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HNNS > HNS17 Sedatives And Hypnotics > Flashcards

HNS17 Sedatives And Hypnotics Flashcards

1
Q

Definitions of Sedative and Hypnotic

A

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)
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2
Q

Anxiety

A

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
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3
Q

Vicious cycle of anxiety

A

Feelings (Physical) —> Thoughts (Negative thinking) —> Fear —> Feelings

Fear of the fear: worry that you will have the bad thoughts / feelings again

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4
Q

Mental features of anxiety

A

Unpleasant emotional state consisting of tension, apprehension, uneasiness and feelings of danger without a real / logical cause

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5
Q

Physical symptoms with anxiety

A
  1. ↑ Muscle tension
  2. Palpitation
  3. SOB
  4. Tachycardia
  5. Dizziness
  6. Restlessness
  7. Sweating
  8. Trembling
  9. Difficulty concentrating
  10. Insomnia
  11. Nervousness
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6
Q

4 types of Anxiety disorders

A
  1. 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)
  2. Obsessive-compulsive disorder (OCD)
    - uncontrollable recurring anxiety-producing thoughts and uncontrollable impulses to carry out rituals e.g. compulsive hand-washing
  3. ***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
  4. Post-traumatic stress disorder (PTSD)
    - recurrent recollections of a traumatic event of unusual clarity which produce intense psychological distress
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7
Q

Types of anti-anxiety drugs / minor tranquillisers

A
  1. Sedative (anxiolytic) drugs
    - reduce anxiety at low dose
    - hypnotic effect at high dose
  2. Hypnotic drugs
    - induce sleep when anxiety cause insomnia
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8
Q

Insomnia criteria

A
  • > 30 min to fall asleep
  • Waking up >30min / night
  • Sleep disturbed >3 nights / week
  • impairment of daytime functioning
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9
Q

Common causes of insomnia

A
  1. Physical disorders
    - CVS
    - sleep apnea
    - asthma
  2. Physiological disturbances
    - late heavy meal
    - noise
    - shift work
  3. Psychological
    - stress
    - tension
    - grief
  4. Psychiatric
    - anxiety
    - depression
    - mania
    - dementia
  5. Pharmacological
    - caffeine
    - alcohol
    - nicotine
    - medicines
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10
Q

***Summary of sedative (anxiolytics) and hypnotic drugs

A
  1. Benzodiazepines (principal chemical class)
    - Midazolam, Triazolam
    - Alprazolam, Lorazepam, Temazapam
    - Chlordiazepoxide, Clonazepam, Diazepam, Flurazepam
  2. Barbiturates (principal chemical class)
    - Thiopentone, Pentobarbital, Phenobarbital
  3. Other sedative (anxiolytic) drugs (Non-benzodiazepines class of drugs)
    - Buspirone
    - Antihistamine e.g. hydroxyzine
    - Antidepressant e.g. SSRI, TCA, MAOI
  4. Other hypnotic drugs
    - Z drugs: Zolpidem, Zaleplon
    - Ramelteon
    - Chloral hydrate
    - Antihistamine
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11
Q

Benzodiazepines (BDZs)

A
  1. Short-acting (t1/2: <5 hrs) —> short-lived / no active metabolite
    - Midazolam (rapid onset)
    - Triazolam (rapid)
    (記: MT)
  2. Intermediate-acting (t1/2: 5-24 hrs) —> short-lived / no active metabolite
    - Alprazolam (rapid)
    - Lorazepam
    - Temazepam (rapid)
    (記: ALT)
  3. Long-acting (t1/2: >24 hrs) —> long-lived active metabolites
    - Chlordiazepoxide
    - Clonazepam (rapid)
    - Diazepam (Valium) (rapid) (most commonly used)
    - Flurazepam
    (記: CCDF)
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12
Q

Metabolism of Benzodiazepines

A
  • 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

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13
Q

Classification of Benzodiazepines based on actions

A 
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)
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14
Q

***MOA of Benzodiazepines

A

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

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15
Q

Pharmacological effects of BDZ

A
  1. ↓ Anxiety and aggression
  2. Sedation + induction of sleep
  3. Anterograde amnesia
  4. ↓ Muscle tone + coordination
  5. Anticonvulsant effect
  6. Effect on respiration: ↓ hypoxic respiratory drive
  7. Effect on CVS: ↓ BP + ↑ HR
  8. NO analgesic / antipsychotic activity
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16
Q

