution in body Fast-acting >> lipid (fat) soluble – results in seconds Long-acting>> water soluble – slower to penetrate CNS (20-30 minutes) Metabolized in liver; eliminated through kidneys Urinalysis detects 30 hours to weeks

  14. Pharmacological Effects With lowered anxiety, also sedation Not analgesic – no sleep/sedation with moderate pain Suppressed dreaming during REM Cognitive inhibition Changes in thinking, judgment, motor skills, behavior – over hours or days

  15. Affects on Other Systems Respiratory Low dose – none High dose – suppression >> death Few effects at low dosage Cardiovascular, gastrointestinal Liver - drug stimulates enzymes that metabolize it >>> tolerance

  16. Psychological Effects Depressed behavior Cognitive/Motor inhibition akin to alcohol inebriation >> impaired driving Low dose – reduced anxiety OR emotional withdrawal, aggression or violence Set/setting determines positive or negative response High doses – general behavioral depression, sleep

  17. Adverse Reactions Side effects Drowsiness; intellectual/motor impairment Effects like alcohol – don’t need to be “drunk” OVERDOSE – no antidote, only life support

  18. Tolerance Two ways to induce tolerance 1) Liver enzymes metabolize drug 2) Neurons in brain adapt to drug Primarily sedative effects Narrow safety margin for brain stem depression

  19. Physiological Dependence Wide range of effects Low dose – sleep difficulties High dose – hallucinations, restlessness, disorientation, life-threatening convulsions

  20. Psychological Dependence Pleasurable effects – Reduced anxiety Sedation Euphoria Lead to compulsive use and abuse

  21. Effects in Pregnancy Mixed results in testing anticonvulsants Some show harm to fetus, others none Best to avoid during pregnancy, but… Need to prevent seizures that could harm fetus

  22. Misc. Nonbarbiturate Sedative-Hypnotic Drugs Most obsolete, not used or prescribed Methaqualone (Quaaludes) –1970’s, 80’s “Love Drug” ?? NOT! Opposite effect like alcohol – set and setting gave it the reputation Meprobamate (Equanil, Miltown) – 1950’s 1st non-barbiturate “tranquilizer” Less respiratory suppression

  23. Misc. Drugs, cont. Chloral Hydrate (Noctec) – since 1880’s Metabolized like alcohol Tolerance like barbiturates Bedtime sedative for elderly “Mickey Finn” (w/alcohol) – 1st date rape drug

  24. Misc. Drugs, cont. Paraldehyde – precedes barbiturates By-product of ethyl alcohol metabolism Used to treat DT’s Dependence – toxicity for stomach, liver, kidneys

  25. General Anesthetics Potent CNS depressants General anesthesia = most severe state of intentional drug-induced CNS depression = opioid narcotic + volatile anesthetic (no pain +unconsciousness) Depression of all CNS functions - sedation, sleep, depressed reflexes, amnesia, unconsciousness

  26. Route of Administration Inhalation – gases or volatile liquids Nitrous oxide – dentistry Abuse with canned whipped cream sniffing = hypoxia (Oxygen deprivation) = brain damage Injection – Thiopental (Pentothal) barbiturate Propofol and others resemble GABA N.T.

  27. GHB Gamma-hydroxybutyrate Naturally occurring 4-carbon molecule in mammal brains Structure like, synthesized from GABA Anesthetic in other countries Use in sleep disorders, alcohol and opioid dependence

  28. GHB Abuse Euphoriant – makes you feel good! Common “date rape” drug Doesn’t enhance body building or sex! Effects – disinhibition, excitement, drunkenness, amnesia Dangerous overdose – stupor, delirium, unconsciousness, coma NO ANTIDOTE – only life support

  29. Antiepileptic Drugs Epilepsy = CNS disorders of brief, chronic , reoccurring seizures (brain electronic disturbance) assoc. with brain lesions How drugs suppress seizures – Limit neuron firing at sodium channels, block depolarization Reduce GABA metabolism, aid GABA release from presynaptic neurons

