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11 THE PHARMACOLOGY OF ADRENERGIC RECEPTORS   This study guide is designed to facilitate the understanding of sympathomimetics and sympatholytics and the adrenergic receptors at which these drugs interact to produce their therapeutic as well as toxic effects. A web site containing this material is also available at: http://www.mc.uky.edu/pharmacology/mtp_research.asp Internet Sources of Drug Information The use of the Internet as a source of drug information has expanded significantly. The following are but a few sites which have drug information. http://www.cp.gsm.com Clinical Pharmacology 2000 provides comprehensive monographs on drugs currently available for clinical use. http://www.merck.com/pubs/ This site links to a variety of publications for health care professionals. http://www.phrma.org/searchcures/newmeds/ Provides information on drugs which are in clinical trials as well as those recently approved for clinical use. http://www.rxlist.com Provides information for both the professional as well as the consumer. Learning Objectives, Lecture I Integrate pharmacodynamic principles to aid in the understanding of adrenergic receptors and the actions of drugs on these receptors. Understand the criteria upon which alpha and beta receptors are defined. Understand the second messenger systems utilized by alpha and beta receptors and how activation of these receptors leads to a change in physiologic function. Understand the effects of alpha and beta receptor activation on the heart and blood vessels. Understand the effects of isoproterenol, epinephrine and norepinephrine on the cardiovascular system. Understand the rationale for the use of epinephrine in dental practice.   Key drugs Isoproterenol - Isuprel Epinephrine - Adrenalin Norepinephrine- Levophed The adrenergic receptors which subserve the responses of the sympathetic nervous system have been divided into two discrete subtypes: alpha adrenergic receptors (alpha receptors) and beta adrenergic receptors (beta receptors). The classification of these receptors, and indeed receptors in general, is based on the interaction of agonists and antagonists with the receptors. PUTATIVE STRUCTURE OF ADRENERGIC RECEPTORS PROPOSED BINDING OF NE TO THE BETA RECEPTOR   Beta Receptors Beta receptors have been further subdivided into beta1 and beta2 receptors. It should be pointed out that beta3 and beta4 receptors have recently been isolated, cloned and characterized. The beta3 receptor may be involved in regulating the metabolism of fatty acids. This receptor could be the site of antiobesity drugs in the future. The functions of the beta4 receptor remains to be discovered. For the purposes of this material we will focus on the beta1 and beta2 receptors only. The classification of beta receptors is based on the the interaction of a series of drugs with these receptors. The ability of epinephrine, norepinephrine and isoproterenol to increase the force of myocardial contraction was examined and the following dose-response curves were obtained. Equilibrium dissociation constants for these ligands were ISO, 80 nm, E, 800 nM, and NE, 1000 nM. Thus, the rank order of affinities for the beta receptor in the heart is ISO>E>NE. A beta receptor with these characteristics is referred to as a beta1 receptor. The equilibrium dissociation constant is often used as a "finger print" to identify a receptor. Regardless of its location, the receptor will interact in the same manner with ligands and have the same dissociation constants for agonists and antagonists.   Conversely, if the ability of the same compounds to produce bronchodilation was examined, a different set of dose response curves and equilibrium dissociation constants were obtained. The dissociation constants were ISO, 80 nm, E, 800 nM, and NE, 10,000 nM Clearly then the receptor in the lung is different from that in the heart and is referred to as a beta2 receptor. It should be apparent how dissociat-ion constants can be used to define and discover new receptors. Beta Receptor Systems Most tissues express multiple receptors. However, the dominant beta receptor in the normal heart is the beta1 receptor while the beta2 receptor is the dominant regulatory receptor in vascular and nonvascular smooth muscle. Tissue Receptor Subtype Heart beta1 Adipose tissue beta1beta3? Vascular Smooth Muscle beta2 Airway Smooth Muscle beta2   Mechanism of Beta Receptor Activation in Cardiac Muscle 1. Agonist binds to the myocardial beta1-receptor. The receptor is a typical G-protein coupled receptor with 7 membrane spanning regions. 