Class 6- anxiety Flashcards
1
Q
COMMON CORE OF ANXIETY DISORDERS
A
The amygdala is responsible for the physiological reactions of fear and anxiety.
Cortico-cortical loops are responsible for the «worry».
The hippocampus is important in the formation of affective memory. It also contributes to the genesis of
anxiety symptoms
2
Q
AMYGDALA Hyperactivity =
A
Physiological reactions of fear and anxiety
3
Q
CORTICO-CORTICAL LOOPS Hyperactivity =
A
Worry
Ruminations
4
Q
TREATMENT OF ANXIETY
CHOOSE ACCORDING TO :
A
- Patient preferences
- Motivation and ability to engage in treatment
- Severity of the disease
- Availability of psychological treatments
- Previous response to treatment
- Comorbidities
5
Q
NON-PHARMACOLOGICAL
MEASURES
A
- Stress Management Strategies
- Avoid caffeine or alcohol consumption
- Avoiding the use of substances that can cause anxiety
6
Q
THERAPEUTIC ARSENAL
A
v Antidepressants v Benzodiazepines v Antipsychotics v Anticonvulsants v Buspirone v Prazosin v Hydroxyzine
7
Q
ANTIDEPRESSANTS
A
q Selective serotonin reuptake inhibitors (SSRIs)
q Serotonin and norepinephrine reuptake inhibitors (NSRI)
q Bupropion
q Mirtazapine
q Tricyclic antidepressants (ATC)
q Monoamine oxidase inhibitors (IMAO)
Not all antidepressants have the official indication of all anxiety disorders, but they are well studied and used in a clinic
8
Q
ANTIDEPRESSANTS
MECHANISM OF ACTION (IN ANXIETY)
A
- Serotonin is an inhibitory neurotransmitter in some anatomical structures, including the cerebral cortex and limbic system including the amygdala and hippocampus;
- Antidepressants increase inhibitory serotonin discharges to the amygdala;
- This will also slow down the activity of all anxiety-causing brain structures that have a relay in the amygdala
9
Q
ANTIDEPRESSANTS
* AT THE BEGINNING OF THE TREATMENT *
A
- Decrease in neuronal discharges secondary to stimulation of 5-HT1A receptors
- Anxiety can be increased at the beginning of treatment
10
Q
5-HT1A RECEPTOR
A
- Pre-synaptic receptor
* Brake on serotonin release
11
Q
SSRI – POST SYNAPTIC EFFECT
A
- Selective inhibition of 5-HT recapture via SERT receptor inhibition
- ↑ 5-HT amount in synapse
12
Q
SSRI – PRESYNAPTIC EFFECT
A
• ↑ 5-HT to bind to 5-HT1A presynaptic receptors
• Brake on 5-HT release
• After a while: “downregulation” of 5-HT1A receptors
• Decrease in the “brake” on the 5-HT release = ↑ 5-HT
This delay before ‘downregulation’ is said to be due to anxiety at the beginning of treatment
13
Q
ANTIDEPRESSANTS DOSES
A
- The same as in the treatment of depression
- OCD is an exception
- requires > 30% dose
- requires longer pharmacological trials
14
Q
DELAY OF ACTION ANTIDEPRESSANTS
A
4 – 8 weeks
15
Q
BENZODIAZEPINES CLINICAL INDICATIONS
A
o Anxiety o Insomnia o Agitation o Epilepsy o Alcohol weaning o Catatonia o Dystonia o Late dyskinesia o And several others.
