Home » 06Adrenergic receptor-activating drugs. Adrenergic receptor-blocking drugs. Sympatholytic agents

06Adrenergic receptor-activating drugs. Adrenergic receptor-blocking drugs. Sympatholytic agents

June 18, 2024

ADRENERGIC AGENTS. ADRENERGIC BLOCKING AGENTS

Adrenergic receptor-activating drugs. Adrenergic receptor-blocking drugs. Sympatholytic agents

The adrenergic drugs affect receptors that are stimulated by norepinephrine or epinephrine. Some adrenergic drugs act directly on the adrenergic receptor (adrenoceptor) by activating it and are said to be sympathomimetic. Others block the action of the neurotransmitters at the receptors (sympatholytics), whereas still other drugs affect adrenergic function by interrupting the release of norepinephrine from adrenergic neurons.

The Adrenergic Neuron

Adrenergic neurons release norepinephrine as the primary neurotransmitter. These neurons are found in the central nervous system (CNS) and also in the sympathetic nervous system, where they serve as links between ganglia and the effector organs. The adrenergic neurons and receptors, located either presynaptically on the neuron or postsynaptically on the effector organ, are the sites of action of the adrenergic drugs.

A. Neurotransmission at adrenergic neurons

Neurotransmission in adrenergic neurons closely resembles that already described for the cholinergic neurons, except that norepinephrine is the neurotransmitter instead of acetylcholine. Neurotransmission takes place at numerous bead-like enlargements called varicosities. The process involves five steps:synthesis, storage, release, and receptor binding of norepinephrine, followed by removal of the neurotransmitter from the synaptic gap.

Synthesis and release of norepinephrine from the adrenergic neuron. (MAO = monoamine oxidase.)

Synthesis of norepinephrine: Tyrosine is transported by a Na⁺-linked carrier into the axoplasm of the adrenergic neuron, where it is hydroxylated to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase.¹ This is the rate-limiting step in the formation of norepinephrine. DOPA is then decarboxylated by the enzyme dopa decarboxylase (aromatic l-amino acid decarboxylase) to form dopamine in the cytoplasm of the presynaptic neuron.

Storage of norepinephrine in vesicles: Dopamine is then trans-ported into synaptic vesicles by an amine transporter system that is also involved in the reuptake of preformed norepinephrine. This carrier system is blocked by reserpine. Dopamine is hydroxylated to form norepinephrine by the enzyme, dopamine β-hydroxylase. [Note: Synaptic vesicles contain dopamine or norepinephrine plus adenosine triphosphate (ATP), and β-hydroxylase, as well as other cotransmitters.] In the adrenal medulla, norepinephrine is methylated to yield epinephrine, both of which are stored in chromaffin cells. On stimulation, the adrenal medulla releases about 80 percent epinephrine and 20 percent norepinephrine directly into the circulation.

Release of norepinephrine: An action potential arriving at the nerve junction triggers an influx of calcium ions from the extracellular fluid into the cytoplasm of the neuron. The increase in calcium causes vesicles inside the neuron to fuse with the cell membrane and expel (exocytose) their contents into the synapse.

Binding to a receptor: Norepinephrine released from the synaptic vesicles diffuses across the synaptic space and binds to either postsynaptic receptors on the effector organ or to presynaptic receptors on the nerve ending. The recognition of norepinephrine by the membrane receptors triggers a cascade of events within the cell, resulting in the formation of intracellular second messengers that act as links (transducers) in the communication between the neurotransmitter and the action generated within the effector cell. Adrenergic receptors use both the cyclic adenosine monophosphate (cAMP) second-messenger system,2 and the phosphatidylinositol cycle,3 to transduce the signal into an effect.

Removal of norepinephrine: Norepinephrine may 1) diffuse out of the synaptic space and enter the general circulation, 2) be metabolized to O-methylated derivatives by postsynaptic cell membrane–associated catechol O-methyltransferase (COMT) in the synaptic space, or 3) be recaptured by an uptake system that pumps the norepinephrine back into the neuron. The uptake by the neuronal membrane involves a sodium/potassium-activated ATPase that can be inhibited by tricyclic antidepressants, such as imipramine, or by cocaine (see Figure 6.3). Uptake of norepinephrine into the presynaptic neuron is the primary mechanism for termination of norepinephrine’s effects.

Potential fates of recaptured norepinephrine: Once norepinephrine reenters the cytoplasm of the adrenergic neuron, it may be taken up into adrenergic vesicles via the amine transporter system and be sequestered for release by another action potential, or it may persist in a protected pool. Alternatively, norepinephrine can be oxidized by monoamine oxidase (MAO) present ieuronal mitochondria. The inactive products of norepinephrine metabolism are excreted in the urine as vanillylmandelic acid, metanephrine, and normetanephrine.

B. Adrenergic receptors (adrenoceptors)

In the sympathetic nervous system, several classes of adrenoceptors can be distinguished pharmacologically. Two families of receptors, designated α and β, were initially identified on the basis of their responses to the adrenergic agonists epinephrine, norepinephrine, and isoproterenol. The use of specific blocking drugs and the cloning of genes have revealed the molecular identities of a number of receptor subtypes. These proteins belong to a multigene family. Alterations in the primary structure of the receptors influence their affinity for various agents.

