Toxicity of CNS Depressants and Stimulants (Test 1)

OD of benzos

A 23yo is ready for a night at the concert. She had a couple shots of alcohol with her friends, and is starting to feel great. Right before leaving to the concert decides to pop Xanax or two. When walking into the venue, she is having balance issues and her speech is slurred. Her friends laugh and call her a lightweight, until she falls over and her breathing becomes shallow.

•What may be happening?

yes, Flumazenil

A 23yo is ready for a night at the concert. She had a couple shots of alcohol with her friends, and is starting to feel great. Right before leaving to the concert decides to pop Xanax or two. When walking into the venue, she is having balance issues and her speech is slurred. Her friends laugh and call her a lightweight, until she falls over and her breathing becomes shallow.

Is there an antidote?

Alcohol withdrawl

A 22yo is fresh out of college and ready to start his new job. He decides its time to put away the nightly beer and "clean up his act" before the job begins. Feeling energized, he hits the gym and stocks up at Whole Foods. The next day, he starts to feel anxious; his heart rate is elevated and he feels clammy. He gets increasingly more irritable throughout the day and is starting to panic.

•What may be happening?

alcohol withdrawl

A 22yo is fresh out of college and ready to start his new job. He decides its time to put away the nightly beer and "clean up his act" before the job begins. Feeling energized, he hits the gym and stocks up at Whole Foods. The next day, he starts to feel anxious; his heart rate is elevated and he feels clammy. He gets increasingly more irritable throughout the day and is starting to panic.

•Is there a treatment?

OD on opioids

You are at a party and see someone passed out on the couch. No one seems to notice but as you walk by, you note that their face is pale and lips are slightly blue. As you get close, you hear they are making a slight gurgle sound. You try to wake them up and their body is limp and unresponsive.

•What may be happening?

yes, Naloxone

You are at a party and see someone passed out on the couch. No one seems to notice but as you walk by, you note that their face is pale and lips are slightly blue. As you get close, you hear they are making a slight gurgle sound. You try to wake them up and their body is limp and unresponsive.

•Is there an antidote?

neurotoxicology

Study of the adverse structural or functional effects of chemical, biological, or physical agents on the nervous system across the lifespan

structural complexities in the nervous system

•Cells with complex geometry

•Communication across extracellular space at the synapse

•Blood brain barrier

-structural complexities

-high metabolic rate

-high brain lipid levels

-limited potential for repair restricts its compensatory ability

-long distances over which electrical impulses must be transmitted, coordinated, and integrated

What are the specialized requirements and unique vulnerabilities in the nervous system?

-disrupt structure

-disrupt energy

-damage lipids

-kill cells

-interfere with transmission

What do toxins do?

neuronopathy

•Injury or death of neuron

•CO, EtoH Pb, methyl mercury, carbon tetrachloride, ROS

axonopathy

•Site of injury/toxicity is axon

•Degeneration of axon, but soma remains intact

•CS2, acrylamide, gold, organophosphates

myelinopathy

•Edema within the myelin or demyelination

•Lead, drugs (amiodarone, disulfiram, etc)

neurotransmission anomaly

-altered electrical signaling

-altered chemical signaling

(stimulants, depressants, nicotine, etc) and toxins (tetrodotoxin, omega-conotoxin -> cone snail, Botox)

Functional deficits in neurotoxicity can be induce by what drugs?

alcohol

-CNS depressant

-can precipitate both short-term and long-term toxicity

-People who misuse ________ have a greater risk of liver disease, heart disease, depression, stroke, and stomach bleeding, as well as cancers of the oral cavity, esophagus, larynx, pharynx, liver, colon, and rectum.

alcohol poisoning

-can occur within hours of consumption

-hyperhidrosis, impaired or loss of consciousness, unresponsive, hypothermia, cyanosis, pallor, failed gag relex, bradycardia, slow/irregular breathing, vomiting, seizures

EtOH (alcohol_

-small and water soluble

-readily absorbs in stomach and small intestine

-distributes in the water content of the body

-reduces neural excitability in most brain regions

-forces GABA-A open

prefrontal cortex disinhibition

What is affected if you have low concentrations of EtOH?

depression of entire cortex (loss of consciousness)

What is affected/what happens if you have increasing concentrations of EtOH?

depress activity of entire cortex (loss of vital control, respiratory depression)

What is affected/what happens if you have increasing concentrations of EtOH?

inhibitory; excitatory

Alcohol depresses CNS activity and promotes ____________ neurotransmission and inhibits ______________ transmission.

vomiting

Increased blood alcohol and the EtOH metabolite acetaldehyde leads to 5-HT3 and D2 activation in the CTZ which results in what?

