Psychopharmacology of Memory, Specific Intent, and Mental Capacity

Transcription

1 Psychopharmacology of Memory, Specific Intent, and Mental Capacity We will explore the relationship between memory and one s ability to legally consent or to act intentionally?

2 Alcohol, Benzodiazepines, Date Rape Drugs, Amnesia and Behavior Robert M. Julien, MD, PhD 23 Becket St. Lake Oswego, Oregon

3 What is memory? What happens when we learn something? Memory involves formation of specific proteins within specific neurons in the brain. Loss of ability to form these proteins is associated with amnesia. Alzheimer s disease, general anesthesia, conscious sedation, and alcohol-blackout are examples. Amnesia can be totally dissociated from behavior, as we will see. Victims as well as the general public does not understand this.

4 What is meant by intent? I am often asked to comment on the effects of alcohol or a related sedative on one s ability to act intentionally to resist, assault, flee, drive, etc. Regarding the ability to act intentionally in a drug-induced demented state, there are variations on the definition of intent, all of which can be affected by the mental aberrations produced by alcohol intoxication.

5 Intent refers to a determination to perform a particular act or to act in a particular manner for a specific reason.

6 Intent implies aimful and goal-directed behavior; purposeful behaviors, or acting with purpose. It involves planning and desire to perform an act. It involves a determination or resolve to do a certain thing. Intent is the planning and desire to perform an act.

7 It is clear, to a degree of medical certainly, that intent cannot be formed when one is in a demented state of brain functioning. While a person may have acted recklessly, unlawfully, and with apparent intent, such actions did not result from intentionally and directed actions or thoughts.

8 Examples Organic dementia: Grandpa signs a contract A colonoscopy you don t remember A drunk patient coming to emergency surgery A post-operative patient gives a confession Classic date-rape case of he said-she said Who s right???? Ambien sleep-driving and sleep-related activities

9 Ethyl Alcohol Our Major Intoxicant, Amnesiac, And Date-Rape Drug

10 Pharmacokinetics of Alcohol Absorption and blood levels: You must know the amount of alcohol in the product you or your client drinks! A drink equivalent is the amount of a beverage that contains cc of absolute ethanol. Metabolism and Excretion: -Male v. female -Concept of zero-order metabolism (one metabolized one drink equivalent per hour)

11 What is a Drink? All beers are not the same One Drink Equivalent: 1 ounce of hard liquor (40%) 3 ounces of 12% wine 12 ounces of 3.2% beer (most are 5-10%) New are 7-10% alcohol drinks (up to 24 ounces/can) containing caffeine. Big new problem!

12 Examples: 22 ounces of 8% fortified beer 22 oz. x 30cc per oz. = 660 cc x.08 = 53cc of ethanol cc ethanol = 1 drink equivalent Therefore this is 5 drink-equivalents or almost a 6- pack of beer (may black-out a 100 lb female) 16 ounces of 40% hard liquor 16 oz. x 30cc per oz. = 480 cc x.,4 = 192cc of ethanol cc ethanol = 1 drink equivalent Therefore this is 19 drink-equivalents (a guaranteed blackout) What does this mean in reality?

13 Achieving a 0.25 BAC in men & women (this a the blackout threshold) Women 100 lbs: 6 drink equivalents 120 lbs: 7 drink equivalents 140 lbs: 8 drink equivalents 160 lbs: 9 drink equivalents 180 lbs: 10 drink equivalents 200 lbs: 11 drink equivalents Subtract one drink equivalent for each hour since the start of drinking Men 120 lbs: 8 drink equivalents 140 lbs: 9 drink equivalents 160 lbs: 10 drink equivalents 180 lbs: 11 drink equivalents 200 lbs: 12 drink equivalents 220 lbs: 14 drink equivalents 240 lbs: 16 drink equivalents From: R.M. Julien A Primer of Drug Action, 11 th edition 2008, p.102

14 Organ System Effects -CNS:neuronal depression, respiratory depression, behavioral disinhibition, cognitive-behavioral depression. Drug-induced organic brain syndrome (amnesia, dementia, blackouts) seen at levels above about grams%

15 Susan Martin, PhD The Links Between Alcohol, Crime and the Criminal Justice System: Explanations, Evidence and Interventions American J. on Addictions 10: , 2001 Alcohol lowers the threshold for violence by impairing the ability to find other solutions to conflict, reducing anxiety about the consequences of assaultive behavior, decreasing impulse control, and increasing preoccupation with dominance and power. Alcohol involved in ½ of homicides and assaults and 40% of violent offenders had been drinking at the time of the offense for which they are incarcerated

16 Martin (continued) Drinking offenders committed 40% of rapes or sexual assaults, ¼ of aggravated or simple assaults but only 16% of robberies By depressing insight, judgment and cognition, it induces a alcohol-myopia that intensifies or contributes to escalation of violence (by narrowing focus of alternative solutions and by reducing anxiety about the consequences of their behavior) Intoxicated persons focus on the present, have reduced anxiety, decreased insight, increased aggression, impaired problem solving abilities, and increase power concerns associated with impaired intellectual function

17 Martin focuses on intoxicating levels of ethanol (perhaps to 0.15) At higher levels, (where blackouts occur), dementia becomes more prominent with further reductions in insight, judgment, intellect, memory, and so on. Here, the dementia becomes more complete as alcohol inhibits the ability of the brain to lay down new memory proteins).