α1 and α2 Receptors: The α-adrenoceptors show a weak response to the synthetic agonist isoproterenol, but they are responsive to the naturally occurring catecholamines epinephrine and norepinephrine (Figure 6.4). For α receptors, the rank order of potency is epinephrine ≥ norepinephrine >> isoproterenol. The α-adrenoceptors are subdivided into two subgroups, α1 and α2, based on their affinities for α agonists and blocking drugs. For example, the α1 receptors have a higher affinity for phenylephrine than do the α2 receptors. Conversely, the drug clonidine selectively binds to α2 receptors and has less effect on α1 receptors.

α1 Receptors: These receptors are present on the postsynaptic membrane of the effector organs and mediate many of the classic effects—originally designated as α-adrenergic—involving constriction of smooth muscle. Activation of α1 receptors initiates a series of reactions through a G protein activation of phospholipase C, resulting in the generation of inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) from phosphatidylinositol. IP3 initiates the release of Ca2+ from the endoplasmic reticulum into the cytosol, and DAG turns on other proteins within the cell.

α2 Receptors: These receptors, located primarily on presynaptic nerve endings and on other cells, such as the β cell of the pancreas, and on certain vascular smooth muscle cells, control adrenergic neuromediator and insulin output, respectively. When a sympathetic adrenergic nerve is stimulated, the released norepinephrine traverses the synaptic cleft and interacts with the α1 receptors. A portion of the released norepinephrine “circles back” and reacts with α2 receptors on the neuronal membrane (see Figure 6.5). The stimulation of the α2 receptor causes feedback inhibition of the ongoing release of norepinephrine from the stimulated adrenergic neuron. This inhibitory action decreases further output from the adrenergic neuron and serves as a local modulating mechanism for reducing sympathetic neuromediator output when there is high sympathetic activity. [Note: In this instance these receptors are acting as inhibitory autoreceptors.] α2 Receptors are also found on presynpatic parasympathetic neurons. Norepinephrine released from a presynaptic sympathetic neuron can diffuse to and interact with these receptors, inhibiting acetylcholine release [Note: In these instances these receptors are behaving as inhibitory heteroreceptors.] This is another local modulating mechanism to control autonomic activity in a given area. In contrast to α1 receptors, the effects of binding at α2 receptors are mediated by inhibition of adenylyl cyclase and a fall in the levels of intracellular cAMP.

Further subdivisions: The α1 and α2 receptors are further divided into α1A, α1B, α1C, and α1D and into α2A, α2B, α2C, and α2D. This extended classification is necessary for understanding the selectivity of some drugs. For example, tamsulosin is a selective α1A antagonist that is used to treat benign prostate hyperplasia. The drug is clinically useful because it targets α1A receptors found primarily in the urinary tract and prostate gland.

***Summary of adrenergic agonists. Agents marked with an asterisk (*) are catecholamines.***

ALPHA AND BETA ADRENERGIC RECEPTOR AGONISTS

History:

Finklemann in 1930 stimulated the sympathetic input to rabbit intestine and found a decrease in spontaneous movements. Perfusate did the same thing to a 2nd piece of intestine. Effects mimicked by “adrenaline”. B. Von Euler 1946 demonstrated that NE, not EPI is the main endogenous catecholamine in sympathetically innervated tissue. C. The study of the sympathetic nervous system is important from a clinical perspective. The SNS is involved in controlling heart rate, contractility, blood pressure, vasomotor tone, carbohydrate and fatty acid metabolism etc. Stimulation of the SNS occurs in response to physical activity, psychological stress, allergies etc. Drugs influencing the SNS are used in treatment of hypertension, shock, cardiac failure and arrhythmias, asthma and emphysema, allergies and anaphylaxis. D. There are three major catecholamines: NE, EPI, and DA naturally found in the body. EPI and NE mediate the response of the sympathoadrenal system to activation, and are also found in the CNS. DA is primarily a CNS neurotransmitter.

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I. Sympathomimetic amines have 7 major classes of action

A. A peripheral excitatory action: ie on smooth muscles of blood vessels supplying skin.

B. A peripheral inhibitory action: ie on smooth muscles of gut, bronchioles, and blood vessels supplying skeletal muscle.

C. A cardiac excitatory action: ie positive chronotropic, dromotropic, and inotropic effects.

D. Metabolic actions: ie enhanced glycogenolysis and lipolysis.

E. Endocrine actions: ie modulation of secretion of insulin

F. CNS actions: ie increased wakefulness and inhibition of appetite.

G. Presynaptic actions: ie inhibition of release of NE, NPY, and ACh at autonomic nerve terminals by activation of alpha 2 receptors. Enhanced release of ACh by activation of presynaptic alpha 2 receptors on somatic motor neurons. Enhanced release of NE, and NPY by activation of Beta 2 receptors.

Classification of adrenergic receptor agonists:

II. Pharmacology of Epinephrine A. Epinephrine is a potent stimulator of both alpha (1 & 2) and beta (1,2, & 3) receptors, therefore, its effects on target organs is complex.

B. Effects of EPI on blood pressure are dose dependent. 1. When given in large doses intravenously, EPI gives a rapid increase in blood pressure. As the response wanes, the mean pressure falls below normal before returning to control levels. The pressor effects are due to A) the positive inotropic effect of EPI, B) the positive chronotropic effect, and C) vasoconstriction in many vascular beds. The depressor effect is due to the activation of vasodilator beta 2 receptors in the vasculature perfusing skeletal muscle. This effect is not seen initially because it is overwhelmed by the vasoconstrictive effect of alpha 1 receptors on vascular smooth muscle at other sites, however vasoconstriction is lost as the concentration of EPI goes down, but the beta 2 mediated vasodilatory effect is retained. If you pretreat a person with an alpha adrenergic receptor blocker, one sees the so-called epinephrine reversal effect ie the unopposed effect of the beta 2 receptors causes a pronounced decrease in total peripheral resistance, and mean blood pressure falls in response to EPI.

