Sedatives & Alcohol

BIOM 3090

What is anxiety, and what feelings are associated with it?

Anxiety is defined as feelings of apprehension, tension, uncertainty, dissatisfaction, and fear

What are the 5 main types of anxiety disorders?

1. PD (panic disorder): frequent, spontaneous attacks + avoidance

2. GAD (generalized anxiety disorder): constant worry & physical symptoms

3. OCD (obsessive compulsive disorder): excessive, repetitive thoughts & behaviours

4. SP (social phobia): embarrassment & humiliation in social situations

5. PTSD (Post traumatic stress disorder): thoughts and experiences of a horrible event

Common symptoms of a panic attack

• Palpitations

• Sweting

• Trembling

• Shortness of breath

• Choking

• Chest pain

• Nausea

• Dizziness

• Fear of losing control, fear of dying

• Paresthesias (pins/needles)

• Hot/cold flashes

What are the main treatments for anxiety disorders?

• Medication

• Psychotherapy

• Cognitive Behavioural Therapy (CBT)

How is anxiety secondary to other disorders like psychosis or depression best treated?

By treating the primary illness causing the anxiety

What are the main types of sedative-hypnotics used to treat anxiety?

Benzodiazepines and barbiturates

What is an anxiolytic?

An anxiolytic is a sedative drug that produces a calming effect and relief of anxiety with little or no effect on motor or mental function

What is a hypnotic?

A hypnotic is a drug that produces drowsiness and induces sleep

According to the dose-response curve, which drug has the highest risk of respiratory death with increasing dose?

Barbiturates - their curve continues steeply to respiratory depression and death

What does the graph indicate about benzodiazepines compared to barbiturates and ethanol in terms of safety?

Benzodiazepines have a plateau in their dose-response curve, indicating a lower risk of fatal respiratory depression at high doses compared to barbiturates and ethanol

What is the brand name of diazepam?

Valium

Describe the phase I metabolism of Diazepam

Phase I involves oxidation by cytochrome P450 enzymes, and all metabolites produced are active

What happens during phase II metabolism of diazepam?

Oxazepam undergoes conjugation with glucuronide to become more water-soluble for excretion

What are the active metabolites of diazepam?

Nordazepam, Temazepam, oxazepam

What is a key pharmacokinetic feature of many benzodiazepines, including Diazepam?

They undergo first-pass metabolism where oxidation leads to active metabolites

What is the primary action of benzodiazepines on neurotransmission?

They enhance GABA neurotransmission

How do benzodiazepines enhance GABA neurotransmission?

They bind to a subset of GABA_A receptors at a site distinct from GABA (GABA binds to the same receptor but at a different part, making the receptor more responsive to GABA)

What effect does benzodiazepine binding have on GABA_A receptors?

It increases the frequency of GABA-mediated Cl- channel opening

Can benzodiazepines activate GABA_A receptors by themselves?

No- they require GABA to be present in order to exert their effect

What happens to Cl- influx when benzodiazepines and GABA both bind?

Cl- channels open more frequently, increasing inhibitory effects

What is an example of a barbiturate?

Phenobarbital

How does the safety margin of barbiturates compare to benzodiazepines?

Barbiturates have a smaller margin of safety than benzodiazepines

Describe the pharmacokinetics of barbiturates

• Phase I: Oxidation by cytochrome P450

• Phase II: conjugation with glucuronide (body prepares it for removal)

Are barbiturate metabolites active?

Metabolites are generally not active

What is the unique pharmacokinetic property of barbiturates regarding liver enzymes?

Barbiturates increase the expression of cytochrome P450 enzymes

What is the mechanism of action of barbiturates?

Enhance GABA neurotransmission

How do barbiturates interact with GABA_A receptors?

Bind to all GABA_A receptors at a site distinct from both GABA and benzodiazepine binding sites

What affect does barbiturate binding have on GABA_A receptors?

Increases the duration of opening of the GABA-mediated Cl- channel

What can barbiturates do at high doses?

• Directly activate GABA_A receptors

• Inhibit glutamate receptors

• Inhibit some sodium and calcium channels

What is the overall effect of enhancing Cl- conductance in neurons?

Increased inhibition of many neurons in many brain regions

What is the effect of GABA binding to GABA_A receptors?

Opens Cl- channels, causing Cl- influx and hyperpolarization of the neuron

What is the structural composition of the GABA_A receptor?

It is a chloride ion channel composed of five subunits (alpha, beta, gamma) forming a central pore

What do benzodiazepines and barbiturates bind on the GABA_A receptor?