NO

Is there an antidote for treating alcohol poisoning?

false

Shower, stimulants, and other forms of trying to work it out, may be more beneficial when treating alcohol poisoning. T or F

limited

Gastric lavage and activated charcoal have a

_________ window of potential efficacy given ease of absorption of alcohol.

benzodiazepines

-CNS depressants

-were developed for clinical use as sedatives and hypnotics

-also called tranquilizers, anxiolytic

-positive allosteric modulators of GABA-A

-have a wider/larger TI

sedative

CNS depressant that 'calms or soothes' for anxiety, panic attacks, muscle relaxation

hypnotics

CNS depressant that 'puts to sleep' for insomnia and PTSD

signs of benzo overdose

•Slurred speech

•Ataxia

•Impaired or loss of consciousness

•Unresponsive

•Hyperhidrosis- clammy skin

•Hypothermia, cyanosis, pallor

•Bradycardia

•Slow or irregular breathing

Flumazenil (Romazicon) and also do vital support

What is the antidote for a benzodiazepine overdose?

Flumazenil

•MOA: Antagonist of benzodiazepine binding sites on GABAA-R

•Unfortunately, frequently not used due to concerns of increased seizure risk and other severe withdrawal phenotypes

•Will not reverse the effects of other toxicants that may have been combined with the BZD

Opioids

-lead to similar phenotypes as CNS depressants BUT THEY ARE NOT

-used primarily for pain, some used for coughing or diarrhea

-endogenous

-natural product

-synthetic

What are the types of opiods?

endogenous

endorphins

natural product opioids

opium from poppy, mitrafynine, salvinorin

MOA of opioids

act as agonist of our endogenous opioid receptors

MOR (mu opioid receptor)

is expressed in the PNS, spinal cord, brain regions regulating pain response (euphoria and reward regions), and brainstem

signs of opioid overdose

•Small, constricted "pinpoint pupils"

•Falling asleep or loss of consciousness

•Slow, shallow breathing

•Choking or gurgling sounds

•Limp body

•Pale, blue, or cold skin

6 fold

Number of opioid OD death increased ________ between 1999-2021.

75%

What % of OD deaths in the US in 2021 involved opioids?

Naloxone (Narcan, Kloxxado) and Nalmefene (Opvee)

What are the antidote options for an opioid OD?

Naloxone MOA

opioid receptor antagonist

-some forms available in otc

Nalmefene MOA

opioid receptor antagonist

stimulant

-a substance that increases CNS activity

-also called psychostimulants or uppers

mechanism of stimulants

increase the release and/or availability of NE and DA in neural synapses

-causes increased fight or flight response

signs of stimulant toxicity or overamping

•Dilated pupils

•Increased HR, BP, and RR

•Hyperthermia

•Dizziness and confusion

•Tremor

•Irritability, mood swings, panic, extreme anxiety

•Nausea and vomiting

•Chest pains or tightness

•Hallucinations, psychosis, delirium

•Seizures

NO

Is there an antidote of stimulant toxicity?

treatment options for stimulant toxicity

•Calming practices

•Maintaining hydration

•Lowering body temperature to reduce complications of hyperthermia

•Activated charcoal if ingested

•ED may utilize BZDs to depress CNS and stop/prevent seizures

3rd

Overdose with an anti-depressant is the _______ leading cause of suicide.

anti-depressent OD MOA

•most anti-depressants increase the availability of serotonin. Too much serotonin can lead to "Serotonin Syndrome"

•Overstimulation of 5-HT receptors in brainstem

serotonin syndrome

•Impaired cognition- mild to delirium and coma

•Hypertension, tachycardia, diaphoresis

•Somatic system responses- rigidity, myoclonus, tremor

tricyclic antidepressants OD

alter cardiac sodium channels leading to arrhythmia, BP changes, and seizures

class

Antidote availability for anti-depressant ODs depends on the ____________ of the anti-depressant.

