1. HYPNO-SEDATIVE DRUGS Martin Štěrba, PharmD. , Ph. D
HYPNO-SEDATIVE DRUGS Martin Štěrba, PharmD., Ph.D. Associate professor Department of Pharmacology, LFHK UK 2016

2. Definition of the terms
Hypno-sedatives – drugs dose-dependently suppressing CNS activity – decreasing vigility (level of consciousness) and responsiveness
Sedation
Milder degree of suppression of CNS activity
Psychomotor calming effect without sleep
Hypnosis – state more or less resembling physiological sleep
Dose dependence:
anxiolysis → sedation → hypnosis (→narcosis = general anesthesia)
→ therefore, hypno-sedatives
Hypno-sedative effects
In other drug classes
Like neuroleptics, antihistamines, antidepressants, myorelaxans
→ these effects might be both desirable and undesirable

3. SEDATIVES
Drugs inducing only sedation without capability to dose-dependently progress further in CNS suppression
Now rarely used
Often non-specific effects
Low toxicity – now often OTC of natural origin
Indications: vegetative dystonia in stress and tension
Natural extracts („extractum siccum“) with different active components
Valerian (Valeriana oficinalis)
Passionflower (Passiflora incarnata)
Hop (Humulus lupulus)
Lemon balm (Melisa ofic.)
Obsolete - brome derivatives
Valerian
Lemon balm
Passionflower
Hop

4. HYPNO-SEDATIVES Drugs used for
Anxiolytic effects – suppression of pathological fear and related response
Sedative effects
Lower doses used for psychomotor calming effects in
In agitation accompanying other diseases (e.g. MI),
In panic reactions (e.g. with resp. alkalosis)
To enhance different diagnostic or therapeutic approaches (e.g. gastroscopy, colonoscopy)
ICU sedation
Intro to general anesthesia, combinational anesthesia
Anticonvulsive effects
Insomnia treatment

5. HYPNO-SEDATIVES in insomnia treatment
Insomnia and its origin (Secondary insomnia!):
Stress, anxiety, depression, chronic pain
Impaired biorhythms – night shifts, „jet lag“…
The primal origin should be treated!
Hypnotics just cover/mask insomnia as the symptom
Non-pharmacological approaches – cognitive-behavioral therapy
Pharmacological treatment
Should not be long-term
Evaluation of the outcomes after 2 weeks
Continual treatment should not exceed 4 weeks
Types of insomnia:
- Problems with falling into the sleep
- Discontinuity of the sleep
- Premature awaking
Non-pharmacological approach:
Sleep hygiene

6. Classification of hypno-sedative drugs
1st GENERATION: - BARBITURATES
- clomethiazol
- sedative H1-antihistamines
- chloralhydrate, glutethimide (largely obsolete)
2nd GENERATION: - BENZODIAZEPINES (BZDs)
- midazolam
- temazepam
- flunitrazepam
- diazepam…
3rd GENERATION : Selective agonists of BZD1–receptors
- zolpidem
- zopiclon and eszopiclon
- zaleplon

7. Mechanism of action GABAA-receptor complex
= Ligand-gated chloride channel (ligand = GABA)
In all CNS regions
Highly in spinal cord, hypothalamus, substantia nigra, hippocamus and cortex
Pentameric transmebrane structure
Subunits: γ
Subunit subtypes (1-6, 1-4, γ1-4) – make up a heterogeneity
Different composition in different brain regions, during the ontogenesis, tolerance development
BZD1-receptors (contains 1 subunit) - hypnosedative effects
BZD2/3-receptors (contains other  subunits) – anxiolytic, anticonvulsive effects
barb
barb
GABA
BZD
GABA

8. Sleep architecture Stage 0 – conscious and active state NREM REM
Stage 1- intermediate state between consciousness and sleep, profound drowsiness, light sleep – reaction on voice
Stage 2 – sleep with no/little reaction on voice, but often reaction to tactile and particularly light-pain stimulus
Stage 3 and 4: deep, slow wave, delta sleep
REM
Dream activity, EEG similar to conscious, depth like S 2/3 NREM

9. Sleep architecture

10. Hypno-sedatives – impact on sleep architecture
↓ Sleep latency
↑ Total sleep duration
↑ S-2 NonREM
↓ S-3/4 NonREM
↓ REM - dreaming!
Different drugs (generations)
= different impact

11. Barbiturates
BZD, zolpidem

12. 1st generation: BARBITURATES
1st modern hypno-sedative drugs (1911)
Strongly lipophilic derivatives of barbituric acid
Clinically not used as hypnotics anymore
Mechanism of action
Allosterically ↑ affinity of GABA to GABA-A receptor
Different binding site for the barbiturates than for BZD!!!
Rather prolongs time of opening than the frequency of opening
In higher doses (anesthetic and/or toxic)
Direct GABA-mimetic effects
Inhibition of excitatory (e.g. glutamate) neurotransmission PK
Extensive distribution though the all barriers
Possible deposition in fat (re-distrubution effects)
Potent inducer of CYP 450 and UGT – risk of interactions and failure of co-administered drugs (warfarin, oral contraceptives and many others)

13. Barbiturates – risks and adverse effects
Strong negative impact on sleep architecture
↓ Duration and quality of REM and ↓ „slow wave“ sleep (delta sleep)
Anxiolytic effect is accompanied by a significant degree of sedation
Low TI
High risk of acute toxicity (medication error, suicide and homicide)
Respiratory and cardiovascular center suppression and paralysis
No specific antidote available (in contrast to BZD),
Possibility of alkalization of urine (barbiturates are weak acids)  ↑ renal clearance
Tolerance
More on therapeutic effects than on toxicity (chronic intoxication)
Drug dependence
Very serious psychological and physical (somatic)
Current indications
Very limited
Thiopental - intro to general anesthesia, ultra-short action
Phenobarbital - drug of choice in convulsion in neonates (e.g. after asphyxia), less in epilepsy and combination treatment of pain
CLOMETHIAZOL
Non-barbiturate hypnotic drug,
Used for sedative and anticonvulsive effects in drug withdrawal therapy

