Dr Khulood Dr Khulood AlsarafAlsarafDr Khulood Dr Khulood AlsarafAlsaraf

Anxiety

Is unpleasant state of tension, apprehension or uneasiness-a fear that seems to arise from an unknown source. The symptoms of severe anxiety are similar to those of fear (such as tachycardia, sweating, trembling,palpitation) & involve sympathetic activation.Episodes of mild anxiety are common life experiences

&don’t need any treatment.While the symptoms of severe chronic anxiety may by treated with anti-anxiety drug.

Insomnia

Includes a wide variety of sleep disturbances such as difficulty in falling a sleep, early or frequent a wakening, & remaining un refreshed after sleep.Use of sedative-hypnotic drugs is one approach to the therapy of

insomnia. 

Other measures include:Maintenance of a proper diet, initiation of an exercise program of

avoidance of stressful or anxiety-provoking situations. 

Most anxiolytic-hypnotic drug produce dose dependent depression of central nervous systems function.

 The ideal anxiolytic drug should calm the patient without causing too much daytime sedation & drowsiness

&without producing physical or psychological dependence. Similarly, the ideal hypnotic drug should allow the patient to fall asleep quickly & should maintain sleep of sufficient

quality of duration so that the patient awakes refreshed without a drug hangover.

 Also, both types of drugs should have very low toxicity or should not interact with other medication in such a way as to produce unwanted or dangerous effect.

 The CNS depression produce by these drugs is

Dose-Dependent

BenzodiazepinesMost of these drugs possess anxiolytic, sedative-hypnotic,

or anticonvulsant properties. Thus, the clinical indication for specific benzodiazepines are not absolute.

AnxiolylicsAlprazolam Chlordiazepoxide Clonazepam Clorazepate Diazepam Lorazepam

BZD antagonist flumazenil

HypnoticsFlurazepamTemazepam Triazolam Midazolam

BenzodiazepinesMechanism of action

 Gamma – aminobutyric acid(GABA) is the major inhibitory

neurotransmitter in the central nervous systems. 

Binding of GABA to its receptor & this receptor called GABA chloride channel complex, on the cell membrane. Triggers an opening of chloride channel, the influx of Cl‑ causes a small

hyper polarization that inhibite the formation of action potential. 

BZD bind to specific, high affinity sites on the cell membrane Which are separate from but adjacent to the GABA receptor.

The BZD receptors are found only in the central nervous systems

 

Organ level effects of BZD

1-Sedative & hypnotic action 1-Sedative & hypnotic action 2-Reduction of anxiety 2-Reduction of anxiety 3-Anticonvulsant 3-Anticonvulsant 4-Muscle relaxant4-Muscle relaxant

1-Sedative & hypnotic action 1-Sedative & hypnotic action 2-Reduction of anxiety 2-Reduction of anxiety 3-Anticonvulsant 3-Anticonvulsant 4-Muscle relaxant4-Muscle relaxant

Clinical uses

1-antianxiety 2-for insomnia 3- to produce sedation, amnesia, & anesthesia before medical & surgical procedures (used I.V with high doses) also used for dental surgery with local anesthesia.4-treatment of epilepsy & seizure state 5-to produce muscle relaxation in specific neuromuscular disorders6-to control alcohol & sedative-hypnotic withdrawal syndroms.

Tolerance: decreased responsive to a drug following repeated exposure, this is

a common feature of sedative hypnotic usage .It may result in an increase in the dose needed

to maintain symptomatic improvement or to promote sleep.

Psychological of physical dependence on BZD can develop if high doses of the drug are given over a

prolonged period of time. Abrupt discontinuation of the BZD results in withdrawal

Symptoms including: confusion, anxiety, agitation ,restlessness insomnia & tension.BZD with short elimination half-life such as triazolam induce

more abrupt & server withdrawal symptoms than those seen with drugs that are slowly eliminated such as flurazepam.

Adverse effects 1-CNS depression (drowsiness, excessive sedation, impaired motor coordination, confusion,& memory loss)2-Pradoxical reactions ( excitement, stimulation, & hyperactivity( 3-Amnesia 4-BZD can affect the GIT & also produce allergic reaction

 

Drug Interaction BZD interact in an additive fashion with other

CNS depressant agents like alcohol, Barbiturates,Phenothiazines, Opioids analgesic.Inhibitors of oxidative metabolism such as cimitidine, disulfiram, isoniazid & omperazol may produce an increase in the effects of BZD.

 

BZD Antagonist Flumazenil It Is BZD competitive antagonist.It used to reversing the CNS depressant effects ofBZD over dose. Flumazenil when given I.V it act rapidly but has short half-life (0.7-1.3 hr.) due to rapid hepatic clearance.

Dizziness, nausea, vomiting & agitation are the most common side effects.

 

Other types of anti anxiety drugs

A- Azapirones (Buspirones)

-No sedation, or hypnotic activity-No anticonvulsant OR muscle relaxant properties

-Partial agonist at brain 5HT1A receptors -No rebound anxiety or with drawal sings -Take several weeks to develop it is anxiolyic effect -Suitable for generalized anxiety & in anxiety with depression -Tachycardia, palpitation, nervousness, GIT abset

B- Antidepressents

-TCA -SSRIs (Escitalopram)-SNRIs (Venlafaxine)They have been shown to be effective when used in the

treatment of several anxiety disorders, including general anxiety, obsessive-compulsive disorders, & several phobias.

Because the SSRIs are less toxic than the tricyclic antidepressants, their use in the treatment of anxiety is safer & less likely to produce serious side effects.

 

Barbiturate

Barbiturate : are used much less commonly than before.They should be used for short-term therapy as sedative or hypnotics.

Barbiturates classify according to their duration of action into:1- ultra short acting (Thiopental) which act with in seconds and has a duration of action of about 30 min. 2- short acting barbital (Amobarbital, Secobarbital, and Pentobarbital)3- long acting (Phenobarbital)

Mechanism of action• interfere with Na and K transport across membrane.• potentiate GABA action on Cl ion entry• do not bind to BZD receptors

Barbiturate

Actions depression of CNS respiratory depression enzyme induction ( barbiturates induce CYP450 in liver, reduces the effect of several drugs that depends on CYP450 in their metabolism)

Clinical uses Anesthesia (thiopental) Anticonvulsant Anxiety

Adverse effects CNS : drowsiness, impaired concentration, and mental and physical disturbances.Occasionally nausea and dizziness may occur.

Barbiturate

Physical dependenceAbrupt withdrawal from barbiturates may cause tremors, weakness, restlessness, nausea and vomiting, seizures, delirium and cardiac arrest.

Poisoning Over dose of barbiturates may cause poisoning associated with severe depression of respiration and central cardiovascular depression results in shock like condition.Treatment include: Artificial respiration Hemodialysis Purging stomach content Alkalinization of urine for phenoparbital.

A-Zolpiden & Zaleplon

-Bind to BZD receptors -Structurally unrelated to BZD - No anticonvulsant OR muscle relaxant properties - It shows few withdrawal effects-Minimal rebound insomnia-Has rapid onset & short duration of action

Other Hypnotic Agents

B-Antihistamins (Diphenhydramine or promethazine)

C-Ethanol

D- Chloralhydrate

before the introduction of the BZD, a no. of differentDrugs & chemical with different pharmacological doses were used in the treatment of anxiety & insomnia. However, these drugs are more toxic & produce

more serious side effects than the BZD.