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Pharmacology > Anxiolytics and hypnotics > Flashcards

Anxiolytics and hypnotics Flashcards

1
Q

what do anxiolytics and hypnotics treat?

A

anxiolytics treat anxiety

hypnotics treat sleep disorders

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2
Q

what is the fear response?

A
  • defensive behaviours
  • autonomic reflexes
  • alertness
  • negative emotion
  • corticosteroid secretion
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3
Q

what is anxiety?

A

anticipatory fear response which is often independent of external events

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4
Q

what are anxiety disorders?

A
  1. panic disorder - overwhelming fear marked by somatic symptoms such as tachycardia chest pains, trembling
  2. social anxiety - fear of interacting with people
  3. phobias - strong fear response to specific objects/situations
  4. PTSD - triggered by recall of a stressful situation
  5. OCD - compulsive, ritualistic behaviour driven by irrational anxiety
  6. generalised anxiety - no clear reason or focus, an ongoing state of excessive anxiety
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5
Q

what are the treatment options for anxiety?

A
  1. anxiolytic/hypnotic agents - benziodiazepines (BZs) and barbiturates
    - BZs have unwanted side effects such as amnesia
    - BZs work instantly and are taken on a needed basis
  2. antidepressants - can take several weeks to produce a response and must be taken continuously
  3. propranolol (beta antagonist) to block somatic symptoms
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6
Q

how are animals used to model anxiety?

A
  • animal behaviours associated with fear can help study and evaluate anxiety drugs
  • different models, experience and conditioning can give different results, reflecting the complexity of anxiety
  • shows how anxiolytic drugs suppress behaviours associated with fear, leading to overcoming fear
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7
Q

what animal models can be used to study anxiety?

A
  1. elevated cross test/light and dark box test
    - makes use of rodent’s fear of unfamiliar environment and desire to hide to avoid danger
    - the time the animal spends in the less exposed environment is measured
    - anxiolytic drugs reduce the fear response and hiding time of the animal
  2. conflict tests - trained response to reward may be interjected with electric shock associated with specific sound
    - in absense of anxiolytics, animal suppresses urge to get the reward when they hear the sound
    - when treated, they ignore the sound and get the reward
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8
Q

what receptors are targets for anxiolytics and hypnotics?

A

GABAa receptors

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9
Q

what are GABAa receptors and their structure?

A
  • chloride-sensitive ionotropic receptors - activation causes hyperpolarisation and reduction in excitability
  • made up of 5 subunits - influences pharmacology
  • in different parts of brain, different subunit combinations are expressed
  • mediate fast inhibitory transmission
  • has multiple binding sites for different ligands: BZs, barbiturates and ethanol can increase GABAa function to inhibit CNS
  • 2 main binding sites - both must be occupied for GABAa to work
  • pentametric stoichiometry: 2alpha, 2beta, 1gamma/delta/epsilon
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10
Q

what is the orthosteric site of a receptor?

A

agonist binding site which is responsible for switching on the signalling by a receptor
- competitive antagonists may bind here to block the action of the agonist

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11
Q

what are the agonists and antagonists of the orthosteric site of GABAa?

A

agonists: GABA, muscimol

antagonist: bicuculline, picrotoxin

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12
Q

what are allosteric sites of a receptor?

A

they do not switch on the signalling of a receptor themselves, but instead modify the function/signalling of the agonist-bound receptor

They only act if the orthosteric site is occupied by an agonist
If agonist is absent at orthosteric site, the allosteric site will not function

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13
Q

what are the agonists and antagonists of the allosteric site of GABAa?

A

agonist - benzodiazepoines e.g. diazepam (positive allosteric modulator)

antagonist - flumazenil (at BZ site)
- antagonist can be used to reverse BZ overdose

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14
Q

what is an allosteric modulator?

A

it does not activate the receptor on its own, but it does modify the behaviour of the receptor when an agonist is bound to the orthosteric site

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15
Q

what is a positive allosteric modulator (PAM)?

A

increases the signalling of an agonist-bound receptor
- BZs increase signalling of GABAa receptors
- only impact receptor if the orthosteric site is occupied by an agonist

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16
Q

what is a negative allosteric modulator?

A

decreases the signalling of an agonist-bound receptor
- beta-carboline decreases the signalling of GABAa receptors (opposite of BZ)

17
Q

what are the physiological effects of BZ agonists?

A
  1. sedation/anxiolytic: decreased responsiveness to constant level of stimulation
  2. hypnosis: latency of sleep onset is decreased
    - stage 2 sleep is increased and duration of rem is decreased
    - duration of slow wave sleep (night terrors) is decreased
  3. anterograde amnesia: prevent memory of events experienced while under influence
  4. anticonvulsant - inhibit development and spread of epileptiform activity
  5. reduction of muscle tone
18
Q

what are benzodiazepines?

