THE PHARMACOLOGY OF
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 basic pharmacology of these receptors and the drugs that interact at these sites. Drugs that interact with these receptors are widely prescribed (for example see, RxList.com) to treat a variety of conditions. This would include over the counter cough and cold preparations, in combination with local anesthetics, the treatment of airways dysfunction, hypertension, ischemic heart disease, congestive heart failure and medical emergencies. As with all classes of drugs ,the blend of basic and clinical knowledge will help understand the types of toxicity that can be manifest with these drugs and minimize the likelihood of toxic events.
The student should be able to explain or describe;
1. The pharmacodynamic principles that aid in the understanding of adrenergic receptors and the actions of drugs on these receptors.
2. The criteria upon which alpha and beta receptors are defined.
3. The second messenger systems utilized by alpha and beta receptors and how activation of these receptors leads to a change in physiologic function.
4. The effects of alpha and beta receptor activation on the heart and blood vessels.
5. The effects of isoproterenol, epinephrine and norepinephrine on the cardiovascular system.
6. The clinical uses and potential toxicities of epinephrine, norepinephrine and isoproterenol with emphasis on epinephrine.
Isoproterenol - Isuprel
Epinephrine - Adrenalin
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 remain 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 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 dose-response curves shown below 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.
Beta Receptor Systems
Most tissues express multiple receptors. However, the receptor mainly utilized by the sympathetic nervous system to affect myocardial function in the normal heart is the beta1 receptor; while in vascular and nonvascular smooth muscle it is the beta2 receptor.
|Vascular Smooth Muscle||beta2|
|Airway Smooth Muscle||beta2|
|Kindney-Renin release from JG cells||beta1|
Cellular Signaling Activated by the Beta Receptor in the Heart
Activation of the beta1 receptor leads to increases in contractile force and heart rate. The increase is myocardial contraction is a result of activation of those beta receptors associated with the atria and ventricle (especially the ventricles) while the increases in rate of contraction are due to activation of those receptors associated with the SA and AV nodes as well as the His-Purkinjie system. Recall that the primary ion channels in the SA and AV nodes are calcium channels while in the His-Purkinjii and ventricular myocardium the electrical current is carried by sodium channels. Activation of the beta receptor increases ion movements through both types of channels. These actions result in an increase in heart rate.
1) Increase slope of phase 4 spontaneous depolarization
2) Increase maximal rate of phase 0 depolarization
3) Increase conduction velocity
4) Decrease refractory period
These electrophysiologic factors contribute to the orderly, rhythmic electrical activity that assures the efficient contractile activity of the heart. In response to beta receptor activation, these parameters increase and the heart beats at a faster rate. However, excess stimulation of the beta receptor by catecholamines can enhance these variables to such an extent that arrhythmias can occur. Rhythm disturbances are a major concern with drugs that activate the beta1 receptor. Drugs to be covered that have a tendency to generate arrhythmias include epinephrine, isoproterenol, norepinephrine, dopamine and dobutamine.
TheBeta1-Adrenergic Receptor as a Therapeutic Target
Agonists- congestive heart failure
Antagonists- hypertension, ischemic heart disease, congestive heart failure
THE BETA2 SYSTEM
The beta2 receptor associated with smooth muscle also utilizes the cAMP signaling system. However, the results of receptor mediated increases in cAMP levels in smooth muscle are different than those occurring in cardiac muscle. Therefore, the consequences of PKA phosphorylation of key structures in smooth muscle lead to relaxation
Structures Phosphorylated in Smooth Muscle
1) sarcolemma - Decrease Ca2+ influx
2) sarcoplasmic reticulum - Enhance Ca2+ uptake
3) decrease actin-myosin interactions - muscle relaxation
The net result of these activities is to inhibit calcium pathways in smooth muscle leading to relaxation.
The Beta2-Adrenergic Receptor as a Therapeutic Target
Agonists- Airways dysfunction, asthma, chronic bronchitis emphysema, tocolytics
Antagonists- No therapeutic uses
Regulation of Receptor Function
Continuous exposure of an agonist results in a phenomenon referred to as desensitization. The same concentration of agonist becomes less and less effective at producing the same level of effect. Recent evidence has suggested potential mechanisms by which desensitization occurs. The receptor becomes phosphorylated in the third cytoplasmic loop and c-terminal tail. The phosphorylated receptor is less efficient at activating G-protein and also exhibits lower affinity for agonists. The receptors can also be removed from and sequestered away from the cell surface. These events indicate that second messengers not only regulate intracellular processes but are also capable of regulating the receptor systems which generate them.
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 obtained: 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 bronchodilation.
