Dr Khulood Alsaraf

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 & dont 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

Benzodiazepines
Most of these drugs possess anxiolytic, sedative-hypnotic, or anticonvulsant properties. Thus, the clinical indication for specific benzodiazepines are not absolute.

Anxiolylics

Hypnotics
Flurazepam Temazepam Triazolam Midazolam

Alprazolam Chlordiazepoxide Clonazepam Clorazepate Diazepam Lorazepam

BZD antagonist flumazenil

Mechanism of action

Benzodiazepines

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 2-Reduction of anxiety 3-Anticonvulsant 4-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 disorders 6-to control alcohol & sedative-hypnotic withdrawal syndroms.

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.

Tolerance:

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 of BZD 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 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
-No sedation, or hypnotic activity

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. 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)

Barbiturates classify according to their duration of action into:

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
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)

Actions

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 dependence
Abrupt 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.

Other Hypnotic Agents

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

B-Antihistamins (Diphenhydramine or
promethazine)
C-Ethanol

D- Chloralhydrate
before the introduction of the BZD, a no. of different Drugs & 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.