2. G-protein complexed with GDP. 3. The receptor promotes exchange of GTP for GDP and release of Gα complexed with GTP. 4. Gα activates adenylate cyclase. 5. ntracellular cAMP increases and activates cAMP dependent protein kinase (PKA). 6-10 PKA phosphorylates cellular effectors leading to a positive inotropic response. 11. Prolonged stimulation can lead to receptor down-regulation via PKA and other protein kinases which induced phosphorylation of the receptor. The other protein kinases which are involved in phosphorylation of the receptor are referred to as G-protein coupled receptor kinases or GRKs. These phosphorylation steps lead to internalization of the receptor.   Effect of Beta Receptor Activation on the Heart: Activation of the beta1 receptor leads to increases in contractile force and heart rate. Excess stimulation by catecholamines can induce significant increases in heart rate and arrhythmias. Arrhythmias are a major concern with drugs such as E, NE and ISO that can activate the beta1 receptor. Effect of Beta Receptor Activation on Smooth Muscle: The beta2 receptor associated with smooth muscle also utilizes the cAMP signaling system. However, the results of receptor activation are different. Stimulation of the beta2 receptor leads to smooth muscle relaxation. This is because in the pathways leading to activation of myofibrillar proteins and contraction are different in smooth muscle when compared to cardiac muscle. Therefore, steps 1-5 in the diagram would be the same. However, the cellular proteins phosphorylated by PKA are different in smooth muscle when compared to cardiac muscle. ALPHA RECEPTORS SYSTEMS: If the ability of isoproterenol, epinephrine and norepinephrine to produce constriction of vascular smooth muscle is studied, the following dose-response curves and equilibrium dissociation constants were obtain E, 5 uM, NE, 6, uM and ISO, 1000 uM. You should begin to understand the reasons why the receptor causing vasoconst-riction MUST be different from that causing cardiac contracti-on or broncodil-ation. The receptor mediating the vasconstrictor actions of catecholamines is referred to as an alpha receptor. The concentration of isoproterenol necessary to activate alpha receptors is so large that isoproterenol can be thought of as a pure beta receptor agonist. Alpha receptors have been further subdivided into alpha1 and alpha2 receptors. Epinephrine and norepinephrine are equipotent at both alpha1 and alpha2 receptors. Three subtypes of the alpha1-receptor, the alpha1A, the alpha1B, and the alpha1D, and 3 subtypes of the alpha2-receptor, the alpha2A, the alpha2B, and the alpha2C have been isolated, cloned and characterized. However, we will refer to only the alpha1 and alpha2 receptors. Postsynaptic Alpha1 And Alpha2 Receptors: Alpha1 and alpha2 receptors exist postsynaptically. Activation of these receptors in vascular smooth muscle leads to Ca2+ influx and release of Ca2+ from intracellular stores. The increased intracellular Ca2+ activates vasoconstriction. Agonist binds to the vascular smooth muscle alpha1-receptor. The receptor is a typical G-protein coupled receptor with 7 membrane spanning regions. G-protein complexed with GDP. The receptor promotes exchange of GTP for GDP and release of Gα complexed with GTP. The G-protein activates phospholipase C leading to an increase of the intracellular second messengers, inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 binds to specific sites on the SR and stimulates the release of intracellular Ca2+. Ca2+ influx is activated. Like the beta-receptors, alpha receptors can also be desensitized and down regulated via phosphorylation of the receptor. However, the alpha receptors, both alpha1 and alpha2 are much more resistant to desensitization and down regulation than are the beta receptors.   Presynaptic Alpha2 Receptors Alpha2 receptors also exist presynaptically associated with nerve terminals. Activation of these receptors inhibits the release of norepinephrine. The mechanism for this regulatory activity may be that prejunctional alpha2 receptors activate a G-protein gated K+ channel leading to membrane hyperpolarization.   