HNS17 Sedatives And Hypnotics Flashcards
Definitions of Sedative and Hypnotic
Effective Sedative / Anxiolytics:
- reduce anxiety
- exert calming effect
- little / no effect on motor / mental functions
Hypnotic:
- produce drowsiness
- encourage onset + maintenance of sleep as far as possible (which can resemble natural sleep state)
Anxiety
Unlike other mental disorder, anxiety can be both:
- normal emotion —> useful to individual acting as a stimulant and increase efficiency
- psychiatric illness —> excessive and disproportional to the situation
- Lifetime prevalence: 30%
Signs and symptoms:
- Negative thoughts
- Shaking
- Palpitation
- ↑ HR
Vicious cycle of anxiety
Feelings (Physical) —> Thoughts (Negative thinking) —> Fear —> Feelings
Fear of the fear: worry that you will have the bad thoughts / feelings again
Mental features of anxiety
Unpleasant emotional state consisting of tension, apprehension, uneasiness and feelings of danger without a real / logical cause
Physical symptoms with anxiety
- ↑ Muscle tension
- Palpitation
- SOB
- Tachycardia
- Dizziness
- Restlessness
- Sweating
- Trembling
- Difficulty concentrating
- Insomnia
- Nervousness
4 types of Anxiety disorders
- Panic disorder (panic attacks)
- rapid-onset attacks of extreme fear
- feeling of heart palpitations
- choking / SOB
—> Phobic anxiety: triggered by particular object / situation (e.g. social phobia) - Obsessive-compulsive disorder (OCD)
- uncontrollable recurring anxiety-producing thoughts and uncontrollable impulses to carry out rituals e.g. compulsive hand-washing - ***Generalised anxiety disorder (GAD)
- extreme feeling of anxiety in the absence of any clear / logical cause
- over a long period of time
- >50% need to seek medical help - Post-traumatic stress disorder (PTSD)
- recurrent recollections of a traumatic event of unusual clarity which produce intense psychological distress
Types of anti-anxiety drugs / minor tranquillisers
- Sedative (anxiolytic) drugs
- reduce anxiety at low dose
- hypnotic effect at high dose - Hypnotic drugs
- induce sleep when anxiety cause insomnia
Insomnia criteria
- > 30 min to fall asleep
- Waking up >30min / night
- Sleep disturbed >3 nights / week
- impairment of daytime functioning
Common causes of insomnia
- Physical disorders
- CVS
- sleep apnea
- asthma - Physiological disturbances
- late heavy meal
- noise
- shift work - Psychological
- stress
- tension
- grief - Psychiatric
- anxiety
- depression
- mania
- dementia - Pharmacological
- caffeine
- alcohol
- nicotine
- medicines
***Summary of sedative (anxiolytics) and hypnotic drugs
- Benzodiazepines (principal chemical class)
- Midazolam, Triazolam
- Alprazolam, Lorazepam, Temazapam
- Chlordiazepoxide, Clonazepam, Diazepam, Flurazepam - Barbiturates (principal chemical class)
- Thiopentone, Pentobarbital, Phenobarbital - Other sedative (anxiolytic) drugs (Non-benzodiazepines class of drugs)
- Buspirone
- Antihistamine e.g. hydroxyzine
- Antidepressant e.g. SSRI, TCA, MAOI - Other hypnotic drugs
- Z drugs: Zolpidem, Zaleplon
- Ramelteon
- Chloral hydrate
- Antihistamine
Benzodiazepines (BDZs)
- Short-acting (t1/2: <5 hrs) —> short-lived / no active metabolite
- Midazolam (rapid onset)
- Triazolam (rapid)
(記: MT) - Intermediate-acting (t1/2: 5-24 hrs) —> short-lived / no active metabolite
- Alprazolam (rapid)
- Lorazepam
- Temazepam (rapid)
(記: ALT) - Long-acting (t1/2: >24 hrs) —> long-lived active metabolites
- Chlordiazepoxide
- Clonazepam (rapid)
- Diazepam (Valium) (rapid) (most commonly used)
- Flurazepam
(記: CCDF)
Metabolism of Benzodiazepines
- High lipid solubility —> cross BBB
Long-acting drugs:
- go through phase 1 microsomal oxidation —> active metabolite (∴ last longer)
- Diazepam —> Nordazepam (active metabolite) —> Oxazepam
- Chlordiazepoxide —> Demoxepam —> Nordazepam
Short-acting / Intermediate-acting:
- NOT go through phase 1 —> NO active metabolite
- directly go through phase 2 glucuronidation (through glucuronyl transferase) —> excreted in kidney
Phase 1, Phase 2 metabolism: within Liver
Classification of Benzodiazepines based on actions
Anxiolytic: - Diazepam (low dose) - Chlordiazepoxide - Alprazolam - Lorazepam - Clonazepam (記ALCC, D low dose)
Hypnotic: - Diazepam (high dose) - Flurazepam - Temazepam - Triazolam (記: TTF, D high dose)
***MOA of Benzodiazepines
Bind to benzodiazepine receptor (BZ1, BZ2) (allosterically in a site between α and γ subunit; part of GABAa receptor-Cl ion channel complex)
—> selectively activate GABAa receptor (NOT GABAa receptor agonist!!!)
