Depressants Lecture Slides PDF

Depressants Dr. Karen Woodall Oct 10, 2024 Todays class 1. Depressant drugs – overview 2. Benzodiazepines 3. Z drugs 4. GHB 5. Death investigations 6. Midterm info  Central Nervous System (CNS) depressants are drugs that slow brain activity Depressan ts...

Depressants Dr. Karen Woodall Oct 10, 2024 Todays class 1. Depressant drugs – overview 2. Benzodiazepines 3. Z drugs 4. GHB 5. Death investigations 6. Midterm info  Central Nervous System (CNS) depressants are drugs that slow brain activity Depressan ts Includes: definition ◦ Sedatives ◦ Hypnotics ◦ Anxiolytics  Sedative drugs decreases activity, moderates excitement, and calms the individual Depressan ts Hypnotic drugs cause drowsiness and facilitate the onset and maintenance of sleep  Sleep-aids Anti-anxiety (GAD and panic disorders) Seizure control To calm individuals during Depressan emergency medical treatment ts - uses Pre-surgery Recreational use Criminal purposes Depressants - types Barbiturates Benzodiazepines Non-benzodiazepines GABA GABA is the major inhibitory neurotransmitter - receptors are found on most cells in the CNS. GABAA receptors regulate Cl– channels, increase Cl– flow into the cell resulting in hyperpolarization.  GABAA is an ionotropic receptor GABAA receptors GABA binds to the receptors and allows negatively charged chloride ions to enter the neuron, thus reducing its excitability Depressants - mechanisms of action GABAA agonists produce inhibitory postsynaptic potential, inhibiting cell firing. Drugs e.g. Barbiturates, benzodiazepines, Z drugs, have binding sites on the GABAA receptor complex and enhance the inhibitory effects of GABA.  Structurally, each receptor contains 5 subunits Typical GABAA receptors contain two α subunits and two ß subunits and one γ GABAA receptors There are multiple isoforms of each subunit e.g. α1-α6 GABAA recept or GABAA receptor subunits Drugs acting via GABAA receptors Benzodiazepines (BDZs) enhance the effect of GABA, but in the absence of GABA, they have no effect on channel opening. Barbiturates also increase the affinity of the GABAA receptor for GABA, and they can open the Cl– channel without GABA. This increases their toxicity compared to BDZs. Benzodiazepines The first BDZ to be introduced was chlordiazepoxide (Librium®). First true anxiolytic that targeted anxiety without producing excessive sedation. Low incidence of tolerance, and a wide therapeutic index. Benzodiazepines Flunitrazepam - (Rohypnol) Lorazepam - (Ativan ) Alprazolam - (Xanax ) Diazepam - (Valium ) Triazolam - (Halcion ) Clonazepam - (Clonapam ) Flurazepam - (Dalmane ) Chlordiazepoxide - (Librium ) Benzodiazepines Core chemical structure contains a benzene ring and a diazepine ring Molecular structure of several benzodiazepi nes and the benzodiazepi ne binding site antagonist flumazenil  Clinical features include but are not limited to: Agitation Aggression Paradoxica Violence l effects Impulsivity Irritability Confusion Lorazepam – adverse effects Information from product monograph: Benzodiazepine effects on the CNS are dose dependent, with more severe CNS depression with higher doses anterograde amnesia, drowsiness, fatigue, sedation, confusion, depression, unmasking of depression, dizziness, amnesia, disinhibition, paradoxical reactions (including anxiety, agitation, excitation, hostility, aggression, rage, sleep disturbances/insomnia, hallucinations) Paradoxical reactions – prevalence First reports of paradoxical reactions to benzodiazepines date back to 1961 The incidence of this adverse effect is hard to predict In a placebo-controlled study of alprazolam in the treatment of panic disorder, 13.7% of patients randomised to alprazolam experienced paradoxical reactions compared with no patients given placebo A study of the efficacy of alprazolam in borderline personality disorder, 58% of patients randomised to alprazolam experienced paradoxical reactions compared with 8% with placebo Paradoxical reactions – prevalence In a review of 45 controlled trials, no difference in the incidence of behavioural disinhibition between patients given triazolam, flurazepam and placebo Another review concluded that, in the general population, the incidence of aggressive dyscontrol after administration of a benzodiazepine is less than 1%, similar to the incidence with placebo, and because overt rage reactions are rare, they are difficult to quantify “Perhaps the single most important factor is underlying personality, as those with a history of aggression and poor impulse control may be more prone to experiencing paradoxical reactions to benzodiazepines” Report example Lorazepam (Ativan®) belongs to the benzodiazepine class of central nervous system depressants and is a drug available via prescription, primarily for the treatment of anxiety disorders1. Lorazepam is the generic name of the drug while Ativan® is