2. When given in small doses, there is little or no effect on the mean blood pressure because the increase in blood pressure resulting from increased heart rate and contractility is counteracted by the decrease in total peripheral resistance due to vasodilation in blood vessels perfusing skeletal muscle. You will recall that these beta 2 receptors have a lower threshold to activation than alpha 1 receptors, therefore the net effect of low doses of EPI is vasodilation.

3. When EPI causes an increase in mean arterial pressure (High doses), it activates a compensatory vagal baroreceptor mediated bradycardia which also helps to return blood pressure toward normal.

C. Effects of EPI on vascular smooth muscle is variable, resulting in a substantial redistribution of blood flow. That is, EPI causes a marked reduction of blood flow through the skin by activating its alpha 1 receptors, while simultaneously redistributing flow through the muscles by causing vasodilation there through the activation of Beta 2 receptors. This has obvious utility in survival of the organism by preparing it for fight or flight. EPI can reduce renal blood flow by 40% in doses that do not effect mean blood pressure. Effects of EPI on Cerebral Circulation. No significant constrictor action on cerebral blood vessels. If you think about it, it is a lucky thing that the blood flow to the brain is not restricted during responses to stressors.

D. Effects of EPI on Cardiac Muscle are mediated primarily by beta 1 receptors, although Beta 2 and alpha receptors are also present in the heart. As indicated before, EPI has a powerful chronotropic and inotropic effect. EPI reduces the time for systole and makes it more powerful without decreasing the duration of diastole. The latter effect occurs because EPI also increases the rate of relaxation of ventricular muscle. Cardiac output is enhanced and the work of the heart and its oxygen consumption are markedly increased. Cardiac efficiency (work done relative to oxygen consumption) is lessened! The chronotropic action of EPI is due to its ability to accelerate the slow depolarization of pacemaker cells of the SA node that takes place during diastole. Large doses may provoke cardiac arrhythmias. Large doses of EPI, or long term elevation of plasma catecholamines damages the myocardium. This may in part explain the beneficial effects of beta blockers in heart failure.

E. Effects of EPI on Other Smooth Muscles. In general GI muscle is relaxed, and resting tone and peristaltic movements are reduced. This is due to the inhibitory effect of beta 2 receptors, and possibly also due to inhibition of release of ACh by activation of inhibitory presynaptic alpha 2 receptors on cholinergic nerve terminals. The response of the uterus is variable depending on phase of the sexual cycle, state of gestation, and dose of the drug. During the last month of pregnancy, EPI inhibits uterine tone and contractions, by activating beta 2 receptors. As a result, selective beta 2 agonists are used to delay the onset of premature labor. Bronchial smooth muscle is powerfully relaxed by EPI via activation of Beta 2 receptors. Selective beta 2 agonists are used in the treatment of asthma. Epi relaxes the detrusor muscle of the bladder by activating beta receptors, and contracts the trigone and sphincter muscles due to alpha agonist effects. the result is urinary retention.

F. Metabolic effects of EPI:

1. Glycogenolysis via activation of beta 2 receptors, results in an increase in blood glucose.

2. Lipolysis via activation of beta 3 receptors, results in an increase in the concentration of free fatty acids in blood.

3. Insulin secretion is inhibited by alpha 2 receptors, and increased by beta 2 receptors, but inhibition predominates in man.

4. EPI promotes a fall in plasma K due to enhanced uptake of K into skeletal muscle via an action on Beta 2 receptors. This action has been exploited in the management of hyperkalemia.

G. Absorption and fate of EPI

1. Absorption of EPI as well as other catecholamines from GI tract is negligible due to rapid conjugation and oxidation in the intestinal mucosa of the GI tract and liver. Subcutaneous absorption slow due to vasoconstriction. Inhaled effects largely restricted to the respiratory tract in low doses. Larger doses can give systemic effects, including arrhythmias. The liver which is rich in both COMT and MAO destroys most circulating EPI.

H. Toxicity and contraindications

1. EPI causes disturbing reactions such as fear, anxiety, tenseness, restlessness, headache, tremor , weakness, dizziness, etc. Hyperthyroid, and hypertensive patients are particularly susceptible.

2. More serious reactions include cardiac arrhythmias, including fatal ventricular arrhythmias when EPI is given to a patient anesthetized with halogenated hydrocarbon anesthetics such as halothane. Also cerebral hemmorhage due to severe hypertension has occurred. Use of EPI in patients receiving nonselective Beta blockers is contraindicated because the unopposed actions of EPI on vascular alpha 1 receptors can lead to severe hypertension and cerebral hemmorhage.

I. Therapeutic uses of EPI

1. Relief of bronchospasm

2. Relief of hypersensitivity reactions and anaphylaxis

3. To prolong the duration of action of local anesthetics.

4. As a topical hemostatic to control superficial bleeding from skin and mucosae

5. To restore cardiac rhythm in patients with cardiac arrest.

III. Pharmacology of Norepinephrine A. Cardiovascular effects of NE

1. NE is a potent agonist at alpha and Beta 1 receptors, and has little action on beta 2 receptors, therefore when given by intravenous infusion of low doses, NE causes a pronounced increase in total peripheral resistance (i.e. because there is no opposing Beta 2 mediated vasodilation). This is combined with its direct inotropic effect on the heart to cause a substantial increase in mean blood pressure, and a reflexly mediated bradycardia. In contrast to EPI, pretreatment with an alpha 1 antagonist will block the pressor effects of NE, but will not cause reversal to a depressor effect. Since the effects of NE are mainly on alpha and Beta 1 receptors, indirectly acting sympathomimetics which act by releasing NE have predominantly alpha mediated and cardiac effects.