18 Amnesia as a marker for impairment All amnestic drugs produce a reversible drug-induced dementia when levels of drug block the formation of memory proteins within specific neurons within the brain, altering synaptic plasticity and inhibiting learning & memory This can be clearly delineated from behavioral activity (vitally important!)

19 Examples A colonoscopy you don t remember A drunk patient coming to emergency surgery Grandpa signs a contract A post-operative patient gives a confession Classic date-rape case of he said-she said Who s right???? Ambien sleep-driving and sleep-related activities

20 Amnesia as a marker for impairment (2) Example: Versed administered for a colonoscopy With amnesia as a marker, sensorium is clouded, time & place may become disoriented, blackout is present, intellect becomes depressed, judgment is altered. However, one can be awake, drive home, engage or initiate sexual activity, and so on. Loss of memory for sex often leads to complaints that one was raped, while the perpetrator insists that the partner was willing, able, participating, and even initiating.

21 The important pharmacological point in this matter is whether or not one is capable of acting, performing, responding, participating, or consenting (by words or actions) in sexual activity during the period when memory is not formed (i.e., during a blackout ).

22 Here, the answer is most definitely yes. As an anesthesiologist, I have induced conscious sedation in literally thousands of persons. I do this so that the patient does not remember the performance of uncomfortable medical procedures (such as a colonoscopy). Here, the person is awake, functioning, conversing, and responding to the procedure even though one has no memory of the event. Indeed, one can even appear to be awake.

23 What happens at BAC = gms% Formation of memory protein stops State of antegrade amnesia follows Behavior is disinhibited by the alcohol Victim thinks she was unconscious and therefore incapable of consent May have been a willing and very active partner In the morning, discovered she had sex; she is angry because she was unconscious, and wants revenge Partner says she was a willing and contributing person Visits emergency room; rape workup, BAC (-), drug screen (-). Must go by drinking history

24 What are Date-Rape Drugs? First & foremost, they are amnestics! As such, they are sedative-hypnotics, used in doses sufficient to induce amnesia They are often used to potentiate the actions of alcohol Therefore, alcohol can be, by itself, a date rape drug

25 A dementing drug is any drug that: Can induce a blackout or drug-induced antegrade amnesia Can induce a drug-induced organic brain syndrome that resembles the memory loss seen in the dementias such as Alzheimer s Disease Causes a loss of short-term memory formation for the duration of drug action Impairs frontal lobe or executive functioning, impairing thought, insight, intelligence, and judgment *Remember, by itself, this has nothing to do with wakefulness or behavior

26 Dementing drugs include: Ethyl alcohol Chloral hydrate (Mickey Finn when mixed with beer) Barbiturates Benzodiazepines - Soma (carisoprodol) (meprobamate is the active metabolite) Methaqualone (Quaalude) Rohypnol (a benzodiazepine) GHB Certain inhalants (e.g.. Anesthetics, nitrous oxide, volatiles)

27 Psychological Effects Mainly restricted to CNS: progressive, dose- and blood level-related decrease in functioning Continuum of effects related to blood level of ethanol

28 Tolerance and Dependence -Tolerance to some effects: not to others: TOLERANCE DOES NOT DEVELOP TO THE BLOOD CONCENTRATION THAT PRODUCES BLACKOUT!!!!!!!! -Psychological dependence: compulsion to use the drug -Physiological dependence: defined by withdrawal signs: can be severe or even fatal (seizures). Delirium tremens

29 Benzodiazepines Booze in a Pill

30 What is a Benzodiazepine? First: A benzodiazepine (BZD) is a drug of a specific chemical structure. It is therefore a structural, not a pharmacological, classification of drugs. Valium and Librium are the classic benzodiazepines. Ativan, Klonopin, Xanax, and Halcion are among several others

31 Clinically useful BZDs potentiate the synaptic actions of GABA, increasing inhibition within the brain, producing or resulting in: Sedation and hypnosis Anxiolysis Anticonvulsant action of limited usefulness Cognitive and psychomotor inhibition Physical dependence

