CLINICAL PHARMACOLOGY OF DRUGS AFFECTING THE NERVOUS SYSTEM

BASIC QUESTIONS Clinical pharmacology of CNS stimulants Clinical pharmacology of antidepressants Clinical pharmacology of antipsychotic/neuroleptic drugs Clinical pharmacology of tranquilizers Clinical pharmacology of sedative - hypnotic agents

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. These drugs are used to enhance mental alertness and reduce drowsiness and fatigue. Stimulants increase alertness, attention, and energy, which are accompanied by increases in blood pressure, heart rate, and respiration.

CNS Stimulants (cont’d) The methylxanthines include theophylline which is found in tea; theobromine found in cocoa; and caffeine. Caffeine, the most widely consumed stimulant in the world, is found in highest concentration in coffee, but it is also present in tea, cola drinks, chocolate candy, and cocoa. Nicotine is the active ingredient in tobacco. Although this drug is not currently used therapeutically nicotine remains important, because it is second only to caffeine as the most widely used CNS stimulant and second only to alcohol as the most abused drug.

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

CNS Stimulants (cont’d) AMPHETAMINE These agents produce a feeling of well being and euphoria. Cocaine and amphetamine have a significant abuse potential because of these mood enhancing effects. Tachyphylaxis or tolerance to the stimulating actions of these agents can develop. These agents produce an increase in systemic arterial blood pressure. Heart rate can either decrease or increase depending on the levels of the drug. Drug toxicity effects multiple organ systems and can result in arrhythmias, hypertension, psychosis and convulsions. The local anesthetic activity of cocaine can also contribute to rhythm disturbances.

Clinical Therapeutics of CNS Stimulants 1) Because of its local anesthetic activity, cocaine has some limited uses as a oral, nasal and ophthalmic local anesthetic. 2) Appetite suppression - amphetamine and analogs 3) Narcolepsy - methylphenidate, amphetamine analogs 4) Attention deficient disorder with hyperactivity (ADHD) - methylphenidate, amphetamine and analogs

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 Selective serotonin reuptake inhibitors Serotonin/norepinephrine re-uptake inhibitors Atypical antidepressants Tricyclic antidepressants Monoamine oxidase inhibitors Drugs used to treat mania and bipolar disorder

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 *Drugs with fewer anticholinergic effects (dry mouth, blurred vision, constipation, difficulty with micturition)

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 Non-selective MAOIs Phenelzine, isocarboxazid, tranylcypromine, iproniazid Inhibitor of MAOA Moclobemide (reversible) Inhibitor of MAOB Selegiline Note that linezolid(an antibiotic) is also a non-selective, reversible MAOI.

Tricyclic antidepressants. Adverse effects Anticholinergic adverse effects are common. Tolerance to these effects develops; it is worth encouraging patients to persevere with treatment if possible. Tricyclic antidepressants are associated with cardiac toxicity, especially in overdose. This is characterized by tachycardia, ventricular arrhythmias, and heart block; prolongation of the QT interval correlates well with the severity of toxicity. Tricyclic antidepressants lower the seizure threshold. Hypotension occurs in up to 20% of patients treated with tricyclic antidepressants. Tricyclic antidepressants can cause the syndrome of inappropriate ADH secretion, resulting in hyponatraemia with confusion. The elderly are especially likely to develop this adverse effect.

Monoamine oxidase inhibitors Second-line treatment of depression (non-selective inhibitors and moclobemide). Especially if there are phobic or other atypical symptoms (e.g. hysteria). Treatment of Parkinson's disease (selegiline).

Monoamine oxidase inhibitors Avoid these drugs in patients with cerebrovascular disease; they are more susceptible to adverse effects. Avoid them in patients with established cardiac disease, hypertension, or arrhythmias. They can cause CNS stimulation; avoid them in patients with a history of psychotic illness. The non-selective MAOIs can cause idiosyncratic liver damage; avoid them in patients with hepatic insufficiency. There is little evidence of harm from these drugs during pregnancy, but use them only when the likely benefits are compelling.

Monoamine oxidase inhibitors Adverse effects from these drugs are very common CNS effects include dizziness, over-stimulation, insomnia, agitation, and anxiety. They may also have autonomic effects: dry mouth, postural hypotension, and blurred vision. Gastrointestinal adverse effects include nausea and vomiting. They can cause hyponatraemia, resulting in confusion and seizures. They are most commonly remembered because they can cause the tyramine (cheese) reaction. Note that selegiline does not cause this adverse effect, and that it is less common with moclobemide. 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) Drugs Other amine drugs Ephedrine, pseudoephedrine (note that these are common components of many decongestant cough and cold cures) Dopamine receptor agonists Levodopa, pergolide, ropinirole, cabergoline, lisuride, apomorphine Direct sympathomimetics Beware lidocaine with adrenaline Indoramin

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 (1) Dopamine receptor antagonists Phenothiazines Chlorpromazine Prochlorperazine Thioridizine Thioxanthenes Flupenthixol Clopentixol Butyrophenones Haloperidol Atypical antipsychoticdrugs Risperidone Clozapine Olanzapine Quetiapine Sertindole

Antipsychotic/neuroleptic drugs (2) Sedative and tranquillizing effects. Treatment of severe anxiety, acute mania, or psychosis. Sedation in acute confusional states. Premedication before general anaesthesia. As an adjunct to analgesia in palliative care. Prochlorperazine for antiemetic actions. Treatment of chronic schizophrenia. Occasionally used for treatment of intractable hiccup.