B. Other responses to NE are not prominent in Man.

C. Toxicity

1. The toxic effects of NE are like those of EPI, except they ar less pronounced and less frequently seen ie anxiety, headache, palpitations, etc. In toxic doses, can get severe hypertension. NE, like EPI is contraindicated in anesthesia with drugs that sensitize the heart to the arrhythmic effects of catecholamines such as halothane. Accidental extravasation of NE during attempted intravenous infusion can cause local anoxic necrosis and impaired circulation through the limb. In pregnant females, NE should not be used because it stimulates alpha 1 receptors in the uterus that cause contraction.

D. Therapeutic uses

1. Currently very little therapeutic use. Sometimes used as a cardiac stimulant in cardiogenic or septicemic shock.

IV. Pharmacology of Dopamine

1. At low doses DA activate D 1 receptors in renal, mesenteric, and coronary vascular beds. This leads to vasodilation. Increased flow through renal blood vessels is useful in cardiogenic and septicemic shock when perfusion of vital organs is compromised. DA activates Beta 1 receptors at higher concentrations leading to a positive inotropic effect. Total peripheral resistance is usually unchanged, although at higher concentrations DA can cause activation of alpha 1 receptors mediating vasoconstriction.

B. Toxicity

1. Toxicity of high doses of DA is similar to that noted above for NE. Since the drug has an extremely short half life in plasma, DA toxicity usually disappear quickly if the administration is terminated.

C. Therapeutic uses

1. Useful in treatment of severe congestive heart failure, particularly in patients with oliguria or impaired renal function. DA is also useful in the treatment of cardiogenic and septic shock in patients with reduced renal function.

C. DA Agonists

1. Fenoldopam is a rapidly acting vasodilator which is used for acute control of severe hypertension. It is a D1 receptor agonist as well as an alpha 2 agonist. It does not effect alpha 1 or beta receptors. The half life of fenoldopam is 10 minutes.

V. Pharmacology of Isoproterenol

A. Cardiovascular effects

1. ISO is primarily a beta receptor agonist, therefore intravenous infusion of ISO leads to a substantial reduction of total peripheral resistance. Simultaneously, ISO causes a direct inotropic and chronotropic effect on the heart. The net result is a reduction in mean pressure.

B. Actions on other smooth muscles.

1. ISO relaxes almost all varieties of smooth muscle, but particularly bronchial and GI smooth muscle. Its effectiveness in asthma may also be due to inhibition of the release of histamine by activation of Beta 2 receptors.

C. Metabolic effects

1. ISO is a potent lipolytic (Beta 3) and glycogenolytic (beta 2) drug. It also strongly releases insulin by activating Beta 2 receptors.

D. Metabolism

1. Primarily by COMT, not MAO. Mainly in the liver.

E. Toxicity

1. Like EPI, but much less pronounced. Cardiac arrhythmias can occur readily.

F. Therapeutic uses

1. Used in emergencies to stimulate heart rate in patients with bradycardia or heart block. Its use in asthma and shock has been discontinued due to development of more selective sympathomimetics.

VI. Pharmacology of Dobutamine

A. The mechanisms of action of dobutamine are complex. It is given as the racemic mixture. The l-isomer is a potent agonist at alpha 1 receptors, while the d-isomer is a potent alpha 1 antagonist. Both isomers are beta receptor agonists with greater selectivity for Beta 1 than beta 2 receptors. The net result of administration of the racemic mixture is more or less selective Beta agonist effects.

B. Cardiovascular effects

1. Total peripheral resistance is not much effected, presumably by the counterbalancing effects of beta 2 agonist mediated vasodilation, and alpha 1 agonist mediated vasoconstriction. Dobutamine has a prominent inotropic effect on the heart, without much of a chronotropic effect. The explanation for this is unclear. Like other inotropic agents, dobutamine may potentially increase the size of a myocardial infarct by increasing oxygen demand.

C. Toxicity is like isoproterenol, esp. arrhythmias

D. Not effective orally. Given by I.V. route, however its half life in plasma is two minutes, therefore it must be given by a continuous infusion. After a few days, tolerance develops to its effects. This has led to short term use repeated intermittently.

E. Therapeutic Uses

2. Used in the short term treatment of congestive heart failure or acute myocardial infarctions, because of its inotropic effect, and because it does not increase heart rate and has minimal effects on blood pressure. These effects minimize the increased oxygen demands on the failing heart muscle.

VII Pharmacology of Selective Beta 2 Agonists

A. These compounds are mainly utilized for treatment of asthma. Their advantage over non-selective beta agonists, is that they do not cause undesired cardiovascular effects by stimulating beta 1 receptors of the heart.

B. Metaproterenol, Terbutaline, Albuterol, Pirbuterol are structural analogues of the catecholamines which have been modified so that they are not substrates of COMT and are poor substrates for MAO. This results in a longer duration of action compared to catecholamines and varies from 3 to 6 hours when administered by inhalation.

C. Formoterol is a selective Beta 2 agonist with similarities to the above agents, however it has the advantages a rapid onset of action (minutes) and a long duration (12 hours).

D. Salmeterol is another long acting Beta 2 agonist however it has a slow onset of action, therefore it is not useful for acute asthmatic attacks. It may also have anti-inflammatory activity.

