Anti-anxiety drugs

Сентябрь 9, 2022

Главная
Химия
Anti-anxiety drugs

Содержание

2. Anti-anxiety drugs Prof. Anatoly Kreinin MD, PhD Director of Psychiatric Department, Maale Carmel Mental Health Center,
3. תרופות נוגדות חרדה.. Benzodiazepines (BZDs) Buspirone Antihistamines Antidepressants Anti-epileptic drugs (AEDs) Atypical antipsychotics
4. תרופות שלא משומשות יותר לחרדה Typical antipsychotics (e.g., thioridazineמלריל -) Barbiturates
5. Benzodiazepines (BZDs) The Problem About 2 per cent of the adult population of the US (around
6. History of benzodiazepines 1912 phenobarbital 1961 chlordiazepoxide (Librium): 1st BDZ 1963 diazepam 1970 highest level of
7. BZD Alprazolam (Xanax) Clonazepam (clonex) Diazepam (Valium,Assival) Lorazepam (Lorivan) Oxazepam (Vaben) Clorazepate (Tranxal) Chlordiazepoxide (Librium)
8. History The first benzodiazepine (benzo) was synthesized by an Austrian scientist - Dr. Leo Sternbach in
9. Structure 2-Keto Benzos Some administered as prodrug All have active metabolites (commonly desmethyldiazepam) Long half-lives (most
10. 2-Keto Benzos First isolated benzo Oxidized to desmethyldiazepam in the liver Indicated for treatment of anxiety
11. 2-Keto Benzos Longest half-life of any benzo (~ 40-250 hours) Indicated primarily for treatment of insomnia,
12. 2-Keto Benzos The original date-rape drug, and the origin of the term “roofie” Pharmacologically very similar
13. 3-hydroxy Benzos Indicated for treatment of anxiety, seizure, insomnia, panic disorder, and alcohol withdrawal. Unique among
14. Triazolo Benzos First benzo approved by FDA for treatment of panic disorder. Also used as an
15. Mechanism of Action Benzodiazepines act as GABA (γ-aminobutyric acid) potentiators. They bind to BZ receptors on
18. The four types of receptors
20. Modulatory interactions at GABAA receptor
21. Benzodiazepines Mechanism of action Increase GABA-mediated inhibition: - spinal cord - cuneate nucleus - cerebellum -
22. Clinical Applications Anxiolytic GAD, PTSD, OCD, etc. Panic Disorder Specific Phobias Anticonvulsant Status epilepticus Myoclonic epilepsy
23. Benzodiazepines CNS - Antianxiety, sedative - Hypnotic - Amnesic - Anticonvulsant - Muscle relaxant
24. Benzodiazepines Antianxiety - sedative effects - relief of anxiety and tension - emotional calming - drowsiness
25. Benzodiazepines Hypnotic effects - ↓ latency of sleep onset - ↓ awakenings - ↑ stage 2
27. Benzodiazepines Anticonvulsant effects - interrupt status epilepticus or any existing seizures – diazepam (i.v.) - prevent
28. Benzodiazepines Muscle relaxant effects ! No effect on NMJ (neuromuscular junction); a CNS effect! Diazepam: i.v.
29. Benzodiazepines Effects on respiration and cardiovascular system -usually insignificant Preexisting respiratory failure can be aggravated by
30. Enhancement of GABAergic inhibition GABA agonistic action enhancement of GABA release enhancement of synthesis depression of
31. Potentiation of GABA-induced Cl- conductance conductance of open channels BARBITURATES life-time of channel openings BENZODIAZEPINES frequency
32. Benzodiazepines Binding sites - 3H-diazepam binding: saturable, reversible, specific - sites unevenly distributed; parallel to GABAA
33. Benzodiazepine binding site ligands Agonists (positive modulators) benzodiazepines Antagonists (null modulators) flumazenil for BZD overdose -
34. Future therapeutic trends of benzodiazepine binding site (BDZ R) ligands Drugs for a given binding site
35. Benzodiazepine pharmacokinetics Absorption rapid: diazepam, triazolam, flurazepam intermediate: lorazepam slow: oxazepam Plasma protein binding high Distribution
36. Benzodiazepine pharmacokinetics Metabolism Oxidative reactions: active metabolites, long half-life, influenced by age, disease and other drugs
37. Benzodiazepines: pharmacokinetics Drug Important differences Diazepam Mean half-life 35-50 h (desmethyldiazepam) metabolites have long half-life Lorazepam
38. Benzodiazepine metabolism
40. Скачать презентацию

Слайд 2

Anti-anxiety drugs
Prof. Anatoly Kreinin MD, PhD
Director of Psychiatric Department, Maale Carmel

