Med Chem Hypnotics Test

Front 1

sedative / hypnotics
Effects

Back 1

depress or slow down the body’s functions

decrease time of onset of sleep, diminish REM sleep, increase total sleep time

most in lower doses induce disinhibition and euphoria

Front 2

Degree of depression depends on in sedative/hypnotics

Back 2

drug potency
dose
route of administration

Front 3

CNS effects and increasing the dose in sedative/hypnotics

Back 3

Sedative
hypnosis
anesthesia
coma

Front 4

The sedative-hypnotics tend to illicit effects that include:

Back 4

-sleep-induction
-anxiolytic effects (anti-anxiety)
-anticonvulsant / anti-seizure properties
-anesthesia, amnestic
-myorelaxant
-[anti-nausea?]

Front 5

Sleep is between what two stages?

Back 5

somewhere between sedation and hypnosis

Front 6

Common sleep problems?

Back 6

-- inability to fall asleep (sleep latency)
-- too short sleep, frequent awakenings
-- excessive daytime sleepiness
-- parasomnias (sleepwalking, night terrors, RMS sleep behavior disorder)

Front 7

Sleep patterns are altered by:

Back 7

--- age
--- sleep history
--- drug ingestion
--- circadian rhythms

Front 8

cholinergic agonists can affect sleep how?

Back 8

can initiate REM sleep from NREM post microinjection
(arecoline, bethanechol, AChEI’s)

Front 9

cholinergic antagonists affect sleep how?

Back 9

hinder the transition to REM sleep
(atropine, scopolamine)

Front 10

Catecholamines affect sleep how?

Back 10

an intact system is necessary for REM sleep
(dopamine, NE agonists/antagonists)

Front 11

ACh levels and memory acquisition?

Back 11

During waking, elevated acetylcholine (ACh) release from the cholinergic basal forebrain may enhance memory acquisition and consolidation

Front 12

Growth hormone secretion and sleep patterns?

Back 12

GH shows stable plasma levels with secretory pulses at the onset of NREM sleep
amount of GH released correlates with NREM sleep time
older people show less GH secretion and less NREM sleep

Front 13

Melatonin and sleep patterns?

Back 13

May effect circadian rhythms, sleep processes
Orally, leads to faster sleep onset, longer sleep time, but mechanism of action is unclear!
Secretion is decreased by bright light, physical activity

Front 14

CNS peptides and sleep patterns?

Back 14

Endogenous peptide sleep substances (messengers of the humoral system) exist
DSIP: delta sleep inducing peptide

Front 15

Melatonin: origins and what does it regulate?

Back 15

melatonin is the only hormone secreted into the bloodstream by the pineal gland

Regulates other hormones responsible for circadian rhythm and also various female reproductive hormones

Front 16

Melatonin OTC uses?

Back 16

-- Has anti-oxidant properties; affects sleep patterns
-- Used for jet lag, seasonal depressive disorders
-- May be useful in MS, epilepsy, SIDS, osteoporosis, heart disease

Front 17

RozeremTM (ramelteon):

Mechanism of action and uses

Back 17

orally active hypnotic, melatonin receptor agonist
(MT1 and MT2).

Used for difficulty in sleep onset.
No dependence / abuse, no rebound insomnia, withdrawal
Maintenance of circadian rhythm.

Front 18

Do hypnotics/sedatives have a common structure?

Back 18

No.

There are several brain regions involved with sleep and it is not clear the specific contribution a region has on sleep.

Front 19

GABA

What is it and what roles does it have in therapy?

Back 19

GABA: A key “inhibitory” neurotransmitter
Roles in anesthesia, seizure, …

Front 20

Anxiety Symptoms:

Back 20

Increased sympathetic nervous activity
Cognitive component: awareness of being frightened
behavioral component: urge to escape

Front 21

What GABA receptor subtype is important for sleep?

Back 21

GABAa

Front 22

Activation of GABAa causes what?