14. 2nd generation: BENZODIAZEPINES
Mechanism of action:
Bind to BZD binding sites on GABA-A receptor complex
Heterogeneity of BZD receptors and effects
BZD1 (Ω1)
1 subunit – hypno-sedative effects
BZD2/3 (Ω2/3)
myorelaxant and anticonvulsive effects
anxiolytic effects (2 subunit?)
COMPLEX effects on CNS: anxiolytic, sedative, hypnotic, myorelaxant, anticonvulsive, amnesic
Alosterically enhance affinity of the GABA binding site to GABA → higher frequency of Cl- channel opening → hyperpolarization and suppression of membrane excitability
FLUMAZENIL: a specific antagonist of BZD on BZD receptors
antidote in intoxications

15. BZD Pharmacokinetics Lipophilic compounds
Well absorbed – first pass effect can be significant
Wide distribution
Pass all biological and anatomical barriers (HEB, placenta)
Biotransformation in the liver:
Often to active metabolites (but not in all drugs!)
Marked prolongation of the effect – t1/2 parent drug + t1/2 of all active metabolites
cytochrome P450 (oxidation-dealkylation), glucuronidation
Renal elimination of conjugates
CYP450 inhibitors (e.g. azole antimycotics or clarithromycin) significantly increase concentrations and effects
NO significant induction of CYP or UGT! (x barbiturates)

16. Benzodiazepines - metabolism
Rang-Dale´s Pharmacology, 6th edition

17. Benzodiazepines classification according to elimination half-life
Short-acting (2-5h):
Midazolam, cinolazepam, tofisopam, triazolam
Intermediate-acting (6-12h)
Oxazepam, alprazolam, bromazepam, lorazepam, flunitrazepam and nitrazepam
Long-acting (16-100h)
Diazepam, clonazepam, chlordiazepoxide
Classification may be slightly variable according to the particular literature and whether active metabolites are included or not etc. Remember the extremes - short and long acting drugs!

18. BZD: indications Anxiety Muscle spasms/tension Sedation Epilepsy
Restless leg syndrome-akathizia
Muscle spasms/tension
Epilepsy
Convulsions – febril, tetanus
Acute withdrawal syndrome (ethanol, opioids
Anxiety
Sedation
Insomnia

19. BENZODIAZEPINES - classification according the major clinical use
Anxiety treatment
oxazepam, alprazolam, bromazepam, chlordiazepoxid
tofisopam – different, not a true BZD
Insomnia treatment
midazolam, triazolam or oxazepam (when anxiety is a comorbidity)
flunitrazepam, temazepam, nitrazepam, diazepam,
Epilepsy and convulsion treatment
clonazepam, diazepam
There are significant overlaps, different effects and indications in different doses and
variing preferable use according to the countries!

20. Benzodiazepines used as hypnotics
The sleep is still not physiological
↓ REM-phase (relatively less affected)
Less impact than barbiturates
↓ 3/4-non-REM phase (more affected, slow wave, delta sleep)
Insomnia connected to anxiety and restlessness
drugs with primal anxiolytic indications
oxazepam, alprazolam, bromazepam

21. BZD: Adverse effects and risks
Short term use:
morning - sedation and drowsiness, feeling of poor relax
confusion, poor motor coordination
anterograde amnesia
paradox excitation and aggression (in children, older patients)
In addition in long-term use:
tolerance and risk of drug dependence
Treatment should not exceed 4 weeks
Withdrawal syndrome: anxiety, sleep disturbances, tremor, restlessness, convulsions….
memory impairment
REM deprivation and subsequent vivid dreams
Intoxication
Higher TI – less risks than in barbiturates
Combination with alcohol can be dangerous (also with other CNS depressants)
Flumazenil – i.v., short T1/2 (vs. benzodiazepines), cave in drug addicts

22. 3rd Generation hypno-sedatives
ZOLPIDEM, ZOPICLON, ZALEPLON
Are not BZDs!
Mechanism of action
Bind preferentially to BZD1-receptors
Contain 1-subunit
Flumazenil is effective as antagonist!
Effects
Selective hypnotic effects!
Anxiolytic effect superseded by dominant hypnotic effects
No myorelaxant and anticonvulsive effects
Indication
Only as hypnotics in the therapy of insomnia

23. ZOLPIDEM, ZOPICLON, ZALEPLON („Z-drugs“)
Onset and duration of action
Fast onset of action
Short biological half-life (1– 2.5 h) – little effect on morning vigility
Small impact on sleep architecture
– REM almost ok
some effects on SWS Phase 3/4 NREM (delta sleep)
Minimal risk of rebound insomnia upon withdrawal
Lower risk of tolerance and drug dependence
Low risk of acute intoxication with the single drug (cave combinations with alcohol and CNS depressing drugs)
Rare adverse effects:
Sudden changes in mood, perception (hallucinations) and behavior
Parasomnias (<1%) – complex changes in behavior associated with sleep after zolpidem (night eating, talking, phone-calling, driving …) with amnesia, predisposition = parasomnias in anamnesis, other psychotropic agents

24. Other drugs in the treatment of insomnia
Melatonin (older patients, „jet-lag“)
H1-antihistamines
Antidepressants with hypnotic effects
Trazodone
Amitriptyline
Mirtazapin…
Antipsychotics