HNNS L18 - Sedatives And Hypnotics Flashcards
Diazepam
Benzodiazepine Both sedative and hypnotic Low dose for acute panic anxiety Fast onset and offset Long acting
Chlordiazepoxide
Benzodiazepine (sedative)
Low dose for chronic anxiety states
Long-acting
Alprazolam
Benzodiazepine (sedative)
Low dose for anxiolytic-antidepressant effect
Intermediate-acting
Lorazepam
Benzodiazepine (sedative)
Intermediate-acting
Clonazepam
Benzodiazepine (sedative)
Fast onset
Long-acting
Flurazepam
Benzodiazepine (hypnotics)
Long acting
High dose for sedative + hypnotic effects
Temazepam
Benzodiazepine (hypnotics)
Intermediate acting
High dose for sedative + hypnotic effects
Triazolam
Benzodiazepine (hypnotics)
Fast onset
Short acting
High dose for sedative + hypnotic effects
Flumazenil
Competitive antagonist of benzodiazepines (for overdose of BDZs and Zolpidem(?), IV)
MoA of Benzodiazepines
Activate GABA-A receptors by binding to BZ1 and BZ2 (between alpha and gamma subunits)
Increase frequency of Cl channel opening
Hyperpolarization
Increase inhibitory signals
Effects of Benzodiazepines
Anxiolytic
Induction of sleep
Reduce muscle tone and co-ordination
Anti-convulsant
Adverse effects of benzodiazepines
- Drowsiness, confusion (most common)
- Decrease in motor coordination
- Decrease in psychomotor performances
- Anterograde amnesia
- Respiratory depression and death if taken with ethanol
- Dependence
- Tolerance
Flumazenil: MoA, Adverse effects
Competitive antagonist of BDZs at GABA-A receptor
- reversal of BDZ overdose (IV)
- Dizziness, confusion, nausea
- Agitation
- Seizure
- (Withdrawal)
Barbiturates: MoA
[1] Potentiate GABA action on Cl- entry into the neuron by prolonging the duration of Cl- channel openings
[2] Block excitatory glutamate AMPA receptors –> decreased glutamate-induced excitation
[3] Anaesthetic (high) concentrations of pentobarbital blocks high-frequency Na+ channels –> decrease neuronal activity
Barbiturates: adverse effects / disadvantages (X8)
- Drowsiness, decreased motor control
- Induction of hepatic CYP450, decrease effect of other drugs metabolized by these enzymes
- High degree of tolerance and dependence + very severe withdrawal symptoms
- High dose: respiratory depression, coma
- Low therapeutic index
- Increase in heme synthesis: contraindicated in porphyrias
- Sleep disturbance
- Used as hypnotics: suppress REM sleep more than other stages
Metabolism of BDZs
Conjugation with glucuronide
Urinary excretion
Midazolam
BDZ (short acting, half life <5 hours)
Long-acting BDZs
Chlordiazepoxide
Clonazepam*
Diazepam (Valium)*
Flurazepam
Intermediate-acting BDZs
Alprazolam
Lorazepam
Temazepam
Short-acting BDZs
Midazolam
Triazolam
Barbiturates: Metabolism
Hepatic metabolism (some to active metabolites) Induction of CYP450 (drug-drug interaction) Increase in heme synthesis
Thiopental
Ultra-short-acting barbiturate (10-20 min)
Pentobarbital
Short-acting barbiturate (2-8 hr)
Amobarbital
Short-acting barbiturate (2-8 hr)
Secobarbital
Short-acting barbiturate (2-8 hr)
Phenobarbital
Long-acting barbiturate (1-2 days)
Ultra-short-acting barbiturates (10-20 min)
Thiopental
Short-acting barbiturates (2-8 hours)
Pentobarbital
Amobarbital
Secobarbital
Long-acting barbiturates (1-2 days)
Phenobarbital
Buspirone (BuSpar): MoA and use
Anxiolytic drug - 5-HT1A - (DA2) - (5-HT2A) Slow onset Used for treating general anxiety disorder (GAD) (with min sedation)
Buspirone (BuSpar): Adverse effects / Disadvantages (X6)
- Headaches, Dizziness
- Nervousness
- Hypothermia
- Increase prolactin (breast enlargement; dopamine receptor)
- GI distress
- Drug-drug interaction: Metabolism by CYP3A4
- Half-life shortened if taken with rifampin (inducer of CYP3A4)
- Half-life lengthened if taken with erythromycin (CYP3A4 inhibitor)
Hydroxyzine
1st generation anti-histamine with anti-emetic activity. Can be used as an anxiolytic.
Antidepressants
[1] SSRI
[2] TCA
[3] MAOI
As an anxiolytic.
Propranolol
Non-selective beta blocker (alleviate somatic manifestations of anxiety caused by marked sympathetic responses)
Zolpidem (Z drug)
As a hypnotic:
Bind selectively to the BZ1 (subtype of BZ receptor family)
- Facilitate GABA-mediated neuronal inhibition
Antagonized by flumazenil
CYP450 metabolism to form inactive products (vs BDZs?)
Zolpidem (Z drug): adverse effects (X6)
- Ataxia (loss of full control of bodily movements)
- Nightmares
- Agitation
- GI upset
- Headache
- Dizziness, daytime drowsiness, confusion
Zolpidem (Z drug): vs BDZs
Adv: 1. Less risk of developing tolerance and dependence with extended use Disadv: 1. No anti-convulsant effect 2. No muscle-relaxing effect
(One is an anxiolytic, one causes agitation)
Zaleplon (Z-drug)
Resemble zolpidem.
- Fewer residual effect on pseudo-motor and cognitive function
Rapid onset and short duration of action.
Ramelteon
Hypnotic agent:
(1st line for insomnia, OTC)
Selective agonist of MT1 and MT2 melatonin receptors in hypothalamus
Ramelteon: adverse effects
- Dizziness, frowsiness
- Fatigue
- Increased prolactin levels –> enlarged breasts
Chloral hydrate
Effective sedative and hypnotic.
For diagnosis: check sleep pattern of patient.
Trichlorinated derivative of acetaldehyde
Converted to trichoroethanol, an active metabolite, in the body
Adverse effects:
- GI distress
- Unpleasant taste
Diphenhydramine (Benadryl, Unisom SleepGels)
Antihistamine with sedating properties.
Adverse effects:
- Dry mouth
- Blurred vision
- Drowsiness
Doxylamine
Antihistamine with sedating properties.
Adverse effects:
- Dry mouth
- Blurred vision
- Drowsiness
Promethazine
Antihistamine with sedating properties.
Adverse effects:
- Dry mouth
- Blurred vision
- Drowsiness
BDZs advantage over barbiturates (X8)
- Higher therapeutic index
- Not induce hepatic microsomal enzyme (CYP450), fewer drug-drug interaction
- Low abuse liability (less marked physical dependence and withdrawal symptoms)
- Lesser distortion of normal sleep (pattern, morning hangover)
- No hyperalgesia
- Not produce anaesthesia in high doses, patients can be aroused
- Not affect respiratory / CVS function (unless taken with ethanol)
- Specific antagonist (Flumazenil)
–> Can be used as daytime anxiolytics