—> enhance binding of GABA to GABAa receptor (↑ affinity)
—> facilitate opening of GABA-activated Cl channels (only help when GABA already bind to receptor)
—> mediate fast inhibitory synaptic response by GABAergic neuron
—> hyperpolarise cell
—> reduce neural excitability
Pharmacological effects of BDZ
- ↓ Anxiety and aggression
- Sedation + induction of sleep
- Anterograde amnesia
- ↓ Muscle tone + coordination
- Anticonvulsant effect
- Effect on respiration: ↓ hypoxic respiratory drive
- Effect on CVS: ↓ BP + ↑ HR
- NO analgesic / antipsychotic activity
Therapeutic use of BDZ
- Treatment of anxiety symptoms secondary to GAD, PTSD, panic disorder, OCD and others
- Panic disorder:
- Alprazolam is effective - Muscle disorder:
- Diazepam (muscle relaxant properties), useful in
—> Skeletal muscle spasms e.g. muscle strain
—> Spasticity from degenerative disorder e.g. multiple sclerosis, cerebral palsy - Anterograde amnesia:
- Midazolam
—> induction of anaesthesia as premedication for anxiety-provoking and unpleasant procedures e.g. endoscopy / bronchoscopy - Seizures (anti-epileptic):
- Diazepam
- Clonazepam
- Lorazepam - Sleep disorder:
- Triazolam for insomnia
Side effects of BDZs
- Drowsiness + confusion (most common)
- Ataxia (neurological sign: lack of voluntary coordination of muscle movement)
- Cognitive impairment
- Anterograde amnesia: temporary impairment of memory
At higher doses:
- Dizziness, lightheadedness
- Impaired motor coordination
- Slurred speech, blurry vision
- Mood swings
- Respiratory depression and death if taken with ethanol
Benzodiazepine antagonist
***Flumazenil
- competitive antagonist of BDZ at GABAa receptor
- reverse BDZ overdose
- IV only
- SE:
—> agitation, dizziness, nausea, confusion
—> withdrawal in dependent patients
—> seizures
Barbiturates
- ***Low therapeutic index
- induce **tolerance, physical **dependence, very severe ***withdrawal symptoms
- ***induce liver drug-metabolising enzymes
- cause ***coma at toxic dose
- when used as hypnotics —> suppress REM stage more than other stages
***Classification of Barbiturates
- Ultra short-acting (10-20 mins)
- Thiopental (IV GA) - Short-acting (2-8 hrs)
- Pentobarbital
- Amobarbital
- Secobarbital - Long-acting (1-2 days)
- Phenobarbital
Metabolism of Barbiturates
- Hepatic metabolism (some to active metabolite)
- Induction of CYP450 —> DDI
- ↑ Heme synthesis —> CI in porphyrias (build up of Porphyrin in blood)
Porphyrias (hereditary disorder of hemoglobin metabolism):
- mental disturbance
- extreme sensitivity to light
- excretion of dark pigments in urine
***MOA of Barbiturates
Bind to separate site on GABAa receptor-Cl ion channel complex (NO antagonist)
- Prolong duration of Cl channel opening (BDZ: ↑ frequency of channel opening)
—> Potentiate GABA action on Cl entry - Block excitatory glutamate AMPA receptor
—> ↓ glutamate-induced excitation - Anaesthetic (High) conc of Pentobarbital
—> block high-frequency Na channels
Overall effect: ↓ Neuronal activity
SE of Barbiturates
- Drowsiness + ↓ motor control
- ***Induction of CYP450 —> ↓ effect of drugs metabolised by same enzymes
- High degree of tolerance and dependence
- Respiratory depression + Coma (high dose)
***Barbiturates vs Benzodiazepine
Barbiturate (not used clinically):
- Low margin of safety (produce loss of consciousness)
- Enzyme inducers (CYP450)
- High abuse liability
- Marked suppression of REM sleep
- ***Hyperalgesic action
- Unacceptable drowsiness
- Respiratory depression and hypotension
- No specific antagonist
Benzodiazepines:
- Less serious CNS SE (less likely coma)
- NOT produce anaesthesia in high dose
- high therapeutic index —> much safer - NOT enzyme inducers —> no DDI
- Very low abuse liability
- produce tolerance and psychological dependence BUT physical dependence and withdrawal symptoms are less marked (compared to barbiturate) - ***Less distortion of normal sleep