Norepinephrine acts at presynaptic alpha2 receptors to inhibit its own release.   Effect of Catecholamines on Vascular Smooth Muscle: Associated with vascular smooth muscle are a large number of alpha1 receptors relative to beta2 receptors. However, epinephrine has a higher affinity for the beta2 receptors when compared to the alpha1 receptors. Therefore, the effect of epinephrine is dependent on which type of receptor is occupied. Recall that receptor occupancy is dependent on the concentration of a drug and its equilibrium dissociation constant. At low doses, epinephrine can selectively stimulate beta2 receptors, thus producing muscle relaxation and a decrease in peripheral resistance. At high doses, epinephrine produces contraction of vascular smooth muscle and an associated increase in peripheral resistance.     Effect of Catecholamines on Vascular Smooth Muscle: (Continued) Norepinephrine has little affinity for beta2 receptors. Therefore, it will stimulate only alpha1 receptors, producing an increase in peripheral vascular resistance. In contrast, isoproterenol will only produce vasodilation due to activation of the beta2 receptors. Effects On The Cardiovascular System Recall that:Blood pressure = Cardiac output X total peripheral vascular resistance (TPR)Cardiac output = Stroke volume X heart rate Therefore: Blood pressure = (stroke volume X heart rate) X Total peripheral vascular resistance For the drugs listed below, indicate how the drugs would affect (increase, decrease, no changes) the indicated hemodynamic parameters. It is important, both from a basic science as well as a clinical perspective, that you understand the actions of these agents on the cardiovascular system. Be sure to make an attempt at answering the question BEFORE you click on the answer. Completed Table Heart Rate Contractile Force TPR Blood Pressure Isoproterenol         Norepinephrine         Low Doses of Epi         High Doses of Epi         Applications to Therapeutics Oral dosing of norepinephrine, epinephrine and isoproterenol is not possible due to rapid metabolism of the catechol nucleus in gastrointestinal mucosa and liver. Therefore, these agents are given I.V., I.M., topically and in aerosol sprays. There is very limited clincial use of norepinephrine. Epinephrine is often used in combination local anesthetic agents to prolong the duration of anesthetic action. This is accomplished because epinephrine can induce vasoconstriction thus limiting the diffusion of the local anesthetic from the site of injection. This serves to reduce the toxicity of the local anesthetic by limiting its systemic absorption. Lidocaine in toxic doses can produce cardiac arrthythmias and convulsions. Epinephrine can also be topically applied in surgical procedures to induce vasoconstriction and thus reduce blood loss. Epinephrine is used in the treatment of shock and in emergency situations related to bronchial asthma. A major concern with using pressors is the effect on systemic arterial pressure. Clinical studies have shown (for example see Table 6.5 in Yagiela et al, p. 109) that epinephrine blood levels increase following its intraoral administration. The risk of this increase is dependent on characteristics of the patient. For example, hypertensive patients or those with other cardiovascular disease or patients taking other drugs that affect sympathetic nervous system function are at higher risk than patients without these conditions. Systemically absorbed epinephrine could also increase heart rate and exacerbate cardiac rhythm disturbances or myocardial ischemia.   Learning Objectives Lecture II   Understand the potential sites of action for sympathomimetics and sympatholytics. Understand the pharmacologic actions and therapeutic effects of dopamine. Understand how the pharmacodynamic actions of dopamine illustrate the properties of a drug that interacts with multiple receptors. Know that there are beta2 agonists, their mechanisms of action and therapeutic uses. Know the mechanism of action and cardiovascular effects of amphetamine and cocaine. Know the effects and therapeutic uses of drugs that can activate the alpha1 adrenergic receptors. Key Drugs* Amphetamine-Adderall Albuterol - Ventolin - 13th leading prescription drug in the US in 2003- source- rxlist.com Cocaine Dopamine - Intropin Methylphenidate - Ritalin - 102nd leading prescription drug in the US in 2003- source- rxlist.com Phenylephrine - Neosynephrine * A more complete list of sympathomimetics and their trade names can be found on p. 110-111 of the Yagiela text.   