Sweatman - Sedative-Hypnotics

Question 1

Why are you less likely to get symptoms of withdrawal with a long-acting BNZ?

Answer 1

• Deu to slow decline in serum drug levels

Question 2

What are the only 2 classes of drugs of abuse with reversal agents? Precautions when using these agents?

Answer 2

• Opioids -> Naloxone, Naltrexone
• BNZ’s -> Flumazenil: antagonizes effects of GABA, so you get a stimulant effect, and can even get seizures
  
  1. Don’t want to use this unless you have to

Question 3

What are the names of the anxiolytics?

Answer 3

• BNZ’s: Alprazolam, Chlordiazepoxide, Clonazepam, Clorazepate, Diazepam, Lorazepam, Oxazepam, Prazepam
  
  1. BNZ’s with short 1/2-life not included here bc lack of durability of effect would require inconvenient dosing regimens
• Non-BNZ: Buspirone, Propranolol

Question 4

What 3 things bind to the GABA receptor? Where? Effects?

Answer 4

• GABA: agonist at GABA binding site that promotes Cl- influx and hyper-polarization
• BNZ’s: allosteric agonists at BNZ binding site, and potentiate effects of GABA by modifying response of GABA receptor to its endogenous ligand -> INC POTENCY
  
  1. They DO NOT activate the receptor independently of the natural ligand
• FLUMAZENIL: competitive antagonist that blocks effects of BNZ’s
• NOTE: all 3 of these act at INDEPENDENT SITES on the ALPHA SUBUNIT of the multimeric chloride ion channel

Question 5

Can you die from a BNZ OD?

Answer 5

• Yes, but it is very difficult for this to happen without the influence of other CNS depressants, like alcohol
• Most pts just sleep it off (if other depressants not involved)

Question 6

Which BNZ’s share a common metabolite? Why is this important?

Answer 6

• Clorazepate, Diazepam, Chlordiazepoxide, Prazepam, and Halazepam all converted metabolically to NORDIAZEPAM -> long 1/2-life and is responsible for LONG DURATION OF EFFECT produced by these agents
  
  1. Hydroxylated to Oxazepam, then metabolized to glucuronide conjugates eliminated in urine
• NOTE: drugs that have longest durability of action more often than not metabolized to pharmacologically active products -> summation of residual effects of parental drug and appearance of metabolized products

Question 7

Which 3 BNZ’s have a short duration of action? Why?

Answer 7

• Lorazepam, Alprazolam, and Oxazepam: simpler metabolism -> rapidly conjugated and eliminated in urine
• NOTE: Alprazolam has one active metabolite, called alpha-hydroxyalprazolam

Question 8

How are the BNZ’s as a group metabolized? Why is this important?

Answer 8

• All undergo hepatic metabolism involving CYP-mediated transformations, EXCEPT Lorazepam and Oxazepam
• Drug-drug interactions leading to loss of drug effect, or intensified drug effect are possible with a wide variety of drugs acting on CYP activity

Question 9

Categorize the BNZ’s by their onset of action, 1/2-lives, and pregnancy categories.

Answer 9

• All of these drugs are CONTRA in pregnancy (CAT D)
• RAPID ACTING, LONG DURATION: Diazepam (*can inject), Flurazepam, Clorazepate
• RAPID, SHORT: Triazolam
• INTERMEDIATE, INTERMEDIATE: Alprazolam, Lorazepam (*can inject)
• SLOW: Oxazepam (short), Temazapam (intermediate), Prazepam (long)
• OTHERS: Chlordiazepoxide intermediate long, and Clonazepam intermediate short
• NOTE: onset of action determined by dissolution rate and speed of absorption from GI tract, and duration involves both parenteral drug and any pharmacologically active metabolites
  
  1. Rapid: 15-30m; Int: 30-45m; Slow: 45-90m
  2. Short:

Question 10

What determines the onset and severity of BNZ withdrawal? Symptoms?

Answer 10

• ONSET and SEVERITY inversely related to duration of action -> short 1/2-life drugs should be tapered
  
  1. Triazolobenzodiazepines (Alprazolam, Estazolam, and Triazolam; TEA) more severe reactions than o/compounds
• SYMPTOMS: generally autonomic -> tremor, sweating, insomnia, abdominal discomfort, tachycardia, systolic HTN, muscle twitching, and photo/audio sensitivity
  
  1. Rebound anxiety and insomnia
  2. CONVULSIONS possible after protracted high doses
• NOTE: physical and psychological dependence, so withdrawal rxns on ABRUPT DISCONTINUATION -> caution with known, suspected, or hx of substance abuse (NOT on the order of magnitude seen with alcohol or barbiturates)

Question 11

What are the clinical utilities of the BNZ’s?

Answer 11

• ANXIETY: intermittent or limited (4-8wks) tx -> Alprazolam, Lorazepam, Clonazepam (all intermediate onset)
• PANIC ATTACKS: respond favorably to Alprazolam, which possesses antidepressant activity like TCA’s
• MUSCLE RELAXATION: ONLY diazepam INH monosynaptic reflexes in spinal cord, leading to mm relaxation -> other BNZ only at supra-clinical doses via polysynaptic blockade
• ALCOHOL WITHDRAWAL: Chlordiazepoxide (long acting) and Diazepam (long acting), or Lorazepam if hepatic impairment bc renal metabolism in addition to hepatic
• NOTE: selecting BNZ depends on matching pharmacokinetics of drug with clinical utility

Question 12

What is the mechanism for the devo of opioid tolerance?

Answer 12

• TOLERANCE develops: 1st to sedative and hypnotic effects, 2nd to anti-convulsant effects, but RARELY EVER to anxiolytic effects (absolute time varies by drug)
  
  1. GABA receptor vaires in different locations of the brain with respect to the structure of its alpha subunits
• MECHANISM: receptor uncoupling, receptor sub-unit down-regulation
  
  1. SENSITIZATION of glutamatergic system: GABA and glutamate are two fast-acting and opposing NT systems that can modulate synaptic plasticity -> glutamate can be up-regulated
  2. CROSSTALK from other G-protein receptor systems: Dopamine, Ach, Serotonin phosphorylate GABA subunits
• NOTE: non-selective BNZ’s allosterically enhance INH actions of GABA by binding b/t alpha-1, 2, 3, or 5 subunit and gamma subunit

Question 13

What are the clinical issues with the BNZ’s?

Answer 13

• Pt should avoid activities requiring mental alertness until drug effects are realized
  
  1. Next-morning dysfunction
• Drug may cause nausea, xerostomia, confusion, HA, or FEELING OF INDIFFERENCE
• Instruct pt to report signs/symptoms of excessive sedation bc it has been associated with RESPIRATORY DEPRESSION
  
  1. Depressed respiration may be tolerated in young, healthy person, but older pt with COPD may not be so accommodating
• Pt should avoid concomitant use of alcohol or other CNS DEPRESSANTS

Question 14

What about the 2 non-BNZ anxiolytics?

Answer 14

• BUSPIRONE: suppresses serotonergic while enhancing noradrenergic and dopaminergic activities
  
  1. As effective as BNZ’s as anxiolytic, but SLOW onset (weeks); no anticonvulsant, mm relaxant, sedative effects
• PROPRANOLOL: beta-adrenergic receptor antagonist
  
  1. Useful for performance anxiety or “stage fright”
  2. Temporarily suppresses somatic and autonomic symptoms of anxiety, but does NOT alter emotional symptoms (no activity in this part of the brain)
  3. Crosses BBB bc lipophilic, unlike Atenolol