D. Ritodrine is a selective Beta 2 agonist which was developed as a uterine relaxant. It is used to delay the onset of premature labor. Other beta 2 agonists have been used for the same purpose in Europe. While these drugs can delay the onset of birth, they may not have any significant effect in reducing perinatal mortality and may increase maternal morbidity. Nifedepine ( a calcium channel blocker: NOT a beta 2 blocker) caused longer postponement of delivery, fewer maternal side effects, and fewer admissions to the neonatal intensive care unit.

E. Adverse effects of Beta 2 agonists

1. Skeletal muscle tremor is the most common adverse side effect. This may be due to the presence of Beta 2 receptors in skeletal muscle, which when activated, cause twitches and tremor. Tolerance generally develops to this side effect.

2. Restlessness, apprehension, anxiety

3. Tachycardia may occur possibly secondary to beta 2 receptor mediated vasodilation. In patients with heart disease particularly, can see arrhythmias.

4. Increased glycogenolysis

5. Some recent epidemiological studies suggest that regular use of Beta 2 agonists may actually cause increased bronchial hyperreactivity and deterioration in the control of asthma. In patients requiring regular use of these drugs, strong consideration should be given to the use of additional or alternative therapies, such as use of inhaled glucocorticoids.

VIII. Pharmacology of Alpha 1 Agonists

A. Phenylephrine and Methoxamine

1. Primarily directly acting vasoconstrictors by activating alpha 1 receptors. The resulting hypertension results in a prominent reflex bradycardia. They are used in the treatment of atrial tachycardia to terminate the arrhythmia by causing a reflex bradycardia. Phenylephrine is also used as a nasal decongestant and mydriatic. They are not metabolized by COMT, therefore they also have a longer duration of action than the catecholamines.

B. Mephentermine and Metaraminol

1. These drugs have two effects: a) They are directly acting alpha 1 agonists, and b) they are indirectly acting sympathomimetics ie they cause the release of endogenous norepinephrine. The direct effect on alpha 1 receptors mediates vasoconstriction and an increased blood pressure. The indirect effect of released NE on the heart is a positive inotropic and chronotropic action that also increases blood pressure. This results in a reflex bradycardia. Both drugs are administered intravenously. Adverse effects are due to CNS stimulation, excessive increases in blood pressure, and arrhythmias. They are used in the treatment of the hypotension which is frequently associated with spinal anesthesia. Metaraminol is also used in the termination of paroxysmal atrial tachycardia, particularly in patients with existing hypotension.

C. Midodrine1. It is an orally effective alpha 1 agonist which is a prodrug. Its activity is due to metabolism to desglymidodrine. Sometimes used in patients with autonomic insufficiency and postural hypotension.

IX. Pharmacology of Alpha 2 Agonists

A. Introduction

1. Selective alpha 2 agonists are used primarily for the treatment of hypertension. Their efficacy is somewhat surprising since many blood vessels, especially those of the skin and mucosa, contain post-synaptic alpha 2 receptors that mediate vasoconstriction. Indeed clonidine, the prototype alpha 2 agonist drug which we will consider was originally developed as a nasal decongestant because of its ability to cause vasoconstriction of blood vessels in the nasal mucosa. The capacity of alpha 2 agonists to lower blood pressure results from their CNS effect, possibly from the activation of alpha 2 receptors in the medulla that diminish centrally mediated sympathetic outflow.

B. Pharmacology of Clonidine

1. Pharmacological effects

a. Intravenous clonidine can cause a transient rise in blood pressure due to its ability to cause vasoconstriction via an alpha 2 agonist effect on vascular smooth muscle of skin and mucosa. This is followed by a decreased blood pressure due presumably to activation of CNS alpha 2 receptors, resulting in a decreased central outflow of impulses in the sympathetic nervous system, although this is an area of intense current research interest, and some evidence suggests that different mechanisms may be more important. Some of the antihypertensive effect of clonidine may also be due to diminished release of NE at sympathetic postganglionic nerve terminals due to activation of presynaptic alpha 2 receptors. Clonidine also stimulates parasympathetic outflow and causes slowing of the heart.

2. Pharmacokinetics

a. Clonidine is well absorbed orally, and is nearly 100% bioavailable. The mean half life of the drug in plasma is about 12 hours. It is excreted in an unchanged form by the kidney, and its half life can increase dramatically in the presence of impaired renal function. A transdermal delivery system is available in which the drug is released at a constant rate for about a week. Three or four days are required to achieve steady state concentrations.

3. Adverse effects

a. The major adverse effects of clonidine are dry mouth, and sedation. Other effects include bradycardia, and sexual disfunction. About 20% of patients develop a contact dermatitis to the transdermal delivery system. In patients with long term therapy with clonidine, abrupt discontinuation is associated with development of a withdrawal syndrome and potentially life threatening hypertension.

4. Therapeutic uses

a. The major use of clonidine is in the treatment of hypertension.

b. Clonidine is useful in the management of withdrawal symptoms seen in addicts after withdrawal from opiates, alcohol, and tobacco. This may be due to its ability to suppress sympathomimetic symptoms of withdrawal.

c. Clonidine is useful in the diagnosis of hypertension due to pheochromocytoma. In primary hypertension, clonidine causes a marked reduction in circulating levels of norepinephrine. This is not seen if the cause of hypertension is pheochromocytoma.

d. Apraclonidine and Brimonidine are structural analogues of clonidine (ie alpha 2 agonists) which are used topically in the treatment of glaucoma by decreasing the rate of synthesis of aqueous humor. Brimonidine also acts by enhancing the outflow of aqueous humor. Its efficacy in reducing intraocular pressure is equivalent to timolol.