Mental Health Center, Affiliated to Bruce Rappaport Medical Faculty, Technion, Haifa, Israel

Слайд 3

תרופות נוגדות חרדה..
Benzodiazepines (BZDs)
Buspirone
Antihistamines
Antidepressants
Anti-epileptic drugs (AEDs)
Atypical antipsychotics

Слайд 4

תרופות שלא משומשות יותר לחרדה
Typical antipsychotics (e.g., thioridazineמלריל -)
Barbiturates

Слайд 5

Benzodiazepines (BZDs) The Problem
About 2 per cent of the adult population of

the US (around 4 million people) appear to have used prescribed benzodiazepine hypnotics or tranquillisers regularly for 5 to 10 years or more. Similar figures apply in the UK, over most of Europe and in some Asian countries.
Surveys of general practices show that there are over 180 long-term prescribed users per general practice.
Despite repeated recommendations to limit benzodiazepines to short-term use (2– 4 weeks), doctors in the UK and worldwide are still prescribing them for months or years.
Dependence upon prescribed benzodiazepines is now recognised as a major clinical problem and the National Performance Assessment Framework for the NHS makes it a national priority to reduce this within each health board area.

Слайд 6

History of benzodiazepines
1912 phenobarbital
1961 chlordiazepoxide (Librium): 1st BDZ
1963 diazepam
1970 highest level

of use
1980s reduced use because of social concerns

Слайд 7

BZD
Alprazolam (Xanax)
Clonazepam (clonex)
Diazepam (Valium,Assival)
Lorazepam (Lorivan)
Oxazepam (Vaben)
Clorazepate (Tranxal)
Chlordiazepoxide (Librium)

Слайд 8

History
The first benzodiazepine (benzo) was synthesized by an Austrian scientist -

Dr. Leo Sternbach in the mid 1950’s while working at Hoffman-La Roche.
The new compound’s potential as a pharmaceutical was not initially recognized, however, Dr. Sternbach’s persistent research eventually uncovered it’s efficacy as a tranquilizer.
In 1959, chlordiazepoxide (Librium) was introduced as the first of many benzos to come.
Just four years later, in 1963, diazepam (Valium) came on the market.
Clinicians quickly recognized the potential of benzos as a safer alternative to the barbiturate class of anxiolytics.

Слайд 9

Structure
2-Keto Benzos
Some administered as prodrug
All have active metabolites (commonly desmethyldiazepam)
Long half-lives

(most in excess of 60 hours)
3-hydroxy Benzos
No active metabolites
Not metabolized in the liver
Intermediate half-lives (most ~ 8-20 hours)
Triazolo Benzos
Additional heterocyclic ring attached at the 1 and 2 positions
Some active metabolites
Short to intermediate half-lives (anywhere from 3-14 hours)

Слайд 10

2-Keto Benzos
First isolated benzo
Oxidized to desmethyldiazepam in the liver
Indicated for

treatment of anxiety and insomnia

Most prolific and versatile benzo
Indicated for treatment of anxiety, seizure, muscle tension, insomnia, and alcohol withdrawal

Chlordiazepoxide (Librium)

Diazepam (Valium)

Слайд 11

2-Keto Benzos
Longest half-life of any benzo (~ 40-250 hours)
Indicated primarily for

treatment of insomnia, may also serve as an anxiolytic

High potentcy (~ 20 times stronger per miliigram than diazepam)
Causes moderate anterograde amnesia
Indicated for treatment of anxiety, also a highly effective anticonvulsant

Flurazepam (Dalmane)

Clonazepam (Klonopin)

Слайд 12

2-Keto Benzos
The original date-rape drug, and the origin of the term

“roofie”
Pharmacologically very similar to clonazepam, but possesses much stronger amnesic properties.
One of only two drugs in the U.S. for which a first possession charge is a mandatory felony. The other of the two is crack cocaine.

Flunitrazepam (Rohypnol)

Слайд 13

3-hydroxy Benzos
Indicated for treatment of anxiety, seizure, insomnia, panic disorder, and

alcohol withdrawal.
Unique among benzos in it’s use as an adjunctive anti-emetic

Indicated for treatment of anxiety, insomnia, and alcohol withdrawal.
Common metabolite of many 2-keto benzos following their oxidation to desmethyldiazepam

Lorazepam (Ativan)

Oxazepam (Serax)

Слайд 14

Triazolo Benzos
First benzo approved by FDA for treatment of panic disorder.
Also

used as an adjunctive treatment for depression while adjusting to SSRIs.

