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 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

• 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 disorderAntipsychotic/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-drugtemazepam: slowly absorbed, intermediate acting drug with no

active metabolites; most highly prescribed hypnotictriazolam: rapid but short-acting drugdiazepam (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 effects3. 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.