CLINICAL PHARMACOLOGY OF DRUGS AFFECTING THE NERVOUS SYSTEM

Central Nervous System Stimulants Stimulants are drugs that exert their action through excitation of the central nervous system. Psychic stimulants include caffeine, cocaine, and various amphetamines.

CNS Stimulants (cont’d) Amphetamine is a noncatecholaminergic sympathetic amine that shows neurologic and clinical effects quite similar to those of cocaine. AMPHETAMINE Levoamphetamine, dextroamphetamine, and methamphetamine (Methedrine)

CNS Stimulants (cont’d) AMPHETAMINE

Clinical Therapeutics of CNS Stimulants

Depression The symptoms of depression are intense feelings of sadness, hopelessness, and despair, as well as the inability to experience pleasure in usual activities, changes in sleep patterns and appetite, loss of energy, and suicidal thoughts.

ANTIDEPRESSANTS

Tricyclic antidepressants - Inhibitors of the reuptake of noradrenaline (norepinephrine) and serotonin (5-HT) in central monoaminergic neurons 1. Sedative Amitriptyline Clomipramine Dosulepin (dothiepin) Doxepin* Maprotiline Mianserin* Trazodone* Trimipramine

Tricyclic antidepressants (TCAs ) 2. Less sedative Amoxapine Imipramine Lofepramine* Nortriptyline *

Selective serotonin reuptake inhibitors (SSRIs) Inhibitors of the reuptake of serotonin (5- HT) in central monoaminergic neurons Fluoxetine Paroxetine Fluvoxamine Sertraline Citalopram

Monoamine oxidase inhibitors (MAOIs) Inhibitors of the enzyme monoamine oxidase –Selegiline

Tricyclic antidepressants. Adverse effects

Monoamine oxidase inhibitors

Monoamine oxidase inhibitors Adverse effects from these drugs are very common The tyramine reaction is characterized by severe hypertension, headache, palpitation, sweating, nausea, and vomiting. It can be fatal. It occurs as a result of ingestion of tyramine-rich foods or co- administration of other drugs that potentiate aminergic neurotransmission. This reaction makes these drugs potentially hazardous and limits their clinical use.

Drugs and foods that can precipitate the tyramine reaction in patients taking MAOIs (not selegiline or moclobemide) Tyramine-rich foods Cheese (especially cheddar) –Not cottage or cream cheeses Meat and yeast extracts Some red wines Hung game and poultry Pickled herring Broad beans Alcoholic and dealcoholized beverages

Psychoses and bipolar disorder Antipsychotic/neuroleptic drugs Dopamine receptor antagonists Phenothiazines –Chlorpromazine –Prochlorperazine –Thioridizine Thioxanthenes –Flupenthixol –Clopentixol Butyrophenones –Haloperidol Atypical antipsychoticdrugs –Risperidone –Clozapine –Olanzapine –Quetiapine –Sertindole

Antipsychotic/neuroleptic drugs

Tranquilizers phenothiazines, indoles, thioxanthenes, butyrophenones, piperazine compounds, and piperidine compounds. Benzodiazepines, known by trade names such as Valium, Xanax, Serax, Ativan, Klonopin, Librium and Tranxene. There are also combination drugs such as Librax.

SEDATIVE - HYPNOTIC AGENTS Drug Classes of Sedative-Hypnotics Barbiturates Benzodiazepines Alcohols/Imidazopyridine

SEDATIVE - HYPNOTIC AGENTS

3.CNS effects: Dose-dependent progression: (lower margin of safety) Sedation → ‘ Hypnosis ’ → Anesthesia → Coma → Death Anticonvulsant/antiepileptic effect

Benzodiazepines (Hypnotics and anxiolytics ) Long-acting Diazepam 5 mg Lorazepam 0.5 mg Nitrazepam 5 mg Chlordiazepoxide 15 mg Short-acting Oxazepam 15 mg Temazepam 10 mg Lormetazepam mg Loprazolam mg Used for epilepsy Clobazam Clonazepam

INDICATIONS Treatment of anxiety, and premedication before operations and procedures. Short-term use for night sedation. Sedation for procedures. Treatment of seizures. Skeletal muscle relaxant to relieve muscle spasm. Adjunct to the treatment of alcohol withdrawal.

Effects and uses: - drugs of choice for sedation and ‘ hypnosis ’ (higher margin of safety) flurazepam: long-acting pro-drug temazepam: slowly absorbed, intermediate acting drug with no active metabolites; most highly prescribed hypnotic triazolam: rapid but short-acting drug diazepam (Valium ® ): long-acting drug; may be useful as adjunct in animal surgery -at sedative doses may cause euphoria and ‘ disinhibition ’ -anticonvulsant (primary drug for initial treatment of status epilepticus) -anxiolytic -muscle relaxation (used in spasticity; largely via effect in spinal cord) -ethanol withdrawal

Adverse reactions: - ‘ hangover ’ (esp. with benzodiazepines with long half-lives: diazepam) -early morning awakening for benzodiazepines with short half-lives: triazolam -impaired motor and cognitive skills -anterograde amnesia

Alcohols/Imidazopyridine: -Chloral HydrateLong (6-10h) [pro-drug] short-acting Zaleplon Zolpidem Zopiclone Short-term treatment of insomnia.

Zaleplon, Zolpidem, Zopiclone Chronic insomnia is rarely helped by treatment with hypnotics. They are more effective for: –Transient insomnia in those who normally sleep well but are subject to a disrupting event (e.g. an operation or jet lag). Give 1 or 2 doses. –Short-term insomnia associated with a specific event (e.g. illness or bereavement). Keep treatment to less than 1 week. These drugs are not licensed for long-term treatment.