32 How do benzodiazepines differ? Primarily by half-lives & active metabolites Valium, Librium, Dalmane, Paxipam, Centrax, and Tranxene have active metabolite and hour half-life (longer in elderly) Ativan = 15 hours, Klonopin = 30 hours, Xanax and Restoril = 12 hours Serax = 8 hours Halcion = 3 hours Versed = 1.5 hours

33 Because of long half-lives of most benzodiazepines, their sedative and cognitive-inhibiting effects are insidious Providers may never have known the patient in a non-cognitively inhibited state: A patient undergoing cognitive-behavioral therapy An elderly patient

34 Problems with Benzodiazepines Not truly anxiolytic (poorly relieve stress) Limited use as anticonvulsants Complicates Cognitive-Behavioral Therapies Cognitive inhibitors Dementing Rebound increases in anxiety and insomnia complicate withdrawal Addicting drugs characterized by physical and psychological dependence Problematic in patients with alcohol and substance abuse problems

35 In the elderly, BZDs are: Dementing, Depressive, and Increase rates of falls and hip fractures: Will increase the risk of hip fracture by 50%, even at low doses (3 mg diazepam equivalent Wang et al, Hazardous Benzodiazepine Regimens in the Elderly: Effects of Half-life, Dosage, and Duration on Risk of Hip Fracture, American Journal of Psychiatry 2001; 158:

36 Verster, et al, Effects of Alprazolam on driving ability, memory functioning, and psychomotor performance, Neuropsychopharmacology 27, 2002; Dutch study of 1 mg alprazolam to 20 volunteers tested in the real world (driving 100 km on a primary highway at 90 km/hr). Memory & divided attention also evaluated All failed the driving test being seriously unsafe. Memory & divided attention also seriously impaired Authors recommended that driving should be prohibited while using alprazolam Nothing unique about alprazolam that does not apply to any benzodiazepine (or non-selective CNS depressant for that matter) Chronic use not studied

37 Benzodiazepines: current uses Treatment of debilitating anxiety Treatment of insomnia Treatment of muscle spasm and tension Intentional antegrade amnesia Symptomatic treatment of panic attacks Nonspecific treatment of anxiety which may accompany other psychological disorders Treatment of alcohol dependence (?)

38 Well-Indicated & Valid Current Uses:* Preanesthetic medication for sedation and amnesia Intentional drug-induced antegrade amnesia *my opinion

39 Options to benzodiazepines for anxiety, for alcohol withdrawal, & to assist with benzodiazepine withdrawal: For severe anxiety: Anticonvulsants (gabapentin & pregabalin) Atypical antipsychotic drugs ( Thymic Stabilizers ): especially quetiapine (Seroquel) For alcohol withdrawal and relapse prevention: Anticonvulsants (gabapentin, pregabalin, oxcarbazepine, topiramate)

40 Where will benzodiazepines hurt your patients? Doom young persons to inferiority! Dement the elderly! Impair psychomotor performance in workers or those who need such performance Depress driving performance Increase effects of opioids and other sedatives Slow rates of metabolism of certain opioids*

41 Opioid metabolic deficiencies: important new issue Suspect in patients who: 1. Do not respond as expected to certain opioids 2. Require high doses of certain opioids 3. Overdose or even die if certain opioids are prescribed to patients with concomitant CYP450 inhibitors (e.g., benzodiazepines, antidepressants, antiinfectives, antihistamines See: Making Practical Sense of Cytochrome P450, in Practical Pain Management, May 2010, pp (download for $5.00). Author: Forest Tennant

42 Cytochrome-P450 enzymes and opioids CYP-3A4, CYP-2D6, and CYP-2C9 account for over 90% of drug metabolism responses CYP-3A6 accounts for 50% of opioid metabolism. No commercial testing available 20-30% of pain patients have a deficiency in metabolism (Practical Pain Management, May 2010) Pro-opioids (conversion necessary for efficacy): Codeine metabolized to morphine Hydrocodone metabolized to hydromorphone Dihydrocodeine metabolized to morphine Tramadol metabolized to O-desmethyltramadol

43 Direct acting opioids (no active conversion) Fentanyl Hydromorphone Methadone Morphine Oxymorphone Meperidine Levorphanol Propoxyphene Tapentadol Oxycodone

44 Opioids that require CYP450 enzymes for metabolism Codeine Methadone Fentanyl Oxycodone Hydrocodone Morphine Opioids that bypass the CYP450 enzyme system & use glucuronide metabolism: Oxymorphone Tapentadol Hydromorphone

