CNS DEPRESSANTS - ANXIOLYTICS

CNS Depressants:
Dose Dependent Therapeutic Effects
Anti-anxiety LOW DOSE
Euphoria/Disinhibition
Sedation
Anticonvulsant
Muscle relaxation
Anesthesia
Coma
Death HIGH DOSE
I. Metabolic
Barbiturates
tolerance - ↑drug metabolism CNS Depressants: Common Side Effects
a. MOA – increases duration of GABA
Pharmacodynamic tolerance - ↓receptor, signaling A Cl- channel opening via positive
Sedation/Sleepiness allosteric
– most modulation
common
i. Can open GABA A Cl- channel without GABA
Pharmacokinetic tolerance - ↑metabolism, ↑excretion at high doses →
Respiratory depression Narrow therapeutic index
b. Uses
Anterograde amnesia – cannot form memories
i. Seizures
GABAA = post-synaptic, pentameric,
ii. Anesthesia Cl-&channel
induction Tolerance – larger dose needed for same effect
conscious sedation
GABAB = pre-synaptic,
iii. Rarely7TM, GCPR →
for anxiety, ↓NT release
insomnia Physical Dependence – withdrawal occurs upon cessation
c. Side Effects - Narrow therapeutic index = Dangerous Abuse/Addiction – behavioral dependence due to euphoria
i. CNS depression (Sedation), Anterograde amnesia
ii. Respiratory depression – can be fatal
iii. Tolerance, Dependence, Abuse
d. Drug interactions – Additive effects w/other CNS depressants (e.g. EtOH)
e. Pharmacokinetics
i. Rate of distribution (blood → brain) depends on lipid solubility
ii. Metabolized by and Inducers of P450s
1. Enhance their own metabolism → metabolic tolerance
2. Can be used in Crigler-Najjar Type II to ↑conjugation of bilirubin

BARBITURATES
Drug T½ Uses
Ultrashort-acting
Methohexital 4 hr Anesthesia induction – can be given rectally to children
Anesthesia induction– duration of action only 5-8 min
Sodium Thiopental 12 hr Effects terminate with redistribution from brain→blood, not by elimination
High lipid solubility → High potency
Thiamylal Anesthesia induction – anterograde amnesia
Short/Intermediate-acting
Secobarbital 15-40 hr Insomnia – rarely used due to narrow safety index (First sedative-hypnotic)
Pentobarbital 15-50 hr Anxiety – rarely used due to narrow safety index (First anxiolytic)
Long-acting
Anticonvulsant – 1st line for young children & infants
Phenobarbital 80-120 hr Long half life allows for Steady state blood levels
Contraindication in absence seizures – NOT for anxiety

II. Benzodiazepines
a. MOA – increases frequency of GABAA Cl- channel opening via positive allosteric modulation
i. Only facilitate GABA action, cannot open Cl- channel (at any dose)→ Higher therapeutic index
b. Uses
i. Anxiety (immediate anxiolytic effects)
ii. Sedative-Hypnotic (night terrors, sleepwalking, insomnia)
iii. General anesthesia & induction of anesthesia (anterograde amnesia, muscle relaxant)
 iv. Spasticity (muscle relaxant)
v. Status epilepticus (anti-convulsant)
vi. Alcohol withdrawal – EtOH & benzo’s have same MOA so benzo’s will alleviate symptoms
c. Side Effects - Higher therapeutic index = Safer
i. CNS depression (sedation), Anterograde amnesia
ii. Respiratory depression (mild)
iii. Tolerance, Dependence, Abuse – short-acting drugs have higher addictive potential
d. Drug Interactions - Additive effects w/ CNS depressants (e.g. EtOH)
i. Can cause fatal respiratory depression in combo
e. Pharmacokinetics
i. Metabolism can result in formation of active metabolites
ii. Many undergo both phase I (oxygenase) and phase II (transferase) reactions
iii. Lorazepam, Oxazepam & Temazepam - only undergo one gluconuridation (phase II) before
elimination (no active metabolites)→ easier on the liver → better for use in alcohol-induced
cirrhosis or impaired liver function (elderly Alzheimer’s patient)
1. Mnemonic: “aLOT less taxing on the liver”
BENZODIAZEPINES
Drug T½ Uses
Short-acting
Conscious sedation – same day surgeries (endoscopies)
Midazolam 2 hr
Induction of anesthesia for short period
Sedative-hypnotic → sleep onset disorders
Triazolam 3 hr
Conscious sedation – off-label
Intermediate-acting
Oxazepam 8 hr Short-term, situational anxiety (fear of flying etc)
Anxiety disorders (old drug)
Chlordiazepoxide 10 hr
Less potent so can use this to wean off of other medications
Temazepam 11 hr Sedative-hypnotic → sleep maintenance disorders
Alprazolam Anxiety disorders, Depression, Panic disorders – rapid brain diffusion
12 hr
(Xanax) Avoided due to dependence w/ repetitive use @ therapeutic dose
Anxiety disorders – wide range (outpatient & inpatient)
Lorazepam Status epilepticus (DOC)– b/c most water soluble benzodiazepine
14 hr
(Ativan) (can give as i.m. injection (hard to start i.v. during seizure)
Pharmacologic restraint – part of “B52” cocktail
Long-acting
Clonazepam Chronic anxiety (outpatient)
23 hr
(Klonopin) Acute anxiety or Schizophrenia/Alzheimer’s agitated states (inpatient)
Diazepam Anxiety disorders, IV Anesthetic
43 hr
(Valium) Status epilepticus (2nd choice): not water soluble → thrombophlebitis
Flunitrazepam
18-26 hr Date rape drug –sedative-hypnotics & anterograde amnesia
(Roofie)
Antagonist
Flumazenil MOA - competitive inhibitor at benzo binding site on GABA A receptor
1 hr
(Romazicon) Use - overdose reversal
B52 Restraint “Cocktail”
Lorazepam
Haloperidol
Diphenhydramine
III. Non-Benzodiazepine Hypnotics – “The Z drugs”
a. MOA – bind to the BZI site
i. Selective for certain subtypes of GABAa receptors
b. Use – Insomnia
c. Adverse effects
i. Less dependence risk & unwarranted side effects than benzo’s
ii. Habit forming – all sleep medications
iii. Sleep walking

