PYB260 Psychopharmacology of Addictive Behaviour Lecture Notes 2024 - Week 11 - PDF

PYB260 PSYCHOPHARMACOLOGY OF ADDICTIVE BEHAVIOUR Week 11: Action & Effects of Anxiolytics & Sedative-hypnotics Melanie White, QUT 1  Lecture Outline What are anxiolytics & sedative-hypnotics? History Administration, distribution & excretion...

PYB260 PSYCHOPHARMACOLOGY OF ADDICTIVE BEHAVIOUR Week 11: Action & Effects of Anxiolytics & Sedative-hypnotics Melanie White, QUT 1  Lecture Outline What are anxiolytics & sedative-hypnotics? History Administration, distribution & excretion Effects of barbiturates & benzodiazepines – physiological & performance Conditioning, tolerance & withdrawal Harmful effects  Reflection Questions (egs, not exhaustive) What are the main differences between anxiolytics and sedative-hypnotics? If a benzodiazepine or barbiturate was being used for presurgical analgesia, what characteristics would distinguish it from anxiolytic or S-H use? What are the similarities and differences in absorption, distribution & metabolism profiles for BBTs, BDZs, & alcohol? + Neurobiological actions? If your friend takes a Valium on a flight after a few alcoholic drinks over the dinner service, what are the likely effects? Why is your Dr more likely to prescribe you a BDZ than a BBT for sleep? What are some of the potential side effects & precautions your Dr should advise? You’ve been taking a BDZ to help you sleep most nights for the past 2 weeks and want to stop. Your housemate has been taking a different BDZ for their anxiety for the past 8 months but also planning to stop this month. How are your withdrawal symptoms likely to differ? What are anxiolytics & sedatives? & The history of their use  What are anxiolytics & sedatives? Anxiolytics & sedative-hypnotics: used to reduce anxiety, sedate, aid sleep, as anticonvulsants & as anaesthetics 3 classes of drugs can be used to achieve these effects (benzodiazepines (BDZ), barbiturates (BBT), other) & these drugs have similar neural mechanisms. Prescription may depend on other drug properties History of anxiolytics & S-H Alcohol & Opiates  Barbiturates  Benzodiazepines  History of barbiturates 1864: Adolf von Baeyer synthesized barbituric acid by condensing malonic acid & urea 1882: barbital synthesized 1903: barbital marketed 1912: phenobarbital marketed 1960’s: illicit use as “downers” Approx. 50 barbiturates marketed & historically used to treat a variety of disorders Phenobarbital – seizures & sedatives Butalbital – headaches Thiopental & amobarbital – anesthetics  History of benzodiazepines 1950’s: research to find a safer anxiolytic/S-H 1957: Chlordiazepoxide (Librium) discovered & marketed 1963: Diazepam (Valium) discovered & marketed 1970’s: peak prescription rate  in prescriptions as anxiolytics since (esp. Valium); More likely to prescribe short-acting BDZs that do not have active metabolites; Prescriptions as S-H has remained stable at relatively high levels Most commonly prescribed of all drugs in the western world  Respiratory Depression BARBS Coma/ Anesthesia BDZs Ataxia Sedation ETOH Anticonvulsant Anxiolytic DOSE  Modern use of BDZs "men just aren't the same today" I hear ev'ry mother say they just don't appreciate that you get tired they're so hard to satisfy. You can tranquilize your mind so go running for the shelter of a mother's little helper and they’ll help you through the night, help to minimize your plight doctor please some more of these outside the door, she took four more what a drag it is getting old Rolling Stones, “Mother’s Little Helper” (1967)  Illicit use of BDZs Controversy about the extent of illicit BDZ use Misused by those with drug addictions & used in ways that are not consistent with optimal therapeutic goals Combined with other drugs (e.g., opiates, alcohol) BDZ are “controlled” substances, according to WHO standards Best practice guidelines for prescription: https://www.racgp.org.au/clinical-resources/clinical-guidelines/key-racgp- guidelines/view-all-racgp-guidelines/drugs-of-dependence (Part B - Benzodiazepines)  Some examples of modern day BDZs Without active metabolites: oxazepam [Serax/Serapax], temazepam [Restoril]) lorazepam (Ativan) clonazepam [Rivotril] With active metabolites diazepam (Valium) chlordiazepoxide [Librium] nitrazepam [Mogadon]) alprazolam (Xanax) flurazepam [Dalmane] bromazepam [Lexotanil]  Examples of BBTs Secobarbital Phenobarbital Pentobarbital Amobarbital Mephobarbital Secobarbital Aprobarbital  Administration, absorption, distribution & excretion of barbiturates & benzodiazepines  Administration & absorption May be administered: orally, parenterally (including i.v. or i.m.), but absorption from digestive system better than i.m. absorption bc of biochemical properties BBTs & BDZs readily absorbed after oral & parenteral routes Choice of route of administration depends on reason for use  Administration & absorption Biochemical