Drugs affecting mood and behaviour
Behaviour and emotions are higher functional properties of the brain that depend on the network of neurons and chemical neurotransmitters that exist throughout the body; however, the means by which neurons achieve changes in behaviour and in mood remains unknown. Nevertheless, certain neurotransmitters, such as the monoamines, norepinephrine, dopamine, epinephrine, serotonin, and acetylcholine, appear to be closely linked to these aspects of brain function. Drugs that influence the operation of these neurotransmitter systems can profoundly influence and alter the behaviour of patients with psychiatric problems.
Drugs that affect mood and behaviour can be classified as follows: antianxiety agents, antidepressants, antipsychotics, antimanics, stimulants, antiappetitives, and antiemetics. Such drugs should be reserved for severe disruptions of normal emotional well-being and should not be used to relieve the boredom, tension, or sadness that may be properly regarded as a normal part of life.
Anxiety is a state of pervasive apprehension that may be triggered by specific environmental personal factors. Anxiety states are generally combined with emotions such as fear, anger, or depression. A person suffering from anxiety may complain of physical symptoms such as palpitations, nausea, dizziness, headaches, and chest pains, as well as sleeplessness and fatigue. When such apprehension is severe and incapacitating, the person is said to suffer from anxiety neurosis, which may require treatment by psychotherapy. Many of the drugs used in the treatment of anxiety are for the most part safe and well tolerated and physicians often prescribe them either as an alternative to psychotherapy in severe cases, or as an aid to coping with different situations in mild cases.
After World War II Swiss pharmacologists discovered muscle relaxant properties in a compound under investigation used as an antibiotic. Modification of that compound led to the tranquilizing drug meprobamate. Another discovery showed that the benzodiazepines, which are complex ringed compounds, had even greater relaxing properties. Hundreds of analogues of the basic benzodiazepine ring were subsequently synthesized. The most widely prescribed compounds, chlordiazepoxide and diazepam, are now giving way to shorter acting compounds that are less likely to produce sedation. Different formulations of the basic benzodiazepine structure in higher dosages are used as muscle relaxants, antiepileptics, and hypnotics.
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The brain exhibits highly specific, high-affinity binding sites that can selectively recognize, or bind, the benzodiazepine compounds. The cellular and subcellular locations of these sites are near ion channels in the membrane that can admit chloride ions into the cell and also near sites where a neurotransmitter, gamma-aminobutyric acid (GABA), acts. Benzodiazepine agonists in general enhance the effects of GABA. In 1985 scientists in the United States showed that brain extracts contain an endogenous inhibitor of benzodiazepine binding. Assessment of its behavioral effects on the brain suggests that this natural compound may cause rather than suppress anxiety and decrease rather than increase GABA transmission.
Acute treatment with benzodiazepines generally begins with doses taken before bedtime to facilitate sleep. Because the need for the drugs depends on the patient's response to psychotherapy and his ability to reshape the events that lead to the anxiety, more or less tolerance may develop to the sedation. There are side effects with the use of benzodiazepines. Because of the alterations in the effectiveness of inhibitory transmitter actions of GABA, which are profound in the cerebellum and cerebral cortex, the patient may also exhibit confusion and loss of motor coordination. Other drugs, especially alcohol, taken with benzodiazepines can interfere with coordination, and use of these drugs during pregnancy may increase chances of fetal malformations.
Sedative-hypnotic drugs
Drugs that reduce tension and calm anxiety at low doses and that produce drowsiness and facilitate the onset of sleep at higher doses are called sedative-hypnotics. Because this state of sleep is one from which a patient can normally be aroused, its production was once attributed to "hypnotic" actions, but the sleep that is induced is actually quite natural. Still higher doses of some sedative-hypnotics can produce deep unconsciousness sufficient to make them useful as general anesthetics.
The dose levels at which calm, sleep, or anesthesia are induced depend on the drug classes and their mechanisms of action. Since similar effects can be obtained with other drugs, such as analgesic opiates or antianxiety beazodiazepines, the principal characteristic of primary sedative-hypnotics is their selective ability to induce these actions without affecting mood or sensitivity to pain.
