SEDATIVE- HYPNOTIC & ANTI ANXIETY DRUGS

Mechanism of Benzodiazepines

o Work by increasing the inhibitory effects at CNS synapses that use the neurotransmitter gamma-aminobutyric acid (GABA). o Enhance relaxation and sleep by boosting the effect of the brain's endogenous inhibitory neurotransmitter (GABA) - Bind to a specific receptor located at certain inhibitory synapses in the reticular formation of the CNS.

3 Components of Receptor affected by Benzodiazepines

▪ (1) binding site(s) for GABA ▪ (2) A binding site for benzodiazepines ▪ (3) An ion channel that is specific for chloride ions

Propranolol can decrease:

▪ Cardiac palpitations ▪ Muscle tremors ▪ Hyperventilation ▪ Other manifestations of anxiety that tend to occur before an important performance.

o A group of CNS depressants that share a common chemical origin: barbituric acid. o Associated with a relatively small therapeutic index; approximately 10 times the therapeutic dose can often be fatal. o Very addictive, and their prolonged use often leads to drug abuse.

Barbiturates

• A family of compounds that share the same basic chemical structure and pharmacological effects. • More known for treating anxiety (e.g., diazepam [Valium]. • Several benzodiazepines are indicated specifically to promote sleep. o These agents have hypnotic effects similar to those of nonbenzodiazepines—such as the barbiturates. o Generally regarded as safer because there is less of a chance for lethal overdose.

Benzodiazepines

• Primary drugs used to treat many forms of anxiety. • In terms of anxiolytic properties, diazepam (Valium) is the prototypical antianxiety benzodiazepine.

Benzodiazepines

Can decrease situational anxiety without producing sedation. o Exert their antianxiety effects through their ability to decrease activity in the sympathetic nervous system—that is, through their sympatholytic effects. o May exert peripheral sympatholytic effects (e.g., blockade of myocardial beta-1 receptors) and decrease central sympathetic tone.

Beta- adrenergic Antagonists (Beta- blockers)

• Is an antianxiety agent (approved in 1986) used to treat general anxiety disorder. • Belongs in a drug class known as the azapirones. • Does not act on the GABA receptor but exerts its antianxiety effects by increasing the effects of 5- hydroxytryptamine (serotonin) in certain areas of the brain. • Basically, a serotonin agonist that stimulates specific serotonin receptors, especially the 5-HT1A serotonin receptor subtype.

Buspirone

o Chemically different from benzodiazepines o They bind to the GABAA which then causes GABA to bind more effectively, thus increase in chloride conductance and the level of inhibition in the neuron. o Increased inhibition in certain areas of the brain results in less arousal and the promotion of sleep.

Nonbenzodiazepine Sedative-Hypnotics

• Benzodiazepine and nonbenzodiazepine sedative hypnotics are usually highly lipid soluble. • Typically administered orally and are absorbed easily and completely from the gastrointestinal (GI) tract. • Distribution is fairly uniform throughout the body, and these drugs reach the CNS readily because of their high degree of lipid solubility.

Pharmacokinetics of Benzodiazepines and Non- Benzodiazepines

o Metabolized primarily by the oxidative enzymes of the drug-metabolizing system in liver cells. o Termination of their activity is accomplished either by hepatic enzymes or by storage of these drugs in non-CNS tissues—that is, sequestering the drugs in adipose and other peripheral tissues negates their CNS- depressant effects. o When the drugs slowly leak out of their peripheral storage sites, they can be redistributed to the brain and can cause low levels of sedation o Excretion of these drugs occurs through the kidney after their metabolism in the liver.

Pharmacokinetics of Sedative Hypnotics

Problems and side effects associated with buspirone include:

o Dizziness o Headache o Nausea o Restlessness

Problems and Adverse Effects of Sedative Hypnotics

o Drowsiness and decreased motor performance the day after taking the drug. o Anterograde Amnesia

The ideal antianxiety drug is

o Nonaddictive o Safe (i.e., relatively free from harmful side effects and potential for lethal overdose) o Not associated with any sedative properties.

