Unit 7 ~ Sedative Hypnotics

What are sedative hypnotics

These are compounds that focus on depressing the CNS and behaviors.

1. Furthermore, they have anxiolytic properties ~ Downers

2. They show additive effects and cross-dependence + cross-tolerance

What are some common examples of Sedative Hypnotics

1. Alcohol

2. Barbiturates

3. Benzodiazepenes

For an increase in any form of sedative there is an increase in what?

A loss of consciousness

Barbiturates have a higher addictive potential than BDZ

Yes, this is true. This is why Barbs were later replaced by BDZ for the treatment of anxiety and insomnia

In what characteristics were Barbs related to a so called Truth Serum

It was thought to lessen inhibitions and thus encourage talking.

Results showed more talking but did not affect the honesty of the matter.

Current Medical Use of Barbs

Barbs are currently used for Anesthesia, Sedation and Epilepsy

Barbs are no longer used for

Barbs are no longer used for Sleep induction, anxiety and alcohol withdrawal

What are some possible side effects of Barb use

1. Reduced REM sleep

2. Reduced Cognitive function

3. Increased Dangers when taken with alcohol

4. Increased tolerance, but a reduced margin of safety

5. Heavy dependence and withdrawal often causing seizures

Barbs and their disruption in sleep regulation

They are initially helpful in getting you to sleep; however, repeated use has shown a reduction in REM sleep and Deep-Wave sleep, thus making harder over time to get good sleep.

What is the lethality of a Barbiturate overdose

This is seen as a common means of suicide or euthanasia.

The mechanism of Death ~ The respiratory centers in the Brainstem will shut down, similar to what happens with alcohol as well.

What are some commons uses for BDZ

Like other sedative-hypnotics, they are widely used for anxiolytics, sedatives, anticonvulsants, and furthermore treatment for alcohol withdrawal & surgical sedation/amnesia.

One of the first drugs marketed for BDZ was…

Valium (1963)

In comparison to Barbs, BDZ has…

There is decreased tolerance and dependence. There is increased safety, and often replaced with barbs for many uses over time.

Different BDZs will show a variance in the duration of actions

There is also redistribution to other sites in the form of Depot Binding

Various metabolic pathways

1. Long-acting BDZ

2. Short-acting BDZ

What are Z-drugs or non-BDZ

These drugs will show similar benefits, side effects, and risks. But Have a different chemical structure from BDZ

How will Z-Drugs act and what are they most commonly used for

They will act at the BDZ binding site for GABA-A receptors.

They are most commonly used for treating sleep disorders

What are the listed Medical uses for BDZ

1. Pathological Anxiety

2. Emotional Distress

3. Agitation and Alcohol Withdrawal

4. Sedation

5. Pre-surgery relaxant and Anterograde Amnesia

6. Anticonvulsant

7. Anesthesia/Amnesia

Why is BDZ far safer than Barbs

1. Less metabolic Tolerance

2. Lower Dependence Abuse'

3. Safer Therapeutic Index

It does not affect the respiratory centers in the brain; furthermore, there is a direct reversal agent (Flumazil which is a competitive antagonist for BDZ)

How are BDZ abused, or seen in Withdrawal

Used for date-rape (Rohypnol)

Withdrawal shows persistent emotional disturbances

BDZ and its relation to DUI dangers

Yeah, weirdly enough, many of the sleep medications that are BDZs will leave people drowsy in the morning and can cause Sleep Driving.

1. In attempts to fix the problem, the dose of Ambien was lowered and there is now a labeled warning.

What are some basic Pharmacodynamics of Sedative-Hypnotics

Sedative-hypnotic will enhance the chloride influx through GABAa Receptors (Ionotropic)

Both Barbs and BDZs have different binding sites on the GABAa receptor.

Alcohol has an unknown mechanism at GABAa, but will show similar activity to Barbs and Benzos.

What is a Quaalude

This is another Sedative-hypnotic.

it is often referred to as the Quiet Interlude and was originally used as a hypnotic, sedative, and muscle relaxant.

Bill Cosby

What is GHB

This is another sedative-hypnotic form

It was synthesized by chemists looking for a GABA analog that could cross the BBB

It will bind to GABAb and GHB receptors.

It was used as a sedative and anesthetic, but has been decreased as it has a very high abuse potential

What are the current uses of GHB

Xyrem is used for Narcolepsy and Cataplexy

It was also used as a common Club Drug and Date-rape drug.

Why is only ethanol (alcohol) consumed and not the many other forms

The other forms are often way too toxic for the human body

Fermentation of Alcohol

This is when alcohol is produced via natural means, where Yeast will consume sugar to produce ethanol and CO2.

This can only produce alcohol concentrations up to 15%

Distillation of Alcohol

This will exploit the lower boiling point of alcohol compared to water and produce spirits or hard liquor which are greater than 15%

Alcohol use is rising with the spread of what new form

The spread of distillation greatly increased the spread of alcohol abuse.

