THE PHARMACOLOGY OF
ADRENERGIC RECEPTORS

M.T. Piascik


This study guide will facilitate the understanding of sympathomimetics and sympatholytics and the adrenergic receptors at which these drugs interact. The educational goal is to understand the uses in dental practice of drugs that interact at the adrenergic receptors as well as toxicities that could occur as a result of these interactions. In addition, dental patients are likely to be taking drugs that act at these receptors. The presence of these drugs could modify the actions of drugs prescribed in dental practice as well as produce interactions that could have serious consequences.

Learning Objectives, Lecture I

1. Integrate pharmacodynamic principles to understand the actions of drugs that interact with the adrenergic receptors and how these interactions are relevant to dental practice.

2. Understand the effects of epinephrine and norepinephrine on the cardiovascular system.

3. Understand the rationale and potential toxicities for the use of epinephrine in dental practice.

4. Understand the mechanisms for drug interactions involving drugs used in cardiovascular therapeutics as they relate to dental practice.


Key drugs
Epinephrine - Adrenalin
Norepinephrine- Levophed

PROPOSED BINDING OF NE TO THE BETA RECEPTOR

The adrenergic receptors which subserve the response 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. The actions of epinephrine, widely used in combination with local anesthetic drugs, are produced as a result of interactions with these 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 non vascular smooth muscle. Epinephrine activates both the beta1 and beta2-receptors. Norepinephrine activates only the beta1-receptor.

Effect of Beta1 Receptor Activation on the Heart: Activation of the beta1 receptor leads to increases in contractile force and heart rate. Drugs that activate the beta1 receptor can be used in heart failure to improve the contractile state of the failing heart. Drugs that activate the beta1 receptor also increase heart rate. Indeed, excess stimulation the beta1 receptor can induce significant increases in heart rate and arrhythmias. Arrhythmias are a major concern with drugs such as epinephrine that can be absorbed systemically after intra-oral injection.

                            

Effect of Beta2 Receptor Activation on Smooth Muscle: Activation of the beta2 receptor leads to vascular and nonvascular smooth muscle relaxation. Drugs that activate the beta2 receptor can be used to treat as asthma (by relaxing airway smooth muscle) and premature labor (by relaxing uterine smooth muscle).

                                                             

ALPHA RECEPTORS SYSTEMS:

The receptor mediating the vasconstrictor actions of catecholamines is referred to as an alpha receptor.
Alpha receptors have been further subdivided into alpha1 and alpha2 receptors. Both epinephrine and norepinephrine activates both the alpha1 and alpha2 receptors.

Presynaptic Alpha2 Receptors
Alpha2 receptors also exist presynaptically associated with nerve terminals. Activation of these receptors inhibits the release of norepinephrine.
Norepinephrine acts at presynaptic alpha2 receptors to inhibit its own release.

Norepinephrine acts at presynaptic alpha2 receptors to inhibit its own release.

Postsynaptic Alpha1 Receptors on Vascular Smooth Muscle:

Associated with vascular smooth muscle are a large number of alpha1 receptors relative to beta2 receptors. Activation of these receptors by sympathetic nervous system transmission or drugs will result in vasoconstriction and an increase in peripheral resistance and systemic arterial blood pressure.

                                    

 

Applications to Therapeutics
Oral dosing of norepinephrine or epinephrine is not possible due to the rapid metabolism of catechol nucleus in gastrointestinal mucosa and liver. Therefore, these agents are given I.V., I.M., topically and in aerosol sprays.

Epinephrine is often used in combination local anesthetic agents to prolong the duration of anesthetic action. This would include articaine, bupivacaine or lidocaine. This combination is used because epinephrine can induce vasoconstriction thus limiting the diffusion of the local anesthetic from the site of injection. This not only prolongs the actions of the local anesthetic but also 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.

Clinical studies have shown 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


1. Understand the potential sites of action for sympathomimetics and the difference between a direct and indirect acting      agonist.

2. Understand the pharmacologic actions and therapeutic actions of drugs that act at the beta1 and beta2 -adrenergic receptors as well as the alpha1 -adrenergic receptor.

3. Know the mechanism of action and effects of amphetamine and cocaine.

4. Understand how the pressure of sympathomimetics alters the dental management of patients.



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.

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. Inhibition of the membrane uptake of catecholamines by drugs such as cocaine and tricyclic antidepressants produce a sympathomimetic effect.

4. Inhibition of monoamine oxidase by drugs such as Tranylcypromine.

                     

 

SYMPATHOMIMETICS ACTING AT BETA RECEPTOR SYSTEMS

EXAMPLES:

Dopamine
Dobutamine
Beta2 agonists

Uses of Dopamine and Dobutamine

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, an increase in the levels of circulating catecholamines and tissue hypoxia. Dopamine and dobutamine activate the myocardial beta1 receptor and thus increase the force of contraction of the failing heart. This will result in an increase in cardiac output. These drugs are reserved for use in the acute management of heart failure.


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.

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.

