Norepinephrine

• See also: Norepinephrine (medication) A large number of important drugs exert their effects by interacting with norepinephrine systems in the brain or body. Their uses include treatment of cardiovascular problems, shock, and a variety of psychiatric conditions. These drugs are divided into: sympathomimetic drugs which mimic or enhance at least some of the effects of norepinephrine released by the sympathetic nervous system; sympatholytic drugs, in contrast, block at least some of the effects. Both of these are large groups with diverse uses, depending on exactly which effects are enhanced or blocked.

Norepinephrine itself is classified as a sympathomimetic drug: its effects when given by intravenous injection of increasing heart rate and force and constricting blood vessels make it very useful for treating medical emergencies that involve critically low blood pressure. Surviving Sepsis Campaign recommended norepinephrine as first line agent in treating septic shock which is unresponsive to fluid resuscitation, supplemented by vasopressin and epinephrine. Dopamine usage is restricted only to highly selected patients.

Antagonists Beta blockers

• Main article: Beta blocker These are sympatholytic drugs that block the effects of beta adrenergic receptors while having little or no effect on alpha receptors. They are sometimes used to treat high blood pressure, atrial fibrillation, and congestive heart failure, but recent reviews have concluded that other types of drugs are usually superior for those purposes. Beta blockers may be a viable choice for other cardiovascular conditions, though, including angina and Marfan syndrome. They are also widely used to treat glaucoma, most commonly in the form of eyedrops. Because of their effects in reducing anxiety symptoms and tremor, they have sometimes been used by entertainers, public speakers, and athletes to reduce performance anxiety, although they are not medically approved for that purpose and are banned by the International Olympic Committee.

However, the usefulness of beta blockers is limited by a range of serious side effects, including slowing of heart rate, a drop in blood pressure, asthma, and reactive hypoglycemia. The negative effects can be particularly severe in people with diabetes.

Alpha blockers

• Main article: Alpha blocker These are sympatholytic drugs that block the effects of adrenergic alpha receptors while having little or no effect on beta receptors. Drugs belonging to this group can have very different effects, however, depending on whether they primarily block alpha-1 receptors, alpha-2 receptors, or both. Alpha-2 receptors, as described elsewhere in this article, are frequently located on norepinephrine-releasing neurons themselves and have inhibitory effects on them; consequently, blockage of alpha-2 receptors usually results in an increase in norepinephrine release. Alpha-1 receptors are usually located on target cells and have excitatory effects on them; consequently, blockage of alpha-1 receptors usually results in blocking some of the effects of norepinephrine. Drugs such as phentolamine that act on both types of receptors can produce a complex combination of both effects. In most cases when the term "alpha blocker" is used without qualification, it refers to a selective alpha-1 antagonist.

Selective alpha-1 blockers have a variety of uses. Since one of their effects is to inhibit the contraction of the smooth muscle in the prostate, they are often used to treat symptoms of benign prostatic hyperplasia. Alpha-blockers also likely help people pass their kidney stones. Their effects on the central nervous system make them useful for treating generalized anxiety disorder, panic disorder, and posttraumatic stress disorder. They may, however, have significant side effects, including a drop in blood pressure.

Some antidepressants function partly as selective alpha-2 blockers, but the best-known drug in that class is yohimbine, which is extracted from the bark of the African yohimbe tree. Yohimbine acts as a male potency enhancer, but its usefulness for that purpose is limited by serious side-effects including anxiety and insomnia. Overdoses can cause a dangerous increase in blood pressure. Yohimbine is banned in many countries, but in the United States, because it is extracted from a plant rather than chemically synthesized, it is sold over the counter as a nutritional supplement.

Alpha-2 agonists These are sympathomimetic drugs that activate alpha-2 receptors or enhance their effects. Because alpha-2 receptors are inhibitory and many are located presynaptically on norepinephrine-releasing cells, the net effect of these drugs is usually to reduce the amount of norepinephrine released. Drugs in this group that are capable of entering the brain often have strong sedating effects, due to their inhibitory effects on the locus coeruleus. Clonidine and guanfacine, for example, are used for the treatment of anxiety disorders and insomnia, and also as a sedative premedication for patients about to undergo surgery. Xylazine, another drug in this group, is also a powerful sedative and is often used in combination with ketamine as a general anaesthetic for veterinary surgery—in the United States it has not been approved for use in humans.

Stimulants and antidepressants

• See also: Stimulant §Mechanisms of action, and Antidepressant §Pharmacology These are drugs whose primary effects are thought to be mediated by different neurotransmitter systems (dopamine for stimulants, serotonin for antidepressants), but many also increase levels of norepinephrine in the brain. Amphetamine, for example, is a stimulant that increases release of norepinephrine as well as dopamine. Monoamine oxidase A inhibitors (MAO-A) are antidepressants that inhibit the metabolic degradation of norepinephrine as well as serotonin and dopamine. In some cases it is difficult to distinguish the norepinephrine-mediated effects from the effects related to other neurotransmitters.

Norepinephrine's history is intertwined with the discovery of the sympathetic nervous system. In 1946, Ulf von Euler at the Karolinska Institute in Stockholm identified norepinephrine as the primary neurotransmitter of the sympathetic nervous system, for which he shared the Nobel Prize in Physiology or Medicine in 1970 with Julius Axelrod and Bernard Katz.

Julius Axelrod's discovery of catecholamine reuptake in the 1960s was foundational for understanding how norepinephrine signaling is terminated and led directly to the development of reuptake inhibitor antidepressants. The first antidepressants discovered, the tricyclics (imipramine, 1957) and MAOIs, were found to work by increasing norepinephrine and serotonin availability.

The role of the locus coeruleus as the primary source of brain norepinephrine was established in the 1960s-1970s by Swedish researchers using the Falck-Hillarp fluorescence method. This small brainstem nucleus, containing only about 50,000 neurons in humans, sends projections throughout the entire brain and is the master regulator of arousal and attention.