Anti-Anxiety drugs

Major mediators of anxiety in the CNS

• norepinephrine

• adrenaline

• serotonin

• dopamine

• gamma-aminobutyric acid (GABA)

risk factors in anxiety disorders

• decreased inhibitory signaling

• decreased GABA in the brain (family history)

• genetic contribution (heritable)

what genes are associated with anxiety?

• COMT

• Adenosine 2A receptor

• CCK

• CCK Receptor B

• 5HT2A receptor

• Monoamine oxidase-A

Glutamate

main excitatory neurotransmitter

GABA

main inhibitory neurotransmitter

what is GABAs normal role?

inhibits brain activity to enable us to relax

Sedative-hypnotics are widely prescribed drugs for...

anxiety and sleep disorders

Sedative-hypnotic drugs are able to....

cause sedation (with concomitant relief of anxiety) or to induce sleep (hypnosis)

Sedative (antianxiety drug) should

reduce anxiety and exert a calming effect with minimal CNS depression

Hypnotic drugs

produce drowsiness and induces the onset and maintenance of sleep

clinical uses of sedative-hypnotics

• treatment of anxiety

• treatment of sleep problems (insomnia)

• management of epilepsy and seizure disorder

• IV agents in anesthesia

• sedative and possible amnestic effects during medical or surgical procedures such as endoscopy and bronchoscopy

• control of ethanol or other sedative-hypnotic withdrawal states

• muscle relaxants in specific neuromuscular disorders

• initial management of mania and the control of drug-induced hyper-excitability states

chemical classifications of anti-anxiety drugs

• Benzodiazepines

• Barbiturates

• newer hypnotics, Zolpidem

Hypnotic effects when compared to sedative..

involve more pronounced depression of CNS

Dose-dependent response for sedative-hypnotics

achieved with many drugs in this class by increasing the dose

Dose-dependent effects of sedative-hypnotics

degree of depression of the CNS

Older sedative-hypnotics (barbiturates/ alcohols) vs newer hypnotics (benzodiazepines)

Barbiturates & Alcohol (older) dose-responde curve

steeper, higher risk of overdose

Benzodiazepines & newer hypnotics dose-response curve

less steep, Safer, lower risk of severe CNS depression.

What is the most commonly prescribed drug for acute anxiety?

benzodiazepines

Acute anxiety symptoms

• shortness of breath

• chest pain

• rapid, fluttering, or pounding heart

Benzodiazepines are used more commonly as

anti-seizure drugs

Benzodiazepine structure

most contain a carboxamide group in the seven-membered heterocyclic ring structure

What is required on a benzodiazepine for sedative-hypnotic activity?

substituents on the 7 position (halogen or nitro group)

What 3 things are commonly included in a benzodiazepine name?

• azepam

• azolam

• -azep

Triazolam (Halcion) absorption

very rapid

Diazepam (valium) absorption

rapid

What benzos are slowly absorbed ?

• Oxazepam (Serax)

• Lorazepam (Ativan)

• Temazepam (Restoril)

why is lipid solubility important for benzodiazepines ?

it affects the rat at which a particular sedative-hypnotic enters the CNS

Thiopental absorption

rapid onset

Diazepam/ Triazolam vs Chlordiazepoxide/Lorazepam

Diazepam/ Triazolam are more lipid soluble and enter the CNS more rapidly

Are sedative-hypnotics safe in pregnancy ?

they cross the placental barrier and during the pre delivery period may cause depression of neonatal vital function

Are sedative-hypnotics detectable in breast milk?

yes, and they may exert depressant effects in the nursing infant

What is necessary for the clearance of benzodiazepines?

Conversion to more water-soluble metabolites in the liver.

What does the elimination half-life of benzodiazepines depend mainly on?

Metabolic transformation.

What happens to most sedative-hypnotics before excretion?

They are biotransformed.

What accounts for clearance of benzodiazepines ?

liver

2 phases of metabolism of benzodiazepines

• Microsomal oxidation (phase 1)

• Metabolite conjugation (phase 2)

Phase 1 reaction of biotransformation of benzodiazepines

microsomal oxidation including N-dealkylation and aliphatic hydroxylation by P450 CYP3A4

Phase 2 reaction of biotransformation of benzodiazepines

metabolites are conjugated to form glucuronides that are excreted in the urine

Benzodiazepines with parent drugs or active metabolites with long-half lives are more likely to....

cause cumulative effects with multiple doses and cause residual effects like excessive drowsiness

Which benzodiazepines have a relatively short half-lives and are metabolized directly to inactive glucuronides?

• Estazolam

• Oxazepam

• Lorazepam

Benzodiazepine mechanism of action

enhance the effect of GABA (inhibitory NT) by binding at the GABAa receptor

What type of ion channels are GABA A receptors?

Chloride ion channels

What happens when GABA binds to GABA A receptors?

The receptors hyperpolarize the neuronal membrane by a influx of Cl-.

What is the result of chloride influx through GABA A receptors?

Inhibition of action potentials

GABA B

G- coupled receptors (metabotropic), Slower, indirect inhibition (G-protein) → Targeted by baclofen (muscle relaxant)

Do benzodiazepines act on GABAB receptors?

No, benzodiazepines primarily target GABAA receptors, not GABAB receptors

spasmolytic drug

muscle relaxant

What do GABAA receptors do compared to nicotinic and NMDA receptors?

• Nicotinic (ACh) & NMDA (Glutamate) Receptors → Excitatory (Depolarization) → Increase neuron activity

• GABAA Receptors → Inhibitory (Hyperpolarization) → Decrease neuron activity

When GABA binds to GABAA receptors what happens?