A
  • used to treat anxiety and insomnia
  • positive allosteric modulatior of GABAa
  • activate midbrain dopamine neurons via GABAa to hijack mesolimbic reward system
  • induce muscle relaxation, control epileptic seizures and can produce amnesia
  • tolerance to the effects can be a sign of dependence - they can be abused after chronic clinical treatment for recreational purposes
19
Q

what mediates the sedative actions of BZs?

A

alpha1-containing GABAa receptors

20
Q

what mediates the anxiolytic actions of BZs?

A

alpha2-containing GABAa receptors

21
Q

what kind of ligand is BZs for GABAa receptors?

A

positive allosteric modulators - BZs increase activity of GABAa
- increase Cl- current across membrane, only in the presence of GABA bound to the receptor

22
Q

how do BZs and barbiturates modulate GABAa receptors?

A

BZs increase probability of GABAa opening

barbiturates increase the mean open time of GABAa

both result in more current flow and a bigger GABAa response

23
Q

what action does beta-carboline have on GABAa?

A

it is a negative allosteric modulator
- decrease channel opening so less inhibition of excitatory neurons
- it is anxiogenic so can increase anxiety
- it is a proconvulsant - can lead to seizures

24
Q

what action does flumazenil have on GABAa?

A

it is an antagonist at the BZ allosteric site
- it binds to an allosteric site so doesnt affect the receptor
- it can be used to reverse the effects of BZ overdose

25
Q

how do PAMs and NAMs affect GABAa receptors?

A

they exert opposite physiological effects:
- PAMs stabilise the receptor in a state with increased affinity for GABA, causing a left shift in conc-response curve
- NAMs stabilise receptor in a state with decreased affinity for GABA, so remains closed and harder to open (right shift)

26
Q

what are the therapeutic uses of BZs?

A
  • short acting compounds can be used as sleeping tablets
  • intravenous diazepam can treat epilepsy
  • some BZs are metabolised to produce active intermediates with a long half-life e.g. diazepam
  • BZ derivatives have anti-CCK activity which is a biological substrate for anxiety
  • sedative and muscle relaxant - causes impaired alertness
27
Q

what are the adverse affects of BZ agonists?

A
  1. tolerance - decreased responsiveness to a drug following continuous exposure
    - may be overcome by increasing dose
  2. misuse
  3. physical dependence characterised by withdrawal
    - increased anxiety, insomnia, CNS excitability, convulsions
    - more problematic with drugs with short half-lives e.g. triazolam may cause daytime anxiety when treating sleep disorders
    - may be alleviated by using a slower-acting drug
  4. sleepiness, impaired psychomotor function, amnesia
  5. can be fatal in overdose when taken with alcohol
28
Q

how do the conc-response curves of BZs and barbiturates differ?

A

barbiturates at high doses act as agonists and increase CNS depression to a fatal point

BZs have their own plateau affect, so at most put patient in deep sleep
- when mixed with CNS depressors such as alcohol however, BZs can be fatal

29
Q

what drugs are used to treat anxiety?

A
  1. benzodiazepines: use is limited, used for acute anxiety and co-administered with anti-depressants
  2. propranolol: beta-blocker to block symptoms of sympathetic drive
  3. antidepressants: SSRIs useful for generalised anxiety, PTSD and OCD
    - SSRIs and SNRIs and buspirone take several days to show effectiveness, so BZs are used in meantime
  4. buspirone: serotonin-1A partial agonist to treat generalised anxiety
    - acts on autoinhibitory GPCRs found on serotonergic neurons found in corticolimbic pathways to increase serotonin release
  5. antipsychotics: olanzapine to treat PTSD and generalised anxiety
  6. anti-epileptic drugs e.g. pregabalin to treat generalised anxiety
30
Q

what drugs can treat insomnia?

A

drug choice depends on underlying cause and whether short-term or chronic
- short-acting BZs e.g. lorazepam and zolpidem
- antihistamines - e.g. pyrromethene can cross the BBB to blocks histamine receptors to reduce alertness
- melatonin receptor agonists
- orexin receptor antagonists
- H1 receptor antagonists e.g. promethazine (sleep aid)

31
Q

what do single patch clamp recordings show about GABAa receptors?

A
  • some GABAa receptors spontaneously become active, even in absence of agonist
  • these moments are short lived
  • referred to as constitutive activity
  • inverse agonists can stabilise the receptor and reduce constitutive activity
32
Q

what are the new developments in treating PTSD?

A

EpiVario: mixing psychotherapy and small molecule drugs
- treats PTSD
- prevents consolidation of memory so people may use it before going into a stressful/traumatic situation e.g. army

Pharmacology (10 decks)

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