properties: weak acids Barbiturates All barbiturates have pKa near 8.0 → almost entirely nonionized at pH of digestive system ( readily absorbed) Variability in lipid solubility Benzodiazepines pKa of about 3.5 to 5.0  readily absorbed from digestive system Range of lipid solubility Absorption may be  by alcohol  Ionization of drug molecules pKA Theoretical curve for weak acid with pKA=8 (adapted from McKim & Hancock, 2013, Fig. 1-7, p.15)  Distribution Determined by lipid solubility Cross placental barrier & present in breast milk Highly lipid soluble BBTs/BDZs will cross BBB → effects may be seen quickly, but also dissipate quickly Drug released slowly from fat deposits → metabolised by liver  Excretion: BDZs 2-phase excretion curve: Phase 1: rapid drop in blood level due to redistribution in fat deposits Half-life ~ 2-10 hours Phase 2: metabolism (liver, CYP450 enzyme) Half-life ~ 27-48 hours Older BDZs almost fully metabolized Active metabolites of these drugs = duration of effect not determined by half-life Metabolism  by repeated administration; slowed (for some BDZs) by alcohol  Excretion: BBT Most fully metabolized by liver enzymes before excretion Repeated administration =  metabolism Metabolism also  by: Anti-psychotics Anesthetics Chronic alcohol use Antihistamines Nicotine  Excretion: BBT Barbiturates also stimulate enzymes that metabolize other drugs: Chlorpromazine Morphine Caffeine General & local anesthetics Overdoses can be treated by making urine more alkaline (because barbiturates are acidic) Half-life variability between drugs Source: textbook (latest edition) Effects of barbiturates & benzodiazepines  Neurophysiology Affects GABAA receptors (ionotropic, mainly postsynaptic, quick response, coupled to Cl- channels) Own receptor sites on GABA-Chloride Ionophore Complex In general, make GABA NT more effective at these sites (positive allosteric modulators):  ability open channel Cl- ions into postsynaptic neuron →  inhibition BBT vs. BDZ mode of action: BBTs: time channel is open → larger Cl- (vs. BDZ) & at high doses, can directly activate GABAA receptors (agonists) BDZs: frequency of channel opening & affinity of GABA for receptor A schematic drawing of the GABA receptor-chloride ionophore complex (Fig 7-2 Text).  Neurophysiology Some BBTs & BDZs act as negative GABAA modulators BBTs & BDZs interact with their own receptor sites An endogenous BDZ-like substance? BDZs may also affect adenosine by blocking re-uptake BDZs & BBTs  DA in nucleus accumbens via GABA  Effects of benzodiazepines On the body Relatively mild  respiration (vs. other CNS depressants) Mild  blood pressure  appetite/ weight gain  muscle relaxation (effect on CNS, not muscles) Anticonvulsant – petit mal seizures & infantile spasms  Effects of benzodiazepines On sleep BDZ widely used for S-H properties Effective as short-term intervention BDZ  time to fall asleep;  awakenings;  total sleep time, but also  REM & Stage 3 & 4 sleep → withdrawal rebound effect Tolerance to effects does not develop But in order to eliminate withdrawal rebound, re-administer drug = dependence  Effects of benzodiazepines Subjective effects Sedation/fatigue/confusion Euphoria & “liking” Anxiolytics (but not in individuals with normal anxiety levels)  Effects of benzodiazepines On performance  visual & auditory acuity  simple RT (at high doses) Explicit memory (even at low doses): Anterograde amnesia (acquisition of new explicit information), but not implicit memory (skill acquisition) Deficits observable on wide variety of tests. A review of 12 different BDZ assessed in 109 controlled instances showed statistically significant drug related impairment, on average, 82% of the times tested. Wittenbom, 1988 LT cognitive impairment? (see harmful effects slides) If clinically anxious, BDZs may improve performance  Effects of benzodiazepines Hangover effects Disruption in mood & performance 12 hrs >administration Amplifies effects of alcohol Effects on driving  collisions (meta-analysis: risk  of 60-80%)  by alcohol (risk x 7.7 times)  risk in first-time users who usually report feeling fine  Effects of barbiturates On the body Significant  respiration Heart rate Blood pressure Anticonvulsants On sleep Sleeping pills -  sleep onset latency;  total sleep time  REM sleep – tolerance after 1 week withdrawal rebound up to 40% of sleep time for several weeks  Effects of barbiturates Subjective effects similar to benzodiazepines On performance  visual acuity overestimate time  steadiness  visual tracking  divided attention  athletic performance  Effects of barbiturates Hangover effects simple RT deficits detected the next day  pursuit tasks  body steadiness after 18 hours On driving equivalent to BAL of.15 Conditioning, discrimination, tolerance & withdrawal effects of barbiturates & benzodiazepines  Conditioning & discrimination Unconditioned behaviour “taming” seen in lab animals