Inhibitory → Lets Cl⁻ in → Slows down neurons

What happens when GABA binds to a GABAB receptor?

1. GABA binds to GABAB receptor

2. Alpha (α) subunit detaches from the G-protein

3. Alpha subunit binds to the effector

4. K⁺ (potassium) channels open → K⁺ flows out

5. Ca²⁺ (calcium) channels close

6. Neuron slows down (inhibition)

Examples of metabotropic receptors

• muscarinic acetylcholine receptors

• serotonin receptors

• histamine receptors

• norepinephrine receptors

GABA A receptor structure

5 membrane-spanning subunits (a2B2y) selected from the polypeptide classes (a, B, Y, E)

GABA A receptors in different parts of the nervous system.....

have different combinations of subunits

How does the variation in GABAA receptors affect benzodiazepine actions?

GABAA receptors in different parts of the nervous system have different combinations of subunits. This heterogeneity creates the molecular basis for the various pharmacological actions of benzodiazepines and related drugs.

Where do benzodiazepines bind?

interface of the a and y subunits on the GABA A receptor

Benzodiazepine binding require what?

the alpha subunits contain a histidine amino acid residue (a1, a2, a3, and a5)

What alpha subunits are necessary for benzodiazepine binding and influence the receptor's pharmacological effects?

• a1

• a2

• a3

• a5

What GABA A receptors do benzodiazepines have no affinity for?

ones containing a4/a6 subunits

why do benzodiazepines show no affinity for a4/a6 ?

they have an arginine instead of histidine residue

What benzodiazepines are associated with stronger hypnotic effects?

high affinity for a1

What benzodiazepines are good for anti-anxiety activity?

those with high affinity for GABA A containing a2 and/or a3

What site does Benzodiazepines bind on GABA receptors?

allosteric site

How do benzodiazepines work to slow down action potentials?

they increase the frequency of opening associated with chloride ion channels and hyperpolarizes the membrane

Benzodiazepines increase the _____________ of the opening of chloride ion channels.

frequency

Benzodiazepines cause more chloride channels to flow in and this.....

potentiates the effect of GABA leading to sedative and anxiolytic effects

Benzodiazepines DO NOT do what?

substitute for GABA

Benzodiazepines ____________ GABA's effects, where?

enhance, allosterically

Benzodiazepines potentiation of GABA results in what?

increased frequency of channel-opening events

Three types of ligan-benzodiazepine/receptor interactions

• agonist

• antagonists

• inverse agonist

What is the role of an agonist ligand in benzodiazepine receptor interaction?

Facilitates GABA actions.

Which non-benzodiazepines act as agonists at benzodiazepine sites containing what subunit? (2 answers, the drugs and the subunit)

Zolpidem, zaleplon, and eszopiclone; a1

What are endogenous agonist ligands?

Naturally occurring substances that activate receptors.

What is the name of the antagonist ligand that interacts with benzodiazepine receptors?

Flumazenil

What does flumazenil block?

The actions of benzodiazepines but not barbiturates

What is flumazenil used for?

To reverse benzodiazepine sedation after surgery or to treat benzodiazepine overdose

What is an inverse agonist ligand in relation to benzodiazepines?

Negative allosteric modulators of GABA-receptor function.

What effect do inverse agonists have on benzodiazepines?

They block the effects of benzodiazepines.

What are the potential consequences of using inverse agonists like B-carbolines?

They can cause anxiety and seizures.

What is an example of an inverse agonist?

n-butyl-B-carboline-3-carboxylate (B-CCB).

What are older and less commonly used sedative-hypnotics primarily used for?

Severe cases of insomnia, seizures unresponsive to other less toxic agents, and induction of anesthesia.

What type of effects do older sedative-hypnotics have?

Sedation to anesthetic effects.

What is the classification of older sedative-hypnotics in terms of their action on the body?

Central nervous system depressant.

What is the route of administration for barbiturates?

Oral administration

What happens after oral administration of barbiturates?

Rapid absorption in the blood stream

What factor determines the onset of action for barbiturates?

Lipid solubility

What is a key characteristic of Thiobarbiturates (Thiopental)?

They are very lipid soluble and rapidly enter the CNS.

What contributes to the rapid time to onset of Thiobarbiturates (Thiopental)?

The lipophilic characteristic of the drug and the significant percentage of cardiac output that goes into the brain.

Describe onset/ duration of Thiobarbiturates (Thiopental)

rapid onset, short duration

What causes the short duration of action of Thiobarbiturates (Thiopental)?

The short duration is due to redistribution from the brain to other compartments, not metabolism.

Phenobarbital / Meprobamate

have low lipid solubility so they penetrate the brain slowly (limitation)

Barbiturates are excreted by what organ?

kidneys

Barbiturates undergo what before being excreted by the kidneys?

extensive biotransformation

What barbiturate is excreted differently? how?

phenobarbital, 20-30% excreted unchanged

Barbiturate metabolism

oxidation by hepatic enzymes to form alcohols, acids, and ketones

Barbiturates excretion

urine as glucuronide conjugates

Barbiturates elimination half-life

long (phenobarbital 4-5 days)

Multiple dosing of barbiturates can....

lead to cumulative effects

Unlike Benzodiazepines and newer hypnotics, barbiturates (phenobarbital and meprobamate) can....

affect hepatic drugs-metabolizing enzymes and cause increased biotransformation and drug interaction

How do barbiturates effect GABA channels?

increase the duration of channel opening