Sympathomimetics: synthetic analogs of naturally occurring catecholamines that mimic the actions of the endogenous neurotransmitters. These agents can be divided into direct and indirect acting sympathomimetics. Sympatholytics: synthetic analogs which bind to beta or alpha receptors or act through other mechanisms to block the actions of endogenous neurotransmitters or other sympathomimetics.   In addition to interacting with receptors, adrenergic agonists and antagonists can interact at sites on the nerve terminal to produce sympathomimetic or sympatholytic effects. These potential sites are indicated by the numbers. A clear majority of drugs are direct acting agonists or antagonists. A small number of drugs work through the other listed mechanisms. Direct acting agonists or antagonists can act at postsynaptic receptors. Indirect acting agonists release neurotransmitters from presynaptic nerve terminals to produce a sympathomimetic effect. Drugs such as Guanethidine can inhibit the Ca2+-dependent release of norepinephrine, thus having a sympatholytic effect. Drugs such as Reserpine cause the destruction of storage granules, and as a result, depletion of the synaptic terminal of norepinephrine which is also a sympatholytic action. Inhibition of the membrane uptake of catecholamines by drugs such as cocaine and tricyclic antidepressants produce a sympathomimetic effect. Inhibition of monoamine oxidase by drugs such as Tranylcypromine.   SYMPATHOMIMETICS ACTING AT BETA RECEPTOR SYSTEMS EXAMPLES: Dopamine Beta2 agonists DOPAMINE-An illustration of the actions of a drug that activates multiple receptorsDopamine has a complex pharmacology. It can activate at least 4 different receptors: the beta1, dopamine1 (DA1), alpha1 and alpha2. DA1 receptors exist in the renal vascular bed. Activation of these receptors produces a decrease in renal vascular resistance and an increase in renal blood flow. Activation of the beta1 receptor increases the force of myocardial contraction. Dopamine has a very unusual action on the heart in that it selectively increases the force of myocardial contraction without a significant effect on heart rate. However, high doses of dopamine, like all catecholamines which activate the beta1 system, can induce rhythm disturbances. The beneficial effects of dopamine are due to stimulated DA1 and beta1 - receptors. Activation of the alpha1 receptor will produce increases in vascular resistance which is counterproductive to the effects on the heart and kidney. The increase in peripheral resistance would increase the pressure the heart has to work against and hence act to decrease cardiac output.   Uses of Dopamine Dopamine can be used to treat congestive heart failure and cardiogenic shock. In congestive heart failure, the failing heart is not able to eject blood as efficiently as the normal heart. As a result there is a decrease in cardiac output which triggers a host of compensatory actions. These include fluid retention, vasoconstriction, an increase in peripheral vascular resistance, and an increase in the levels of circulating catecholamines and tissue hypoxia. Dopamine is particularly effective in these situations because of its actions on the heart and renal vasculature. The actions on the heart will increase cardiac output while the effects on renal blood flow will produce diuresis and loss of excess fluid.   Pharmacokinetics of Dopamine Dopamine is similar to epinephrine and norepinephrine as it has a short plasma half life and can only be used I.V.     SELECTIVE BETA2 AGONISTS These agents have a higher affinity (lower equilibrium dissociation constant) for beta2 receptors when compared to beta1. Therefore, they selectively activate beta2 receptors when compared to beta1. The cellular action of these drugs is mediated by cAMP. Uses 1) Airways dysfunction; bronchial asthma, chronic bronchitis, emphysema In airways dysfunction, beta2 selective agonists relax airways thus decreasing airways resistance. 2) Premature labor In premature labor, the beta2 selective agonists relax uterine smooth muscle. Drugs that relax uterine smooth muscle are referred to as tocolytic agents.   