Drawbacks of Benzodiazepines

o Residual effects the day after they are administered. o Prolonged use can also cause tolerance and physical dependence.

alpha-2, beta-3 and gamma-2

Decreased Anxiety

Is the onset of withdrawal symptoms if drug administration is ceased.

Dependence

• Will decrease anxiety without major sedative effects. • The antianxiety properties of benzodiazepines involve a mechanism similar or identical to their sedative-hypnotic effects (i.e., potentiating GABAergic transmission). • Increase inhibition in the spinal cord = skeletal muscle relaxation = antianxiety effects by making the individual feel more relaxed.

Diazepam (Valium)

Facilitates chloride entry into the neuron and results in hyperpolarization, or a decreased ability to raise the neuron to its firing threshold.

Increased chloride conductance

▪ Decrease neuronal transmission; this causes fairly widespread CNS depression, which accounts for the subsequent sedative effects of such compounds.

Alcohol

The patient may have trouble recalling details of events that occurred for a certain period of time before the drug was taken.

Anterograde Amnesia

Can help decrease the tension and nervousness associated with many of these syndromes until the situation is resolved or until the individual is counseled effectively in other methods of dealing with his or her anxiety.

Antianxiety Drugs

Fear or apprehension over a situation or event that an individual feels is threatening.

Anxiety

Is the need to take more of a drug to exert the same effect.

Drug TOlerance

Primary neurotransmitter that causes inhibition at presynaptic and postsynaptic neurons throughout the brain and spinal cord.

GABA

▪ Cause inhibition by increasing chloride entry. ▪ Mediates the therapeutic effects of Benzodiazepines: • Sedation • Hypnosis • Decreased anxiety

GABAA

▪ May cause inhibition by affecting potassium channels and decreasing calcium entrance into CNS neurons. ▪ The muscle relaxant baclofen (Lioresal) may be somewhat more selective for GABAB receptors in the spinal cord.

GABAB

Cause inhibition by increasing chloride entry.

GABAC

Barbiturates may affect the GABA-benzodiazepine-chloride ion channel receptor. ▪ Bind directly to the GABAA receptor at a site that is different from the binding site for GABA or benzodiazepines. ▪ At higher doses, for instance, barbiturates may directly increase the release of inhibitory transmitters such as glycine and reduce the effects of excitatory transmitters such as glutamate.

MOA of Barbiturates

▪ Withdrawal after short-term benzodiazepine

May be associated with problems such as sleep disturbances (i.e., rebound insomnia).

▪ Used to treat anxiety related to post- traumatic stress disorder (PTSD). ▪ May provide a useful alternative to more traditional antianxiety drugs in people with various trauma- related anxiety.

Propranolol

▪ Alternative to traditional sedative- hypnotic benzodiazepines ▪ Similar in structure and function to melatonin. ▪ Helpful in facilitating sleep onset and in maintaining normal sleep patterns in certain individuals. ▪ May also have a lower risk of side effects, including a reduced incidence of next day "hangover"

Ramelteon

Anxiety can return or exceed pretreatment levels when benzodiazepines are suddenly discontinued.

Rebound Anxiety

Most common side effect of anxiolytic benzodiazepines, even though this effect is not as pronounced as with their sedative-hypnotic counterpart

Sedation

alpha 1, beta-2 and gamma-2 subunits

Sedation

• Fall into two general categories: Benzodiazepines and Nonbenzodiazepines. • These agents are used to promote sleep, especially in relatively acute or short-term situations where sleep has been disturbed by illness, injury, or other factors.

Sedative- Hypnotic Drugs

Barbiturates are effective sedative hypnotics because of their specificity for neurons in the midbrain portion of the reticular formation as well as some limbic system structures. - True or False

True

Benzodiazepine and nonbenzodiazepine sedative hypnotics are usually highly lipid soluble. - True or False

True