lecture 8 - depressants: anxiolytics & ethanol

anxiolytics

reducing anxiety (reduces brain activity)

anxiety: showing rapid increases in college-aged populations

• spike in anxiety of Gen Z around 2014

• regular for milenials & Gen X

barbituates

addictive, prone to overdose, heavily sedating, first prescribed for anxiety, dangerous w/ alcohol

Benzodiazepines: some history

• drugs first created in 1957, first big blockbuster drug in this category was diazepam (valium) in 1963

  • less of everything of barbituates

  • Valium was most prescribed psychotropic until 1980s, earning $600M/yrs. at its peak

  • others followed that differed mainly by duration

    • alprazolam (Xanax) - short

    • clonazepam (Klonopin) - intermediate

    • diazepam (Valium) - long

      • contains active metabolites

    • in schedule IV

Depressants & GABA_A Receptor Complex

• benzodiazepines & ethanol are positive allosteric modulators (PAMs) for GABA_A receptors

• Hypofunction of GABA_A receptors (genetic?) may increase risk of anxiety/anxiety disorder

• current research is looking at GABA_A receptors to target subunit sites for sedation vs. anxiolytics vs. cognitive impairment

Benzodiapines: sites of action in the brain

• high amount of GABA receptors in the amygdala

• Brain areas high in GABA receptors

  • anxiolytic effects: limbic system → amygdala, orbitofrontal cortex (OFC), cingulate cortex

  • side effects:

    • prefrontal cortex → cognitive

    • hippocampus - amnesia

    • brainstem - sedation 

• evidence: increased amygdala activity during anxiety; reduced GABA_A receptor binding found in PTSD or panic disorder patient

benzodiazepines: side effects, overdose, NEW FDA Warning

• overdose deaths have been increasing

• FDA putting out more warnings

Top Psychiatric Medications for Anxiety

most drugs now treated for anxiety are anti-depressants

“3rd-Generation” Anxiolytics: Trazodone & Buspar

• trazedone (Desyrel) → FDA-approved for depression, off-label (but increasingly common) for anxiety

  • unique mechanisms of action by: inhibiting-SERT [serotonin transporter] while also being a 5-HT₂ antagonist

  • side-effects: less sexual side effects & sedation comapred to SSRIs as only half of NE & histamine receptors blocked

• buspirone (Buspar) → unique as partial agonist at pre-synaptic 5-HT₁ receptors

  • 2-3 wks for therapeutic effect 

  • less side effects than other anxiolytics

  • non-sedating, no amnesia, no significant interactives w/ other GABAergic drugs or alcohol, low abuse potential

Alternatives to Drugs: MBSR

• both groups showed reduction in anxiety

• MBSR treatment had equivalent effect to drugs

Pharmcokinetics: Ethanol Administration & Distribution

• oral administration: rapid absorption stomach, intestines

  • dose: “serving” or “drink” defined as alcohol by volume (ABV%) or in grams (14 grams)

• some ethanol absorbed rapidly from stomach, most through upper intestine; food slows absorption, allows enzymes more metabolization

  • ethanol irraitates stomach, increases hydrochloric acid & pepsin

• distribution: distributes easily throughout body fluids & tissues; both water & lipid soluble

  • ethanol freely penetrates BBB; placenta as well

Pharmcokinetics: Ethanol Metabolism

• Metabolism: 20% occurs in stomach as first-pass metabolism remaining 80% occurs in liver

1. Ethanol → Acetaldehyde

• by alcohol dehydrogenase (ADH)

2. Acetaldehyde → Acetic Acid

• by aldehyde hydrogenase (ALDH)

3. Acetic Acid → CO2 & H2O

• by adenosine triphosphate (ATP) (source of calories)

• Ethanol metabolism depends on (short-term) limited pool of enzymes, along w/ sex, ethnicity, BW, individual metabolism, etc.

  • ~30-120 mins/dose

  • ~25% of tolerance due to ADH up-regulation

  • disulfiram (Antabuse) can treat alcoholism by enzyme inhibition of ALDH

Ethanol: Metabolism

• Sex Differences: women have higher BAC w/ some # of drinks

  • (~7% increase in BAC compared to men); due to average higher body fat %, lower alchol dehydrogenase enzymes in stomach

• Ethnic Differences: high % of East Asians (Japan, Korea, Parts of China) have mutations aldehyde dehydrogenase (ADH) gene

  • even small amounts ethanol = headache, dizziness, skin flush, rapid HR, nausea

Hangover Causes: Dehydration, Headache, Fatigue

• main psychological causes of hangover:

  • headache: dilution of blood vessels surrounding brain; increased levels of 5-HT (implicated in migraines) & histamines 

  • dehydration (“cotton mouth”): nausea, dizziness, thirst, weakness; ethanol blocks pituitary vasopressin (antidiuretic hormone)

  • fatigue: low dose ethanol sedates, but sleep quality reduced REM sleep & increased BPAR, sudden drops in blood sugar

isn’t some alcohol good for you? Brain shrinkage?

shows less gray & white matter w/ more than 1 drink/day

Pharmacodynamics: inhibition of brain activity in 2 ways

• positive allosteric modulators (PAM) @ GABA_A receptors

• negative allosteric modulators (NAM) @ Glu NMDA receptors

  • “sluggish” Glu receptors, prevents flow of Na+, Ca2+

  • during withdrawal → Glu over excitation can induce seizures (possibly fatal)

• ethanol also causes mesolimbic DA release esp. 1st doses 

• chronic alcohol downregulates GABA_A receptors & upregulates NMDA_Rs (increases stress response) 

• Ethanol heavily affects:

  • frontal lobes: impaired EF (impulse control, judgement, WM)

  • amygdala: relaxation, sociability

  • hippocampus: interferes with attention & memory

  • cerebellum & caudate-putamen: impaired coordination, movement

treating alcohol dependence

• naltrexone (Revia): opioid antagonist can reduce desire for alcohol

• Glu NMDA antagonists & GABA agonists drugs have been evaluated (original use as anti-seizure & migraine drugs)

  • topiramate (Topamax): decreases heavy drinking drugs 

  • acamprosate (Campral): 1st drug designed both for detoxification & increasing abstinense from alcohol