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Alcoholic beverages and alcoholic extracts of opium were traditionally used as sedative-hypnotics, but the first substance introduced specifically as a sedative and as a hypnotic was a liquid solution of bromide salts. In 1869 chloral hydrate became the first synthetic organic molecule to be employed specifically for its sedative-hypnotic effect, and it was followed by several others, notably paraldehyde. (Chloral hydrate was used notoriously as "knock-out" drops.) Barbiturates, with their more complex organic ring structure, were introduced in the early 1900s, and hundreds of barbiturate analogues were then synthesized with varying potencies and durations of action. Potent analogues of barbiturates have been used to induce surgical anesthesia and to reduce voluntary inhibition during psychiatric interviews (for which they have sometimes been dubbed "truth serums"). Most of the barbiturates were discontinued after the development in the 1950s of the benzodiazepines, many of which exhibit the ideal properties of a short-acting, intense facilitator of natural sleep, with a reduced risk of adverse effects.
The means by which alcohol depresses brain function and produces sleep is not clear, however, it is certain that intoxicating doses of alcohol greatly incapacitate the processing of information, reduce reaction times, and depress skilled locomotor behaviours. No single neurotransmitter system has been definitively shown to be the locus of these behavioral effects, and multiple mechanisms may be involved. Barbiturates and benzodiazepines have similar but not identical actions at the behavioral and cellular level to those of alcohol. The benzodiazepines act on the inhibitory sites at which gamma-aminobutyric acid (GABA) is the neurotransmitter.
In certain persons low doses of alcohol, barbiturates, and some benzodiazepines produce transiently enhanced mood or euphoria, along with antianxiety effects. These behavioral effects can lead to abuse of these substances and to dependence upon them with prolonged use. High doses can depress critical centres in me brain stem for the regulation of cardiovascular and respiratory function.
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When sedatives are taken frequently as sleeping tablets, tolerance and a reduction in effectiveness occurs. Despite popular beliefs to the contrary, alcoholic beverages in particular are only of modest benefit to induce sleep. On frequent exposure to alcohol the nervous system adapts to the drug, and this results in early morning awakening. Barbiturates can be selected to provide both early onset of sleep and a prolongation of sleep. Analysis of electroencephalographic patterns during barbiturate-induced sleep, however, shows that there is more disruption of sleep. There have been reports that some benzodiazepines used as sleep inducers produce less disruption of the sleep phases, a property that makes them especially useful for persons with sleep disturbances.
Antidepressants
Severe emotional disorders, generally termed the affective psychoses, are those in which the patient is severely disabled because of long-lasting depression accompanied by weight loss, sleeplessness, and often by contemplation of suicide; in such cases a family history of similar depression is often found. This severe form of depression accounts for a large number of admissions to psychiatric hospitals each year. Chemotherapy and electroshock therapy have significantly improved and subsequently stabilized mood in affected patients.
In 1957 imipramine emerged as the first therapeutically useful antidepressant. An accidental discovery led to the finding that the drug iproniazid caused some patients to become extremely euphoric and hyperactive by inhibiting monoamine oxidase, a liver and brain enzyme that normally breaks down norepinephrine and other monoamines. Drugs that were better at blocking the activity of this enzyme were even more effective in evoking euphoria. Shortly thereafter, the monoamine oxidase inhibitors, as they were later called, were introduced for the treatment of depression.
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The most useful of the imipramine-like compounds all share the basic three-carbon ring structures of the early antipsychotic antihistaminic drugs, and for this reason they have been named tricyclic antidepressants. Clinically useful tricyclic drugs almost all inhibit the active re-uptake of the monoamines norepinephrine, serotonin, and sometimes dopamine into the presynaptic neuron. Inhibiting the active re-uptake of the monoamines allows them to remain in contact longer with their postsynaptic receptors. This mechanism seems to support the hypothesis that depression is due to altered monoamine transmission because, by allowing the accumulation of the monoamine neurotransmitters, me antidepressant corrects a deficiency in the monoamine transmitter pathway. The activity of monoamine oxidase inhibitors also supports this concept since their ability to relieve depression is based on their actions to inhibit the enzyme that breaks down the monoamines. Ten to 14 days are typically required to produce significant improvement in a depressed patient, even though these drugs almost completely block monoamine re-uptake or the catabolic actions of monoamine oxidase enzyme within hours after treatment begins. The reason for this delay is not known.