a brand name; however, both contain the same active ingredient and would be expected to produce the same effects on an individual2. Typical doses of lorazepam range from between 1 to 4 mg/day and the specific effects will depend on an individual’s tolerance to the drug 3. Side effects may include memory loss (anterograde amnesia) drowsiness, fatigue, sedation, confusion, and depression4. The usual response when taking a benzodiazepine (including lorazepam) are relief from anxiety and a general calming effect; however, paradoxical reactions, also known as disinhibitory reactions may sometimes occur3. These types of reactions are uncommon and cannot be predicted but are the opposite to the typical drug effects and can include anxiety, excitation, agitation, hostility, and aggression3. Possible risk factors for experiencing a paradoxical reaction to a benzodiazepine include genetic factors, a history of alcohol abuse and certain psychiatric conditions 6. The concurrent use of alcohol has also been associated with paradoxical reactions to benzodiazepines5. It is possible that the use of lorazepam could produce a paradoxical Case 1 Death of Karissa Grandine Case Background She was 5 months pregnant when she was discovered in a bathtub by her husband The cause of death was drowning Toxicology report found therapeutic Lorazepam in her postmortem blood sample Thought s? Case background Her husband had been having an affair and had agreed to marriage guidance and to stop viewing on-line porn She had suspicions that he had not actually stopped the affair (or watching porn) Computer logs contain searches such as “Would 100 mg of Ativan be fatal?” “Will you die from 100 mg of lorazepam tabs” Case background He had allegedly drugged her twice previously and on one occasion she ended up in the ER department Judges comments Defense counsel went further and suggested that the jury must have found that the online inquiries concerning Ativan and lorazepam on October 14 and 15 reflected the accused’s interest in finding out what had happened to his wife on October 13 that necessitated her going to the emergency ward on October 14. Again, I see no reason to conclude that the jury must have made this finding of fact. Not only is the conclusion not necessarily implied by the jury’s verdict, it is without any factual foundation. No toxicological screen was performed on the blood taken from the deceased at St. Michael’s Hospital until after her death. That was so because, as earlier noted, Dr. Spence, a trained emergency room physician, said she was told nothing and observed nothing about Karissa Grandine to suggest a toxicological screen was necessary. Therefore, unless the accused knew that she had been given the drug (which presumably, could only be because he gave it to her), he could not have had any inkling on October 14 or 15 of the need to research lorazepam/Ativan as the possible cause of his wife’s distress. Z - drugs Zolpidem Zopiclone Zaleplon Z - drugs Prescription drugs used to treat insomnia Considered an ideal hypnotic drug* due to: Rapid onset of action (within 30 mins) Short half-life (1-7 hours) *An ideal drug to treat insomnia is a hypnotic during night- time without causing residual sleepiness during the daytime Pharmacology Agonist at the GABAA receptor Increases GABA activity (remember, GABA is one of the major inhibitory neurotransmitters in the CNS) Z-drugs bind to the same binding site as benzodiazepines, both of which rely on the presence of GABA to exert their effects—hence the term “GABAergic activity” Pharmacology Strong hypnotic qualities Poor anxiolytic qualities Pharmacology Drug Half- life Zolpide 2.5-3 m hrs Zaleplo 1 hr n Zopiclon 5-6 hrs Z - drugs Over the last 15 years increasing reports of complex and bizarre behaviour have lead to increased warnings associated with the drugs Hypnosedative-Induced Complex Behaviours Literature review (Dolder and Nelson 2008; 22 1021- 1035 CNS Drugs) Most commonly reported complex behaviours: ◦ Sleep eating ◦ Sleepwalking with object manipulation ◦ Sleep conversations ◦ Sleep driving ◦ Sleep sex ◦ Sleep shopping Incidence could be underreported – common theme is lack of memory of the incident upon waking next day  Gamma- hydroxybutyr ate (GHB)  Properties of exogenous GHB first described in the 1960’s Early studies showed it produced sedation and anesthesia but was not widely used 1980s - In North America it began to History be marketed as a nutritional supplement for body builders 1990s - OTC sales were banned 2000s - USA ScheduledⅠcontrolled substance  Drug classification: CNS depressant Exogenous drug Endogenous GHB neurotransmitter/neuromodulator  GHB: Appearance GHB Water After After shaking: shaking: appears appears viscous and clear bubbly Structure Structurally related to GABA Uses 1. Prescribed for sleep disorders e.g. narcolepsy 2. Illicit use: ◦ Club drug ◦ To facilitate sexual assaults ◦ Body builders Availability Prescription Sodium Oxabate (Xyrem®) GHB salt Oral solution, taken at night in 2 divided doses. The recommended starting dosage is 4.5 g per night up to a maximum dosage of 9 g per night Instructions - Take this medication only at bedtime and while in bed, as it may cause you to fall asleep too quickly. Do not walk around after taking this medication. Availability Illicit Easy to manufacture Powder or liquid Dose 1-3 g Forensic cases Sexual assaults Impaired driving Homicides Assaults General effects Rapid onset – within 30 minutes Sense of well-being Euphoria Sedation Amnesia Pharmacology Three different receptors GHB GABAA GABAB GABAB Receptor Exogeneous administration significantly elevates GHB concentrations in the brain Effects of GHB are blocked by GABAB receptor antagonists Only activated at high concentrations (weak agonist) G-protein coupled receptor G protein linked receptors Also called metabotropic receptors Cause K+ ions to flow out of the neuron and less likely to fire an action potential  Some studies show GHB can also act GABAA as partial agonists at some GABAA Receptor receptors  Confirmed in humans in 2007 The existence of a specific receptor for GHB was predicted by the action GHB of GHB and related compounds that Receptor primarily act on the GABAB receptor, but also exhibit a range of effects which were found not to be produced by GABAB activity. It was suspected of being produced by a novel receptor GHB Receptor G-protein coupled receptor At low doses, GHB binds almost exclusively to the GHB receptor, stimulates the release of glutamate As the dose of GHB increases, GHB binds to, and activates, the GABAB receptor. This leads to the sedative/hypnotic effect of GHB May explain why people who take GHB to sleep would wake up 2-3 hours after dosing. After the initial dosing, the GABAB receptor was being stimulated, leading to CNS depression, but as the GHB concentrations decreased, the excitatory GHB receptor became the main receptor being activated  From Erowid: The doctors and emergency room people had never seen a case of GHB poisoning before. They had absolutely no knowledge about the situation and were entirely unwilling to listen to the information or suggestions the friend had. They said he would be in a coma for '1-2 days' and wouldn't even begin to listen when told GHB that a GHB coma lasts 3-6 hours. As predicted the individual awoke at T+4 induced hours, and was fully conscious and ready coma to go at T+6 hours. It took a very intense and determined fight with the hospital to get them to release the individual. This hospital visit cost 8300$. The whole experience was pretty unwanted and unpleasant, but when put in the position of making decisions like that, I can't imagine deciding to let someone who is in a coma, convulsing, vomiting, and aspirating their vomit to just lie there.  Endogenous vs exogenous Endogenous: Pharmacolo GHB receptors gy Exogeneous: GABAB receptors Pharmacology Very short half life 30 – 60 mins Presence of GHB in various beverages Highest in red wines vs white The amount found in wine is pharmacologically insignificant and not sufficient to produce psychoactive effects Other items: Soy sauce Grape juice Forensic significance If GHB in a non-biological item is not pharmacological significant why does it matter? Death investigations Role of psychoactive drugs in death investigations Accidental Motor vehicle collisions SIU investigations Workplace deaths Homicides For the following cases: 1. Do you think testing for psychoactive drugs is relevant? 2. Would additional information be helpful in deciding what (if any) analyses should be conducted? If so, what additional questions would you want to ask? 3. If you do think drug testing is relevant, what drug categories would you test for and why? Example 1 - Traumatic injury History: A person is found outside an apartment building. There are obvious signs of trauma, paramedics arrive and transport the individual to hospital. The individual is a male and he is pronounced dead shortly after arrival at hospital. Additional history - he lives in an apartment on the 12th floor. Approximately 30 mins before his body was discovered he was seen on cctv footage from the lobby acting erratically. Example 2 - Workplace death A construction worker falls from scaffolding at a work site and is pronounced dead at the scene. At autopsy, cause of death is determined to be blunt force trauma. The ministry of labour is called in to investigate the company. Allegations were made that the individual was not using mandated safety equipment. Midterm info In class 11:10 a.m. to 12:40 p.m. 30 multiple choice questions 4 short answer questions (total 15 marks) 2 case interpretations (total 15 marks) No class after the midterm You may answer in point form Good luck!