Very rapid onset
Very short half-life
Possesses amnesic properties similar to clonazepam
Used almost exclusively as a pre-op anesthetic

Alprazolam (Xanax)

Triazolam (Halcion)

Слайд 15

Mechanism of Action
Benzodiazepines act as GABA (γ-aminobutyric acid) potentiators. They bind

to BZ receptors on the GABA-BZ receptor complex, which allows them to allosterically modulate and enhance the activity of GABA. This results in increased hyperpolarization at target neurons, making them less responsive to excitatory stimuli.

Слайд 16

Слайд 17

Слайд 18

The four types of receptors

Слайд 19

Слайд 20

Modulatory interactions at GABAA receptor

Слайд 21

Benzodiazepines
Mechanism of action
Increase GABA-mediated inhibition:
- spinal cord
- cuneate nucleus
- cerebellum
- brain

stem
- hippocampus
- neocortex

Слайд 22

Clinical Applications
Anxiolytic
GAD, PTSD, OCD, etc.
Panic Disorder
Specific Phobias
Anticonvulsant
Status epilepticus
Myoclonic epilepsy
Muscle relaxant
Sleep aid
Pre-operative

anesthesia
Alcohol withdrawal

Слайд 23

Benzodiazepines
CNS - Antianxiety, sedative
- Hypnotic
- Amnesic
- Anticonvulsant
- Muscle relaxant

Слайд 24

Benzodiazepines
Antianxiety - sedative effects
- relief of anxiety and tension
- emotional calming
-

drowsiness (tolerance)
- motor incoordination (tolerance)

Слайд 25

Benzodiazepines
Hypnotic effects
- ↓ latency of sleep onset
- ↓ awakenings
- ↑ stage

2 NREM sleep
- ↓ stage 3 & 4 NREM sleep
- ↓ REM sleep
- ↑ total sleep time

Слайд 26

Слайд 27

Benzodiazepines
Anticonvulsant effects
- interrupt status epilepticus or any
existing seizures – diazepam

(i.v.)
- prevent infantile myoclonus, absence seizures – clonazepam (orally)
tolerance → escape from seizure control

Слайд 28

Benzodiazepines
Muscle relaxant effects
! No effect on NMJ (neuromuscular junction); a

CNS effect!
Diazepam:
i.v. - tetanus
- stiff-man syndrome
- endoscopy, orthopedic manipulations
orally - not well documented

Слайд 29

Benzodiazepines
Effects on respiration and cardiovascular system
-usually insignificant
Preexisting respiratory failure can be

aggravated by any hypnotic - sedative drug

Слайд 30

Enhancement of GABAergic inhibition
GABA agonistic action
enhancement of GABA release enhancement of

synthesis depression of metabolism
depression of GABA uptake
allosteric enhancement of action at GABAA receptor

Слайд 31

Potentiation of GABA-induced Cl- conductance
conductance of open channels
BARBITURATES
life-time of channel

openings
BENZODIAZEPINES
frequency of channel openings

Слайд 32

Benzodiazepines
Binding sites
- 3H-diazepam binding: saturable, reversible, specific
- sites unevenly distributed; parallel

to GABAA receptors
cortex high
striatum
cerebellum
spinal cord low
- affinity of various BDZ derivatives for the receptor correlates with biological and therapeutic potency

Слайд 33

Benzodiazepine binding site ligands
Agonists (positive modulators)
benzodiazepines
Antagonists (null modulators)
flumazenil
for BZD overdose

- ( 0.5 mg ½ min repaid after ½ min (max 3 mg)
Inverse agonists (negative modulators)
β-carbolines

Слайд 34

Future therapeutic trends of benzodiazepine binding site (BDZ R) ligands
Drugs for a

given binding site subtype:
BDZ R1 agonist sedative, amnesic,
(anticonvulsant)
BDZ R2 agonist anxiolytic, muscle relaxant
BDZ R partial agonist ↓ dependence
BDZ R inverse agonist ↓ ethanol intake
abnormal BDZ R specific disorder

Слайд 35

Benzodiazepine pharmacokinetics
Absorption
rapid: diazepam, triazolam, flurazepam
intermediate: lorazepam
slow: oxazepam
Plasma protein binding high
Distribution
non-equilibrium: blood

flow, lipid solubility
equilibrium: lipid solubility

Слайд 36

Benzodiazepine pharmacokinetics
Metabolism
Oxidative reactions: active metabolites, long half-life, influenced by age, disease

and other drugs - diazepam
Conjugation: loss of activity, far less influenced by age, disease and other drugs - lorazepam, oxazepam, active metabolites