16
Q
BENZODIAZEPINES CLINICAL INDICATIONS ANXIETY
A
- Acute anxiety or agitation
- Adjuvant at the beginning of treatment to overcome the time frame of action of antidepressants (2 - 3 weeks)
- Used in the majority of anxiety disorders
• Avoid using them in OCD and PTSD
17
Q
FORMULATIONS BENZODIAZEPINES
A
- Tablet (e.g. lorazepam)
- Sublingual tablet (e.g. lorazepam SL)
- Capsule (e.g. temazepam)
- Solution for injection
- Diazepam, lorazepam, midazolam
- For psychiatric emergencies
18
Q
MECHANISM OF ACTION BENZODIAZEPINES
A
GABAA RECEPTOR AGONIST
- In the absence of GABA, there is no effect
- Simultaneous use of the receptor by benzodiazepines AND GABA produces potentiation
19
Q
GABAA RECEPTOR
A
- Includes several sub-units
- Benzodiazepines are mainly linked to sub-units α, β and γ
Example of effect by sub-unit:
• α1 : sedation
• α2 : anxiolytic
• α 5 : anterograde amnesia
20
Q
Oral absorption BENZODIAZEPINES
A
- Well absorbed (lipophils)
* Effect appears 30 minutes to 2 hours after taking
21
Q
Distribution BENZODIAZEPINES
A
• Go through the BBB (lipophiles)
22
Q
Metabolism BENZODIAZEPINES
A
• Many generate active metabolites, which can accumulate and cause more side effects
23
Q
do not produce active metabolites
A
- LOT * : metabolised by glucuronoconjugation, do not produce active metabolites and their elimination is not affected by liver function - good choices in the elderly
24
Q
Clonazepam Onset of action Half-life Duration of action
A
Intermediate 20 to 80 h Intermediate
25
Diazepam Onset of action Half-life Duration of action
Rapid > 100 h Long
26
Lorazepam Onset of action Half-life Duration of action
Intermediate 10 to 20 h Intermediate
27
good choice for reg dose not PRN
Temazepam low onset intermediate duration
28
'POPULAR' CHOICES benzo
v Glucoronoconjugated benzodiazepines : better for the elderly or those with liver failure
• Lorazepam
• Oxazepam
• Temazépam
v Clonazépam: directly targets rumination
v Alprazolam
29
INTRODUCING TREATMENT benzos
üUse the smallest dose possible
| üSeparate into several takes during the day
30
Precautions / Contraindications benzos
- Sleep apnea
- Severe respiratory disorder
- Substance abuse disorder
31
SIDE EFFECTS benzos
```
• Drowsiness, sedation
• Weakness
• Ataxia
• Dizziness
• Light-headed feeling
• Dry mouth
• Headache
• Confusion, disorientation
• Tachycardia, palpitations
• Anterograde amnesia
Generally few side effects if used in the short term at an adequate dose
```
32
MANAGEMENT OF SIDE EFFECTS benzos
« Hangover » effect
• Administer a shorter-acting BZD
Paradoxical effect
• Especially children, elderly, behavioral disorder, borderline personality disorder, autistic
• Stop immediately!
33
Benzos Long-term use leads to
a reduction in the synthesis of certain sub-unit= Loss of efficacy or tolerance
34
WITHDRAWAL benzos
Cessation or decrease= The "brake" is cut = Release of excitatory neurotransmitters Withdrawal symptoms
35
WITHDRAWAL SYMPTOMS benzos
* Muscle stiffness
* Weakness
* Gastrointestinal disorders
* Paresthesia
* Influenza-like
* Visual/olfactory disorders
* Tachycardia
* Anxiety
* Agitation
* Insomnia
* Depersonalization
* Cognitive disorders
* Delirium/ hallucinations
* Depression
36
The duration and severity of withdrawal symptoms depend on the : benzos
* Half-life
* Potency
* Exposition
37
Short-to-middle half-life benzos withdrawal
- Peak: 2-3 days
- Duration: 7-10 days
- Moderate intensity
38
Long half-life benzos withdrawal
- Peak: 7-10 days
- Duration: 17-21 days
- Low intensity
39
RULE OF THUMB benzos withdrawal
25 % reduction in dose per week until 50 % of the dose is reached, then reduce dose by 1/8 every 4 – 7 days
40
Therapy > 8 weeks : taper benzos
slow taper over 2 – 3 weeks
41
benzos Therapy > 6 months : slow taper over
4 – 8 weeks
42
benzos Therapy > 1 year : slow taper over
2 – 4 months
43
BENZODIAZEPINES TAPER
| THERAPEUTIC GOALS
1. Complete cessation
2. Avoid the onset of withdrawal symptoms
3. Prevent the rebound effect
44
BENZODIAZEPINES TAPER
| HOW TO TAPER : 1st
1. Lunch
2. Dinner
3. Morning
4. Bedtime
45
TAPER – LONG VERSION benzos
SUBSTITUTION TO DIAZEPAM (VALIUMTM)
o Long-acting benzodiazepine : fewer rebound or withdrawal symptoms
o Smaller doses, more practical formulation for the final steps
• Half a 2 mg tablet = 1 mg
o Tapering over about 20 weeks
o Increased chances of success
• It's better to go too slowly than too fast
46
TAPER – ELDERLY benzos
SUBSTITUTION TO OXAZEPAM (SERAXTM)
o Intermediate half-life