Cyproheptadine

can be used to antagonize certain serotonin receptor overdoses

Sodium bicarbonate

can be used to uncouple tricyclics from the cardiac ion channels

vital sign support and emptying gastric contents with gastric lavage or activated charcoal (maybe anti-seizure meds or BZDs to reduce seizure risk)

How are anti-depressant overdoses typically treated?

substance use disorder

defined by experiencing at least 2 of the symptoms in a giver year

(impaired control, social impairment, risky use of substance, pharmacological criteria)

addiction

chronic, relapsing disorder characterized by compulsive drug seeking and use despite adverse consequences (NIH)

substance use disorder pathology

involves functional changes to brain circuits involved in reward, stress and self-control

tolerance

•When the person no longer responds to a dose of the drug in the way that person initially responded

•Often due to changes in circuitry

physical dependence/withdrawal

-Continued administration is needed to prevent withdrawal syndrome

-Increased heart rate, hypertension, sweating, tremor, confusions, seizures

(Can occur with prescription and non-prescription medications)

NOT (THEY ARE DIFFERENT)

Tolerance and dependence are ___________ interchangeable.

•Intervention programs/plans

•Pharmacotherapies (for withdrawal too)

•Psychotherapies

How are substance use disorder and dependence treated?

chronic

Relapse happens in ________ disease. Can be life threatening if dosing was based on a tolerant state (overdose common).

OUD intoxication

•Recent opioid use and problematic behavioral or psychological changes

•Constriction of pupils in addition to one of the following:

•Drowsiness or coma

•Slurred speech

Diminished attention or memory

OUD Withdrawal

•Cessation or reduction of heavy or prolonged use OR administration of an opioid antagonist

•3 or more of the following:

•Dysphoria

•N/V

•Myalgias

•Lacrimation or rhinorrhea

•Mydriasis, piloerection, or sweating

•Diarrhea

•Yawning

•Fever

Insomnia

-supportive care

-begin maintenance meds (buprenorphrine, methadone)

How do you treat opioid withdrawal?

Naltrexone (Revia, Vivetrol)

•MOA- opioid receptor antagonist

•Indication: Alcohol use disorder and opioid use disorder

Buprenorphrine (Subutex, Butrans, Probuprhine, Sublocade, Buprenex, Bulbuca)

•MOA- partial MOR agonist

Indication: Opioid use disorder, pain management

Methadone (Methadose, Dolaphine)

•MOA- opioid receptor agonist and NMDA-R antagonist

•Indication: Opioid use disorder, short-term opioid withdrawal, chronic pain management

15 drinks/week

What is the CDC definition of "heavy alcohol use" for men?

8 drinks/week

What is the CDC definition of "heavy alcohol use" for women?

greater than or = to 5 drinks in one sitting

What is the CDC definition of "binge drinking" for men?

greater than or = to 4 drinks in one siting

What is the CDC definition of "binge drinking" for women?

AUD Intoxication

•Recent alcohol use and problematic behavioral or psychological changes

•One or more of the following occurs:

•Slurred speech

•Incoordination

•Unsteady gait

•Nystagmus

•Inattention or memory impairment

Stupor or unconsciousness

AUD withdrawal

•2 or more of the following occur after cessation or reduction of use:

•Autonomic hyperactivity

•Hand tremor

•Insomnia

•Hallucinations or illusions

•Psychomotor agitation

•Nervousness

Seizure activity

Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar)

What is used to assess withdrawal severity in alcohol withdrawal treatment?

mild withdrawal, med not necessary

If you have a CIWA-Ar score of < 8 then what?

moderate-severe withdrawal, med indicated

If you have a CIWA-Ar score of > 8 then what?

BZDs (symptom triggered dosing) in addition to multivitamin and thiamine

What is the treatment of choice for alcohol withdrawal treatment?

Naltrexone (ReVia, Vivetrol)

•MOA- opioid receptor antagonist

•Indication: Alcohol use disorder and opioid use disorder

Disulfiram (used to be called Antabuse)

•MOA- aldehyde dehydrogenase inhibitor

•Boxed warning- never administer when intoxicated or without their knowledge

•AE is the desired effect- throbbing in head and neck, flushing, nausea, vomiting, thirst, confusion..

•Indication: Alcohol use disorder

Acamprosate (used to be called Campral)

•MOA- unclear.. Similar structure to GABA so likely GABA related

•Does not cause negative effects like disulfiram, simply reduces alcohol intake

•Indication: Alcohol use disorder