Transcript Results

Benzodiazepine
19.03.2013
•S•S•A•M•
Dr. med. Robert Hämmig
Psychiatrie & Psychotherapie FMH
Präsident Schw. Gesellschaft für Suchtmedizin
Leitender Arzt Schwerpunkt Sucht
Universitäre Psychiatrische Dienste Bern
Direktion Psychiatrie
Vorläufer: Alkohole
• Alkohol und ähnliche
– Choralhydrat (Nervifen®, Chloraldurat®)
– Methylpentynol (Oblivion®, Dormison®)
– Paraldehyd
– Ethchlorvynol (Placidyl®, «jelly-bellies», «pickles»)
Vorläufer: Brom und Monoureide
•
•
•
•
Kaliumbromid (ältestes Antiepileptikum)
Bromal
Carbromal
Bromisoval
• Bromismus
(Eliminationshalbwertszeit Bromid-Ionen: 12 Tage)
– übermäßige Sedierung, Schwindel, Kopfschmerzen,
Konzentrationsmangel, Gedächtnisverlust, Halluzinationen oder
Bromschnupfen.
– Häufig Hauterscheinungen wie die Bromakne oder das
Bromoderm mit schmerzhaften eitrigen Hautknoten (zumeist an
den Gliedmasssen).
Johann Friedrich Wilhelm Adolph
von Baeyer 1835 - 1917
• 1864 Entdeckung der
Barbitursäure
• 1905 Nobelpreis für
Chemie für Entwicklung
der organischen
Chemie und der
chemischen Industrie
durch seine Arbeiten
über die organischen
Farbstoffe und die
hydroaromatischen
Verbindungen
Vorläufer: Barbiturate
• Wirkung: Hemmung des ZNS
– Sedativ, hypnotisch, narkotisch
– Antikonvulsiv
• Nebenwirkungen
–
–
–
–
–
–
Katersymptome
Allergische Reaktionen
Enzyminduktion
Gewohnheitsbildend
Porphyrie
Akzidentielle & suizidale OD relativ häufig
Kuschinsky G & Lüllmann H. Kurzes Lehrbuch der Pharmakologie. 1974, Stuttgart: Thieme
Barbiturate
Vorläufer: andere
• Piperidindione (strukturelle Abwandlungen
der Barbiturate)
– Glutethimid (Doriden®)
– Methyprylon (Noludar®)
– Pyrithyldion (Persedon®
– Thalidomid (Contergan®)
• Chinazolinonderivat
– Methaqualon (Toquilone®, Quaalude®, Mandrax®)
Vorläufer: Erster «Tranquilizer»
Bernard John Ludwig & Frank Milan Berger, 1950
• («Tranquilizer» in Abgrenzung zu den
Barbituraten als Tagessedativum):
• Meprobamat (Miltown® , Meprodil®,
Pertranquil® , Quaname®)
• Indikation:
– Emotionelle Angst-, Spannungs- und
Erregungszustände; Affektlabilität; Neurosen,
psychoreaktive Syndrome, vegetative Störungen,
Muskelspasmen, Schlafstörungen, Petit mal.
General

1955
: Sternbach: unexpected ring extension of a
quinazoline-3-N-oxide derivative
 first benzodiazepine!
[LH Sternbach, The Benzodiazepine Story, J. Med. Chem. 22, 1, 1979]
N
N
N

1960

1963
1975

NHCH3
O
CH3NH2
N
: First benzodiazepine introduced in therapy,
chlorodiazepoxide (Librium ).
: Diazepam (Valium ).
: Flunitrazepam (Rohypnol ).
U
B
Pharmacodynamic perspective
• BZDs increase the affinity of GABA for its own
binding site.
• GABA binding leads to opening of the chloride
channel followed by hyperpolarization of the
target cell.