45 Many persons are rapid metabolizers and achieve little pain relief with drugs that use CYP450 enzymes for inactivation Some are poor metabolizers and serum concentrations rise Poor metabolism can also be caused by other meds that inhibit metabolism (BZDs, SSRIs, some anticonvulsants (valproate), some antibiotics, antihypertensives, antihistamines or bronchodilators. These persons become opioid toxic!!! Best to use oxymorphone, hydromorphone or tapentadol

46 Methadone requires multiple CYP enzymes for metabolism. Therefore, the opioid most susceptible to serious drug interactions from enzyme inhibition. Huge elevations with concomitant benzodiazepines and SSRIs.. Often resulting in unexpected deaths

47 Tapentadol (Nucynta) Quite similar to tramadol without the CYP- P450 enzyme interaction potential Schedule!!, therefore more prescription requirements than with tramadol May be safer when CYP inhibitors are used (many pain patients are taking benzodiazepines or SSRIs)

48 Tapentadol (Nucynta), continued Like tramadol, agonist of mu opioid receptors and is a norepinephrine reuptake blocker Immediate release in U.S. and extended release available in Europe (maybe here later) mg every 4-6 hours about equal to oxycodone mg every 4-6 hours Do PubMed search to review studies in moderate to severe pain

49 BZRAs: benzodiazepine receptor agonists Cases of sleep-related activities in patients taking prescribed Ambien: Driving & crashing and/or DUI with assault charges and no memory Sleep eating, having sex while asleep, suffering anxiety attacks and not remembering, and so forth

50 Gamma-hydroxybutyrate & Gamma-butyrolactone GHB and GHL

51 GHB In Europe: an induction anesthetic Overdose: lethargy, coma, respiratory depression, hypothermia, miosis, bradycardia, emesis, myoclonus, & maybe seizures Associated with youth raves & date rape GBL is related: readily absorbed and rapidly metabolized in vivo to GHB GBL is sold as RenewTrient, Revivarant, Blue Nitro, Remiforce, GH Revitalize, Gamma G etc.

52 GHB, continued Duration of action: about 1-hour Metabolized to CO2 and water Little appearance in urine Short duration in blood Therefore, difficult toxicological detection Increasing popularity as a recreational drug and as a date-rape drug

53 Legal GHB (Xyrem) May be approved by FDA for the treatment of catapexy associated with narcolepsy. Would be taken at bedtime and repeated after 4 hours to treat disturbed patterns of sleep Very short half-life allows for this w/o daytime sedation. Half-life is about 1 hour. GHB is metabolized to carbon dioxide & water. Thus, no active metabolites. Little drug in urine. Split Scheduling for GHB: Use & misuse is schedule I; Xyrem for narcolepsy is Schedule III

54 INHALANTS Anesthetics: especially nitrous oxide - Industrial or household solvents Office solvents Gases: butane, propane Aerosol propellants: paint, hair sprays, fabric protector sprays Nitrites & organic solvents: amyl nitrite

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56 Inhalants Signs of inhalant use paint or stains on body or clothing spots or sores around the mouth red or runny eyes or nose chemical breath odor drunk, dazed or dizzy appearance nausea, loss of appetite anxiety, excitability, irritability

57 Acute Intoxication v. Chronic Effects Acute: sneezing, coughing, etc. progressing to drunken behavior, disorientation, ataxia, hallucinations. Can lead to severe depression, coma, death. Pulmonary includes wheezing, dspnea, and rales. Can persist for >2 hrs. Chronic: Liver and heart are severely affected Cardiac is not forgiving: cardiac arrhythmias and death. Accidents also involved as cause of death (asphyxia or aspiration not suicides!

58 Neuropsychiatric Effecs: Chronic use can lead to generalized cerebral and cerebellar atrophy, particularly in the hippocampus Develops after 2-3 times/week use for 6 months Solvent ingestion can can more rapid white matter degeneration which can lead to more rapid deterioration in memory, attention, auditory discrimination & visual-motor function Reductions in IQ parallel damage with psychomotor and attentional dysfunction, depression, irritability and tremor. Hypoxia potentiates direct toxicity. Solvent abusers often come from deprived backgrounds and both lead to cognitive compromise

59 Conclusions: -Second most commonly abused illicit drugs by year olds; use is increasing. Now the most commonly abused drug by 12 year-olds. -Inhalant abuse is prevalent and serious, but little discussion, attention or research paid to it Abused a least once by 6% of fourth graders, 20% of 8 th graders & 17% of 12 th graders. Also used by polysubstance abusers and certain cultural classes (Native Americans, Latinos) Incidence of death is of even more concern than prevalence of use

60 Books: 1. R. Baselt: Disposition of Toxic Drugs and Chemicals in Man, 8 th ed., J.C. Garriott: Medical-Legal Aspects of Alcohol 3. R. Julien: A Primer of Drug Action, 12 th ed., 2011