Antipsychotic/neuroleptic drugs (4) Acute treatment The doses of these drugs are lower when they are given by intramuscular injection than by mouth. This is particularly true if patients are very physically active (agitated), as this will increase the speed of absorption from the muscle. Review the dose daily to avoid over-sedation. Antipsychotic drugs are more effective for the acute psychotic symptoms of schizophrenia, rather than chronic withdrawal symptoms. They are a specific treatment for schizophrenia, but not for any other diagnoses. They can provide a window of time in which to assess and investigate an acutely unwell patient. Always consider the underlying cause for the patient's symptoms and treat that, if it is possible. Do not withdraw antipsychotic drugs suddenly.

Antipsychotic/neuroleptic drugs (5) Antipsychotic drugs can cause the neuroleptic malignant syndrome. This is characterized by fever, anorexia, rigidity, lowered level of consciousness, and autonomic disturbances (tachycardia, hyperthermia), and can be fatal. Stop the drug immediately. There are no established effective treatments, but cooling, bromocriptine (a dopamine receptor agonist), and dantrolene can be helpful. The syndrome usually lasts 5-7 days.

Antipsychotic/neuroleptic drugs (7) The antidopaminergic actions can also cause prolactin release, leading to galactorrhoea, gynaecomastia, and menstrual disturbances. The anticholinergic actions can cause dry mouth, blurred vision, and urinary retention. Antipsychotic drugs can cause dizziness, but are also used to treat acute vertigo (see prochlorperazine, p. 62). Hypersensitivity phenomena, such as photosensitive rash, are common. These drugs can cause cardiac arrhythmias, usually by prolonging the QT interval. The risk is greatest with droperidol, haloperidol, thioridizine, and sertindole. Antipsychotic drugs can cause hypotension, especially in hypovolaemic patients. Take care postoperatively. Antipsychotic drugs can lower body temperature.

Tranquilizers Tranquilizers are divided into a Major Tranquilizer and Minor Tranquilizer group. Major Tranquilizers include phenothiazines, indoles, thioxanthenes, butyrophenones, piperazine compounds, and piperidine compounds. Trade names include drugs such as Thorazine, Haldol, Clozaril and Risperdal. These drugs are referred to as Neuroleptics and are most commonly prescribed as anti-psychotics. This type of tranquilizer is not widely abused. Minor Tranquiliers are the more common of the tranquilizers. These include the Benzodiazepines, known by trade names such as Valium, Xanax, Serax, Ativan, Klonopin, Librium and Tranxene. There are also combination drugs such as Librax. These drugs are very commonly prescribed as anti-anxiety drugs, or anxiolytics. They are often referred to as Sedative/Hypnotics. They are central nervous system depressants with specific sites of action. Slang references to these drugs include Libs, Tranks, Benzos, and Vees. The primary route of administration for these medications is oral, swallowed as a tablet, capsule, or liquid. They are also available in solution form for intravenous use.

SEDATIVE - HYPNOTIC AGENTS Drug Classes of Sedative-Hypnotics Barbiturates Benzodiazepines Alcohols/Imidazopyridine Barbiturates: Duration of Action Onset Phenobarbital Long (6-12 h) 20 min Pentobarbital Intermediate (4-6 h) 3 min Secobarbital Short-Intermediate (3-6 h) 2 min Thiopental/ Short (15- 30 min) few seconds Methohexital [All are derivatives of barbituric acid]

SEDATIVE - HYPNOTIC AGENTS 1. Sites of Action: Barbiturates act at multiple levels of the CNS. Sedative-Hypnotic effect involves, in particular, the reticular activating system. 2. Mechanism of Action: facilitate the action of GABA at GABAA receptors by increasing the duration of channel openings (bind at a distinct site from that bound by benzodiazepines) reduce glutamate-induced depolarization via inhibitory action on AMPA-type glutamate receptors at high doses, reduce the responsiveness of voltage-dependent Na+ channels and directly active GABAA receptors

SEDATIVE - HYPNOTIC AGENTS 3. CNS effects: Dose-dependent progression: (lower margin of safety) Sedation → ‘Hypnosis’ → Anesthesia → Coma → Death Anticonvulsant/antiepileptic effect - all barbiturates stop convulsions in progress if given IV at high enough dosage - some can prevent seizures (eg. phenobarbital), but are not drugs of first choice owing to sedative effect (except for children); used to maintain control of status epilepticus

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 0.5-1.0 mg Loprazolam 0.5-1.0 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 - chronic use/dependence: more intense withdrawal symptoms with benzodiazepines having short half-lives, ‘rebound’ insomnia (and/or anxiety), restlessness and even seizures (severity and frequency of dependence less than that found for barbiturates)

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

1. Chloral hydrate rapidly metabolized in liver to triethanolamine - pharmacologically active (also metabolized to trichloroacetic acid, which is toxic and may accumulate); mechanism of action is not known 2. Zolpidem: non-benzodiazepine that acts via subtype of GABAA receptor - an effective, short-acting hypnotic agent (most highly prescribed hypnotic) - much lower risk of tolerance and dependency; but some mild cognitive impairment during onset - little anticonvulsant or muscle relaxant effects 3. Zaleplon: an alternative non-benzodiazepine that also acts via the GABAA receptor - similar to Zolpidem, but without effects on cognitive function

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. Take a single dose at night if unable to sleep.