C. Pharmacology of Guanfacine and Guanabenz

1. Guanfacine and guanabenz are alpha 2 receptor agonists which are also believed to lower blood pressure by activation of central sites. Their pharmacological effects and side effects are quite similar to clonidine. Guanfacine has a longer mean half life in plasma than clonidine (12-24 hrs).

X. Miscellaneous Adrenergic Agonist Drugs A. Amphetamine

1. Amphetamine is an indirectly acting sympathomimetic which causes release of NE from adrenergic nerve endings, and also blocks its reuptake into the cytoplasm of the nerve terminal. As such it has potent peripheral effects on alpha 1 & 2 receptors, and Beta 1, but not beta 2 receptors. It is also a potent CNS stimulant which is orally effective.

2. Cardiovascular effects of amphetamine include increased blood pressure, and reflex bradycardia. In larger doses see cardiac arrhythmias.

3. Other smooth muscles respond to amphetamine as they do to previously described sympathomimetics. The contractile effect on the sphincter of the urinary bladder is particularly pronounced and has been used for the treatment of incontinence.

4. Amphetamine is one of the most potent sympathomimetic amines in stimulating the CNS. The d-isomer is 3 to 4 times more potent than the l-isomer. CNS effects include increased wakefulness and alertness; decreased sense of fatigue; elevation of mood, with increased initiative, self-confidence, and ability to concentrate; elation and euphoria; depressed appetite; physical performance in athletes is improved; performance of simple mental tasks is improved, however although more work is accomplished, the number of errors increases. The most striking improvement with amphetamine occurs when performance is reduced by fatigue and lack of sleep. The behavioral effects of amphetamine depend both on the dose and the mental state or personality of the individual. Prolonged use or high doses are nearly always followed by depression and fatigue. Tolerance develops to the appetite suppressant effects rapidly. Amphetamine stimulates the respiratory center. When respiration is depressed by centrally acting drugs, amphetamine can stimulate respiration.

5. Toxicity includes: restlessness, dizziness, tremor, irritability, insomnia, confusion, assaultiveness, anxiety, delirium, paranoid hallucinations, panic states, and suicidal or homicidal tendencies. The psychotic effects of amphetamine, including vivid hallucination and paranoid delusions, which are often mistaken for schizophrenia is the most common serious effect, and can be elicited in any individual taking sufficient quantities of amphetamine for a long period of time. Cardiovascular effects are common and include cardiac arrhythmias, hypertension or hypotension, and circulatory collapse. GI symptoms include dry mouth, nausea, vomiting, and diarrhea. Fatal poisoning usually terminates in convulsions, stroke, and coma. Repeated use leads to the development of tolerance and psychological dependence.

6. Therapeutic uses include treatment of narcolepsy, obesity, and attention-deficit hyperactivity disorder.

7. Methamphetamine, in low doses, has prominent CNS effects like amphetamine, without significant peripheral actions. It has a high potential for abuse. It is used principally for its central effects which are more pronounced than amphetamine. Methylphenidate is a mild CNS stimulant whose pharmacological properties is essentially the same as amphetamine but which may not lead to as much motor activation. Pemoline is another CNS stimulant which has minimal cardiovascular effects. It is used in the treatment of attention-deficit hyperactivity disorder and is given once daily due to its long half-life.

B. Ephedrine

1. Ephedrine is an alkaloid isolated from the plant Ephedra sinica. Extracts of this plant have been used in Chinese herbal medicine for atleast 2000 years. Ephedrine has both directly- and indirectly- mediated sympathomimetic effects. That is, it stimulates both alpha and beta receptors, and it causes release of NE. Ephedrine was the first sympathomimetic drug which was effective orally. Its spectrum of effects is similar to EPI, another sympathomimetic with both alpha and beta agonist effects, however it has a longer duration of effect. In addition it has CNS effects similar to amphetamine, but less intense. In the past it was used as a CNS stimulant for treatment of narcolepsy, and as a bronchodilator in asthma. More selective agents have replaced ephedrine.

C. Ethylnorepinephrine

1. It is primarily a beta agonist with some alpha agonist effects. It is administered IM or SC to cause bronchiolar dilation as well as vasoconstriction in the bronchioles, which reduces bronchial congestion.

D. Oral sympathomimetics used primarily for relief of nasal congestion include phenylephrine, pseudoephedrine, and phenylpropanolamine.

E. Topical sympathomimetics used primarily as nasal decongestants or mydriatics include naphazoline, tetrahydrozoline, oxymetazoline.,and xylometazoline

XI. A Summary of Therapeutic Uses of Sympathomimetics

A. Uses that relate to vascular effects of sympathomimetics

1. Control of superficial hemmorhage, ie in facial, oropharyngeal, and nasopharyngeal surgery. EPI

2. Decongestion of mucous membranes.

a. Usually get temporary relief, but it is often followed by a rebound swelling.

3. To prolong the duration of action of local anesthetics: EPI

4. In the treatment of hypotension and shock.

a. Use controversial because autoregulatory phenomena usually cause intense sympathetic activation, and sympathomimetics may compromise perfusion of vital organs. DA!

B. Uses that relate to CNS effects of sympathomimetics

1. Narcolepsy (amphetamines)

2. Weight Reduction (amphetamines)

3. Attention deficit-hyperactivity disorder (amphetamines, methylphenidate)

C. Uses for cardiac effects

1. Phenylephrine and methoxamine used in PAT by causing a reflex bradycardia.

2. Epinephrine used in emergency treatment of cardiac arrest.

3. DA is useful in the treatment of cardiogenic or septicemic shock especially in patients with compromised renal function.