Therapeutic use of BDZ

A
  1. Treatment of anxiety symptoms secondary to GAD, PTSD, panic disorder, OCD and others
  2. Panic disorder:
    - Alprazolam is effective
  3. 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
  4. Anterograde amnesia:
    - Midazolam
    —> induction of anaesthesia as premedication for anxiety-provoking and unpleasant procedures e.g. endoscopy / bronchoscopy
  5. Seizures (anti-epileptic):
    - Diazepam
    - Clonazepam
    - Lorazepam
  6. Sleep disorder:
    - Triazolam for insomnia
17
Q

Side effects of BDZs

A
  1. Drowsiness + confusion (most common)
  2. Ataxia (neurological sign: lack of voluntary coordination of muscle movement)
  3. Cognitive impairment
  4. Anterograde amnesia: temporary impairment of memory

At higher doses:

  1. Dizziness, lightheadedness
  2. Impaired motor coordination
  3. Slurred speech, blurry vision
  4. Mood swings
  5. Respiratory depression and death if taken with ethanol
18
Q

Benzodiazepine antagonist

A

***Flumazenil
- competitive antagonist of BDZ at GABAa receptor
- reverse BDZ overdose
- IV only
- SE:
—> agitation, dizziness, nausea, confusion
—> withdrawal in dependent patients
—> seizures

19
Q

Barbiturates

A
  • ***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
20
Q

***Classification of Barbiturates

A
  1. Ultra short-acting (10-20 mins)
    - Thiopental (IV GA)
  2. Short-acting (2-8 hrs)
    - Pentobarbital
    - Amobarbital
    - Secobarbital
  3. Long-acting (1-2 days)
    - Phenobarbital
21
Q

Metabolism of Barbiturates

A
  • 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
22
Q

***MOA of Barbiturates

A

Bind to separate site on GABAa receptor-Cl ion channel complex (NO antagonist)

  1. Prolong duration of Cl channel opening (BDZ: ↑ frequency of channel opening)
    —> Potentiate GABA action on Cl entry
  2. Block excitatory glutamate AMPA receptor
    —> ↓ glutamate-induced excitation
  3. Anaesthetic (High) conc of Pentobarbital
    —> block high-frequency Na channels

Overall effect: ↓ Neuronal activity

23
Q

SE of Barbiturates

A
  1. Drowsiness + ↓ motor control
  2. ***Induction of CYP450 —> ↓ effect of drugs metabolised by same enzymes
  3. High degree of tolerance and dependence
  4. Respiratory depression + Coma (high dose)
24
Q

***Barbiturates vs Benzodiazepine

A

Barbiturate (not used clinically):

  1. Low margin of safety (produce loss of consciousness)
  2. Enzyme inducers (CYP450)
  3. High abuse liability
  4. Marked suppression of REM sleep
  5. ***Hyperalgesic action
  6. Unacceptable drowsiness
  7. Respiratory depression and hypotension
  8. No specific antagonist

Benzodiazepines:

  1. Less serious CNS SE (less likely coma)
    - NOT produce anaesthesia in high dose
    - high therapeutic index —> much safer
  2. NOT enzyme inducers —> no DDI
  3. Very low abuse liability
    - produce tolerance and psychological dependence BUT physical dependence and withdrawal symptoms are less marked (compared to barbiturate)
  4. ***Less distortion of normal sleep
    - as hypnotics (high dose):
    —> NOT alter normal sleeping pattern
    —> NOT produce morning hangover
  5. NO hyperalgesia
  6. Can be used as ***daytime anxiolytics
  7. NOT / Less severely affect respiratory / CVS function
  8. Specific antagonist available: Flumazenil (treat overdose)
25
Q

Buspirone

A

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
26
Q

Hydroxyzine (Antihistamine)

A

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)

27
Q

Antidepressant

A

Proven efficacy in managing long-term symptoms of Chronic anxiety disorders

  1. SSRI (selective serotonin reuptake inhibitors)
  2. TCA (tricyclic antidepressants)
  3. MAOI (monoamine oxidase inhibitors)
28
Q

Propranolol

A

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)

29
Q

Hypnotics: Z-drugs: Zolpidem

A

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
30
Q

Zaleplon

A
  • resembles Zolpidem
  • rapid onset
  • short duration of action
  • fewer residual effect on pseudo-motor and cognitive function compared with Zolpidem
31
Q

Eszopiclone

A
  • 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
32
Q

Summary

A

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

33
Q

Ramelteon

A
  • 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
34
Q

Chloral hydrate

A

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
35
Q

Antihistamine (H1 receptor antagonists)

A 
OTC antihistamine with sedating properties:
1. Diphenhydramine (Unisom SleepGels)
2. Doxylamine
3. Promethazine
—> ALL 1st generation (cross BBB)

SE:

  • dry mouth
  • blurred vision
  • drowsiness

HNNS (58 decks)

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