Side effects related to dental practice

1. Xerostomia, with inhaler usage.

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 two structural classes of alpha1 agonists phenethylamines which are closely aligned in structure to epinephrine and the imidazolines, compounds structurally unrelated to epinephrine. Levonordeferin is a phenyethylamine that has been used in dental practice in combination with local anesthetics.

Uses
1. Hypotension-to increase blood pressure during a surgical procedure where a general anesthetic has induced hypotension

2. Ophthalmic preparations-to induce mydrasis also in topical preparations for symptomatic release of eye irritation.

3. Cough and cold preparations-Induces constriction of nasal mucosa decreases resistance to air flow.


Indirect Acting Sympathomimetics
These agents require the presence of endogenous catecholamines to produce their effects. They have little activity if catecholamines are depleted.

                            

Cocaine:  Blocks reuptake of monoamines into nerve endings. Cocaine also has local anesthetic activity.

Amphetamine: Promotes the release of NE from nerve endings. Amphetamine can also block the reuptake of norepinephrine.
 

Amphetamine-like compounds

1. Methylphenidate

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. As a result the drugs carry a significant abuse liability. Both cocaine and amphetamine are on the FDA schedule 2.

Uses of Cocaine (# 1 below), Amphetamine and Amphetamine-like agents (2-4 below)

1. Cocaine has limited use as a local anesthesic and vasoconstrictor in surgical procedures involving oral, laryngeal or nasal cavities.

2. Appetite suppression

3. Hyperactivity in children

4. Narcolepsy

 

Cautions Relevant to Dentistry


1) Cocaine and amphetamine-like agents (tricyclic antidepressants as well) could potentiate the effects of direct acting agonists such as epinephrine. Recall that epinephrine can be absorbed systemically after intraoral administration. This epinephrine can be taken up by nerve terminals and this uptake contributes to the the termination of the actions of epinephrine. 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.

2) An analog of amphetamine, methamphetamine, is produced illegally and is a widely abused substance. Methamphetamine can be produced from over the counter cough and cold medications such as pseudoephedrine. Lithium, muriatic acid, sulfuric acid, red phosphorus and lye are used in this preparation. When smoked these highly corrosive agents are vaporized resulting in significant damage to teeth and gums.

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.

Learning Objectives Lecture III

1. Review the pharmacodynamic properties and characteristics of antagonists.

2. Understand the pharmacologic properties and therapeutic uses of clonidine, prazosin analogs, the beta blockers and MAO-inhibitors.

3. Understand the special precautions that exist 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


Actions and Therapeutic Uses
1. This drug stimulates alpha2 receptors in the nucleus tractus solitarius (NTS) to decrease sympathetic outflow to the heart and blood vessels.

2. The decrease in sympathetic tone results in a decrease in peripheral vascular resistance.

3. Clonidine is used in dental practice in the management of chronic pain. It can be given orally or in patch form. Clonidine is a second-line antihypertensive that has many other uses including opiate withdrawal, nicotine withdrawal, vascular headaches, diabetic diarrhea, glaucoma, ulcerative colitis and Tourette's syndrome.

Side Effects
The use of clonidine 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.


SELECTIVE ALPHA1-ANTAGONISTS
Prazosin and analogs, terazosin, doxazosin, trimazosin.


Effects on the Cardiovascular System:
1. Relaxes arterial and venous smooth muscle as well as nonvascular smooth muscle.

2. Decreases peripheral vascular resistance and venous return with a resultant decrease in systemic arterial blood pressure.


Uses

1. Hypertension

2. Benign prostatic hypertrophy

Tamsulosin specifically blocks the alpha1-receptor associated with the prostate and is used to treat benign prostatic hypertropy.

The Relevance of Orthostatic Hypotension to Dental Practice

Orthostatic hypotension is a problem with prazosin analogs and to a lesser extent tamsulosin. Significantly, orthostatsis is a problem that can be seen with any vasodilator that affects the tone on venous smooth muscle. This would include, organic nitrates, hydralazine, clonidine, 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 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, inhibit the sympathetically mediated vasoconstriction associated with postural changes. Hence, orthostatic hypotension can occur. Drugs like clonidine cause orthostasis due to its CNS actions that block the sympathetic reflexes. Vasodilators such as nitrates, minoxidil, hydralazine or impotence medications cause orthostasis because of their actions directly on the vasculature. 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.

BETA ADRENERGIC RECEPTOR BLOCKERS

Cardiovascular Uses
Hypertension, ischemic heart disease, supraventricular tachyarrhythmias.


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 beta2
antagonists.

                        

3. Propranolol is the prototype Beta Blocker as well as the prototype of a nonselective beta blocker.

4. By blocking the myocardial beta1 receptor beta blockers, a) decrease the force and rate of myocardial contraction, b) Decreases renal renin secretion with the net result of c) decreasing systemic arterial blood pressure

5. 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.

6. Atenolol is the prototype selective beta1 receptor beta blocker.

Applications to Dentistry
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 epinephrine. 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.

Side Effects
1. Sedation, fatigue

2. Exacerbation of peripheral vascular disease, airway dysfunction

Monoamine Oxidase Inhibitors
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. 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.

4. 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.

Uses
1. Hypertension

2. Depression


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 -----