Patients with affective psychosis have unpredictable spontaneous remissions, which makes it impossible to conclude firmly that the antidepressant drug was responsible for the recovery. Monoamine oxidase inhibitors are known to be more effective than placebos but less effective in general than the tricyclic compounds. Important complications of these drugs are the increased sensitivity of the sympathetic nervous system and cardiac irregularities.
Local anesthetics
Local anesthetics produce a loss of sensation in a specific area as a result of their administration into a restricted region, usually by injection. Thus, local anesthetics are useful in minor surgical procedures, such as the extraction of teeth. The first known and generally used local anesthetic was cocaine, an alkaloid exacted from coca leaves obtained from various species of Erythroxylon. In the 1880s cocaine was first introduced to the field of ophthalmology for anesthetizing the cornea; later it was used in dental procedures.
The feeling of pain depends upon the transmission of information from a traumatized region to higher centres in the brain. The information is passed along fine nerve (sensory) fibres from the peripheral areas of the body to the spinal cord and then to the brain. If these pain fibres are sectioned, pain sensations from their origins in the periphery are lost. Local anesthetics cause a temporary blocking of conduction along these nerve fibres, producing a temporary loss of pain sensation.
Local anesthetics can block conduction of nerve impulses along all types of nerve fibres, including motor nerve fibres that carry impulses from the brain to the periphery. It is a common experience with normal dosages of an anesthetic; however, that while pain sensation may be lost, motor function is not impaired. For example, use of a local anesthetic in a dental procedure does not prevent movement of the jaw. The selective ability of local anesthetics to block conduction depends on the diameter of the nerve fibres and the length of the fibre that must be affected to block conduction. In general, thinner fibres are blocked first, and conduction can be blocked when only a short length of fibre is inactivated. Fortunately, the fibres conveying the sensation of dull aching pain are among the thinnest, and the most susceptible to local anesthetics. If large amounts of local anesthetic are used, pain is the first sensation to disappear, followed by sensations of cold, warmth, touch, and deep pressure.
There are many synthetic local anesthetics available, such as procaine, lidocaine, and tetracaine. It is the convention to end the names of local anesthetics with "-caine," after cocaine, which was the first local anesthetic known. In general they are secondary or tertiary amines linked to aromatic groups by an ester or amide linkage. Thus one end of the molecule is hydrophilic ("water loving") while the other end is hydrophobic ("water hating"). The hydrophobic nature of the molecules makes it possible for them to penetrate the fatty membrane of the nerve fibres and exert their effects from the inside. When an impulse passes along a nerve, there are transient changes in the properties of the membrane that allow small electrical currents to flow. These currents are carried by ions, especially sodium ions. The influx of these sodium ions through small channels that open briefly in the surface of the nerve membrane during excitation transports the impulse. Local anesthetics block these channels from the inside, preventing the movement of the sodium ions and small electrical currents. The action of a local anesthetic is terminated as the agent is dispersed, metabolized, and excreted by the body. Its dispersal from the injection site depends, in part, on the blood flow through the region. Cocaine, for example, causes blood vessels to constrict, reducing the dispersal rate; other local anesthetics do not have this effect
Local anesthetics are used to induce limited areas of anesthesia. The limited area is achieved largely by the site and method of administration and partly by the physiochemical properties of the drug molecules. The drug may be injected subcutaneously around sensory nerve endings, enabling minor operations such as tooth extraction to be performed. This is called infiltration anesthesia. Some local anesthetics are applied directly to mucous membranes, such as those of the conjunctiva of the eye or those of the nose, throat, larynx, or urethra. This is called surface or topical anesthesia.A familiar example of topical anesthesia is the use of certain local anesthetics in throat lozenges to relieve the pain of a sore throat. Local anesthetics may be injected near a main nerve trunk in a limb to produce what is called conduction or regional nerve block anesthesia. In this situation, conduction in both motor and sensory fibres is blocked, enabling operations to be carried out on a limb while the patient remains conscious.
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