B. Dell’osso, M. Lader / European Psychiatry 28 (2013) 7–20
GABA A receptors:
five transmembrane glycoprotein subunits arranged around the
central chloride channel (ligand-gated ion channel)
Benzodiazepinwirkungen
4 Hauptwirkungen:
• Reduktion von Angstzuständen und
Panikattacken
• Schlafanstoss
• Verminderung des Muskeltonus
• Verminderung der Krampfbereitschaft
BZD use
•
•
•
•
•
•
anxiety and affective disorders,
sleep disorders,
Alcohol withdrawal,
delirium,
violent and aggressive behaviours in psychoses
neuroleptic-induced disorders
– neuroleptic-induced tardive dyskinesia
– neuroleptic-induced acute akathisia
B. Dell’osso, M. Lader / European Psychiatry 28 (2013) 7–20
BZD: efficacy?
•
•
•
•
•
•
•
•
•
General Anxiety Disorders: yes
Obcessive Compulsive Disorder: no
Social Anxiety Disorder: yes
PTSD: no
Affective disorders: no
Insomnia: yes
Alcohol withdrawal: yes
Delirium: no
Agitated, aggressive and violent behaviours in psychoses:
only short term (1h) benefit
• Neuroleptic-induced tardive dyskinesia: maybe
• Antipsychoticinduced acute akathisia: yes
B. Dell’osso, M. Lader / European Psychiatry 28 (2013) 7–20
BZD effects
• acute administration induced sedation,
drowsiness, impairment of learning,
psychomotor slowing, and anterograde amnesia
• Chronic cognitive effects are modified by
tolerance to some, but not all, of the acute
effects. Sedation and impaired attention appear
to wane
• A wide range of cognitive and psychomotor
effects show persistent impairment during longterm use and may persist after withdrawal
B. Dell’osso, M. Lader / European Psychiatry 28 (2013) 7–20
BZD chemical types
• BZDs may be subdivided on the basis of their
chemical structure into different subgroups
including
– 2-keto (e.g., diazepam, Valium®),
– Triazolo (e.g., alprazolam, Xanax®),
– 7-nitro (e.g., clonazepam, Rivotril®) and
– 3-hydroxy (e.g., lorazepam, Temesta®)
• compounds.
B. Dell’osso, M. Lader / European Psychiatry 28 (2013) 7–20
pharmacokinetic perspective
• Generally well absorbed and highly proteinbound (95%).
• Depending on their half-life, they may be
subdivided in
– short (i.e., < 6 hours; e.g., triazolam),
– intermediate (i.e., 6–20 hours; e.g.,
alprazolam, lorazepam) and
– long half-life compounds (i.e., > 20 hours;
e.g., diazepam, clonazepam).
B. Dell’osso, M. Lader / European Psychiatry 28 (2013) 7–20
pharmacokinetic perspective
• According to their chemical structure, BZDs may
undergo different types of metabolism including
– glucuronidation (e.g., lorazepam and
alprazolam),
– nitroreduction (e.g., clonazepam),
– demethylation and oxidation (e.g.,
diazepam).
• Furthermore, BZD metabolites may be active
(e.g., nordiazepam) or inactive, and may, in turn,
be subdivided according to their halflife.
B. Dell’osso, M. Lader / European Psychiatry 28 (2013) 7–20
BZD differences
• BZDs also differ in terms of
– potency,
– onset of action,
– duration of action (which depends on the
elimination half-life),
– route of administration and
– metabolic pathways.
• On the other hand, BZDs have similar efficacy as
well as pharmacological and clinical activity
B. Dell’osso, M. Lader / European Psychiatry 28 (2013) 7–20
Anxiolyse & sedativ-hypnotische Wirkung
Vergleich BZD & Barbiturate
BZD
• Intensivierung der GABAAntwort
• In hohen Dosen Plateau der
Wirkung -> kein Koma
• Antagonist vorhanden
• Tod durch Intoxikation mit
BZD alleine unbekannt
• Abhängigkeit erzeugend
(Toleranzentwicklung)
Barbiturate
• Verlängerung der GABAAntwort
• In hohen Dosen GABAmimetisch -> Koma
• Kein Antagonist
• Tod durch Überdosierung
(akzidentell, suizidal)
• Abhängigkeit erzeugend
(Toleranzentwicklung)
Nebenwirkungen
•
•
•
•
•
•
•
•
generelle zentralnervöse Dämpfung
Schläfrigkeit
Ataxie
Lethargie
geistige Verwirrung
Desorientiertheit
verwaschene Sprache
Amnesie (manchmal auch erwünscht, z.B.