• Benzodiazepines bind at a site between the alpha and gamma subunits

• Barbiturates bind at a different allosteric site on the receptor

What are sedative-hypnotics commonly used to treat in psychiatric conditions?

Anxiety and psychosis (initial management)

How are sedative-hypnotics used in the treatment of sleep disorders?

They are used to treat insomnia

What is the role of sedative-hypnotics in surgical settings?

• Induce sedation and amnesia prior to surgery

• Used as a component of total anesthesia

How are sedative-hypnotics useful in neurobiological conditions?

• Epilepsy: control seizures

• Muscle relaxation: reduce muscle spasms or rigidity

What role do sedative-hypnotics play in substance use disorders?

They are used in the management of alcohol withdrawal

What is the dose-dependent effect of sedative-hypnotics on the CNS?

They can cause impaired judgment/motor skills → amnesia → coma → death

Why should sedative-hypnotics not be combined with other CNS depressants (eg. opioids, alcohol, antihistamines)?

They can cause additive CNS depression, increasing the risk of severe side effect like respiratory depression or death

What occurs with prolonged use of sedative-hypnotics?

Withdrawal symptoms may develop when the medication is stopped

Who is at increased risk of adverse effects from sedative-hypnotics?

Individuals with impaired liver function (due to impaired drug metabolism)

What is meant by tolerance in the context of sedative-hypnotics?

Over time, higher doses are needed to achieve the same effect

How do barbiturates affect drug metabolism?

They alter metabolism of both themselves and other drugs via induction of cytochrome P450 enzymes

What role does the endocannabinoid system play in anxiety regulation?

It regulates anxiety and stress response by dampening excitatory signals that involve the neurotransmitter glutamate

How do exogenous cannabinoids from marijuana affect anxiety?

They can reduce anxiety initially

What happens with chronic use of marijuana?

Chronic use down-regulates cannabinoid receptors (highly expressed in the amygdala), which paradoxically increases anxiety

What vicious cycle can chronic marijuana use create in anxiety?

It can lead to increased marijuana use to relieve the now-heightened anxiety, sometimes resulting in addiction

Define endocannabinoids and where they are produced

• They are lipid neuromodulators

• Produced on-demand in the postsynaptic neuron

How do endocannabinoids regulate neurotransmitter release?

• Act retrogradely: released from postsynaptic neuron and bind to CB1 receptors on presynaptic terminal

• Cause inhibition of transmitter release (GABA or glutaamate)

• Supress excitatory signaling

How does Marijuanna affect CB1 receptors

• Compounds in marijuana (like THC) activate CB1 receptors

• mimic endocannabinoid activity

• can reduce neurotransmitter release (initial anxiolytic effect)

What happens to endocannabinoids after release?

• Rapidly metabolized by fatty acid amide hydrolase (FAAH)

• helps limit duration of their effect

What are the acute effects of ethanol on the CNS?

• Dose dependent CNS depression:

  • decreases membrane excitability

  • Increases GABA_A activation

  • decreases NMDA activation

• Results in decreased anxiety, slurred speech, impaired judgement

What are other acute effects of ethanol beyond the CNS depression?

• Diuresis (increased urine)

• Initial increase followed by decreased in myocardial contractility (muscular heart tissue)

  • Toxic doses lead to CNS and respiratory depression

What are the chronic effects of ethanol on the body?

• Fatty liver → hepatitis → cirrhosis → liver failure

• Pancreatitis & gastritis

• Malnutrition

How is ethanol primarily metabolized in the body?

• Over 90% is metabolized by the liver via oxidation

• Major pathway: alcohol dehydrogenase

• Minor pathway: Cytochrome P450 (MEOS = microsomal ethanol oxidizing system)

How much ethanol is excreted unchanged, and by which organs?

• less than 10% excreted unchanged

• via kidney and lung

What type of kinetics does ethanol elimination follow and what does it imply?

• Zero-order kinetics

• Clearance rate is constant, regardless of concentration

• So, blood ethanol levels continue to rise if consumption exceeds elimination

Why is ingesting hand sanitizer dangerous, and what type of poisoning can it cause?

• Ingesting alcohol-based hand sanitizer can cause methanol poisoning

• methanol is toxic and can lead to impaired vision, seizures, hospitalization or death

• It should never be ingested

What makes methanol toxic and how is methanol poisoning treated?

• methanol has CNS depressant effects similar to ethanol

• metabolized to formic acid, which accumulates in the retina leading to optic nerve damage which can lead to blindness

  • Treatment: ethanol

Why is ethanol used as a treatment for methanol poisoning?

• Ethanol competes with methanol for alcohol dehydrogenase and has a higher affinity for it

• Slows methanol metabolism which reduces the production of toxic formic acid