Pharmacology Notes

This chapter presents drugs that are used to treat various sleep and psychogenic disorders, such as anxiety, depression, and psychotic disorders.

Sedatives reduce anxiety, tension, or excitement. Some degree of drowsiness commonly accompanies sedative use.

Benzodiazepines are used in various clinical situations and exert either a primary or a secondary sedative or hypnotic effect. Benzodiazepines used primarily for their sedative or hypnotic effects include:

Benzodiazepines used primarily for the treatment of anxiety include:

The rate of absorption determines how quickly the drug will work; flurazepam and triazolam have the fastest onset.

The duration of effect is determined by the extent of distribution. Triazolam binds quickly to fat and is widely distributed; therefore, it has a short duration of action.

At low dosages, benzodiazepines decrease anxiety by acting on the limbic system and other areas of the brain that help regulate emotional activity. The drugs can usually calm or sedate the patient without causing drowsiness.

At higher dosages, benzodiazepines induce sleep, probably because they depress the RAS of the brain.

Benzodiazepines increase total sleep time and reduce the number of awakenings. In most cases, benzodiazepines don’t decrease the time spent in rapid-eye-movement (REM) sleep, the state of sleep in which brain activity resembles the activity it shows when awake; the body’s muscles relax, and the eyes move rapidly. Because benzodiazepines don’t decrease the duration of REM sleep, they have a significant advantage over barbiturates.

 

During each sleep cycle the sleeping person progresses from stage 1, which is drowsiness, to stages 3 and 4, which are deep-sleep stages. Benzodiazepines reduce the amount of time spent in stages 3 and 4. The decrease in stage 4 sleep is accompanied by a reduction in nightmares.

When benzodiazepines are taken with other CNS depressants (including alcohol and anticonvulsants), the result is enhanced sedative and CNS depressant effects, including reduced level of consciousness, reduced muscle coordination, respiratory depression, and death.

Hormonal contraceptives may reduce the metabolism of fluraze pam hydrochloride, increasing the risk of toxicity.

Triazolam may be affected by inhibitors of the CYP3A system (such as erythromycin and ketoconazole). 

Low doses of barbiturates depress the sensory and motor cortex in the brain, causing drowsiness. High doses may cause respiratory depression and death because of their ability to depress all levels of the CNS.

These drugs appear to act throughout the CNS; however, the RAS of the brain, which is responsible for wakefulness, is a particularly sensitive site.

Patients develop tolerance to barbiturates more quickly than to benzodiazepines, and physical dependence on barbiturates
may occur even with a small daily dosage. In comparison, benzodiazepines are relatively effective and safe and, for these reasons, have replaced barbiturates as the sedatives and hypnotics of choice.

Chloral hydrate and zaleplon lose their effectiveness by the end of the second week. Zolpidem is usually effective for up to 35 days. Eszopiclone and ramelton are approved for long-term treatment of insomnia.

Chloral hydrate may increase the risk of bleeding in patients taking oral anticoagulants. Use with I.V. furosemide may produce sweating, flushing, variable blood pressure, and uneasiness.

Antidepressant and mood stabilizer drugs are used to treat affective disorders’disturbances in mood, characterized by depression or elation.

SSRIs are absorbed almost completely after oral administration and are highly protein-bound.

SSRIs inhibit the neuronal reuptake of the neurotransmitter serotonin.

SSRIs are used to treat the same major depressive episodes as TCAs and have the same degree of effectiveness. Fluvoxamine, fluoxetine, sertraline, and paroxetine are also used to treat obsessive-compulsive disorder. Fluoxetine has also been approved for the treatment of bulimia. Paroxetine is also indicated for social anxiety disorder.

 

Venlafaxine is an antidepressant drug that’s chemically different from other antidepressants and has unique properties in terms of absorption and mechanism of action. It has been particularly effective in patients with very severe depression.

SSRIs may also be useful in treating panic disorders, eating disorders, personality disorders, impulse control disorders, and anxiety disorders. Several SSRIs are approved for premenstrual (dysphoric) disorder.

The use of SSRIs with MAOIs can cause serious, potentially fatal reactions. Individual SSRIs also have their own particular interactions. 

All of the TCAs are active pharmacologically, and some of their metabolites are also active. They’re absorbed completely when taken orally but undergo first-pass effect.

The extreme fat solubility of these drugs accounts for their wide distribution throughout the body, slow excretion, and long half-lives.

After a neurotransmitter has performed its job, several fates are possible, including rapidly reentering the neuron from which it was released (or reuptake). Preventing reuptake results in increased levels of these neurotransmitters in the synapses, relieving depression.

TCAs are much less effective in patients with hypochondriasis, atypical depression, or depression accompanied by delusions. When given with a mood stabilizer, they may be helpful in treating acute episodes of depression in bipolar I disorder.