- as hypnotics (high dose):
—> NOT alter normal sleeping pattern
—> NOT produce morning hangover - NO hyperalgesia
- Can be used as ***daytime anxiolytics
- NOT / Less severely affect respiratory / CVS function
- Specific antagonist available: Flumazenil (treat overdose)
Buspirone
MOA:
- **Partial agonist at **5-HT1a receptor presynaptically —> ***inhibit Serotonin release
- Some affinity for DA2 (dopamine) receptors + 5-HT2a receptor
Indication:
- GAD but takes 1-2 weeks to produce anxiolytic effects (slow onset)
—> prescribe Diazepam in the meantime
- **Pure anxiolytic effect:
- NO anticonvulsant, muscle relaxant properties
- NO sedative / hypnotic effect
Metabolism:
CYP3A4
- taken with rifampin (inducer) —> shorten t1/2
- taken with erythromycin (inhibitor) —> lengthen t1/2
SE:
- headache
- dizziness
- nervousness
- hypothermia
- ↑ prolactin (due to binding to dopamine receptor —> inhibit dopamine release)
- GI distress
Hydroxyzine (Antihistamine)
Antihistamine with Anti-emetic activity
Indication:
- Useful in patients with anxiety who have history of drug abuse
- Sedation prior to dental procedures / surgery
SE:
- Drowsiness (mild)
Antidepressant
Proven efficacy in managing long-term symptoms of Chronic anxiety disorders
- SSRI (selective serotonin reuptake inhibitors)
- TCA (tricyclic antidepressants)
- MAOI (monoamine oxidase inhibitors)
Propranolol
Non-CNS drug
—> NOT cross BBB
—> ***NO CNS effect
***Non-selective β blocker
—> antagonism at β-adrenoceptors
—> block action of excessive catecholamine (e.g. NE) release due to anxiety
—> no sympathetic response
Indication:
- Very effective in alleviating **somatic manifestations of anxiety (e.g. social phobias, performance anxiety) caused by marked **sympathetic response (e.g. tachycardia, palpitations, tremor, sweating)
Hypnotics: Z-drugs: Zolpidem
MOA:
- binds selectively to ***BZ1 (subtype of BZ receptor family)
—> facilitate GABA-mediated neuronal inhibition
- Little effect on stages of sleep —> a commonly used hypnotic
- Can be antagonised by Flumezenil
- But ***NO muscle-relaxing and anticonvulsant effects (unlike BDZ)
- risk of tolerance and dependence with extended use is less than that of BDZ
Metabolism:
- Liver oxidation by CYP450 to inactive products
SE:
- Ataxia (loss of full control of bodily movements)
- nightmare
- agitation
- headache
- GI disturbance
- dizziness
- daytime drowsiness
- confusion
Zaleplon
- resembles Zolpidem
- rapid onset
- short duration of action
- fewer residual effect on pseudo-motor and cognitive function compared with Zolpidem
Eszopiclone
- Derived from Z-drug
- Also act on BZ receptor
- effective for insomnia esp. long term treatment
SE:
- anxiety
- dry mouth
- headache
- peripheral edema
- drowsiness
- unpleasant taste
Summary
BDZs, Zolpidem:
1. Act at BZ site of GABAa complex
—> ↑ ***frequency of Cl channel opening
—> ↑ inhibition
Barbiturates:
1. Act at barbiturate site of GABAa complex
—> ↑ ***duration of Cl channel opening
—> ↑ inhibition
2. Blockage of excitatory glutamate AMPA receptor
—> ↓ glutamate-induced excitation
Ramelteon
- Only produce hypnotic effect
MOA:
- Selective agonist at MT1, MT2 subtypes of **melatonin receptors in **hypothalamus (endogenous ligand: melatonin)
—> induce + promote sleep
Indication:
- Insomnia
SE:
- dizziness
- fatigue
- drowsiness
- ↑ production of prolactin
Chloral hydrate
Trichlorinated derivative of **Acetaldehyde
—> converted to **Trichloroethanol (active metabolite)
Effective sedative and hypnotic
—> induce sleep ~30mins and duration of sleep can last up to 6 hours
Use:
- Diagnostic use in studying sleep pattern of patients during daytime
SE:
- unpleasant taste
- GI distress
Antihistamine (H1 receptor antagonists)
OTC antihistamine with sedating properties: 1. Diphenhydramine (Unisom SleepGels) 2. Doxylamine 3. Promethazine —> ALL 1st generation (cross BBB)
SE:
- dry mouth
- blurred vision
- drowsiness
