Lecture 19: Sleep disorders and their treatment

Question 1

What are the 5 stages of sleep?

Answer 1

Stage 1: ~5-10 mins. Transition from awake to sleep (loss of muscle tone, easily aroused).

Stage 2: ~20 mins. Light sleep (50% of total), movement stops, HR and body temp drop.

Stages 3 & 4: ~30 mins each, deep or slow wave sleep (restorative)

Stage 5: REM (rapid eye movement). 25% of total time. Increase brain activity (dreaming). Processing and consolidation of information and emotions.

Stages 1-5 make up the sleep cycle lasting about 90mins. Cycle is repeated 5-6 times a night.

Question 2

Describe the neurotransmitters in sleep

Answer 2

High neuronal activity in histaminergic, noradrenergic and seratonergic pathways during wakefulness - decrease during non rapid eye movemnt and almost stops during REM sleep

Cholinergic activity slows during non REM but increases in REM dreaming

Dopamine in the transition from awake to sleep

GABA induces relaxation and sleep

Melatonin releasedmfrom pineal gland - regulated circadian rythym

Orexins - from hypothalamus regulate sleep - wake cycle

Question 3

What are the sleep disorders?

Answer 3

Characterised by disturbances of usual sleep patterns or behaviours that cause distress and impair daytime functioning

Affects 10-37% of the population

Insomnias: initiating and maintaining sleep

Parasomnias: Disturbance or arousal-sleep maintennace mechanisms (polysomnography PSG often required)

Sleep apnoea: restriction of airflow, interrupts breathing

Narcolepsy: neurological disorder where the brain is unable to regulate the sleep-wake cycle

Question 4

What is the management of sleep disorders & insomnia?

Answer 4

Treat underlying condition e.g depression, coughs/itch/pain/ increase frequency of urination

Sleep hygiene – change in behaviours prior to sleep, sleep diary

Psychological therapies- e.g Cognitive Behaviour Therapy (CBT)

Complementary Therapies – acupuncture, herbal remedies

Medication to increase brain inhibition via GABA/BZ receptor OR decrease excitation by blocking 5HT or histamine receptors

Question 5

What is insomnia?

Answer 5

Is a symptom, not a disorder

1 in 5 complain of insomnia

It is inability to get to sleep, inability to stay asleep, waking too early, unsatisfying sleep eg tiredness during the day, sleep disturbance alongside significant daytime dysfunction

Total time asleep declines with age- less active, daytime napping BUT should NOT dismiss as very common in those with a psych disorder- persistent, disabling, contributes to poorer outcomes and lower quality of life

Question 6

What is sleep hygiene?

Answer 6

Maintain an environment conducive to sleep, decrease noise/ heat in the bedroom

Avoid caffeine drinks, decrease alcohol intake

Relaxation - avoid exercise later in day

Bed time routines ie the rest - activity cycle. Take cues from the environemnt eg as we we asleep, there is a drop in body temperature. The temperature rises as the body gears up in its physiological function- leads to waking up.

Question 7

How do medications help with sleep disorders?

Answer 7

Medication such as hypnotics eg BZP or Z drugs, melatonin, chlormethiazole decrease time to sleep onset and episodes of waking, but get an increase total sleep time - short term use only ie 6 weeks

Goal: to restore normal restful sleep without a residual hangover and to return to normal sleep pattern

Question 8

How is the GABA receptor activated?

Answer 8

2 molecues of GABA activate the receptor by binding to the alpha subunit

Question 9

How do enzodiazepines (BZs) and the ‘z drugs’/z hypnotics act in sleep disorders?

Answer 9

Bind to GABAa receptor and enhance inhibitory effect of GABA - activation of the GABA receptor leads to influx of Cl ions into the neuron, reduces its excitability thereby reducing activity in the brain - so sedation, induces sleep

BZs supress stage 4 ( deep sleep and decrease the REM

Z drugs decrease stage 1 but increase stage 2, little effects on stages 3,4 and REM

Question 10

What are the kinestics of BZDs?

Answer 10

Rapidly absorbed from the GI tract and extensively metabolised by oxidation in the liver - some active metabolites eg oxazepam

Long, medium and short acting BZs - based ypon plasma half life and duartion of action

Substrates for several CYP enzymes - caution when co prescribed with inhibitors or inducers

Additive or synergic effects with other psychotropic drugs - increase impairments of motor/ intellecutual function or worsen respiratory depression

Various formulations - oral, IM and IV for acute/ rapid sedation (agitation/pre-operatively) and for emergency treatment of seizures. Low water solubility so administered with solvents or as emulsion.

Question 11

What are BZ hypnotics?

