C.N.S

Drugs acting on the CNS

Nervous System
CNS
PNS
Somatic
Autonomic
Parasympathetic
Sympathetic

Central neurotransmitter

Aminoacid : A-Glutamate B- GABA Actylcholine Monoamines A-Dopamine B- Norepinephrine C-Hydroxytryptamine Peptide Nitric Oxide Endocannabinoid

Anxiolytic and

Hypnotic Drugs



Definitions Sedative & Hypnotics
Anxiety is an unpleasant state of tension, apprehension, or a fear that seems to arise from an unknown source. Anxiolytics : Drugs that calm the patient and reduce anxiety without inducing normal sleep. Hypnotics : Drugs that initiate and maintain the normal sleep.


Classification of hypnotic drugs 1. Benzodiazepines ( BDZ ) 2. Barbiturates 3. Miscellaneous ( non BDZ non barbiturate drugs). Zolpidem Zaleplon 4. H1-antihistamines with sedative activity

Benzodiazepines

Benzodiazepines are the most widely used anxiolytic drugs. Benzodiazepines are more effective and safer than barbiturate.

Benzodiazepines Chemistry

consists of a benzene ring coupled to a seven-member heterocyclic structure containing two nitrogens (diazepine) at positions 1 and 4.

Benzodiazepines receptors

There are 3 types of BZ receptors : 1-BZ1 central receptor linked to sleep 2-BZ2 central receptor linked to cognition & motor function 3-periphral BZ receptors (not our field here)

Gamma-aminobutyric acid receptor (GABA)

Benzodiazepines Mechanism of action
The benzodiazepines bind with high affinity to specific benzodiazepine-binding sites ( BZ1 and BZ2 receptors subtypes) of the receptors of Gamma-aminobutyric acid (GABA), which is the major inhibitory neurotransmitter in the mammalian brain.


Mechanism of Action Benzodiazepines combine with BZ receptors  increase GABA action on GABA receptors  chloride channels opening   chloride influx to the cell  cell membrane hyperpolarization  inhibition of propagation of action potential  inhibitory effect on different sites of the brain especially motor cortex & limbic system.

Benzodiazepines action on CNS Pharmacological effects :

Reduction of anxiety and aggression ( α2-GABAA receptor in the limbic system) . Sedation and induction of sleep (hypnotic action)amnesia Anticonvulsant effect . Muscle relaxant .General Anesthetics often in combination with other agents.

Benzodiazepines

CV: In healthy adults , normal doses of BZ cause few changes in cardiac out put & BP , in greater doses it cause decrease BP & decrease cardiac out put . Respiratory: BZ are respiratory depressants.

Benzodiazepines Pharmacokinetics

Benzodiazepines are usually given orally and are well absorbed by this route from the small intestine benzodiazepines also can be given parenterally.(I.V,IM) Diazepam and lorazepam are available for I.v.

Benzodiazepines Pharmacokinetics

most clinically available benzodiazepines are converted in the liver to one or more active metabolites. In several cases the active metabolites have a much longer half-life than the parent.

Benzodiazepines Pharmacokinetics

Benzodiazepines therapeutic uses
Anxiety disorders : Both acute and chronic anxiety Anxiolytic effect is less subjective to tolerance. Diazepam is used for long period.



Benzodiazepines therapeutic uses
Muscular disorders: Diazepam used in muscle spasms & spasticity in degenerative disorders Amnesia: short acting used of Benzodiazepines endoscopy, bronchoscopy & angioplasty.

Benzodiazepines therapeutic uses

Seizures: Clonazepam in chronic epilepsy Diazepam is the drug of choice in grand mal and status eplipticus Diazepam & Oxzepam in treatment of alcohol withdrawal.

Benzodiazepines therapeutic uses

Sleep disorders: Reduced REM and Slow-Wave sleep leads to REM rebound when drug is discontinued.
Effective drugs Triazolam. Temazepam. Flurazepam Zolpidem. Zaleplon.
Nonbenzodiazepens
Benzodiazepines


Flurazepam Long-acting effect. Reduce Sleep-induction time & number of awakenings Little rebound insomnia Day time sedation.

Triazolam.

Short acting Induce sleep in patient with recurrent insomnia Rebound insomnia Better to be used intermittently (because tolerance develops within a few hours )

Benzodiazepines Adverse Eeffects

occur at normal therapeutic dose (especially with Elderly.) Drowsiness; Confusion. Ataxia (in high doses). Impaired Motor Performance. Cognitive impairment. Note: Triazolam, tolerance is frequent, rebound insomnia, day time amnesia & confusion.


5- Interaction with alcohol.6-Dependency: (Compulsion to repeat dose) Physical Addiction: related to the production of “withdrawl effects”Psychological addictionHigh dose.Prolong treatment

Symptoms: Withdrawal

Confusion. Anxiety. Agitation. Restlessness Insomnia Tension. Note: More sever symptoms in short acting agents (Triazolam).

Precautions

Liver diseases Alcohol & CNS depressant
NOTE: Drug-induced CNS depression is additive interaction . Benzodiazepines Barbiturates Opioids Alcohol Some antipsychotics and antidepressants

Antagonists of Benzodiazepines

Benzodiazepine Antagonists: Flumazenil
Act as selective competitive antagonists on GABA receptor. intravenously, flumazenil acts rapidly (produce effects within1-2 min) but has a short half-life (45–80 minute) due to rapid hepatic clearance. Undergoes extensive first pass metabolism

Reversing the central nervous system depressant effects of benzodiazepine overdose & coma of BZ .


Antihistamines Several H1 histamine antagonists (e.g.diphenhydramine, promethazine, and hydroxyzine)


Hydroxyzine 1. is an antihistamine with anti emetic activity 2. Used in patient with anxiety .

Ethanol (ethyl alcohol)

It's a CNS depressant. Producing sedation and hypnosis with increasing dosage. Has antianxiety and sedative effects. It's toxic potential . .

Ethanol is metabolized primarily in the liver, first to acetaldehyde by alcohol dehydrogenase, and then to acetate by aldehyde dehydrogenase Disulfiram blocks the oxidation of acetaldehyde to acetic acid by inhibiting aldehyde dehydrogenase, This results in the accumulation of acetaldehyde in the blood, causing flushing, tachycardia, hyper- ventilation, and nausea.

Disulfiram Mechanism of action

Theraputic uses
Disulfiram has found some use in the patient seriously desiring to stop alcohol ingestion.