  30. Research Findings Multiple effects of drug – sedation, anxiolytic, antiepiletic, antimanic>>>>> Help several disorders – bipolar, explosive psych. disorders, mania Reinforces previous knowledge – Stabilizes neurons by aiding inhibition or limiting excitation

  31. Traditional Antiepileptics Barbiturates (Phenobarbital) – still used occasionally, but hard on children (hyperactivity & learning problems) Hydantoins (Dilantin) - common use as anticonvulsant Benzodiazepines (Clonazepan) – anticonvulsant, hard on children (personality changes and learning problems)

  32. Modern Antiepileptics Resemble GABA & act on GABA receptors Inhibit glutamate action – “brain protection” from hypoxia & ischemia NEWEST CLASS – Epalons - steroid derivatives No hormonal action, but traditional effects Bind to steroid-sensitive GABAA receptors

  33. Antiepileptics and Pregnancy Stillbirth and infant mortality rate higher Antiseizure meds in early months increase birth defects Balance danger of seizures with possible birth defects – discontinue meds or move to single drug at lowest effective dose

  34. Benzodiazepines and Second –Generation Anxiolytics Laureen Trail University of Idaho Spring 2003

  35. History Benzodiazepines (BDZ) introduced in 1960’s 40 years - drug of choice Still widely used – 1 in 5 prescriptions Many properties – anxiolytic, sedative, anticonvulsant, amnestic, relaxant Anxiolytic synonymous with BDZ Newer antidepressants rapidly replacing

  36. Effects Safer than barbiturates – much less respiratory depression - lg. doses rarely fatal (except w/alcohol) CNS toxicity in chronic use/high doses - headaches irritability, confusion, impaired memory, depression

  37. Mechanism of Action BDZs - agonists of GABA-BDZ-Chloride receptor complex, facilitate GABA binding Action >> aids influx of Cl- ions >> hyperpolarization of postsynaptic neuron >> excitability depressed

  38. Sites of Action MRIs, PETs research - fear and anxiety responses in amygdala, orbitofrontal cortex, insula Decreased GABAergic function >> elevated anxiety states

  39. Pharmacokinetics 15 BDZ derivatives used in U.S. -differ in pharmacokinetics parameters a. Metabolism rates to active intermediates b. Plasma ½ life of parent + active metabolite = long- or short-acting

  40. Familiar BDZs Long-acting (6) Valium & Librium (50-100 hrs.) Intermediate-acting (4) Ativan & ProSom (10-50 Hrs.**) Short-acting (5) Halcion & Xanax (1.5-35 hrs.)

  41. Absorption >>> Excretion BDZs taken orally well absorbed Peak plasma concentration >> I hour Most psychoactive drugs metabolized to inactive, water-soluble product Exceptions for some BDZs Some long-acting ones transformed to long-acting metabolites - nordiazepam 60 hrs.

  42. Problem Population CAUTION with elderly patients! Metabolize BDZs much more slowly -up to I month to eliminate single dose BDZs can easily cause dementia -too often overlooked in elderly

  43. Pharmacological Effects BZDs facilitate GABA-induced neuron inhibition at GABAA receptors in many CNS areas Complete agonists dependably aid GABA binding Partial agonists bind to subgroups of GABAA receptors

  44. Specific Sites and Actions Cerebral cortex and hippocampus - Mental confusion and amnesia Amygdala, orbitofrontal cortex & insula - Alleviation of anxiety, agitation and fear Spinal cord, cerebellum & brain stem - Muscle relaxation (also anxiolytic) Cerebellum and hippocampus - Antiepileptic action Ventral tegmentum and nucleus accumbens - Rewarding behavioral effects (depend/abuse)

  45. Uses and Effects of BDZs Severe anxiety relief – PRIMARY - usually psychological relief leads to physiological relief Sedative – hypnotic effect for insomnia - fast-acting = no daytime sedation - long-acting = some daytime sedation Muscle relaxant - direct physiological relief or indirect with psychological relief

  46. Uses and Effects, cont. Amnestic effect - before or during surgery Panic Attacks and Phobias (controversial) Somewhat effective – Serotonin-type antidepressant better ++ anxiety relief, minimal side effects, patient compatibility --- impaired psychomotor and alertness, potential for dependence/abuse

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