Zwangsmassnahmen, Chirurgie)
• Demenz
BZD & traffic
• Two meta-analyses showed that BZDs are associated
with a 60–80% increase in the risk of traffic accidents
and a 40% increase in ‘‘accident responsibility’’.
• Taking alcohol and BZDs together increased the
accident risk 7.7 times. The increased risk of an
accident in the elderly taking BZDs (pooled OR 1.13)
was lower than that in younger drivers (OR 2.21).
• Daytime anxiolytics impaired driving performance
irrespective of half-life. Both short- and long-acting
BZDs taken as hypnotics impaired driving at least
during the first 2–4 weeks of ingestion.
B. Dell’osso, M. Lader / European Psychiatry 28 (2013) 7–20
Langzeitwirkungen
• Erhebliche Störung des Schlafmusters (REM
Phasen)
• Bleibende kognitive Störungen
• Results In the course of the 10 year-follow-up, 3.9% of
subjects were defined as occasional users of
benzodiazepine and 7.5% as long-term users. The analysis
revealed a significant alteration of long-term memory in
women whereas there was no significant association in
men.
• Conclusions Long-term use of benzodiazepine leads to
specific impairment in long-term memory only in women.
Langzeitkonsumenten
Ocassional BD users
Long-term BD user
Substanz
Bromazepam (Lexotanil®)
Zopiclon (Imovane®)
Zolpidem (Stilnox®)
Tetrazepam
Clonazepam (Rivotril®)
3.9%
7.5%
2.7%
1.7%
1.3%
1.1%
0.7%
f
m
4.8% 3.2%
8.3% 6.7%
f
m
3.9% 1.7%
Gender differences
•
Results: Of 879 admissions to the addiction unit during
the seven-year period, 281 were for benzodiazepines.
The percentage of patients addicted only to benzodiazepines was higher among females than males.
Benzodiazepine consumption had started as a drug
addiction behavior in only 10% of cases. The main
sources of prescription identified were general practitioners (52% of cases) or compliant pharmacists (25%).
•
Overall, 15 different benzodiazepines were abused,
with lormetazepam being the most commonly used
(by 123 patients, 43.8% of the total).(Loramet®,
Noctamid®)
Paradoxical reactions
• disinhibitory effects of the BZDs can produce increased
anxiety, acute excitement and hyperactivity. Aggressive
impulses may be released with the emergence of
hostility and rage; criminal acts such as assault and
rape are possible. Estimates of incidence range from
less than 1% to at least 20% of those taking BZDs.
• High-risk patients include those with borderline
personality disorders, impulse control disorder and
persistent alcohol problems. The combination of a BZD
and alcohol is particularly likely to lead to paradoxical
reactions. The patient may have complete or partial
amnesia.
Results: Buprenorphine-treated patients performed statistically significantly better in a
simple reaction time test than methadone-treated ones. No other significant
differences between groups in cognitive performance were found. In each OST drug
group, approximately 10% of the attention performance could be predicted by drug
treatment variables. Use of benzodiazepine medication predicted about 10% of
performance variance in working memory. Treatment with more than one other
psychoactive drug (than opioid or BZD) and frequent substance abuse during the past
month predicted about 20% of verbal memory performance.
•
•
We compared visuomotor skills (Trail-Making Test A and Choice Reaction Time),
executive functions (viz attentional set-shifting: Trail-Making Test B; and planning:
Stockings of Cambridge Task from the Cambridge Neuropsychological Test Automated Battery), working memory (Letter-Number Sequencing), and impulsivity
and decision making (Cambridge Neuropsychological Test Automated Battery
Information Sampling) in 107 patients with CNS-D overdose (benzodiazepines,
opioids, or antipsychotics) with a control group of 68 with nonYCNS-D overdose
(acetaminophen, selective serotonin reuptake inhibitors, and serotonin
noradrenaline reuptake inhibitors) on discharge from hospital.
Compared with the controls, patients in the CNS-D group were significantly
impaired in all domains.