ALPHA1 AGONISTS Direct Acting Agents These are synthetic agents that directly activate the alpha1 -adrenergic receptor. These structural modifications of the parent catecholamine nucleus result in drugs that are orally active and have longer plasma half-lives. However, these same modifications result in lower affinity for the receptor than do the endogenous agonists (epinephrine or norepinephrine). There are 2 structural classes of alpha1 agonists: Phenylethylamines Imidazolines Phenylephrine Oxymetazoline Methoxamine Naphazoline Metaraminol Tetrahydrozoline Ephedrine   _____________________________________________________________________________   _____________________________________________________________________________ Indirect Acting Agents Indirect Acting Agents that activate Alpha Receptors These agents require the presence of endogenous catecholamines to produce their effects. They have little activity if catecholamines are depleted. Cocaine:  Blocks reuptake of NE into nerve endings.     Amphetamine: Promotes the release of NE from nerve endings. The NE is not released from vesicles but from the cytoplasmic stores of NE. This is also referred to as the mobile pool. There is only a limited amount of NE in this mobile pool. Therefore, tachyphylaxis to the sympathomimetic actions of amphetamine can develop. Amphetamine can also block the reuptake of norepinephrine. Amphetamine-like congeners 1.     Methylphenidate 2.     Pemoline 3.     Methamphetamine A major site action of cocaine, amphetamine and amphetamine-like agents is in the CNS. These drugs produce a feeling of well being and euphoria. There is very limited therapeutic use of cocaine and amphetamine. Analogs of amphetamine are used to treat hyperactivity in children and act as appetite suppressants. In addition to its effects on the uptake of neurotransmitters, cocaine also has local anesthetic properties. It is used for local anesthesia and vasoconstriction in surgical procedures involving oral, laryngeal or nasal cavities. Applications to Therapeutics Dental-The use of epinephrine and other pressor agents in dental practice has previously been discussed. Hypotension-to increase blood pressure during a surgical procedure where a general anesthetic has induced hypotension Ophthalmic preparations-to induce mydrasis also in topical preparations for symptomatic release of eye irritation. Cough and cold preparations-Induces constriction of nasal mucosa decreases resistance to air flow. CNS actions - Amphetamine and congeners a. Appetite suppression - b. Hyperactivity in children - Cocaine and amphetamine-like agents could potentiate the effects of direct acting agonists such as epinephrine. Recall that epinephrine can be absorbed systemically after intraoral administration. Thus, the risk of hypertension and other problems associated with systemic absorption of epinephrine will be greater in patients taking cocaine or amphetamine-like drugs. This is because the actions of epinephrine are terminated in part by uptake into the synaptic terminal. Learning Objectives Lecture III Understand how activation of α2 receptors decreases sympathetic outflow and cause hypotension. Understand the pharmacologic properties and therapeutic uses for prazosin-like drugs. Understand the pharmacologic properties of propranolol and atenolol and the therapeutic uses of beta-adrenergic receptor blockers. Understand the special precautions needed for sympatholytic drugs in dental practice.   Key Drugs* Atenolol - Tenormin and various trade names - 4th leading prescription drug in the US in 2003- source- rxlist.com Clonidine - Minipres, various trade names Propranolol - Inderal - various trade names Terazosin - Hytrin * A more complete list of sympatholytics and their trade names can be found on p. 123 of the Yagiela text.Alpha2 Agonists As Sympatholytics Clonidine Methyldopa Guanabenz   Actions These drugs stimulate alpha2 receptors in the nucleus tractus solitarius (NTS) to decrease sympathetic outflow to the heart and blood vessels. The decrease in sympathetic tone results in a decrease in peripheral vascular resistance. Clonidine and guanabenz are active drugs. Methyldopa is a prodrug which must first be converted to α-methylnorepinephrine. SELECTIVE ALPHA1-ANTAGONISTSPrazosin and analogs. Prazosin was the first selective alpha1-receptor antagonist that was developed. Several analogs have since been developed. Effects of Prazosin and Analogs on the Cardiovascular System: Relaxes arterial