D. Uses in allergic reactions

1. Epinephrine is the drug of choice to reverse the manifestations of serious acute hypersensitivity reactions due both to its cardiovascular effects and its ability to suppress release of histamine.

2. Asthma is preferentially treated with selective beta 2 agonists (Metaproterenol, terbutaline, albuterol).

E. Uses in ophthalmology

1. Sympathomimetics cause mydriasis ie phenylephrine and epi. These two drugs also cause a reduction in intraocular pressure in wide angle glaucoma.

F. Uses in obstetrics

1. Beta 2 agonist (Ritodrine) blocks onset of premature labor by inhibiting contractility of uterus

G. Nasal decongestion

Adrenoblockers, Sympatholytics agents

All beta-blockers (BBs) except esmolol and sotalol are approved for treatment of hypertension and one or more of following indications: angina pectoris, myocardial Infarction, ventricular arrhythmia, migraine prophylaxis, heart failure and perioperative hypertension.

Only sotalol delays ventricular repolarization and is effective for maintenance of sinus rhythm in patients with chronic atrial fibrilation. Esmolol has short half-life and is given for hypertensive (perioperative) urgency and for atrial arrhythmias after cardiac surgery.

Beta-blockers act by blocking the action of catecholamines at adrenergic receptors throughout the circulatory system and other organs. BBs major effect is to slow the heart rate and reduce force of contraction. BBs via inhibition of receptors at justaglomerular cells inhibit renin release.

Some beta-blockers have intrinsic sympathomimetic activity – ISA (i.e., they stimulate β receptors when background sympathetic nervous activity is low and block them when background sympathetic nervous activity is high). Therefore, theoretically BBs with ISA are less likely to cause bradycardia, bronchospasm, peripheral vasoconstriction, to reduce cardiac output, and to increase lipids. BBs with ISA are less frequently used in the treatment of hypertension.

Beta Blocker

Relative

Cardiac

Selectivity

Intrinsic Sympathomimetic

Activity

Daily

Dosing

Frequency

Lipid

Solubility

b₁ + a₁

Acebutolol SECTRAL

Moderate

–

Atenolol TENORMIN

–

Low

–

Betaxolol KERIONE

–

Low

–

Bisoprolol ZEBETA

–

Low

–

Carteolol CARTROL

–

Low

–

Carvedilol COREG

–

High

Esmolol BREVIBLOC

–

i.v.

Moderate

–

Labetalol TRANDATE

NORMODYNE

–

Moderate

Metoprolol LOPRESSOR

–

1 or 2

Mod. / High

–

Nadolol CORGARD

–

Low

–

Penbutol LEVATOL

–

High

–

Pindolol VISKEN

+++

Moderate

–

Propranolol INDERAL

–

High

–

Timolol BLOCADREN

–

Low / Mod.

–

Lipophilic beta blockers may enter CNS more extensively and readily which may lead to increased CNS side effects. Labetalol and carvedilol have both β₁– and α₁-blocking properties, and decrease heart rate and peripheral vascular resistance. Both agents possess the side effects common for both classes of drug. Beta-blockers tend to be less effective in the elderly and in black hypertensives. To reduce side effects in hypertensive patients it is recommended to use a beta-blocker with high cardioselectivity, low lipid solubility and long half-life that allows once daily dosing.

Adverse effects: BBs slow the rate of conduction at the atrio-ventricular node and are contraindicated in patients with second- and third-degree heart block. Sinus bradycardia is common and treatment should be stopped if patient is symptomatic or heart rate falls below 40 b/min. Because of blockade of pulmonary ß₂ receptors, even small doses of BBs can cause bronchospasm (less common with cardioselective agents), and all beta-blockers are contraindicated in asthma. Blockade of ß receptors in the peripheral circulation causes vasoconstriction and may induce particularly in patients with peripheral circulatory insufficiency adverse affects such as cold extremities, Raynaud’s phenomenon, and intermittent claudication. Nevertheless, they are reasonably tolerated in patient with mild peripheral vascular disease. Lipid-soluble agents can cause central nervous system side effects of insomnia, nightmares and fatigue. Exercise capacity may be reduced by BBs and patients may experience tiredness and fatigue. BBs can worsen glucose intolerance and hyperlipidemia and in diabetic patients mask signs of hypoglycemia. However, diabetic hypertensive patients with previous MI should not be denied BB because of concerns about metabolic side effects.

Alpha-1 adrenergic receptor blockers ( …. OSIN )

Prazosin [MINIPRESS] Terazosin [HYTRIN] Doxazosin [CARDURA]

Alfuzosin [UROXATRAL] Tamsulosin [FLOMAX]

The β₁-adrenoceptor blockers produce vasodilatation by blocking the action of norepinephrine at post-synaptic β₁ receptors in arteries and veins. This results in a fall in peripheral resistance, without a compensatory rise in cardiac output. Doxazosin, terazosin, and, less commonly, prazosin are used as oral agents in the treatment of hypertension. They are relatively more selective for a_1b– and a_1d-receptors which are involved in vascular smooth muscle contraction. Alfuzosin and tamsulosin are used for symptomatic treatment of begin prostatic hyperplasia (BPH), since compared to other oral α₁-blockers, they have less antihypertensive effects and are relatively more selective as antagonists at the α_1asubtype, the primary subtype located in the prostate.

Based on ALLHAT study data, alpha blockers are not longer considered first-line drug for treatment of hypertension. They are drugs of choice for treatment of hypertensive patient with BPH. Adverse effects include first dose hypotension, dizziness, lethargy, fatigue, palpitation, syncope, peripheral edema and incontinence.