Non-Benzodiazepine: Sedative- Hypnotics

Drugs T½ Uses/other
Zolpidem
2 hr
(Ambien)
Zaleplon Insomnia
1 hr
(Sonata)
Eszopiclone Binds to benzodiazepine type-1 receptor (BZ-1)
(Lunesta) Commonly induce sleepwalking
Zopiclone
(Zimovane, Imovane)

IV. Other CNS Depressants

d. Buspirone
i. MOA – 5HT1A receptor agonist
ii. Uses – Generalized anxiety disorder (esp. mild forms)
1. Long latency for anxiolytic effects vs. immediate benzo’s
2. Not effective for panic disorder
iii. Adverse effects – headache, dizziness, nausea
e. Beta-blockers (e.g. propranolol)
i. MOA – block Beta-adrenergic receptors
ii. Uses – prevent performance anxiety
f. Chloral Hydrate
i. MOA – Alcohol → GABAA receptor positive allosteric activator
ii. Uses – Insomnia (esp. in pediatrics)
iii. Side Effects – SHOULD NOT USE!!!
1. Zero order metabolism → drug can accumulate
2. Carcinogenic metabolites
3. No reversal agent like Benzo’s
g. Anti-Histamines (e.g. hydroxyzine, diphenhydramine/Benadryl, most “PM” formulation)
i. MOA – H1 receptor antagonists
ii. Uses – Insomnia
h. Melatonin
i. MOA – MT receptor agonists, 5HT precursor
ii. Uses – Mild sleep disorders
1. Long onset of action – need to take many hours before going to sleep
iii. Side Effects – Tolerance (Receptor mediated)
i. Meprobamate
i. MOA – unknown (prob. GABA receptor effects)
ii. Use - approved as anti-anxiety, popular as sedative-hypnotic
j. Carisoprodol – skeletal muscle relaxant
i. MOA – active metabolite is meprobamate, unknown (prob. GABA receptor effects)
ii. Use – skeletal muscle relaxant, sedative-hypnotic
iii. Side Effect – abuse potential, popular street drug
Drug Class Overdose/Intoxication Withdrawal
Barbiturates Marked respiratory depression (life-threatening) Delirium
Rx – Assists respiration, ↑BP (life support) Life-threatening cardiovascular collapse
Rx – Benzodiazepine
Benzodiazepines Minor respiratory depression, Ataxia Sleep disturbance, depression, rebound
Rx – Flumazenil (Competitive Benzo antagonist) anxiety, seizure (severe)
Rx – Benzodiazepine

Other Hypnotics (sleep aides)

Drugs MOA Uses/other Side/Adverse effects
Melatonin Binds MT receptor
Antidepressants
Trazodone
Doxepin
Antihistamines
Hydroxyzine Blocks Histamine
Diphenhydramine receptor

Miscellaneous sedative-hypnotics
SHOULD NO LONGER BE USED
Chloral Hydrate
Like giving a bunch of alcohol
Miscellaneous Anxiolytics
Meprobamate Anxiety Abuse
Genaralized Anxiety Disorder
Buspirone 5HT1A agonist
Mild anxiety
Beta blockers Block sympathetics Toast Masters type Anxiety
Centrally-acting muscle relaxants
Upset stomach, xerostomia,
Cyclobenzaprine
sedation, dizziness
Carisoprodol Active metabolite is
ABUSE
(Soma) meprobamate
Miscellaneous drugs that produce CNS depression
Anti-spasticity drug for trigeminal
Baclofen
neuralgia, MS, ALS
2 agonist
Tizanidine
Acts by pre-synaptic Anti-spasticity drug
(Zanaflex)
inhibition
Prevention & Tx for Malignant
Dantrolene
Hyperthermia