Lec 16- Hypnotics and insomia

Question 1

Hypnotics and insomnia

Answer 1

• Sleep disturbance may consist of
  
  • Difficulty in falling asleep
  • Frequent nocturnal awakenings
  • Early morning awakening
  • General dissatisfaction with the quality of sleep
• The major problem for insomniac is not the lack of sleep, but the consequence of this on performance on he next day

Question 2

Treatment of insomnia- Sleep Hygiene

Answer 2

• Go to bed and get up at the same time every day
• Avoid caffeine and alcohol in the evening
• Avoid daytime naps
• If you cannot sleep get up and occupy yourself until you feel sleepy

Question 3

Treatment of insomnia- Hypnotics

Answer 3

• Zopiclone- Non-selective and longer half-life than zolpidem
• Zolpidem- relatively selective for the GABA_A receptors containing an Alpha-1 subunit
• Zaleplon- Similar selectivity to zolpidem with a shorter half-life

Question 4

Pharmacokinetics of BZs

Answer 4

• Lipophilic BZ is rapidly absorbed; peak blood levels at about 1 hour after oral administration
• All BZs are highly protein bound (80-95%)
• Active metabolites are formed from many of the BZs: Diazepam elimination half-life 6-8 hours but for N-desmethyl diazepam, the primary metabolite it is 80 hours
• Despite this, they are frequently given in multiple divided daily doses (control of sedation)

Question 5

Anxiolytics and hypnotics: Differences in dose

Answer 5

• The difference in doses between anxiolytics and hypnotics
• This is about receptor activation
• Different doses change the number of receptors activated
• BZs show this
• Low activation = anxiolytic
• High = Sedative

Question 6

Anxiolytic and hypnotics: Differences in pharmacokinetics

Answer 6

• Anxiolytics= Long half life= Not washed out quickly, therefore, don’t want repeating doses
• Sedative= shorter half-life= Need to be washed out of the system to be ready for the next day

Question 7

Hypnotic BZs

Answer 7

Question 8

Side effects

Answer 8

• The BZs have a high therapeutic index
• Sedation is the main side efect of the BZs and patients must be cautioned about driving on initial treatment
  
  • The sedative effects show a rapid and almost complete tolerance within one week of initiation of treatement
    
    • There is a marked exacerbation of sedation by alcohol
• Other side effects include fatigue, poor concentration and confusion
  
  • They may also produce respiratory depression in those with a pre-exsiting condition
• Doses escalation is rare with the BZs though it may occur in those individuals who are prone to drug abuse

Question 9

Tolerance

Answer 9

• A decrease in physiological response to BZs
• Tolerance develops to the sedative effects rapidly (1 week)
• Tolerance develops to the anti-convulsant effect more slowly but precludes their use in the prophylactic treatment of epilepsy
• There is little evidence that the anxiolytic and hypnotic effects in man show any significant tolerance over many months of treatment

Question 10

Dependence on BZs

Answer 10

• There is significant evidence that psychological dependence does decelop to the BZs in some patients (estimates range upto 25%)
• Withdrawal effects can occur on cessation of treatment and these include anxiety and insomnia
• Withdrawal effects are more pronounced with the short acting BZs- dose tapering significantly reduces the withdrawal syndrome
• Concern about these phenomena have been responsible for a significant decline in the use of these agents over the past decade

Question 11

Alternate hypnotics

Answer 11

• While barbiturates have been used as sedative their major disadvantage is their low therapeutic index (between 3:1 and 30:1)
• The anti-histamines produce significant mental clouding
• Aliphatic chlorinated derivatives show rapid tolerance

Question 12

Drug interactions of BZs: PK

Answer 12

• Other CNS depressants will exacerbate their sedative effects and lead to decreases in psychomotor performance
  
  • Anti-depressants, narcotic analgesics, anti-psychotics, anti-histamines and alcohol
• The BZs alone are rarely life-threatening but may prove fatal in combination with one of the above
  
  • Flumazenil, a BZ antagonist may be used to reverse the effects of ONLY the BZ
  • NB- flumazenil has a short half-life and multiple use is often required in BZ overdose

Question 13

Zolpidem (Stilnox, Ambien)

Answer 13

• Imidazopyridine
• Rapid onset, short-acting hypnotic
• Displaces classical BDZ, acts at BDZ binding site
• Alpha-1 subunit-containing receptors
• Brain-injured & PVS patients