o No pharmacokinetic alteration in the elderly
o Find the equivalent dose and then remove 2,5 mg
• ¼ of 10 mg tablet per month until the end
47
Taper benzol monitor
```
BENZODIAZEPINES WITHDRAWAL
SYMPTOMS QUESTIONNAIRE
SCORE
o > 20 = change strategy
o increase in 3-point score = change strategy
```
48
INTERACTIONS benzos
* Plasma protein binding (e.g. diazepam)
* Cytochrome P450 3A4 mainly
* Increased drowsiness
* Alcohol
* Antihistamines
* Opiates
* Some antidepressants
* Some antipsychotics
49
– ATYPICAL ANTIPSYCHOTICS
| MECHANISM OF ACTION
Anxiolysis is thought to be mediated by 5-HT1A receptor agonism
50
CLINICAL USE IN ANXIETY– ATYPICAL ANTIPSYCHOTICS
v Evidence for monotherapy is sparse
• Quetiapine XR
v Some evidence as augmenting agents
• Risperidone, olanzapine, aripiprazole
51
PREGABALINE MECHANISM OF ACTION
* Does not act on GABA, but decreases neuronal activity and neurotransmission
* Antiepileptic, anxiolytic and analgesic properties
52
CLINICAL USE IN ANXIETY PREGABALINE
v TAG and social anxiety
| v Sometimes allows long-term benzodiazepines to be taper
53
DELAY OF ACTION PREGABALINE
Rapid effect vs antidepressants
| about 1 week
54
SIDE EFFECTS PREGABALINE
* Dizziness
* Drowsiness
* Peripheral edema
* Dry mouth
* Constipation
55
BUSPIRONE MECHANISM OF ACTION
* Partial agonist of 5-HT1A receptors
| * Slowing electrical impulses in amygdala
56
CLINICAL USE IN ANXIETY BUSPIRONE
v Unlike benzodiazepines, is not useful if used in single or occasional doses
v Mixed effect, poorly constructed clinical studies
57
DELAY OF ACTION BUSPIRONE
• A few weeks
58
SIDE EFFECTS BUSPIRONE
* Dizziness, nausea, headache
* No sedative effect
* No addiction or withdrawal
* Interesting in patients with respiratory disorder, as it does not cause respiratory depression
* High dropout rate in studies (ineffective?)
59
PRAZOSIN MECHANISM OF ACTION
* Antagonist of alpha1-adrenergic receptors
| * Antihypertensive drug
60
SIDE EFFECTS PRAZOSIN
* Hypotension
* Nausea
* Drowsiness
* Headache
61
HYDROXYZINE MECHANISM OF ACTION
H1 receptor antagonist (antihistaminic)
62
CLINICAL USE IN ANXIETY HYDROXYZINE
GAD
63
DELAY OF ACTION HYDROXYZINE
* 30 minutes for sedative effect
| * Longer-term effect is uncertain
64
SIDE EFFECTS HYDROXYZINE
* Anticholinergic effects
* Cognitive function
* Constipation
* Blurred vision
* Sedation
65
Medications RISK factors GAD
• Toxicity (e.g. anticholinergics,
corticosteroids, bronchodilatators)
• Withdrawal (e.g. alcohol, benzodiazepines)
• Stimulants, thyroid hormone, etc.
66
Drugs with an anxiolytic effect ???? NE release
decrease
67
Drugs that reduce anxiety and produce sedation target ???? receptor
GABAa
68
Abnormalities in serotonergic functioning occur through release and uptake at the
* Presynaptic autoreceptors (5-HT1A/1D)
* Serotonin reuptake transporter site
* Postsynaptic receptors (5-HT1A, 5-HT2A, 5-HT2C)
69
GAD, panic, PTSD, SAD Continue treatment for at least ??? following response to treatment, then reassess
1 year
70
panic If discontinuation of treatment is considered, do it over
4 to 6 months
71
PATHOPHYSIOLOGY PTSD
ALPHA1 ADRENERGIC POST-SYNAPTIC
RECEPTORS: Over-activation of these receptors to
activate symptoms related to PTSD, especially those related to sleep (nightmares)
ALPHA2 ADRENERGIC POSTSYNAPTIC
RECEPTORS: Involved in cognitive processes and
response to stimuli
72
FIRST LINE TREATMENT: NIGHTMARES & INSOMNIA
- Non-pharmacological measures
73
PTSD PSYCHOTIC SYMPTOMS
| • x% of patients
40
74
PHARMACOLOGICAL TREATMENT : PTSD
1. SSRIs or SNRIs to treat PTSD (psychotic symptoms may be related to it)
2. Flash-back, hypervigilance, dissociation and paranoia can respond to anticonvulsants
3. Atypical antipsychotic
75
SAD pathophys
NE
• Involved especially if performance-related anxiety
DA
• Dysfonction
• Decreased ability to bind to D2 receptors 5-HT
• Hypersensitivity of 5-HT2 receptors
76
performance-related anxiety
USING BETA BLOCKERS?
• Possibly useful if performance-related anxiety
• Decrease in tremors, palpitations and blushing
e.g. propranolol 10 mg 2 hours before performance (watch out for bradycardia!)
77
SAD when discontinue, taper over
3 - 4 months
78
PATHOPHYSIOLOGY OCD
Abnormalities in the transmission of 5-HT, DA and glutamate
79
WHAT ABOUT BENZODIAZEPINES? OCD
No
80
Recommended long-term treatment after OCD
2 to 4 relapses
81
A treatment duration of ???? is generally
| recommended before considering a cessation of treatment
12 to 24 months