Back 22

opens a Cl- ion channel, (agonist activity), inhibits neuronal activity

mediates post-synaptic inhibition

Front 23

Increasing or decreasing Cl- ion flow through GABA receptor causes what?

Back 23

Increase Cl– anxiolytic, anticonvulsant
Decrease Cl– produce anxiety, seizures

Front 24

The GABA receptor is what type of receptor?

Back 24

Ligand gated ion channel

Front 25

BZD and barbiturates work by?

Back 25

Act by enhancing the ability of GABA to activate the GABAa receptors.

Front 26

RECEPTORS MEDIATING SEDATION

Back 26

alpha-1

Front 27

RECEPTORS MEDIATING AMNESIA

Back 27

alpha-1

Front 28

RECEPTORS PROTECTING AGAINST SEIZURES

Back 28

Partially alpha-1

Front 29

RECEPTORS FOR ANXIOLYSIS

Back 29

alpha-2

Front 30

RECEPTORS MEDIATING MYORELAXATION

Back 30

alpha-2 only at high doses

Front 31

Zaleplon binds preferentially to what receptor?

Back 31

alpha-1

Front 32

Picrotoxin site on GABA receptor and what does it do?

Back 32

Binds Cl- ion channel and causes it to remain closed
Antagonist

Front 33

Bicuculline and its effect on the GABA receptor?

Back 33

GABA antagonist

Isoquinoline alkaloid from Dicentra cucullaria and other plants
Competitive inhibitor of GABAa
Also antagonizes nicotinic acetylcholine receptors…

Front 34

BZD receptor and its effect on GABA receptor?

Back 34

BZR ligands modulate GABA binding to its receptor
(and do not directly alter transmembrane chloride conduction)

Front 35

Flumazenil

What does it do in the body and what is it used for?

Back 35

pure antagonist of the BZR
(used to treat BDZ overdose)

Binding of antagonist to BZR does not alter Cl- influx but can displace agonist or inverse agonist!

Front 36

DMCM

What type of agonist is it? What does it cause in the body?

Back 36

inverse antagonist

(anxiogenic in low doses, seizures in high doses!)

Front 37

Barbiturates: effects on the body

Back 37

Usage as sedative, hypnotic, anticonvulsant, anesthetic (dose dep.)
- depressant effect on cerebrospinal axis
- depress neuronal activity
- depress skeletal muscle, smooth muscle, cardiac muscle

Front 38

Barbiturates: effects on the neural synapse

Back 38

Reduces excitability of the postsynaptic cell: decreases functional activities in the brain
Reduces excitatory synaptic transmission: antidepolarizing blocking agents
May enhance inhibitory synaptic transmission: potentiate GABAa ion channel

Front 39

Barbiturates and adverse effects:
Reason for little use as sedative/hypnotic

Back 39

- can cause greater CNS depression / smaller therapeutic window / respiratory depression
- can induce a variety of P450’s, liver metabolic enzymes
- many other effects (inhibit electron transport system, brain carbonic anhydrase, …)
- can lead to tolerance & dependence

Front 40

Physical dep and sudden withdrawal of barbiturates

Back 40

Sudden withdrawal: extreme agitation, grand mal seizures, possibly leading to spasm of respiratory musculature…

Front 41

Ethanol and how it works in body.

Back 41

non-specific drug that disrupts membrane function by binding to specific sites on membrane proteins and/or to membrane lipids

Front 42

Alcohols and lipophilicity
Effect on activity?

Back 42

Activity correlates with lipophilicity and decreasing tendency towards metabolism
--- longer the chain, greater activity (until after 8 carbons)

Front 43

Alcohols and branching
Effect on activity?

Back 43

- branching decreases metabolic susceptability (increases activity)

Front 44

Alcohols and halogenation or decreasing saturation
Effect on activity?

