L12: CNS stimulant & depressant

Addictive drugs increase ___ release in the Mesolimbic pathway

Dopamine

Drug dependance MOA

Increase in glutamate receptors and structural proteins after previous overstimulation (increased glutamate release via sensory cues) from drug abuse

Mechanism of Relapse

• Occurs when cellular excitation in the Nucleus Accumbens (NAc) is retriggered

  • Stress → DA release from VTA

  • Sensory cues → release glutamate

  • Drug re-exposure → reactivates sensitized circuitry

Alcohol acute use

• GABA(A) receptor positive allosteric modulator → inhibits neuronal function

• Limits NMDA receptors

Alcohol withdrawal mechanism

• Decreased GABA inhibition

• Increased Glutaminergic excitation

• Expressed as anxiety, insomnia, & seizures

Alcohol withdrawal Sx

• Tremor, Tachycardia, Sweating, Hallucinations, HTN

• Chronic alcohol abuse → respiratory depression & death from overdose

Alcohol metabolism

• Alcohol → Acetaldehyde via ADH → Acetate via ALDHD

  • Dehydrogenases

• Genetic influences

  • Alcohol dehydrogenase ADH1B*2 and ADH3 → higher metabolism

  • ASP40 of mu receptor → enhanced euphoric response

What type of Benzos are needed to treat Alcohol withdrawal

Long-acting

(Chlordiazepoxide, Clorazepate, Diazepam, Oxazepam)

Which mu-opioid receptor antagonist cannot help treat alcohol withdrawal

Naltrexone (do not give if already taking opioids)

Disulfiram for alcohol withdrawal

• Inhibits Aldehyde Dehydrogenase (ALDH)

• Accumulates acetaldehyde

  • N/HA, Orthostatic hypotension, Vomiting, Respiratory difficulty

• Only for abstinent patients

Acamprosate for Alcohol withdrawal

• “artificial alcohol” to relieve symptoms by blocking glutamate receptors → enhance GABA signaling

• Only for abstinent patients

• Contraindicated in severe myocardial disease, coronary occlusion, pregnant/nursing women

Cocaine MOA

Blocks reuptake of dopamine transporter (DAT) → increased DA effect → intense euphoria

Cocaine formulations

• Buccal & Intestinal mucosa → lower absorption

• Nasal mucosa → rapid absorption

• IV / Inhalation → rapid rise in plasma & high peak concentration

“Speedball” → deadly if overdose

Cocaethylene (Cocaine + Alcohol)

Cocaine toxicity AEs

Hyperthermia, Convulsion, Chest pain

Treatments for Cocaine withdrawal

• Diazepam & Lorazepam

• Despiramine (TCA) & Fluoxetine (SSRI) → reduce drug craving

• Disulfiram & Topiramate (antiepileptic)→ cocaine dependence

• Bupropion (antidepressant)

Amphetamine MOA

• stimulates presynaptic neurotransmitter release

• Inhibits NE/5-HT/DA reuptake

• Similar neuro & clinical effects as cocaine

Methamphetamine (meth, crystal, chalk, ice) AEs

Long-term use → extreme weight loss, severe dental issues (meth mouth), skin sores via scratching

3,4-methylenedioxy-methamphetamine (MDMA, Ecstasy, Molly) effects

• stimulant & hallucinogenic by blocking 5-HT reuptake

• Toxic effects → dehydration, renal failure, hyperthermia, serotonin syndrome

Treatment for Methamphetamine Dependence

Naltrexone and Bupropion

Lysergic acid diethylamide (LSD) MOA

• Activates 5-HT 1 & 2 And Sympathetic nervous system

  • Hallucinogenic

  • causes Mydriasis (dilated pupils), increased body temp and blood sugar

LSD AEs

Mood alternations, Sleep disturbances, Severe anxiety, Intense depression, Suicidal thoughts, and Schizophrenic episode

Chronic LSD use

Temporary psychosis or psychedelic crisis “bad trip”

Treatment for LSD

Diazepam

Benzo & Barbiturate indications

• sedative & hypnotic agents

• Euphoric feelings

• Barbiturate overdose are common in geriatric suicide

Benzo & Barbiturate withdrawal symptoms

• Seizures, Sleep disturbance, Dizziness, Fear, Panic

• Severe withdrawal → rapidly eliminated compounds (Triazolam and Amobarbital)

• Less severe → slower eliminated compounds (diazepam, phenobarb)

Benzo + Alcohol reaction

Fatal from synergistic effect on respiratory depression

Benzo + ___ results in respiratory arrest

Buprenorphine

Benzo withdrawal treatment

Phenobarbital loading dose

OR

Long-acting Benzo tapering dose

High dose nicotine AEs

Respiratory paralysis

Nicotine indication

Alleviate symptoms of depression and anxiety

Nicotine replacement therapy

• Nicorette gum/lozenge, nicotine patch and nasal spray

  • Low absorption levels

• Varenicline (chantix)

  • Partial nicotinic RA → prevents stimulation of mesolimbic DA pathway

  • alleviates cravings & withdrawal Sx

• Bupropion

  • Inhibits Epi & DA reuptake of nicotinic ACh receptors (nACh)

Phytocannabinoids (THC, CBD, CBN, CBDV, CBG) MOA

• THC → activates CB1 & CB2 receptors→ psychoactive

• Cannabidiol act as a negative allosteric molecule for CB1 receptor → inhibits CB1R action

CB1 receptor reward pathway activation

• Enhance DA release in NAc

• activation → decrease GABA release → activates DA

Rimonabant MOA

CB1 antagonist

Dronabinal (Marinol, Syndros) MOA

• synthetic THC

• CB1R agonist → relieve nausea & vomiting in chemotherapy

• Reversed severe weight loss in patients with AIDs → increase food intake

Epidiolex Indication

• Cannabidiol used for seizures associated with Lennox-Gastaut syndrome or Dravet syndrome (2yo+)

Epidiolex MOA

• Blocks GPR55 receptors

• Desensitized TRPV1 channels → promotes neuronal depolarization

• Inhibits Adenosine reuptake