Слайд 37

Benzodiazepines: pharmacokinetics Drug Important differences
Diazepam Mean half-life 35-50 h (desmethyldiazepam)
metabolites have

long half-life
Lorazepam Mean half-life 12-20 h, rapid oral absorption,
disposition not altered appreciably by liver
disease, aging or inhibitors of drug metabolism
Oxazepam Mean half-life 6-10 h, slower absorption than
lorazepam, disposition not altered appreciably
by liver disease, aging or inhibitors of drug metabolism
Triazolam Mean half life 2-3 h, rapid absorption,
disposition not altered appreciably by liver disease, aging or drugs

Слайд 38

Anti-anxiety drugs

Содержание

Anti-anxiety drugsProf. Anatoly Kreinin MD, PhDDirector of Psychiatric Department, Maale Carmel

תרופות נוגדות חרדה..Benzodiazepines (BZDs)BuspironeAntihistaminesAntidepressantsAnti-epileptic drugs (AEDs)Atypical antipsychotics

תרופות שלא משומשות יותר לחרדהTypical antipsychotics (e.g., thioridazineמלריל -)Barbiturates

Benzodiazepines (BZDs) The ProblemAbout 2 per cent of the adult population of

History of benzodiazepines1912 phenobarbital1961 chlordiazepoxide (Librium): 1st BDZ1963 diazepam1970 highest level

BZDAlprazolam (Xanax)Clonazepam (clonex)Diazepam (Valium,Assival)Lorazepam (Lorivan)Oxazepam (Vaben) Clorazepate (Tranxal) Chlordiazepoxide (Librium)

HistoryThe first benzodiazepine (benzo) was synthesized by an Austrian scientist -

Structure2-Keto BenzosSome administered as prodrugAll have active metabolites (commonly desmethyldiazepam)Long half-lives

2-Keto BenzosFirst isolated benzo Oxidized to desmethyldiazepam in the liverIndicated for

2-Keto BenzosLongest half-life of any benzo (~ 40-250 hours)Indicated primarily for

2-Keto BenzosThe original date-rape drug, and the origin of the term

3-hydroxy BenzosIndicated for treatment of anxiety, seizure, insomnia, panic disorder, and

Triazolo BenzosFirst benzo approved by FDA for treatment of panic disorder.Also

Mechanism of Action Benzodiazepines act as GABA (γ-aminobutyric acid) potentiators. They bind

The four types of receptors

Modulatory interactions at GABAA receptor

BenzodiazepinesMechanism of actionIncrease GABA-mediated inhibition: - spinal cord - cuneate nucleus - cerebellum - brain

Clinical ApplicationsAnxiolyticGAD, PTSD, OCD, etc.Panic DisorderSpecific PhobiasAnticonvulsantStatus epilepticusMyoclonic epilepsyMuscle relaxantSleep aidPre-operative

BenzodiazepinesCNS - Antianxiety, sedative - Hypnotic - Amnesic - Anticonvulsant - Muscle relaxant

BenzodiazepinesAntianxiety - sedative effects- relief of anxiety and tension- emotional calming-

BenzodiazepinesHypnotic effects- ↓ latency of sleep onset- ↓ awakenings- ↑ stage

BenzodiazepinesAnticonvulsant effects- interrupt status epilepticus or any existing seizures – diazepam

BenzodiazepinesMuscle relaxant effects ! No effect on NMJ (neuromuscular junction); a

BenzodiazepinesEffects on respiration and cardiovascular system -usually insignificant Preexisting respiratory failure can be

Enhancement of GABAergic inhibitionGABA agonistic actionenhancement of GABA release enhancement of

Potentiation of GABA-induced Cl- conductanceconductance of open channelsBARBITURATES life-time of channel

BenzodiazepinesBinding sites- 3H-diazepam binding: saturable, reversible, specific- sites unevenly distributed; parallel

Benzodiazepine binding site ligandsAgonists (positive modulators) benzodiazepinesAntagonists (null modulators) flumazenil for BZD overdose

Future therapeutic trends of benzodiazepine binding site (BDZ R) ligandsDrugs for a

Benzodiazepine pharmacokineticsAbsorption rapid: diazepam, triazolam, flurazepam intermediate: lorazepam slow: oxazepamPlasma protein binding highDistribution non-equilibrium: blood

Benzodiazepine pharmacokineticsMetabolism Oxidative reactions: active metabolites, long half-life, influenced by age, disease

Benzodiazepines: pharmacokinetics Drug Important differencesDiazepam Mean half-life 35-50 h (desmethyldiazepam) metabolites have

Benzodiazepine metabolism

Похожие презентации