Back 44

adding halogens or decreasing saturation (increases lipophilicity) increases activity

Front 45

Alcohol and breakdown in the body

Back 45

Alcohol+Alcohol dehydrogenase goes to acetaldehyde (toxic)

Acetaldehyde + acetaldehyde dehydrogenase goes to acetic acid

Front 46

Disulfiram (Antabuse ®)
Mechanism of action in body

Back 46

Blocks acetaldehyde dehydrogenase in the breakdown of acetaldehyde from alcohol consumption.

Front 47

SEDATIVE-HYPNOTICS: General Principles

Back 47

CNS active, hence must cross blood-brain barrier: Lipophilicity is a major SAR feature

Duration of action depends on distribution and metabolism

SAR only within a given drug class, not across classes

Front 48

What will effect distribution and metabolism of sedatives/hypnotics?

Back 48

Uncharged from more readily absorbed and cross BBB.
Too lipophilic drugs will get sequestered into the fat. Lipophilicity increases potency and activity
More hydrophilic leads to faster elimination

Front 49

How else might we modify the barbiturate structure to increase CNS activity?

Back 49

C5 must be disubstituted. Potency goes up with increasing substituent size but..
there is a maximum of 6 carbons per substituent
maximum of 10 carbons for both substituents

Branching of the C5 substituents increases potency and duration of action. Branching is most effective at 1st carbon. Polar substituents decrease potency, halogens increase potency

N-methylation shortens duration of action and shortens onset. Only one of the nitrogens can be substituted. (Ethyl and larger can lead to convulsant properties)

Replacement of O with S at C2 results in compounds with very short onset and short duration. Two sulfur substitutions (for O) results in inactive compounds with too much lipophilicity

Front 50

SAR of Hydantoins

Back 50

Most of the clinically used drugs in this class possess bulky aromatic ring in position C5 that confers usefulness in generalized seizures, partial seizures and status epilepticus but not well for absence seizures

Lacking a carbonyl compared to barbiturates and results in sodium salt being more basic.

Front 51

Oxazolidinediones
Structure

Back 51

Replacement of the N-H group at position 1 of the hydantoin with an oxygen atom yields the oxazolidine-2,4-dione system

Drug and metabolites are toxic

Front 52

Succinimides
SAR

Back 52

Ethosuximide is lacking bulky groups attached at C3 which corresponds to C5 in the other related structures and thus is good for absence seizures

Methsuximide has a bulky group at C3 which is good for absence but also picks up some partial seizures activity

Phensuximide possesses the bulky group at C3 which is good for absence but also picks up some generalized tonic-clonic activity

Front 53

BENZODIAZEPINES
Therapeutic considerations

Back 53

-- relatively safe compared to barbiturates, but similar activity
-- wide margin of safety between anti-anxiety doses and sedation, respiratory depression doses
-- low enzymatic induction
-- cross reaction with other drugs is lower
-- short onset times
-- duration varies with compound

Front 54

BZD's and mechanism of action on vomiting center

Back 54

Inhibition of central cortex to the VC

Front 55

BZD's and places in therapy regarding nausea/vomiting.

Back 55

Anticipatory emesis, break-through, and refractory emesis

Front 56

BZD's and R7 substitutions

Back 56

electronegative groups lead to highest activity

Front 57

BZD's and R5 substitutions

Back 57

aromatic group is required. Ortho halogen or CF3 group increases activity (as well as 2,6 substitution). Other substituents on ring decrease activity.

Front 58

BZD's and R3 substitutions

Back 58

R3 substitution decreases activity except for –OH which is as active (but more quickly eliminated)

Front 59

BZD's and R1 substitutions

Back 59

Permissive, but best activity with CH3 than H

Front 60

BZD's and X substitutions

Back 60

Oxygen is preferred. S is OK by decreases activity. -NHR is OK but is less active

Front 61

BZD's and SAR miscellaneous concepts

Back 61

Can fuse ring at 1-2 and alter activity profiles (i.e. triazolam is more potent and more sedative than diazepam)


--- substitution at other positions (than Rn or X) decreases activity
--- oxidation of N4 decreases activity
--- saturation of 4-5 double bond decreases activity
--- shifting double bond to 3-4 decreases activity