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.

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.