Drugs and Poisons Chapter 8 - 25 B. The Adrenergic System We will proceed with this neurotransmitter system much as we did with the cholinergic system. Keep in mind that the main neurotransmitter here is norepinephrine and that adrenergic neurons are found in the sympathetic (fight or flight) portion of the autonomic, peripheral nervous system. There are a variety of receptors in the α- and β-families. α1 receptors predominate in the adrenergic system. They are present on the smooth muscles of the eyes, gut, skin, veins, arterioles, and salivary glands among other sites. Stimulation of α1 receptors usually results in contraction. α2 receptors are pre-synaptic and referred to as autoreceptors, that is, their stimulation results in the regulation of NE release from the pre-synaptic neuron. β1 receptors are found on heart muscle and kidney tissue. Stimulation results in an increase in heart rate as well as contraction of heart muscle. In the kidney agonism will promote the release of renin which plays a role in cardiovascular regulation. β2 receptors are also found on smooth muscle. However, its stimulation results in relaxation. The result is a decrease in GI motility, bronchodilation and vasodilation in skeletal and cardiac muscle. Agonism of β2 receptors in metabolic tissue will cause an increase in glycogenolysis in liver. β3 receptors reside on adipose tissue and stimulation results in lipolysis. 1. Adrenergic agonists (sympathomimetics) These compounds cause general stimulation of both α- and β- receptors. a. Amphetamines have a great deal of structural similarity to norepinephrine. Keep this in mind when you are correlating the structures to their activities. Amphetamine were once the drug of choice for appetite suppression (PNS and CNS effects) and were also used for asthma. Effects related to their peripheral activity are anorexia, increased blood pressure, nausea, vomiting, diarrhea, and cardiac arrhythmias. Amphetamine was once used in nasal inhalers but was banned in 1959 because abusers removed the inner filling and chewed it. Now propylhexedrine, with about half the potency of amphetamine, is used. This still causes problems in that some desperate souls will leach the compound from the inhaler's cotton wick and inject the extract (formerly called "crank"; crank is now a term for methamphetamine). This presents all kinds of CH2CHCH3NHRCH2Other names for amphetamine include dexedrine (d-form),benzedrine (d,l), phendrine, psychodrine.; benzphetamineR = R = -H ; amphetamine R = -CH3; methamphetamineDrugs and Poisons Chapter 8 - 26 problems not the least of which is what happens if a piece of cotton is injected by accident. Ephedrine, originally isolated from the Chinese plant Ma Huang, causes general alpha and beta receptor stimulation as well as enhances the release of NE. Besides having CNS effects, it can be used as a bronchodilator. Notice that ephedrine has two chiral carbons. This would give rise to four possible optical isomers- two pairs of enantiomers and four sets of diastereomers. One of the diastereomers is called pseudoephedrine. Both compounds are used widely in over-the-counter decongestants. Table 7.4 OTC Products with Adrenergic Stimulants OTC products containing ephedrine OTC products containing pseudoephedrine Bronkaid® Bronkotabs® Actifed® Afrinol® Ephedrol® Marax® Dimacol® Drixoral® Nyquil® Quibron® Neobid® Novafed® Quibron Plus® Tedral® Sudafed® Common side effects of ephedrine Common side effects of pseudoephedrine nervousness, headache, rapid heartbeat agitation, insomnia The use of products containing ephedra has been linked to heart attack and strokes. These products can be found in various stores promoting body building and health foods. Some labels include Metabolife 356®, Ripped Fuel, Xenadrine RFA-1® ThermiCare®, among many others. CHCHNHCH3CHCHNH2OH CH3OHCH3phenylpropanolamineephedrineEphedra Mormon TeaDrugs and Poisons Chapter 8 - 27 b. Phenylpropanolamine was a popular OTC ingredient used until the end of 2000 for both its appetite suppressing qualities and for its decongestant properties. The following is only a partial list of decongestant preparations that contained this drug: A.R.M, Bayer Decongestants, Breacol, Combtrex, Congestprin, Contac, Coricidin, Coryban-D, CoTylenol, Covangesic, Dristan, Formula 44-D, Hold, Novahistine, Ordinex, Ornacol, Ornex, Robitussin, Sine-Aid, Sine-Off, Sinutab, Triaminic. Most of these products were a combination of ingredients one of which was an antihistamine. See the ASIDE with a discussion of antihistamines used in the treatment of immune responses and ulcers. Products containing phenylpropanolamine were removed from consumer use during 2001. The natural adrenergic stimulant tyramine was discussed in Part One in the section on enzyme inhibitors. If you will recall, certain foods such as ripe cheeses, red wine and herring contain tyramine. You may add to the list of tyramine sources mistletoe and ergot (rye fungus-which is the source of some other interesting stuff). If someone is taking monoamine oxidase (MAO) inhibitors, they could have a hypertensive crisis after ingesting tyramine-containing foods. Phenylephrine is a specific α-agonist with very little effect on β-receptors. The other name for this drug, a brand name, is Neosynephrine® and it can be found in nasal decongestant sprays and as a dilator in opthamology. It can also be used with the antihypertensive drug phenoxybenzamine and the smooth muscle relaxant papaverine in order to treat impotence in males. c. Tetrahydrozoline, oxymetazoline and xylometazoline are sympathomimetics that can be found in eye drops ("get the red out") and decongestants. Because of their ability to cause vasoconstriction in peripheral blood vessels they can relieve swelling in the vessels of the mucous membranes and the eyes. NNCH2CH3CH3HC(CH3)3(Octrivin®, Neosynephrine II®)(Afrin®, Dristan®, Duration®, 4-Way®,NTZ®, Neosynephrine12-hour®, Nostrilla®,Sinex® - all are"long-acting" nasal sprays)xylometazolineoxymetzoline(-OH)HO CH2CH2NH2HOCHCH2NHCH3OH(Adrianol®, Neo-Synephrine®, etc)(Mydrial®, Uteramin®)phenylephrinetyramineHNN(0.05% ophthalmic-Visine®, Murine Plus®;0.05-0.10% nasal- Tyzine®)tetrahydrozolineDrugs and Poisons Chapter 8 - 28 Beta agonists - There are some drugs which are