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. 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.

 www.phrma.org/newmedicines/ 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

1. Integrate pharmacodynamic principles to aid in the understanding of adrenergic receptors and the actions of drugs on these receptors.
   
2. Understand the criteria upon which alpha and beta receptors are defined.
   
3. Understand the second messenger systems utilized by alpha and beta receptors and how activation of these receptors leads to a change in physiologic function.
   
4. Understand the effects of alpha and beta receptor activation on the heart and blood vessels.
   
5. Understand the effects of isoproterenol, epinephrine and norepinephrine on the cardiovascular system.
   
6. Understand the rationale for the use of epinephrine in dental practice.

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.

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. Consider the following dose-response curves showing the ability of epinephrine, norepinephrine and isoproterenol to increase the force of myocardial contraction. You should begin to apply the principles of pharmacodynamics to these dose response curves to make reasonable inferences about drugs and receptors. For example, which of the drugs illustrated below has the highest affinity for the receptor under investigation? What about the intrinsic activity of the drugs? 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 dissociation constants can be used to define and discover new receptors.

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.

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. Intracellular 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 desensitition and down-regulation via PKA and other protein kinases which induced phosphorylation of the receptor.  A desensitized receptor remains on the cell surface but is less able to be activated by agonist.  A down regulated receptor remains on the cell surface but is less able to be activated by agonist. A down-regulated receptor internalizes in the cell and hence unable to be stimulated by neurotransmitters or drugs.

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 vasoconstriction MUST be different from that causing cardiac contraction or broncodilation.

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 alpha_1A, the alpha_1B, and the alpha_1D, and 3 subtypes of the alpha₂-receptor, the alpha_2A, the alpha_2B, and the alpha_2C 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.

1. Agonist binds to the vascular smooth muscle alpha₁-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. The G-protein activates phospholipase C leading to an increase of the intracellular second messengers, inositol trisphosphate (IP3) and diacylglycerol (DAG).
   

5. IP3 binds to specific sites on the SR and stimulates the release of intracellular Ca²⁺.
   

6. Ca²⁺ influx is activated.
   

7. Like the beta-receptors, alpha receptors can also be desensitized and down regulated via phosphorylation of the receptor. 

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.

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.

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.

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 would include articaine, bupivacaine to lidocaine. Epinephrine is also included in combination with anticancer drugs to limit the diffusion of the anticancer drugs from the site of infusion 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.

1. Understand the potential sites of action for sympathomimetics and the differences between a direct and indirect acting agonist.
   
2. Understand the pharmacologic actions and therapeutic effects of dopamine and how its pharmacodynamic actions illustrate the properties of a drug that interacts with multiple receptors.
   
3. Know that there are beta₂ agonists, their mechanisms of action and therapeutic uses.
   
4. Know the mechanism of action and cardiovascular effects of amphetamine and cocaine.
   
5. Know the effects and therapeutic uses of drugs that can activate the alpha1 adrenergic receptors.

Key Drugs*

Amphetamine-Adderall

Albuterol - Ventolin - 13^th 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.

1. Direct acting agonists or antagonists can act at postsynaptic receptors.
   
2. Indirect acting agonists release neurotransmitters from presynaptic nerve terminals to produce a sympathomimetic effect.
   
3. Drugs such as Guanethidine can inhibit the Ca²⁺-dependent release of norepinephrine, thus having a sympatholytic effect.
   
4. 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.
   
5. Inhibition of the membrane uptake of catecholamines by drugs such as cocaine and tricyclic antidepressants produce a sympathomimetic effect.
   
6. Inhibition of monoamine oxidase by drugs such as Tranylcypromine.

SYMPATHOMIMETICS ACTING AT BETA RECEPTOR SYSTEMS

Dopamine 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.

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.

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.

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

Phenylephrine

Levonordeferin-is a vasoconstrictor formulated with local anesthetics

Methoxamine

Metraminol

Ephedrine

Imidazolines

Oxymetazoline

Naphazoline

Tetrahydrozoline

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-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

1. Dental-The use of epinephrine and other pressor agents in dental practice has previously been discussed.
   
2. Hypotension-to increase blood pressure during a surgical procedure where a general anesthetic has induced hypotension.
   
3. Ophthalmic preparations-to induce mydrasis also in topical preparations for symptomatic release of eye irritation.
   
4. Cough and cold preparations-Induces constriction of nasal mucosa decreases resistance to air flow.
   
5. CNS actions - Amphetamine and congeners
   
   a. Appetite suppression -

   b. Hyperactivity in children -

    6. Cocaine and amphetamine-like agents (tricylclic antidepressants as well) 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

1. Review the properties and characteristics of antagonists.
   
2. Understand how activation of α₂ receptors decreases sympathetic outflow and cause hypotension.
   
3. Understand the pharmacologic properties and therapeutic uses for prazosin-like drugs.
   
4. Understand the pharmacologic properties of propranolol and atenolol and the therapeutic uses of beta-adrenergic receptor blockers.

5. Understand the special precautions needed for sympatholytic drugs in dental practice.

Key Drugs*

Atenolol - Tenormin and various trade names - 4^th 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.

1. Relaxes arterial and venous smooth muscle as well as nonvascular smooth muscle.
   
2. Decreases peripheral vascular resistance and venous return.
   
3. Decreases systemic arterial blood pressure without a significant increase in heart rate.
   
4. 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 Effects

1. 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 than 20 mm Hg 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.

1. These drugs are competitive antagonists of the beta adrenergic receptors.
   
2. Beta blockers are either selective for the beta₁ receptor or nonselective beta₁ and beta₂antagonists.

SELECTIVE AND NONSELECTIVE BETA BLOCKERS

Propranolol - The Prototype Beta Blocker:

1. Blocks myocardial beta₁ receptors which is a major site of therapeutic action.
   
2. Cardiovascular effects:
   
   a. Decreases force and rate of myocardial contraction

   b. Decreases renin secretion

   c. Decreases blood pressure

   
   

3. Blocks beta₂ receptors, the blockade of receptors produces unwanted side effects

1. Hypertension

2. Ischemic heart disease

3. Supraventricular tachyarrhythmias

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. The prototype beta₁selective blocker is atenolol. However, this selectivity is only relative and in higher doses selective antagonists will also block beta₂ receptors.

1. Sedation, fatigue
   
2. Exacerbation of peripheral vascular disease, airway dysfunction

1. These drugs inhibit monoamine oxidase and are used as antidepressants in psychiatric practice.
   
2. A side effect that is not clearly understood is that these drugs can also produce hypotension.
   
3. Can precipitate a hypertensive crisis.

1. Hypertension
   
2. 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 Implications

A 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 Interactions

Because 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.