The receptor that produces vasoconstriction is referred to as an alpha receptor (affinity rankings of E $ NE >>>ISO). Observe how the structure of each drug affects that ability of these ligands to activate the 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 also been subdivided into alpha1 and alpha2 receptors. Epinephrine and norepinephrine have equal affinity at both alpha1 and alpha2 receptors. However, other drugs were found to have higher affinity for one receptor over another and these differences in affinity were the evidence used to subclassify the receptors into alpha1 and alpha2. More recently, three subtypes of the alpha1-receptor, the alpha1A, alpha1B and alpha1D have been isolated, cloned and characterized. Similarly, 3 subtypes of the alpha2-receptor, the alpha2A, the alpha2B and the alpha2C have also been identified. There is little doubt that these receptor subtypes subserve different physiologic functions.
Postsynaptic Alpha1 and Alpha2 Receptors
Alpha1 and alpha2 receptors exist postsynaptically. Like the beta receptor, these receptors are G-protein coupled receptors, thus they activate cellular signaling subsequent to interaction with a G-protein. Activation of these receptors on vascular smooth muscle leads to vasoconstriction. The mechanism linking the alpha2 receptor to contraction is not well understood.
Presynaptic Alpha2 Receptors
Alpha2 receptors exist presynaptically. Activation of these receptors inhibits the release of norepinephrine. The mechanism of this regulatory action involves the stimulation of a G-protein gated K+ channel leading to membrane hyperpolarization.
Norepinephrine acts at presynaptic alpha2 receptors to inhibit its own release.
Effect of Epinephrine 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 receptor relative to the alpha1 receptor (see above). Activation of the beta2 receptor would produce vasodilation while activation of the alpha1 receptor would result in vasoconstriction. Therefore, the effect of epinephrine on smooth muscle is dependent on its relative affinity for alpha1 and beta2 receptors and its concentration. At low doses, epinephrine can selectively stimulate beta2 receptors producing muscle relaxation and a decrease in peripheral resistance. However, once epinephrine concentrations are reached that bind to the alpha1 receptor, vasoconstriction will occur.
The two effects (smooth muscle relaxation and contraction) will oppose one another.
Effects of Norepinephrine and Isoproterenol on Smooth Muscle
Recall that norepinephrine in physiologically relevant concentrations has little affinity for beta2 receptors. Therefore, it will stimulate only alpha1 receptors producing an increase in peripheral vascular resistance. In contrast, the lack of activity at the alpha1-receptor means that isoproterenol will produce only a beta2-receptor mediated vasodilation.
Other Cardiovascular Functions
Alpha1 receptors also exist on the myocardium. These receptors increase force without affecting rate. The role of these receptors in physiologic regulation of myocardial performance or as a site of drug action is unclear.
Effects on the Cardiovascular System
For the drugs listed below, indicate how the drugs would affect (increase, decrease, no changes) heart rate, contractile force, total peripheral resistance (TPR) and systemic arterial blood pressure. Recall the equations below. Remember also that the effectors in the cardiovascular system (brain, kidney, heart and blood vessels) are all involved in the integrated regulation of blood pressure.
Blood pressure = Cardiac Output x TPR
Cardiac output = Stroke Volume x Heart Rate
Blood pressure = (Stroke volume x Heart rate) x Total peripheral vascular resistance
|Low Doses of Epi|
|High Doses of Epi|
Applications to Therapeutics
Oral dosing of epinephrine, norepinephrine or isoproterenol is not possible due to rapid metabolism of the catechol nucleus in gastrointestinal mucosa and liver. Therefore, these agents must be given by routes that avoid the stomach.
Epinephrine is a very versatile drug that has many uses and is administered in many dosage forms.
Routes of administration and uses of Epinephrine
1) Epinephrine can be given by injection (s.c., i.m. i.v) or inhalation for the treatment of respiratory distress or bronchspasm caused for example by asthma (i.e. status asthmaticus) or anaphylaxis as a result of allergic responses. A particular note is made of the Epipen that can be carried by individuals prone to bronchospasm. In this instance the salutatory effects of epinephrine would be its bronchodilatory actions at the beta2-receptor.
2) Epinephrine is also used in cardiopulmonary resuscitation because of its ability to activate the myocardial beta1-receptor.
3) Epinephrine can be given by injection or topically in combination with local anesthetics such as articaine, bupivacaine or lidocaine to prolong the duration of anesthetic action. 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 duration of actions of the local anesthetic action but also reduces the toxicity of the local anesthetic by limiting its systemic absorption. For example, lidocaine in toxic doses can produce cardiac arrthythmias and convulsions.
4) Epinephrine can also be topically applied in surgical procedures to induce vasoconstriction and thus reduce blood loss.
5) 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.
Norepinephrine and Isoproterenol
For the same reasons as epinephrine, isoproterenol can be used to treat bronchospasm. Norepinephrine can be used to produce vasoconstriction, via the alpha1-receptor, in the treatment of cardiogenic or septic shock.