Drugs acting on the CNS

Nervous System CNS PNS Somatic Autonomic Parasympathetic Sympathetic

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

Anxiolytic and Hypnotic Drugs

Definitions Definitions Sedative & Hypnotics Anxiety is an unpleasant state of tension, apprehension, or a fear that seems to arise from an unknown source. 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 H1-antihistamines with sedative activity 4. H1-antihistamines with sedative activity

Benzodiazepines Nomenclature End with suffix azolam or azepam Alprazolam Estazolam Triazolam Lorazepam Diazepam Oxazepam Temazepam Nitrazepam

Classification of benzodiazepines According to duration of action : - Short acting: (3-5 hours). Triazolam - Intermediate: (6-24 hours) (LEOTAN). Lorazepam Estazolam Oxazepam Temazepam Alprazolam Nitrazepam

- Long acting: ( hours) Chlordiazepoxide Diazepam Flurazepam

According to uses Anxiolytics: Lorazepam Chlordiazepoxide Diazepam Clonazepam Hypnotics : short: Triazolam Intermediate: Lorazepam Long: Flurazepam, Preanesthetics Diazepam- Midazolam

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

Benzodiazepines 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 : 1. Reduction of anxiety and aggression ( α Reduction of anxiety and aggression ( α 2 -GABA A receptor in the limbic system). 2. Sedation and induction of sleep (hypnotic action) 3. amnesia 4. Anticonvulsant effect. 5. Muscle relaxant. 6. General Anesthetics often in combination with other agents.

Benzodiazepines CV: 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. 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: Respiratory: BZ are respiratory depressants.

BenzodiazepinesPharmacokinetics 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.

BenzodiazepinesPharmacokinetics Benzodiazepines Pharmacokinetics Half Life Active Half Life of of Drug Metabolite Metabolites Category of Drug Metabolite Metabolites Category Lorazepam(Ativan)12 hoursNoneShort Oxazepam8 hoursShort Temazepam(Normison)8 hours-NoneShort Diazepam(Valium)32 hours Nordiazepam60 hoursLong Chlordiazepoxide(Librium)12 hours Nordiazepam60 hoursLong Nitrazepam(Mogadon)28 hoursLong Halcion(Triaxolam)Short Action Short Flurazepam(Dalmane)1 day Desalkyl- flurazepam 60 hoursLong Bromazepam(Lexotan) Intermediate

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

Benzodiazepinestherapeutic uses Benzodiazepines therapeutic uses 2. Muscular disorders: Diazepam used in muscle spasms & spasticity in degenerative disorders Diazepam used in muscle spasms & spasticity in degenerative disorders 3. Amnesia: short acting used of Benzodiazepines short acting used of Benzodiazepines endoscopy, bronchoscopy & angioplasty. endoscopy, bronchoscopy & angioplasty.

Benzodiazepinestherapeutic uses Benzodiazepines therapeutic uses 4. Seizures: Clonazepam in chronic epilepsy Diazepam is the drug of choice in grand mal and status eplipticus Diazepam & Oxzepam in treatment of alcohol withdrawal.

Benzodiazepinestherapeutic uses Benzodiazepines therapeutic uses 5. Sleep disorders: Reduced REM and Slow-Wave sleep leads to REM rebound when drug is discontinued. Effective drugs 1. Triazolam. 2. Temazepam. 3. Flurazepam 4. Zolpidem. 5. Zaleplon. Nonbenzodiazepens Benzodiazepines

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

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

Benzodiazepines Adverse Eeffects occur at normal therapeutic dose (especially with Elderly.) occur at normal therapeutic dose (especially with Elderly.) 1. Drowsiness; Confusion. 2. Ataxia (in high doses). 3. Impaired Motor Performance. 4. 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 ” Physical Addiction: related to the production of “ withdrawl effects ” Psychological addiction Psychological addiction 1. High dose. 2. Prolong treatment

Symptoms: Withdrawal 1. Confusion. 2. Anxiety. 3. Agitation. 4. Restlessness 5. Insomnia 6. Tension. Note: More sever symptoms in short acting agents (Triazolam). Note: More sever symptoms in short acting agents (Triazolam).

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

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

Ethanol is metabolized primarily in the liver, first to acetaldehyde by alcohol dehydrogenase, and then to acetate by aldehyde dehydrogenase 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, 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. 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. Disulfiram has found some use in the patient seriously desiring to stop alcohol ingestion.