first restricted to  defensive aggression Conditioned behaviour  responding to punished stimuli  avoidance behaviour  Conditioning & discrimination Discrimination Barbiturates Not able to discriminate different types of BBTs Generalized to other BBTs, BDZs, etc. – not to amphetamines or LSD Can discriminate alcohol Benzodiazepines Animals readily discriminate BDZs from saline Generalize to other BDZs & BBTs, but not antipsychotics Discrim effects can be blocked by drugs that block BDZ receptor  Tolerance: BBTs Acute & chronic tolerance may develop Chronic tolerance Develop at different rates for different effects Examples: Antiepileptic effects = no tolerance RT/coordination ~ 1 week Total sleep time ~70 days  Tolerance: BDZ Acute (selective) tolerance Can develop during single administration Behaviour & motor-impairing effects Chronic tolerance Depressant effects develop tolerance 1st Locomotor, ataxic, muscle relaxant & anticonvulsant effects Anti-anxiety: variable in humans Drowsiness Sleep: after ~4wks Short-acting drugs avoid residual effects but progress to tolerance quicker REM suppression does NOT develop tolerance  Tolerance: Cross-tolerance Barbiturates cross tolerant with each other, alcohol & BDZs considerable cross-tolerance with other depressants cross-tolerance with metabolizing enzymes induced by BBTs Benzodiazepines other depressant drugs alcohol & BBTs  BBT Withdrawal Differs for individuals & depends on dose Low doses – REM rebound High doses – can precipitate medical emergency Symptoms commence 12-24hrs (or 48-72 hrs for long-acting) after final dose & may last up to 2 wks  BBT Withdrawal Symptoms Tremors Anxiety Insomnia Nausea Delirium Seizures – death Hallucinations Disorientation Confusion Fear Agitation REM rebound Most symptoms gone in 2 weeks Similar to those that result from high-dose BDZ withdrawal  BDZ Withdrawal McKim & Hancock (2013), Fig 7.2, p.176 2 types of withdrawal 1. Sedative-hypnotic withdrawal 2. Low-dose withdrawal Text, Fig 7-2  BDZ Withdrawal cont. Sedative-hypnotic withdrawal Occur with high doses > ~ 1 month Usually seen in benzodiazepines with short half-lives Usually gone 6mths) Duration 2 weeks or up to 1 year Usually come in waves Sensitive to resuming treatment Particularly notable symptoms anxiety panic irregular HB  memory  concentration  BP sensory sensitivity distortion of reality  BBT self-administration in animals Reinforcing properties demonstrated using various reinforcement schedules Reinforcement properties of short vs. long-acting barbiturates Monkeys  consumption until stable, then constant level of administration  BDZ self-administration in animals IV & oral Short & long-acting Not as reinforcing as BBTs Reinforcing properties can be enhanced by priming with the drug, BBTs or other BDZs Especially for longer-acting BDZs, past use determines how reinforcing they are  BBT self-administration in humans Experimental self-administration Not chosen more often than placebo in lab studies Reinforcing for those with a history of use Non-experimental self-administration 1. Street use: Usually in high-dose binges combined with other drugs Injected with heroin or amphetamines 2. Iatrogenic use: Initially prescribed for variety of symptoms Reinforcing properties lead to abuse & ‘doctor shopping’ Overall, BBTs are readily self-administered by humans  BDZ self-administration in humans Experimental self-administration Not chosen more often than placebo in lab studies even by those with high anxiety (exceptions: high dose (placebo > BDZ), P history, task demands) Non-experimental self-administration 1. Street use: Usually combined with another drug (esp. alcohol/ methadone) Rohypnol 2. Iatrogenic use: Prescribed for anxiety Overall, BDZs are readily self-administered by humans  Harmful effects of barbiturates & benzodiazepines  Harmful effects of barbiturates Reproduction: effects on babies (BBT in pregnancy): Baby needs to go through withdrawal when born – usual onset 7 days Birth defects Cleft lip & palate Abnormalities of heart, skeleton & CNS Brain weight Neurological development  later male sexual behaviour ( testosterone) Learning disabilities,  IQ, psychosocial problems  Harmful effects of barbiturates Overdose Low TI Additive effect with alcohol E.g., BAL.1 +.5mg secobarbital = lethal Poisoning Unconsciousness  HR & BP Blisters  urine flow  temperature regulation - hypothermia Respiratory depression  Respiratory Depression BARBS Coma/ Anesthesia BDZs Ataxia Sedation ETOH Anticonvulsant Anxiolytic DOSE  BDZ: harmful effects Reproduction Inconclusive research, but suggestion that BDZ may: Cause birth defects (e.g., cleft lip); stress response in rats across lifespan or Fetal benzodiazepine syndrome similar to FAS Malformed face Poor muscle tone Hand-eye coordination Tremors Delayed mental development Learning disabilities Withdrawal in infants similar to opiate withdrawal, start