and venous smooth muscle as well as nonvascular smooth muscle. Decreases peripheral vascular resistance and venous return. Decreases systemic arterial blood pressure without a significant increase in heart rate. Prazosin analogs - terazosin, doxazosin, trimazosin; the beneficial effects of these drugs are the same, but they differ in pharmacokinetic properties. Uses 1. Hypertension 2. Benign prostatic hypertrophy Side Effects1. Orthostatic hypotension. Orthostatic hypotension is a problem with prazosin as well as vasodilators that affects the tone on venous smooth muscle. This would include, organic nitrates, hydralaizne, minixodil and the many drugs used to treat impotence. Orthostatic hypotension or postural hypotension occurs when systemic arterial blood pressure falls by more aht 20 mmHg upon standing. In this situation, cerebral perfusion falls and an individual may become light headed, dizzy or pass out. In changing from the supine to the standing position, gravity tends to cause blood to pool in the lower extremities. However, several reflexes, including sympathetically mediated venoconstriction minimize this pooling and maintain cerebral perfusion. If these reflex actions do not occur, then orthostatic hypotension could result. By blocking the alpha1-receptors associated with venous smooth muscle, prazosin-like drugs, blood the sympathetically mediated vasoconstriction associated with postural changes. Hence, Orthostatic hypotension can occur.BETA ADRENERGIC RECEPTOR BLOCKERS These drugs are competitive antagonists of the beta adrenergic receptors Beta blockers are either selective for the beta1 receptor or nonselective beta1 and beta2antagonists.   SELECTIVE AND NONSELECTIVE BETA BLOCKERS   Propranolol - The Prototype Beta Blocker: Blocks myocardial beta1 receptors which is a major site of therapeutic action Cardiovascular effects: a. Decreases force and rate of myocardial contraction b. Decreases renin secretion c. Decreases blood pressure Blocks beta2 receptors, the blockade of receptors produces unwanted side effects Cardiovascular Uses 1. Hypertension 2. Ischemic heart disease 3. Supraventricular tachyarrhythmias Disadvantages of Nonselective Beta Blockers A major disadvantage of nonselective beta blockers is the fact that they will block beta2 receptors associated with airway or vascular smooth muscle. This is a problem in treating patients with airway dysfunction or peripheral vascular disease such as alpha1 adrengeric receptor-mediated vasoconstrictor tone will be unoppsed by the beta2 receptors. To overcome this disadvantage, antagonists that selectively block the beta1 receptor have been developed. However, this selectivity is only relative and in higher doses selective antagonists will also block beta2 receptors. Endocrine Effects Non-selective beta blockers are contraindicated in diabetic patients. Selective beta1 blockers should be used with caution in patients with diabetes. This is because catecholamines utilize the beta2 receptor to promote glycogenolysis and mobilize glucose. This effect would be blocked by non-selective beta blockers. In addition all beta blockers mask the tachycardia associated with hypoglycemia. As a result, the diabetic patient is deprived of one of the earliest physiologic responses to hypoglycemia. Side Effects Sedation, fatigue Exacerbation of peripheral vascular disease, airway dysfunction   Monoamine Oxidase Inhibitors These drugs inhibit monoamine oxidase and are used as antidepressants in psychiatric practice. A side effect that is not clearly understood is that these drugs can also produce hypotension. Can precipitate a hypertensive crisis. Uses Hypertension Depression Applications to Therapeutics-excerpted from Chapter 7, p.123 of the Yagiela text Many of the agents discussed in this chapter are widely used to treat hypertension, ischemic heart disease, congestive heart failure and rhythm disturbances. This has important implications in the practice of dentistry and signals the dentist's need to pay heed to potential risks associated with these conditions. Physical ImplicationsA consideration for patients being treated with some sympatholytics is the patient's position during and after dental procedures. Suddenly standing upright after being in a supine position in the dental chair is very apt to cause syncope. This is particularly true for the antihypertensive drugs more