It is important to note that there were multiple attempts to banning alcohol in the US

1. Temperance Movement

2. Prohibition in 1919

However, it was nearly impossible to enforce and was thus reappealed in 1933

Absorption and Distribution of Alcohol

Alcohol is a small non-ionized molecule that has a increased ability to diffuse across many membranes. 10% of which will be absorbed in the stomach and 90% in the small intestine (which has a larger surface area) thus distributing it throughout the body.

Presence of food in the stomach will slow gastric emptying and absorption, so more alcohol is being degraded prior to absorption (First-Pass metabolism)

Metabolism and Excretion of Alcohol

A minuscule amount will be eliminated through sweat, tears, urine, and breath (10%)

Most alcohol will be broken down by ADH in the stomach and liver (Alcohol Dehydrogenase) and then ALDH (Aldehyde Dehydrogenase)

Some variance in ADH and ALDH

ADH

1. 60% more gastric ADH in men

2. Aspirin can inhibit ADH

ALDH

1. 50% of certain Asian groups have reduced ALDH Function

Alcohol shows Zero-Order Kinetics, since they are cleared from the blood at a constant rate, as metabolism and excretion processes are saturated.

How is Alcohol typically measured

The standard measure for Blood Alcohol Content is grams of alcohol per 100ml of blood

A BAC of 0.2-0.3 ~ Quite Drunk

A BAC of 0.45 ~ Death (Due to respiratory centers in the Brain shutting down)

Thus, there is a fairly low margin of safety

What are some other effects seen with Alcohol usage

1. Increased Blood Circulation

2. Inhibition of ADH (Anti-diuretic Hormone)

3. Modified Sleep Patterns (Impaired REM sleep)

4. Blackouts (Amnesia)

Alcohol effects on the Vestibular System

Makes the blood less dense, and these changes in the density of the Cupula liquid, as compared to surrounding fluid, mean it won’t be able to float normally. The sensation of the movement will also trigger the vestibular-ocular reflex

What causes an Hangover from Alcohol

This is caused by dehydration, low blood sugar, irritation of the digestive system, decreased REM, and residual acetaldehyde.

Funny enough, drinking more will relieve some of these symptoms, thus showing us that a Hangover is partly a mini-withdrawal

Withdrawal from Chronic Use in Alcohol

Withdrawal is dangerous and can be fatal.

Delirium Tremens ~ Seizures, hallucinations, tremors, hyper-excitable state

It is often treated by using another sedative-hypnotic due to cross-dependence.

What are some Acute Alcohol health risks

1. Overdose

2. Drunk Driving

3. Injuries, violence, and other risky behavior

What are some chronic health risks

1. Fatal withdrawal

2. Alcoholism

Other effects on the body: liver disease, cancer, brain damage, and dementia

Alcoholism

11.3% of US adults had a Alcohol Use Disorder

What are some risks for alcoholism

1. Stress has a very important role in the initiation, maintenance, and relapse

2. Lifetime anxiety, Early-life stress, or increased novelty seeking

3. Family history of alcoholism

   1. 3x to 7x greater risk for alcoholism

   2. Greater cortisol response to stress

   3. Greater ability for alcohol to decrease stress effects

Chronic Heavy Use of Alcohol Shows

Liver damage in (10%-20%) of drinkers (Cirrhosis)

There is also brain damage (Korsakoff syndrome)

1. Deficiency in vitamin B, confusion, and anterograde amnesia.

Alcohol Will Increase Cancer Risk

Yes, it will.

Fetal Alcohol Syndrome

Alcohol has the ability to readily cross the placenta, thus influencing brain development

Characteristics of FAS

1. Lower Birth Weight

2. Craniofacial Malformations

3. Other neurological problems (Retardation, learning disabilities and more)

Self-Administration of Alcohol in Animals.

Most animals will drink only a little alcohol, and that usually is not to a level of intoxication

However, selectively bred rodent populations have drunk more alcohol or abstained from it, showing a very genetic component to alcoholism.

What is a simple pharmacodynamic mechanism of Sedative-hypnotics

They will enhance Cl- influx through the GABAa receptors, thus causing inhibition.

GABA synthesis

GABA is formed from glutamate (an immediate precursor) via the enzyme GAD (Glutamic Acid Decarboxylase)

GABA transmission and Inactivation

GABA will be packaged into vesicles via VGAT (a GABA and Glycine transporter)

It will then be transported out of the synapse with GAT1, GAT2, and GAT3

Finally in the end, it will be degraded by GABA-T (GABA aminotransferase)

GABAa characteristics

It is ionotropic

Ligand Gated Cl- Channels

Pentameric

GABAb characteristics

Metabotropic

Unlike most, it has two different subunits

Used as an autoreceptor on GABA terminals.

GABAa composition

Has 5 receptor subunits, which will surround a central pore (Cl- Ion Channel)