Adrenergic Receptors

Adrenergic responses are those activated by "adrenaline"-like compounds. Within the body, Epinephrine (the generic name for adrenaline), and Norepinephrine are the primary adrenergic transmitters. Isoproterenol is an example of an extrinsic drug which stimulates some adrenergic responses. When the target responses of adrenergic stimulation are examined in various body systems, they fit into several categories of response, as summarized in the following table:

These diverse responses to adrenergic stimulation results from the activity of two different classes of adrenergic receptor, named Alpha and Beta by Ahlquist in 1948 on the basis of their pharmacology. Each of these classes is further subdivided into subclasses. Their properties are outlined below. Alpha Receptors

Epinephrine (E) and norepinephrine stimulate about equally well, and both are much more effective than isoproterenol (I). E >= NE >> I. Selectively stimulated by Phenylephrine. Selectively blocked by Phentolamine and Phenoxybenzamine. Two subclasses of alpha receptor have since been identified:

Alpha1

Predominant form of alpha receptor in the body. Found primarily in the smooth muscles of arterioles, eye, gut, skin, veins, etc., as well as in some other cell types (like salivary glands). Usually causes contraction of smooth muscle cells.

Alpha2

Found at pre-synaptic terminals of adrenergic nerves. Functions as an autoreceptor. If stimulated, it decreases the subsequent release of transmitter.

Beta Receptors

Isoproterenol stimulates best, epinephrine is also effective, and norepinephrine is often weaker. I > E >= NE. Blocked by propranalol. Several subclasses of beta receptor have been identified on the basis of their detailed pharmacology:

Beta1

Found in heart muscle, and in the kidney. Causes increased heart rate and contractility. Promotes release of renin from the kidney. EPI and NE are about equally effective in their ability to stimulate beta1 receptors.

Beta2 Found in smooth muscle that relaxes upon stimulation, and in metabolic tissues. Causes:

Decrease in gastrointestinal motility. Bronchodilation. Vasodilation in skeletal and cardiac muscle. Glycogenolysis in the liver.

EPI is much more effective than NE. EPI can also stimulate beta2 receptors at lower concentrations than required to stimulate alpha receptors.

Beta-3

Found in adipose tissue (fat cells). Stimulates lipolysis, increasing fatty acids in the blood. EPI and NE are about equally effective in their ability to stimulate beta3 receptors.

Adrenergic Drugs I

Introduction: Adrenergic nerves release norepinephrine as the neurotransmitter for the sympathetic nervous system. The sympathetic system activates and prepares the body for vigorous muscular activity, stress, and emergencies. Adrenergic drugs stimulate the adrenergic nerves directly by mimicking the action of norepinephrine or indirectly by stimulating the release of norepinephrine. Therapeutically, these drugs are used to combat life-threatening disorders, which include acute attacks of bronchial asthma, shock, cardiac arrest, and allergic reactions. In addition these drugs are used in nasal decongestants and appetite suppressants. Adrenergic Nerve Transmissions: Adrenergic nerves release the neurotransmitters: Norepinephrine (noradrenaline, NE), epinephrine, EP, and dopamine DA. The synthesis of the neurotransmitters DA and NE and EP and the hormones NE and EP takes place by a pathway that involves 5 enzymes. Tyrosine is generally considered the starting point to synthesize DOPA (1a), DA (1b), and NE (1c). Norepinephrine is stored at (2). Norepinephrine is released from the nerve ending in response to a nerve impulse or drug (3). NE interacts with alpha and beta receptor sites at (4). Its receptor action is terminated by recapture and storage in the original nerve ending or inactivated by an enzyme. For example chloropheniramine, an antihistamine, can inhibit the mechanism for uptake and recapture of norepinephrine. There are at least two adrenergic receptor sites (alpha or beta). Norepinephrine activates primarily alpha receptors and epinephrine activates primarily beta receptors, although it may also activate alpha receptors. Stimulation of alpha receptors is associated with constriction of small blood vessels in the bronchial mucosa and relaxation of smooth muscles of the intestinal tract. Beta receptor activation relaxes bronchial smooth muscles which cause the bronchi of the lungs to dilate. In addition beta receptor stimulatory effects cause an increase in the rate and force of heart contractions. As a result increased amounts of blood leave the heart and is diverted from nonactive organs to areas that actively participate in the body's reaction to stress such as skeletal muscles, brain, and liver.

Adrenergic Receptor Sites: Alpha Receptor Site: Important features of the site include in order of importance: 1) An anionic site - which binds the positive ammonium group. 2) One hydrogen bonding area 3) A flat area non-polar area for the aromatic ring. Beta Receptor Site: Important features of the site include in order of importance - also see the graphic on the left: 1) An anionic site - shown as Asp anionic negative acid group which binds the positive ammonium group. 2) Two hydrogen bonding areas - shown as two Serine with alcohol (OH) groups hydrogen bonding to the phenol OH groups of the NE. 3) A flat area non-polar area for the aromatic ring. Tissue Heart Adipose tissue Receptor Subtype beta1 beta1, beta 3? Agonists NE, EP, dobutamine, xamoterol Antagonists atenolol, metoprolol.

Vascular Smooth Muscle Airway Smooth Muscle Smooth muscle contraction

beta 2 beta 2 alpha 1

EP, salbutamol, terbutaline, salmeterol terbutaline, salbutamol, salmeterol and zinterol, NE, EP, phenylephrine, oxymetazoline) clenbuterol, alphamethylnoradrenaline, dexmedetomidine, and mivazerol, clonidine, clenbuterol Receptor Sites beta-receptor vasodilation (b2) cardioacceleration (b1) intestinal relaxation (b2) uterus relaxation(b2) bronchodilation (b2)

butoxamine butoxamine prazosin, doxazocin yohimbine, idazoxan, atipamezole, efaroxan, and rauwolscine

Inhibition of transmitter release alpha 2 Hypotension, anaesthesia, Vasoconstriction

alpha-receptor Vasoconstriction iris dilation intestinal relaxation intestinal sphincter contraction bladder sphincter contraction