prone to cause orthostatic hypotension (e.g., prazosn and other α1 -adrenergic receptor blocking drugs, drugs with combined α- and β-receptor blocking activity and adrenergic neuron blocking agents). Accidents ranging from broken teeth and restorations to fractured mandibles and worse have resulted from falls. Contemporary practice standards require the monitoring of blood pressure in dental patients. Such monitoring is particularly important in hypertensive patients. Drug InteractionsBecause nonselective β-blockers block β2-receptor mediated vasodilation, there is a risk of a hypertensive episode following administration of local anesthetic agents that contain vasoconstrictors or the use of epinephrine-impregnated retraction cords. In this situation, the vasoconstrictor actions of epinephrine at α1 -receptors are not opposed by the vasodilatory actions of β2-receptors resulting in an exaggerated blood pressure response that could be deleterious in patients with hypertension or ischemic heart disease. Clonidine and the other selective β2-adrenergic receptor agonists are among the drugs that cause xerostomia. This effect also occurs with reserpine and, less frequently, with α-adrenergic receptor antagonists. The use of such drugs may result in clinical symptoms related to dry mouth, such as difficulty in swallowing and speech. Chronic use of xerostomia-producing drugs is associated with a higher incidence of oral candidiasis and dental caries. The use of β -adrenergic receptor blockers is likely to alter the composition of salivary proteins. The effects of these changes have not been fully explored; however, there is a concern that they could adversely influence oral health. The effect of drugs that alter the function of adrenergic nerve endings on salivary proteins is also not well explored. Patients taking MAO inhibitors must not be given drugs that have indirect sympathomimetic activity or are inactivated by MAO. Occasionally, the dentist may find reason to use the vasoconstrictor phenylephrine. Because it causes even a minor release of norepinephrine from adrenergic nerves and is subject to metabolism by MAO, phenylephrine must be avoided in patients taking MAO inhibitors. Epinephrine and levonordefrin, which are most commonly found in local anesthetic solutions, are not contraindicated, since they are direct agonists and are largely inactivated by catechol-O-methyltransferase. Nonetheless, the avoidance of hemostatic preparations containing high concentrations of epinephrine is recommended. Opioids and other CNS depressants should be used cautiously and usually at lower doses in patients who are taking MAO inhibitors. Meperidine is absolutely contraindicated. The dentist should reinforce the physician's instructions to the patient about dietary restrictions and contraindications of several drugs for patients taking MAO inhibitors. For the drugs bretylium, reserpine, guanadrel and guanethidine, a condition resembling denervation supersensitivity may be clinically significant; the intensity of the response to exogenous amines may be increased several fold as a result. This increased sensitivity does not usually contraindicate the use of vasoconstrictors in local anesthetic solutions; however, caution must be exercised to avoid accidental intravenous injection and giving high amounts of a vasoconstrictor. The use of adrenergic hemostatic agents, as found in certain gingival retraction cords, is best avoided. The following is a list of trade names for the drugs mentioned in this handout. It is provided for your information.   Epinephrine Adrenalin Chloride Phenylephrine Neo-synephrine Isoproterenol Isuprel Norepinephrine Levophed Methoxamine Vasoxyl Metaraminol Aramine Clonidine Catapres Methyldopa Aldomet Guanabenz Wytensin Oxymetazoline Afrin Naphazoline Naphcon Forte Ophthalmic Tetrahydrozoline Tyzine Prazosin Minipress Terazosin Hytrin Doxazosin Cardura Acebutolol Sectral Atenolol Tenormin Betaxolol Betopic, Kerlone Bisoprolol Zebeta Esmolol Brevibloc Metoprolol Lopressor, Toprol XL Carteolol Cartrol Nadolol Corgard Penbutolol Levatol Pindolol Visken Propanolol Inderal Sotalol Betapace Timolol Blocadren Labetalol Trandate, Normodyne Salmeterol Serevent Albuterol Proventil, Ventolin Bitolterol Tornalate Isoetharine Bronkosol Metaproterenol Alupent, Metaprel Pirbuterol Maxair Terbutaline Serevent Guanethidine Ismelin Reserpine -----