Answer 11

Induce sleep within 30 mins (stages 1-3)

Residual effect likely esp with nitrazepam - caution in the elderly

Side effects - headache, confusion, blurred vision, amnesia, affect driving performance, disinhibition, respiratory depression (IV route)

Driving offence - All BZDs can impair driving ability but clonazepam, diazepam, lorazepam named

Question 12

What are the adverse effects of BZDs?

Answer 12

Short term use Max 6 weeks for severe, disabling insomnia

Tolerance - decrease in effect despite continued administration

Dependence - a need for repeated doses to maintain wellbeing or prevent withdrawal symptoms. Dependance can be psychological or physical

Psychological - a craving or cumpulsion to maintain wellbeing

Physical - depends on extent of dependance/ period of use

Mild - irratability, tremor, headache, nausea

Moderate - flu like symptoms, decrease appetite, abnormal sensation of movemnt

Severe - seizures, psychosis

Question 13

What are the safety Issues in Benzodiazepine Use [hypnotics/anxiolytics]?

Answer 13

Increase propensity for dependance - 2 weeks acute treatment is the ideal but not the reality

Increased propensity for tolerance - consider PRN use - so need to increase dose, or prescribe an alteranative

Require a ‘tapered withdrawal’
regime to avoid withdrawal
effects

Question 14

What are the Z drugs?

Answer 14

Zopiclone, zolpidem, zaleplon

Alternative to BZs - lower risk of dependance/ tolerance and abuse

Agonist at alpha 1 subunit of GABA receptor, increase GABA mediated calcium influx in the cell so inhibits neurotransmission

Rapid onset and relatively short duration - decrease hangover effect, congnition function

Side effects - metallic taste (mainly zopiclone), GI disturbance, dizziness, headache

Question 15

What is the OTC management of sleep?

Answer 15

Sedative antihistamine (diphenhydramine, promethazine)

Herbal products (valerian, lavender, CBD/cannabidiols)

For short term only

Try and understand patients motives; psychological issues, anxiety, worries, stress. Addressing the underlying cause is more effective than sleeping tablets

Question 16

Describe antihistamines in the management of sleep

Answer 16

Only those that cross the BBB –i.e antagonists at the H1 receptor thereby causing sedation
Primarily used in children (lack of alternatives)
Promethazine (5-10mg at night). However, has a long t1/2, but low abuse potential
Diphenydramine (25-50mg at night). Increase potential for abuse - affects cognitive function
Also available as OTC products e.g Nytol

Question 17

Describe melatonin in the management of sleep

Answer 17

Natural hormone produced by the pineal gland regulating circadian rhythm of sleep i.e stimulated by nightfall, peak levels 2-4am, then decrease.
Promotes sleep initiation- resets the circadian clock.
Agonist at M1,M2 and M3 receptors
Efficiency for primary insomnia is poor –much better for conditions like jet lag.
Relatively short duration of action, rapidly excreted (T1/2 is 30-60mins)

Question 18

Describe melatonin as a hypnotic in children?

Answer 18

Assist in the management of sleep disorders in children with neuro-developmental disorders.

Limited evidence from small RCTs suggest that melatonin 2.5-7.5mg is effective in reducing sleep onset latency in children with neuro-developmental disorders (i.e ADHD, ASD, LD etc).

Appears to be safe and well tolerated during short term use - impact on the frequency of seizures is unclear
No serious side effects during follow up periods of 2yrs of longer
Systematic study of longer term use and effect on puberty still needed

1. Various brands of unlicensed (mainly imported) IR & SR preparations e.g 1mg, 3mg, 5mg
2. Unlicensed ‘Specials’- mainly liquid e.g 1mg/ml soln
3. Licensed UK Products with different indications
   Circadin 2mg MR (monotherapy for the short term treatment of primary insomnia characterised by poor quality sleep in patients aged 55 yrs or over)
   Colonis 1mg/ml oral solution for jet-lag [The strawberry-flavoured oral solution is lactose and sugar-free, provides “maximal dose flexibility” and can be used by patients across a “wide age range”] 130ml bottle costs NHS £130
   Slenyto 1mg & 5mg CR tablets- for the treatment of insomnia in children and adolescents aged 2-18 with Autism Spectrum Disorder (ASD) and / or Smith-Magenis syndrome, where sleep hygiene measures have been insufficient.

Question 19

What are the instalment requirments for melatonin?

Answer 19

First instalment must be dispensed within 28 days of the ‘appropriate date’
The instalment quantity & intervals between supplies must be stated on the Rx.
Prescription must be endorsed with the date of dispensing of each supply (PC70)
Missed instalments cannot be issued after the due date
Clients are not required to sign for each instalment
Must be marked by supplying pharmacy with name & address (stamp) – PC70