L3. Sedatives and Hypnotic Drugs

Sedatives are used to

sedate / tranquilize

Hypnotics are used to

induce sleep

True / False: The same drug can be a sedative (tranquilizer) as well as a hypnotic (a sleep inducting drug)

true

Arousel levels from a continuum from

wakefulness

sedation

sleep

anesthesia

coma

The two prominent classes of drugs that are classified as sedatives/hypnotics are ---- and ---

benzodiazepines and barbiturates

What drugs are first in line to treat a seizure?

Benzodiazepines

--- are the most commonly used agents for sedatives-hypontics

Benzodiazepines

Which drugs do not extend into the anesthesia/coma/death end of the arousal scale?

Benzodiazepines

What parts of the arousal scale do benzodiazepines influence?

Sedation / sleep

--- are potent sedative-hypnotic agents

Barbiturates

Which drugs can not extend into the anesthesia/coma/death end of the arousal scale?

Barbiturates

What is the therapeutic index of barbiturates?

Small TI = dangerous

What do benzodiazepines and barbiturates have in common?

act on GABA receptor = gamma amino butyric acid

GABA stands for

gamma amino butyric acid

Where do benzodiazepines and barbiturates act on?

GABA ionophore

What is the GABA ionophore?

complex of receptors and binding sites that regulate chloride ion conductance

What is unique about the GABA ionophore complex?

it is not a uniform structure

made up of different subunits throughout the CNS

different subunits = different pharmacological properties

GABA ionophores can be a combination of --- and --- OR --- and --- that are distributed differetntiztlly throughout the CNS

GABA and benzodiazepine receptors

GABA and barbiturate receptors

GABA (gamma amino butyric acid) is a ubiquitous ---- neurotransmitter widely expressed ub the CNS

inhibitory

GABA is derived from --- via ---

glutamate via glutamic acid decarboxylase

When GABB is bound to its receptor it increases ----

chlorine conductance

There are at least 3 classes of GABA receptors:

GABAa

GABAb

GABAc

What blocks GABA receptors?

bicuculline

picrotoxin

How does bicuculline block GABA receptors?

interfere with GABA binding

How does picrotoxin block GABA receptors?

blocks chloride channels

What are the 3 ligand for benzodiazepine receptors?

Agonists

Antagonists

Inverse agonists

Benzodiazepine

- agonist

lorazepam

diazepam

triazolam

Benzodiazepine

- antagonist

Flumazenil

Diazepam binding inhibitor

Flumazenil

blocks the actions of benzodiazepines but not other sedatives / hypnotics

Diazepam binding inhibitor

endogenous peptide

binds to benzodiazepine binding site on GABAa receptor

blocks diazepam from binding

Benzodiazepine

- inverse agonist

beta carboline

Beta carboline

endogenous mediator of anxiety

product of serotonin breakdown

Beta carboline

- mechanism of action

GABAa receptor agonist

produce anxiety, convulsion activity, seizures

True / False: benzodiazepines are not only used as sedatives but also for anxiety and epilepsy

true

What is the benzodiazepine site for hypnotic action

reticular activating system in the brainstem

Characteristics of benzodiazepines at GABA synapse

1. bind at separate sites of GABA ionophore

2. increase chloride conduction

3. increase amplitude of IPSP caused by GABA

4. enhance action of GABA

5. modulate GABA

Benzodiazepines modulate but do not mimic GABA meaning that if GABA were to be depleted there would be ---

no action to modulate / no response

Benzodiazepines produce ---

active metabolites

Benzodiazepines have --- effects on ---, ---, and --- in therapeutic doses

minimal effects of respiratory, cardiovascular, and GI

What happens if benzodiazepines are combined with other CNS such as alcohol

severe depression of the CNS

Which has a higher depend and abuse potential: benzodiazepines or barbiturates

barbiturates

What metabolizes benzodiazepines?

liver microsomal enzymes

What is important about benzodiazepines and liver microsomal enzymes?

They do not induce the synthesis of liver microsomal enzymes

do not accelerate metabolism of other drugs

Characteristics of the barbiturates at the GABA synapse

1. bind at separate site of GABA ionophore

2. increase duration of chloride channel opening

3. increase duration of IPSP by GABA release

4. block re-uptake of GABA

5. GABA mimetic at high concentrations

Which is a GABA mimetic at high concentrations: benzodiazepines or barbiturates

barbiturates

Which increases frequency of chloride channel opening:

- benzodiazepines or barbiturates

benzodiazepines

Which increases duration of chloride channel opening?

- benzodiazepines or barbiturates

barbiturates

Which increases amplitude of IPSP GABA signal

- benzodiazepines or barbiturates

benzodiazepines

Which increases duration of IPSP GABA signal?

- benzodiazepines or barbiturates

barbiturates

Do barbiturates produce active metabolites?