TCAs are also used for preventing migraine headaches and in treating phobias (panic disorder with agoraphobia), urinary incontinence, attention deficit disorder, obsessive-compulsive disorder, neuropathic pain (chronic pain that can occur with peripheral neuropathies, herpes zoster infections, traumatic nerve injuries, and some types of cancer or cancer treatments), diabetic neuropathy, and enuresis.

MAOIs are absorbed rapidly and completely from the GI tract and are metabolized in the liver to inactive metabolites. These metabolites are excreted mainly by the GI tract and, to a lesser degree, by the kidneys.

MAOIs appear to work by inhibiting MAO, an enzyme that’s widely distributed throughout the body and that normally metabolizes many neurotransmitters, including norepinephrine, dopamine, and serotonin. This leaves more norepinephrine, dopamine, and serotonin available to the receptors, thereby relieving the symptoms of depression.

The indications for MAOIs are similar to those for other antidepressants. MAOIs are particularly effective for treating panic disorder with agoraphobia, eating disorders, posttraumatic stress disorder, and pain disorders.

MAOIs may be more effective than other antidepressants in the treatment of atypical depression. Atypical depression produces signs opposite to those of typical depression. For example, the patient gains weight, sleeps more, and has a higher susceptibility to rejection.

MAOIs may be used to treat typical depression resistant to other therapies or when other therapies are contraindicated. For example, tranylcypromine is the preferred MAOI for patients with depression who have liver disease. Other uses include treatment for:

Certain foods can interact with MAOIs and produce severe reactions. The most serious reactions involve tyramine-rich foods, such as red wines, aged cheese, and fava beans. Foods with moderate tyramine contents’for example, yogurt and ripe bananas’may be eaten occasionally, but with care.

The paths these antidepressants take through the body may vary:

Much about how these drugs work has yet to be fully understood:

These miscellaneous drugs are all used to treat depression. Trazodone may also be effective in treating aggressive behavior and panic disorder.

All of these antidepressants may have serious, potentially fatal, effects when combined with MAOIs. Each of these drugs also carries its own specific risks when used with other drugs:

When taken orally, lithium is absorbed rapidly and completely and is distributed to body tissues.

It’s theorized that in mania, the patient experiences excessive catecholamine stimulation. In bipolar disorder, the patient is affected by swings between the excessive catecholamine stimulation of mania and the diminished catecholamine stimulation of depression.

Lithium’s exact mechanism of action is unknown. It may regulate catecholamine release in the CNS by:

Researchers are also examining lithium’s effects on electrolyte and ion transport. Lithium may also modify the actions of second messengers such as cyclic adenosine monophosphate.

Other uses of lithium being researched include preventing unipolar depression and migraine headaches and treating depression, alcohol dependence, anorexia nervosa, syndrome of inappropriate antidiuretic hormone, and neutropenia.

Lithium has a narrow therapeutic margin of safety. A blood level that is even slightly higher than the therapeutic level can be dangerous.

A patient on a severe salt-restricted diet is susceptible to lithium toxicity. On the other hand, an increased intake of sodium may reduce the therapeutic effects of lithium.

Drugs used to treat psychoses have several different names, including:

Regardless of what they’re called, all antipsychotic drugs belong to one of two major groups:

Atypical antipsychotics are absorbed after oral administration.

Atypical antipsychotics typically block the dopamine receptors, but to a lesser extent than the typical antipsychotics, resulting in far fewer extrapyramidal adverse effects. Additionally, atypical antipsychotics block serotonin receptor activity.

These combined actions account for their effectiveness against the positive and negative symptoms of schizophrenia with minimal extrapyramidal effects.

Atypical antipsychotics are commonly used to treat behavioral and psychotic symptoms in patients with dementia. Dosages are significantly lower for these patients than for patients with schizophrenia.

Atypical antipsychotics counteract the effects of levodopa and other dopamine agonists. 

Based on their chemical structure, nonphenothiazine antipsychotics can be divided into several drug classes, including:

Although the mechanism of action of phenothiazines isn’t fully understood, researchers believe that these drugs work by blocking postsynaptic dopaminergic receptors in the brain.

The mechanism of action of nonphenothiazines resembles that of phenothiazines.

The antipsychotic effect of phenothiazines is due to receptor blockade in the limbic system. Their antiemetic effect is due to receptor blockade in the chemoreceptor trigger zone located in the brain’s medulla.

Phenothiazines also stimulate the extrapyramidal system (motor pathways that connect the cerebral cortex with the spinal nerve pathways).

Other therapeutic uses have been found for phenothiazines:

As a group, nonphenothiazines are used to treat psychotic disorders. Thiothixene is also used to control acute agitation. Haloperidol and pimozide may also be used to treat Tourette syndrome.

Nonphenothiazines interact with fewer drugs than phenothiazines. Their dopamine-blocking activity can inhibit levodopa and may cause disorientation in patients receiving both medications. Halo-peridol may boost the effects of lithium, producing encephalopathy (brain dysfunction).

Stimulants are well absorbed from the GI tract and are distributed widely in the body. Methylphenidate undergoes significant first pass effect.