pharmacotherapy of anxiety and sleep disorders Flashcards
GABA modulators
- Benzodiazepines
2. Non-BZD (Z-compounds)
Benzodiazepines (general information)
• The most frequently used sedative-hypnotics.
• They have a binding site at the GABA-A receptor, called BDZ (benzodiazepine) receptor importance of α subunit:
α1 – sedative, hypnotic,
α2 - anxiolytic
• Benzodiazepines via activating BDZ receptors promote the GABA binding to its own binding site.
• Benzodiazepines do not substitute for GABA but enhance the GABA’s effects without directly activating GABA receptors or opening the associated chloride channels.
• Benzodiazepines potentiate the GABAergic inhibition by increasing the frequency of Cl- channel opening events.
BDZ receptors ligands - agonist
- Agonists (positive allosteric modulators): eg. diazepam
• They cause an allosteric change in the structure of the GABA receptor - chloride channel complex that promotes the GABA binding at its own receptor, thereby increasing the frequency of chloride channel opening. So they exert anxiolytic, sedative and hypnotic effects.
BDZ receptors ligands - antagonists
- Antagonists (neutral allosteric modulator): flumazenil
• It occupies the BDZ receptors, inhibits agonist binding.
BDZ receptor ligands - Inverse agonists
- Inverse agonist: eg. β-carbolines
• They are negative allosteric modulators, inhibiting GABA binding at its own receptor, thereby causing anxiety and seizures.
Pharmacological actions of benzodiazepines
- anxiolytic (sedative)
- hypnotic (nREM2 (increase), REM (decrease), nREM3,4 (decrease))
- no complete general anesthesia
- antiepileptic
- skeletal muscle relaxant (centrally mediated)
- amnesia
The pharmacological actions of the different
benzodiazepines (receptor agonists) are more or less the
same, they differ mainly pharmacokinetically from each
other
benzodiazepines and their indications
- Anxiolytic (sedative): chlordiazepoxide, diazepam, clonazepam, alprazolam, oxazepam, lorazepam, medazepam, clorazepate, clobazam, halazepam, prazepam
- Hypnotic: midazolam, nitrazepam, flunitrazepam, triazolam, lorazepam, flurazepam, brotizolam, estazolam, quazepam, temazepam, lormetazepam
- For panic attacks (alprazolam, clonazepam)
- As a centrally acting skelatal muscle relaxants (diazepam, tetrazepam)
- Antiepileptics:
- - acute – epileptic state (diazepam, lorazepam),
- - chronic – absence seizures (clonazepam) - As a premediacation before general anesthesia (diazepam)
- For induction of general anesthesia, part of TIVA: (midazolam)
- Alcohol withdrawal, delirium tremens: (diazepam)
- Endoscopy (diazepam, midazolam)
Benzodiazepines: pharmacokinetics
• They are lipophilic drugs with good oral bioavailability (>80%).
• They are distributed very well, cross the blood-brain barrier and the placenta.
• They bind extensively to plasma proteins (60-95 %),
without important clinical consequences.
• They are metabolized in the liver (active metabolites!) and excreted with the urine.
Benzodiazepines Half-life from short to long acting
Midazolam 1,5-2,5 Triazolam 2-5 Oxazepam 5-15 Lorazepam 13-16 Alprazolam 12-15 Nitrazepam 18-30 Clonazepam 30-40 Chlordiazepoxid 5-30 (48-96 - metabolites) Diazepam 24-48 (30-90) Flurazepam
Benzodiazepines: metabolism
• Diazepam-type: active metabolites with long half life
(30-90 hours), they can be accumulated.
• Triazolam-type (tetracyclic BDZs): active metabolites
with short half-life only.
• Oxazepam-type: no active metabolites, they are
conjugated directly.
Benzodiazepines: unwanted effects
• sedation, interaction with ethanol or other sedatives
• „hangover” effect, daytime sedation (hypnotic use)
• mild dependence (more pronounced in case of drugs with short half-life) – withdrawal: rebound anxiety
• tolerance (especially to antiepileptic action)
• anterograde amnesia, impaired ability to learn new informations
• elderly - confusional states in (due to overdose?), increased risk of falls (ataxia)
• paradox effects (more often in elderly): aggression, violence, impulsivity
• not completely „physiologic” sleep, rebound effects after hypnotic use (insomnia, REM (decrease): nightmares), worsening of sleep apnea
• Benzodiazepines are relatively safe drugs, they depress the cv. and resp. functions usually only in case of underlying disease after administration of high doses,- in case of intoxication they have an antagonist: flumazenil
NB: With ethanol or too rapid iv. use
– can be dangerous
Benzodiazepine antagonist
flumazenil
Non-BDZ Hypnotics
Z- compounds (Cyclopyrrolon or imidazopyridine derivatives):
- (es)zopiclone
- zolpidem
- zaleplone
z-compounds (general information/compared to BDZ)
• prefer BDZ receptors with α1 subunits.
• less muscle relaxing, anxiolytic and antiepileptic effects.
• They cause minor effects on sleep patterns, and the risk of the development of tolerance and dependence is lower than with the use of benzodiazepines.
• Zaleplone has a half-life of 1 hour. It decreases the sleep latency but has little effect on total sleep time and architecture. (Favourable in patients who have
difficulty falling asleep.) Amnestic effects are less common.
Non-GABAergic anxiolytics
- SSRI (fluoextine etc)
• antidepressants, used also for the treatment of mental illnesses with anxiety
• one of the major group to treat panic attacks – only chronically (acute may even ↑ anxiety) - Buspirone
• Buspirone is a selective anxiolytic with no sedative, hypnotic, anticonvulsant or muscle relaxant properties
• It does not influence the GABAergic transmission, it is a partial agonist at brain 5-HT1A receptors.
• Advantages: no dependence, no sedation, no interaction with sedatives or ethanol.
• Disadvantages: slow onset of anxiolytic effect (1-3 weeks), used in generalized anxiety, but NOT effective in panic disorders.
Slow onset (1-3 weeks), no acute effect