Mögliche Funktionen bei Abhängigen
• Schutz vor Angstzuständen und Panikattacken
• Linderung von Schlaflosigkeit wegen
Kokainkonsums oder Opiatentzugssyndroms
• zentralnervöse Dämpfung und Amnesie zur
Stress Erleichterung
• chronic pain
– back problems (42%)
– connective tissue disease (24– 27%)
– nontraumatic joint disorders (20–23%)
• anxiety (23–42%), mood disorders (39–51%)
• antidepressants (47–56%), benzodiazepines (47–56%).
http://dx.doi.org/10.1016/j.jsat.2012.11.004
• Results: The investigated benzodiazepine addicts differed
significantly from the control group in particular psychological
dimensions, such as higher neuroticism and introversion,
prevalence of emotional rather than task based coping
mechanisms. There were also significant correlations between the
addiction and situational factors such as BZD — treatment
circumstances and adverse life events previous to the treatment.
withdrawal
•
•
•
•
•
•
•
•
•
•
•
muscle tension and spasm, or weakness
pins and needles in the extremities
flu-like symptoms
perceptual hypersensitivity
depersonalisation/derealisation
anxiety and insomnia
nightmares
memory and concentration impaired
depressive symptoms for the first time
occasionally, epileptic fits, total or partial
paranoid or a confusional psychosis
• brotizolam, midazolam, triazolam, zolpidem and zopiclone
• All five rapidly eliminated hypnotics showed statistically
significant initial efficacy.
• Tolerance with intermediate and long-term use was clearly
developed with triazolam and was only marginal with
midazolam and zolpidem; it could not be estimated for
brotizolam or zopiclone because of insufficient data.
• Rebound insomnia on the first withdrawal night was
intense with triazolam and mild with zolpidem; data were
unavailable for brotizolam and inadequate for midazolam
and zopiclone.
End BZD
• The prognosis with a slow tapering schedule is usually
fairly good with about two-thirds of patients achieving total
cessation.
• Others achieve a reduction in dosage but this is an
inadequate outcome as there is a high rate of relapse.
Those that fail to discontinue have a poor prognosis and
repeated failure may ensue, demoralising the patient.
• Predictive factors include previous failed attempts, comorbid depression or physical conditions, a personality
problem, a history of alcohol-related problems, an
unsympathetic general practitioner, lack of family or social
support and older age.
B. Dell’osso, M. Lader / European Psychiatry 28 (2013) 7–20
• Progressive withdrawal (over 10 weeks) appeared
preferable if compared to abrupt since the number of dropouts was lower and the procedure judged more favourable
by the participants. Short half-life benzodiazepine,
associated with higher drop-out rates, did not have higher
withdrawal symptoms scores. Switching from short half-life
benzodiazepine to long half-life benzodiazepine before
gradual taper withdrawal did not receive much support
from this review.
Pharmacological interventions for benzodiazepine mono-dependence management in outpatient settings (Review)
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Z-Substanzen
• Zaleplon (kurz wirksam,
Eliminationshalbwertszeit 1h)
• Zolpidem
• Zopiclon
• Eszopiclon (s-Enantiomer von Zoplicon)
• Results: Patients who were initially randomized to double-blind placebo
and then switched to open-label eszopiclone (n=111) significantly
reported the following:
• (1) decreased sleep latency, wake time after sleep onset, and number of
awakenings;
• (2) increased total sleep time and sleep quality; and
• (3) improved ratings of daytime ability to function, alertness and sense of
physical well-being compared to baseline (p≤0.0001 all monthly
endpoints). There was no evidence of tolerance on any measure in either
group.
• Taken together, the evidence indicates that MT1/MT2 receptor agonists
like ramelteon or agomelatine may be valuable pharmacological tools for
insomnia and for depression-associated insomnia.
• “Here, we report three cases of
benzodiazepine addicts with histories of
unsuccessful withdrawal attempts who
experienced marked reductions in craving and
improved relapse prognoses under add-on
administration of agomelatine.”
• Results Campaigns aiming to reduce the use
of BZD/Z-drugs failed when they were not
associated with the availability and market
uptake of PR-melatonin.
Prolonged-Release Melatonin: Circadin®