General Anesthesia

ANXIETY AND ANXIETY

DISORDERS

ANXIETY AND ANXIETY DISORDERS

 Anxiety is a sense of apprehensive expectation.

 Anxiety in reasonable amounts and at appropriate times is helpful (e.g., anxiety before an examination may cause a student to initiate an appropriate study plan).

 Anxiety can be considered pathological when it is either completely inappropriate to the situation, or is in excess of what the situation normally should call for.

 Anxiety is that level of anxiety that interferes with normal social or occupational functioning

 Examples of anxiety disorders: specific phobias, generalized anxiety disorder (chronic abnormally high level of worry), social phobia (e.g., fear

Etiology of Anxiety Disorders

• Altered blood flow or utilization of glucose in certain brain areas has been found in patients with anxiety conditions.

• A variety of neurotransmitters, neuromodulators (e.g., adenosine), and neuropeptides (e.g., cholecystokinin, corticotropin-releasing factor, and neuropeptide Y) are suggested to be involved in the pathophysiology of anxiety.

• Currently, abundant evidence exists to document the involvement of the neurotransmitters γ-aminobutyric acid (GABA), norepinephrine, and

serotonin in anxiety

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 The Majority of GABA_A receptors are made up of a mixture to subunits types (_1-6, β_1-3, γ_1-3, θ, ε, δ and π) with the majority of receptors composed of , β and γ subunits in the ratio of 1:2:1

 The major combinations of subunits are ₁β₂γ₂ of the GABA_A receptors.

 The drug interacting with ₁ subunit receptors are involved in the modulation of sedative, amnesic, and seizure protection, whereas drugs binding with the ₂ subunits receptors provide anxiolytic and myo-relaxant properties.

 The current generation of benzodiazepines binds with comparable affinity at both GABA_A receptors subtypes.

 The compound specific for ₂ subunit would be "nonsedative" whereas compound specific to ₁ subunits would primarily sedative-hypnotic.

Mechanism of Action of Anxiolytic

Benzodiazepines

Drugs Used in the Treatment of Anxiety

• The major factors considered when selecting an agent include rate and extent of absorption, presence or absence of active metabolites, and degree of lipophilicity.

• An agent which is rapidly absorbed, highly lipid soluble, and without active metabolites would be useful as a hypnotic, but less useful for treatment of a chronic anxiety state

• On the other hand, a compounds with slower absorption, active metabolites, and low lipophilicity would be a more effective anti-anxiety agent, but less helpful as a hypnotics

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Development of benzodiazepine Anxiolytics

 Chlordiazepoxide was the first benzodiazepine to be marketed for clinical use in 1960.

 Chlordiazepoxide was synthesized by medicinal chemist Sternbach in 1950 due to unexpected rearrangement to 6-chloro-2-chloromethyl -4- phenylquinazoline-3-oxide with methylamine.

Development of benzodiazepine Anxiolytics…..

 Structural modifications to Chlordiazepoxide had been done to improve the pharmacological properties and to minimize the unacceptable physiochemical properties.

 Diazepam (Valium®) contains no basic nitrogen moiety, however, was found to be 3- to 10-fold more potent than chlordiazepoxide and was marketed in 1963 as the still popular anxiolytic drug.

 Thousands of benzodiazepine derivatives were synthesized, and more than two dozen benzodiazepines are in clinical use.

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The SARs for benzodiazepine anxiolytic derivatives at the BZR/GABA receptor

• Ring A is an aromatic or heteroaromatic ring. It is believed to participate in π/π stacking with aromatic amino acid residues of the receptor.

• Substituents on ring A, are known to have varied effects on binding of benzodiazepines to the BZR:

 An electronegative group (e.g., halogen, nitro) substituted at the 7- position markedly increases anxiolytic activity.

 On the other hand, substituents at positions 6, 8, or 9 generally decrease anxiolytic activity; so, these positions should be kept un-substituted for optimum activity.

• Other 1,4-diazepine derivatives in which ring A is replaced by a heterocycle generally show weak binding affinity in vitro and less pharmacologic activity in vivo when compared to phenyl-substituted analogs.

Ring B

• A proton-accepting group (e.g., the carbonyl group ) in the position 2 of ring B appears to be necessary for optimal activity, to interact with a receptor histidine residue that serves as a proton source.

• Substitution of sulfur for oxygen at the 2-position may affect selectivity for binding to GABA BZR but, anxiolytic activity is maintained

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• substitution at the position 3 with a hydroxy does not affect activity. However, the presence or absence of the 3-hydroxyl is important pharmacokinetics.

 Compounds without the hydroxyl are nonpolar, have long half-lives, and undergo hepatic oxidation.

 Compounds with a 3-hydroxy moiety have comparable potency to non-hydroxylated analogs, but they are more polar and readily excreted as glucuronide.

 Esterification of a 3-hydroxy moiety also is possible without loss of potency.

•

Many clinically used analogs are not N

¹

-alkylated.

 long N-alkyl side chains do not dramatically decrease BZR affinity,

 Sterically bulky substituents like tert-butyl drastically reduce receptor affinity and in vivo activity.

• Saturation of the 4,5 double bond or a shift of it to the 3,4 position decreases activity.

•

The

4-oxide moiety of chlordiazepoxide can be removed

without loss of anxiolytic activity.

•

An additional

"electron-rich" (i.e., proton acceptor) ring,

such as

triazole

or

imidazole,

results active benzodiazepine derivatives with high affinity for the BZR.

 For example, the triazolobenzodiazepines, triazolam, alprazolam, and estazolam and the imidazo- benzodiazepine, midazolam, are popularly prescribed, clinically effective, anxiolytic agents.

• The 5-phenyl ring may contribute favorable hydrophobic or steric interactions to receptor binding and its relationship to ring A planarity may be important.

• Substitution at the 4'-(para)-position is unfavorable for agonist activity

• However, ortho (2') or diortho (2’, 6’) substitution with electron withdrawing groups increases activity.

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An electronegative group (e.g., halogen, nitro)

Positions 6, 8, or 9 should be kept un- substituted for optimum activity

A proton-accepting group (e.g., the carbonyl group ) necessary for optimal activity

The presence or absence of (OH) is important

pharmacokinetics Sterically bulky

substituents like tert-butyl

Saturation of the 4,5 double bond or a shift of it to the

3,4 position

Addition of "electron-rich" (i.e., proton acceptor) ring, such as triazole or imidazole increase affinity for the BZR

Substitution with electron withdrawing groups

SAR of Benzodiazepines