L40 Anxiolytic drugs Flashcards
What are the different types of anxiety? (7)
- General anxiety disorder: an ongoing state of anxiety with no clear reason
- Social anxiety disorder: fear of social interactions
- Phobias
- Panic disorder: sudden attacks of overwhelming fear
- Post-traumatic stress disorder: associated with recall of traumatic event
- Obsessive compulsive disorder: compulsive behaviour driven by irrational anxiety
- Body dysmorphic disorder: anxiety caused by distorted view of body/appearance
What is anxiety?
- anticipation of fear in the absence of external stimuli
What is the first line interventions for anxiety patients?
- Drug therapy is NOT recommended for first line treatment
- For general anxiety disorder:
1st line= education and monitoring; 2nd line= self-help and group cognitive behavioural therapy; 3rd line= high intensity psychological interventions/ pharmacological intervention
-For Obsessive compulsive disorder and body dysmorphic disorder:
1st line= cognitive behavioural therapy; and pharmacological intervention is considered if no improvement
What are the types of pharmacological interventions? (6)
- antidepressants: onset of action is delayed
- benzodiazepines: act quickly but induce dependence
- 5-HT1a receptor agonists: onset of action is delayed
- some anti-epileptic drugs, eg gabapentin, pregabalin, tiagabine and sodium valproate (can be effective in treating general anxiety disorder)
- beta adrenoceptor antagonists
- anti-psychotics
What is the important property of anxiolytics?
- they can become sedative and even hypnotics if they are in a high concentration!!
What drugs are anxiolytic, sedative and hypnotic?
- Benzodiazepines, zopicolone related drugs, barbiturates
* barbiturates require careful dosage= can be fatal
What drugs are anxiolytic?
- antidepressants, buspirone, beta adrenoceptor antagonists
What drugs are hypnotic?
- anti-histamines, chloral hydrate, sodium oxybate
Anti-depressants
- generally first drug class to try
- there is a delay for onset of action so NOT GOOD for patients with severe depression
- Selective serotonin reuptake inhibitors are commonly used: eg. sertraline, citalopram, fluoxentine
OR - Serotonin–norepinephrine reuptake inhibitors could be useful
- MAO inhibitors/ tricyclic antidepressants are not used commonly due to their severe side effects
Benzodiazepines
- eg nitrazepam
- SHOULD NOT routinely be used to treat anxiety but may be useful in patients with acute and severe symptoms in short term (4 WEEKS MAX!)
- CANNOT combine with alcohols= respiratory depression
SIDE EFFECTS: drowsiness, confusion, amnesia (a partial loss of memory)
Benzodiazapines: Loprazolam
- half life: 6-12 hours
- exerts both hypnotic and anxiolytic properties
Benzodiazapines: nitrazepam
- half life: 16-40 hours
- exerts hypnotic and anxiolytic effects
Benzodiazapines: diazepam
- half life: 20-40 hours
- exerts anxiolytic and anticonvulsant effects
Why don’t we use benzodiazepines for prolonged period of time?
- because common to develop tolerance and physical dependence
Tolerance: repeated use reduces effectives
= it is more commonly seen in anti-convulsant action but may occur when apply as anxiolytic. Not really seen when used in hypnotic actions
Physical dependence: can cause anxiety, tremor, dizziness, weight loss and sleep disturbances when withdrew
Mechanism of action of benzodiazepines
- binds to GABAa receptors (like alcohols)
- enhance affinity for GABA binding so increase the probability of channel opening.
- so can fire MORE inhibitory signals out
Structure of GABAa receptor structure
- 5 subunits: 2 alpha, 2 beta and 1 gamma
- there are several different subtypes for alpha, beta and gamma subunits
Which subunits of GABAa receptors are sensitive to benzodiazepines?
- alpha 4 and alpha 6 receptors are INSENSITIVE to benzodiazepines
- gamma 2 required for benzodiazepines sensitivity
- alpha 1 receptor induce sedation and amnesia
- alpha 2, 3 benzodiazepines are anxiolytic
- most abundant combination of GABAa receptors= alpha1beta2gamma2
What are benzodiazepine antagonists?
- eg. Flumazenil
- Reverse actions of benzodiazepine, for example patients who have extreme drowsiness after benzodiazepines or after overdose
What are barbiturates?
- eg phenobarbitone
- potentiate GABAa receptors but they are non-selective which means can also bind to other ligand-gated ion channels eg inhibit NMDA receptors
- was commonly used before benzodiazepines
- produces tolerance and dependence
- produce anaesthesia and death in overdose
SO NOT RECOMMENDED to prescribe
What is the mechanism of action for barbiturate?
- binds to GABAa receptors at site distinct from benzodiazepine binding sites
- low conc= prolongs openings produced by GABA; high conc= opens channels even in absence of GABA
(Depress neurones to such extent that can cause death! As lots of GABA action)
How do the 5-HT1A agonists work?
- eg buspirone, ipsapirone, gepirone
- they are 5-HT1A receptor partial agonists
- have less sensation and more motor coordination than benzodiazepines
- side effects: drowsiness, dizziness, headaches (less than benzodiazepines)
Buspirone
- doesn’t show tolerance/ physical dependence
- ineffective against panic attacks/ severe anxiety
- only license for short-term use, although therapeutic actions take days/ weeks to develop
- long term effectiveness is not proven
- may INCREASE anxiety initially
What are the adaptive changes when there’s a repeated buspirone exposure?
- 5HT1a receptors are somatodendritic autoreceptors on serotonergic neurones in raphe nucleus (autoreceptors: exert negative feedback on the neurones)
- 5HT1a receptors desensitise on repeated exposure so enhances 5HT release = more AP released= achieved anxiolytic effect
- that’s why it takes a while to work as take time for neurones to become desensitised
What are the other anxiety treatments?
1)beta adrenoceptor antagonists
- they remove the peripheral symptoms of anxiety but DO NOT treat anxiety eg palpitations, tremors, by blocking peripheral receptors
2) anti-psychotics eg olanzepine, risperidone
- maybe useful in some cases, eg general anxiety disorder/ post-traumatic stress disorder
- greater incidence of side effects
= NOT a recommended treatment