No - benzodiazepines produce active metabolites

What happens when barbiturates are administered with other depressant agents?

severe CNS depression

What metabolizes barbiturates?

liver microsomal enzymes

What is important about barbiturates and liver microsomal enzymes?

induce microsomal liver enzymes

accelerate metabolism of other drugs

What drugs do barbiturates accelerate the metabolism of?

anticoagulants

contraceptives

phenytoin

vitamin D and K

corticosteroids

Clinical uses of benzodiazepines

sedative/hypnotic

anti-epileptic

anti-anxiety

anti-depressant

anesthetic adjunct

Clinical uses of barbiturates

sedative/hypnotic

anti-epileptic

anesthetic adjunct

What are the advantages of benzodiazepines over barbiturates?

safety TI

Do not produce anesthesia and unconsciousness

less interactions with other drugs

less severe withdrawal effects

What are the withdrawal effects of barbiturates?

seizures on withdrawal with epileptics

What

Generally the word alcohol when used alone refers to

ethanol

in chemistry an alcohol is an organic compound in which a --- group is bound to a carbon atom

hydroxyl group

Ethanol is also known as

ethyl alcohol

What is the most widely used depressant?

alcohol

Alcohol is a CNS depressant that shares many pharmacological properties with ----

nonbenzodiazepine sedative hypnotic

Where is alcohol absorbed?

stomach

large and small intestine

colon

What is the rate of absorption for alcohol?

30-90 min following ingestion

rate decreases up to 50% if food is present

Alcohol has a --- and --- distribution in the body

rapid and uniform

What is permeable to alcohol?

placenta and blood brain barrier

True / False: The Central Nervous System although represents only 1/50 of total body weight receive roughly 1/5 of the total body blood supply and therefore it receives a corresponding high proportion of the alcohol present in the body

true

Alcohol is --- to --- and water

oxidized to carbon dioxide and water

Alcohol metabolism takes place in the ---

liver

What enzymes metabolize alcxohol?

alcohol dehydrogenase and aldehyde dehydrogenase

Conditions that determine the rate of alcohol metabolism

Body weight (liver weight)

•Drinking Habits (teetottler, chronic alcoholic)

•Genetics

How does body weight affect alcohol metabolism?

The larger in body weight the higher the rate of metabolism

alcohol is distributed over a larger volume of body water, leading to a lower blood alcohol concentration

How do drinking habits affect alcohol metabolism?

the more alcohol consumed the quicker the activation of alcohol dehydrogenase

What is activated in people who drink large quantities of alcohol?

Microsomal Ethanol Oxidizing System

Microsomal Ethanol Oxidizing System

uses NADH instead of NAD like alcohol dehydrogenase

Since --- can also be induced by barbiturates, alcohol metabolism is accelerated when these drugs are used in combination

microsomal ethanol oxidizing systems

Alcohol

- CNS effects

CNS depressant = acts like sedative-hypnotic

enhances GABA, acetylcholine, and serotonin transmitter systems

inhibits glutamate

Alcohol

- cardiovascular effects

cutaneous vasodilation

Alcohol

- GI tract effects

increased gastric acid secretion

Alcohol

- liver effects

increase in fat production

Why does alcohol use lead to increase in liver fat production?

breakdown of alcohol forms acetyl CoA

excess acetyl CoA from alcohol used used for fatty acid synthesis

Alcohol

- interaction with drugs

acute = decrease in metabolism of drugs

chronic = increase in metabolism of drugs

Why should aspirin be avoided with alcohol?

increased risk for GI bleeding

increased acid secretion

Alcohol inhibits the metabolism of --- an oral hypoglycemic and leads to a --- of blood glucose levels

tolbutamide

stronger reduction of blood glucose

What happens when alcohol is given with tolbutamide?

alcohol decreases blood glucose levels

tolbutamide stimulates insulin release

causes unpredictable fluctuations in blood glucose

Wernicke's encephalopathy

thiamine deficiency causes loss of maxillary bodies

Wernicke's encephalopathy leads to

Korsakoff's psychosis

anterograde amnesia, retrograde amnesia, and hallucinations

Disulfiram (Antabuse)

- drug interaction with alcohol

inhibit alcohol dehydrogenase

What happens when disulfiram is given with alcohol?

no alcohol dehydrogenase = build up of acetaldehyde

N/V due to acetylaldehyde build up

Naltrexone is an --- antagonist used to help diminish drug (alcohol) seeking behavior

opiate

Acamprostate (Campral)

blocks glutaminergic N methyl D aspartate receptors

stabilizes chemical balance in brain that would otherwise be disrupted by alcoholism

Insomnia categories

transient

short term

long term

A hypnotic drug produces 2 effects

1. decrease in time to go to sleep

2. increase in time spent asleep

Rapid eye movement sleep is also known as

paradoxical sleep

What is the best policy for insomnia treatment?

prescribe hypnotics as sparingly as possible

True / False: hypnotics are an abused class

true

Prescribing hypnotic drugs for transient insomnia

small dose of rapidly eliminated hypnotic for 1-3 nights

Prescribing hypnotic drugs for short term insomnia

small dose of rapidly eliminated hypnotic for 3 weeks