Antianxiety & Hypnotic Drugs

Question 1

Definitions

Sedatives, Hypnotics, Anxiolytics

Answer 1

Sedatives: cause sleepiness and interfere with intellectual functions. May be a side effect of some drugs

Hypnotics: induces normal sleep with some changes in EEG

Anxiolytics: Anxiety reducing drugs, no sleepiness

Question 2

The two large drug groups in anxiolytics and hypnotics

Answer 2

Benzodiazepines
Usually as anxiolytics
Act between alpha and gamma subunits

Barbiturates
Usually as hypnotics and sleeping pills
Transmembrane, act only on alpha subunit

Question 3

Medical Uses

Answer 3

Hypnotic Effect
Th of long term sleep deprivation; decrease REM–> used to treat vivid dreams, decrease time to fall sleep, increase time in sleep
Generally short or intermediate acting drugs
Upon withdrawal–> rebound insomnia (increase REM)

Anxiolytic Effect
Anxiety due to: Phobia, OCD, Panic attacks, general
anxiety
Depression: although SSRIs more effective
Schizophrenia: in combo with antipsychotics

GA
Benzos: premedication
Barbiturates: short acting given IV for short surgeries (bone setting, replacing a joint)

Anticonvulsants

Central Muscle Relaxants

Question 4

GABA R

Answer 4

Both Barbiturates and Benzos act on the GABA R (A mainly), are allosteric modulators but act on different sites of GABA R.
Act by increasing affinity for GABA (inhibitory CNS transmitter) –> increase frequency of GABA (experimental)

GABA-A R
Pentamer, Cl- channel–> increase Cl influx–> hyperpolarisation–> reduction of excitability

GABA-B R
G protein coupled R: Gi (inhibition of adenylate cyclase–
> inhibition of cAMP
1) Inhibition of voltage gated Ca channels–> reduction of transmitter release
2) Opening of K+ channels–> reduction of postsynaptic excitability

Question 5

General ‘Bad Effects’

Answer 5

Dependance can develop within a few weeks

Rebound Insomnia: acute anxiety, sleeping disorder, weariness

Tolerance and cross tolerance can develop

Question 6

Benzodiazepines

Structure, Effects, Side Effect, Pharmacokinetics

Answer 6

One Ring with 7C and two Benzene rings

Effects: Potentiate GABA R
   Reduction of anxiety and depression
   Induction of sleep and sedation
   Reduction of muscle tone and coordination 
   Anticonvulsant effect 

Side Effects:
Deep sleep, respiratory depression, anterograde amnesia, daytime drowsiness, increased appetite, decreased libido,

Pharmacokinetics:
Good oral absorption
Enters CNS, fetus, milk, fat accumulation (rapid onset)
Hepatic Metabolism
Clearance decreased in those with hepatic diseases and elderly

Safer than barbiturates
Extreme high dose can be used as GA
Can cause euphoria–> addictive

Question 7

Short acting Benzodiazepines

Names and characteristics

Answer 7

Triazolam, Midazolam
given orally 1-2 hrs pre anaesthesia, given as sleeping pill too

Zolpidem
used by pilots to establish artificial day/night cycle
“Z” drugs do not have benzodiazepine structure

Question 8

Intermediate acting Benzos

Names and characteristics

Answer 8

Alprozolam, Brotizolam

Alprozolam used as day time anxiolytic

Question 9

Long acting Benzos

Names and characteristics

Answer 9

Diazepam
prototype, anxiolytic and anticonvulsant
combo with ethanol–> resp depression
Esp rapid onset–> danger of abuse

Nitrazepam

Clonazepam (popular antiepileptic)

Lorazepam

Medazepam

Question 10

Benzo R Antagonist

Name and characteristics

Answer 10

Flumazenil
Used in th for hepatic encephalopathy (used to suppress abnormal neurotransmitter on BDZ R)

Contraindicated in withdrawal as Flumazenil can make withdrawals worse and precipitate convulsions

Question 11

Barbiturates

Effects, Side Effect, Pharmacokinetics

Answer 11

Effects:
Sedation, anti anxiety, antiepileptic
Elevate seizure threshold

Side Effects: Prolong GABA R activity
Deep sleep, euphoria, resp depression

Pharmacokinetics:
Metabolised in liver into inactive metabolite
T1/2: increases with age and liver disease
Redistribution resp for short duration of highly lipid soluble barbiturates

Withdrawal can be life threatening (convulsions)
No antagonist available
Contraindicated in those with pulmonary diseases and porphyrias

Question 12

Short acting barbiturates

Names and characteristics

Answer 12

Thiopental
extreme lipophilicity–> sequestered in fat if given into plasma
–> no longer active in brain (but can pass BBB)
T1/2: 12 hours
Readmin of full dose can lead to resp depression

Hexobarbital

Used for IV GA

Question 13

Intermediate acting barbiturates

Names and characteristics

Answer 13

Pentobarbital, Amobarbital
quickly absorbed and can cross BBB

Uses:
Regional anaesthesia, sedation, hypnosis

Question 14

Long acting barbiturates

Name and characteristics

Answer 14

Phenobarbital
Small dose: antiepileptic
High dose: hypnotic (too long to be therapeutic)

T1/2: 2 days, slow onset of action

Metabolised in liver, half excreted unchanged renally
Long term use–> enzyme induction

Side Effect: Resp depression

Question 15

Barbiturate like drugs

Names and characteristics

Answer 15

Glutethimide
Sleep inducer

Thalidomide
Used for immune modulation

Melatonin
Th of jet lag

Chlomethiazole
Structually related to thiamine (B1)
Sedative, hypnotic, anticonvulsant, muscle relaxant

Question 16

5 HT 1A R Agonists (Partial)

General Info

Answer 16

Buspirone, Gepirone, Ipsaprione

5-HT1 R= Gi coupled R–> neural and vasomotor center inhibition

Do not induce sedation or hypnosis

Requires > 1 week until th effect is reached

Side Effects
   Nervousness
   Restlessness
   Tachy
   GI distress

Question 17

Differences Benzos vs Barbiturates concerning CNS depression

Answer 17

Benzos reach a plateau in CNS depression (at medullary depression)

Barbiturates (and alcohol) do not–> coma