Sedatives and Hypnotics

Question 1

Dopamine pathway in the CNS

Answer 1

1. Nigrostriatal
2. Mesolimbic
3. Mesocortical
4. Tubero-hypohyseal

Question 2

GABAA receptors - chloride ion channel (5)

Answer 2

• ionotropic
• present in high concentrations in the limbic system
• GABA binds to it –> channels open –> Cl- going in –> hyperpolarization –> no action potential
• benzodiazepines, zolpidem (hypnotic), flumanezil (antagonist) –> bind to the alpha subunit
• barbiturates –> bind to alpha and beta subunit

Question 3

Benzodiazepines

-pharmacological effects (5)

Answer 3

1. relief of anxiety and aggression (alpha-2)
2. induction of sleep (alpha-1)
3. sedation
4. anti-convulsants effects
5. anterograde amnesia

other clinical uses: withdrawal states, muscle relaxation

Question 4

Benzodiazepines

-names (7)

Answer 4

1. Alprazolam
2. Chlordiazepoxide
3. Diazepam
4. Lorazepam
5. Midazolam
6. Oxazepam
7. Flumazenil (antagonist)

Question 5

Benzodiazepines

• pharmacokinetics (4)
• biotransformation

Answer 5

• high lipid soluble - accumulate in body fat
• excreted by the kidney - can cross-blood brain barrier
• increase the affinity of GABA for the receptors and increase the frequency of channels opening
• conjugation in the liver
• diazepam, chlordiazepoxide –> nordazepam –> oxazepam –> conjugation –> urinary secretion
• lorazepam, oxazepam –> conjugation –> urinary secretion
• alprazolam –> alpha-hydroxy metabolites –> conjugation –> urinary secretion

Question 6

Benzodiazepines

-duration

Answer 6

Midazolam –> very short
Lorazepam, Oxazepam –> short
Alprazolam –> medium
Diazepam –> long

Question 7

Benzodiazepines

-unwanted effects (4)

Answer 7

• acute overdose: prolonged sleep, respiratory and cardiovascular depression
• psychomotor function impairment: confusion, amnesia, impaired motor coordination
• decreased reaction time
• tolerance and dependance

Question 8

Hypnotics

• name
• mechanism of action
• clinical use

Answer 8

• zolpidem, zopiclon
• selective BZ1 receptor (bind to a subgroup of GABAA receptors), enhances the activity of GABA –> decreases neuronal excitability = sedative and hypnotic effects
• used in sleep disorders

Question 9

Zolpidem, zopiclon

-pharmacokinetics (4)

Answer 9

• rapid onset with few amnestic effects or day-after psychomotor depression
• half-life 1-3h (zolpidem 2-3, zopiclon 1)
• CYP substrates
• urine excretion

Question 10

Zolpidem, zopiclon

• unwanted effects (7)
• interaction

Answer 10

• daytime sleepiness, headache, nausea, diarrhea, memory problems, hallucinations, abuse
• additive CNS depression with ethanol and many other drugs