Adverse Reactions: The adverse effects of beta-blockers are generally mild and temporary; they usually occur at the onset of therapy and diminish over time. Most adverse reactions of beta-blockers are extensions of their therapeutic effects. Bradycardia and hypotension are rarely serious and can be reversed with IV atropine, if necessary. AV block, secondary to depressed conduction at the AV node, might necessitate sympathomimetic and/or pressor therapy or the use of a temporary pacemaker. Congestive heart failure is more likely to occur in patients with preexisting left ventricular dysfunction and usually will respond to discontinuation of beta-blocker therapy.

Adverse CNS effects include dizziness, fatigue, and depression. Although much less common with hydrophilic beta-blockers, CNS depression can occur, resulting in mental disorders, fatigue, and, in some cases, vivid dreams. Diarrhea and nausea/vomiting are the most common GI adverse effects during therapy with beta-blockers. Bronchospasm and dyspnea are more likely to occur with nonselective beta-blockers or with high doses of cardioselective agents because the beta selectivity of the drug is lost. Patients with preexisting bronchospastic disease are at greater risk.

Both hypoglycemia and hyperglycemia can occur during beta-blocker therapy. Beta-blockers can interfere with glycogenolysis to cause hyperglycemia and can also mask signs of hypoglycemia. Beta-blockers should be used cautiously in brittle diabetics.

beta-blockers have little effect on total cholesterol and plasma LDLs, but have been shown to increase triglycerides and decrease plasma HDLs. The role that the characteristics of cardioselectivity and intrinsic sympathomimetic activity of beta-blockers play in these effects are more controversial. In a recent meta-analysis, it was shown that agents with intrinsic sympathomimetic activity or cardioselectivity tend to have less effect on triglycerides and HDLs. Agents with both characteristics tended to reduce total cholesterol and LDLs.

Adverse reactions from ophthalmic beta-blockers are usually limited to their ocular effects, such as transient burning, stinging, and blurred vision however, these preparations can be absorbed causing systemic adverse reactions, similar to oral or parenteral beta-blockers. Ophthalmic betaxolol appears to cause less systemic effects compared to ophthalmic timolol and levobunolol.

Comparison of agonists, antagonists, and partial agonists of β adrenoceptors.

Despite the current knowledge of the diversity and function of beta-receptors within the human body, much remains to be learned about some of their regulatory roles in physiologic homeostasis. Although the variety of beta-receptor antagonists that are currently available is plentiful, the pharmacologic uses for beta-receptor antagonists is likely to continue to grow.

Adrenergic receptor-activating drugs. Adrenergic receptor-blocking drugs. Sympatholytic agents

ALPHA AND BETA ADRENERGIC RECEPTOR AGONISTS

History:

I. Sympathomimetic amines have 7 major classes of action

A. A peripheral excitatory action: ie on smooth muscles of blood vessels supplying skin.

B. A peripheral inhibitory action: ie on smooth muscles of gut, bronchioles, and blood vessels supplying skeletal muscle.

C. A cardiac excitatory action: ie positive chronotropic, dromotropic, and inotropic effects.

D. Metabolic actions: ie enhanced glycogenolysis and lipolysis.

E. Endocrine actions: ie modulation of secretion of insulin

F. CNS actions: ie increased wakefulness and inhibition of appetite.

Classification of adrenergic receptor agonists:

II. Pharmacology of Epinephrine A. Epinephrine is a potent stimulator of both alpha (1 & 2) and beta (1,2, & 3) receptors, therefore, its effects on target organs is complex.

3. When EPI causes an increase in mean arterial pressure (High doses), it activates a compensatory vagal baroreceptor mediated bradycardia which also helps to return blood pressure toward normal.

F. Metabolic effects of EPI:

1. Glycogenolysis via activation of beta 2 receptors, results in an increase in blood glucose.

2. Lipolysis via activation of beta 3 receptors, results in an increase in the concentration of free fatty acids in blood.

3. Insulin secretion is inhibited by alpha 2 receptors, and increased by beta 2 receptors, but inhibition predominates in man.

4. EPI promotes a fall in plasma K due to enhanced uptake of K into skeletal muscle via an action on Beta 2 receptors. This action has been exploited in the management of hyperkalemia.

G. Absorption and fate of EPI

H. Toxicity and contraindications

1. EPI causes disturbing reactions such as fear, anxiety, tenseness, restlessness, headache, tremor , weakness, dizziness, etc. Hyperthyroid, and hypertensive patients are particularly susceptible.

I. Therapeutic uses of EPI

1. Relief of bronchospasm

2. Relief of hypersensitivity reactions and anaphylaxis

3. To prolong the duration of action of local anesthetics.

4. As a topical hemostatic to control superficial bleeding from skin and mucosae

5. To restore cardiac rhythm in patients with cardiac arrest.

III. Pharmacology of Norepinephrine A. Cardiovascular effects of NE

B. Other responses to NE are not prominent in Man.

C. Toxicity

D. Therapeutic uses

1. Currently very little therapeutic use. Sometimes used as a cardiac stimulant in cardiogenic or septicemic shock.
IV. Pharmacology of Dopamine

A. Cardiovascular effects

B. Toxicity

C. Therapeutic uses

C. DA Agonists

V. Pharmacology of Isoproterenol

A. Cardiovascular effects

B. Actions on other smooth muscles.

C. Metabolic effects

1. ISO is a potent lipolytic (Beta 3) and glycogenolytic (beta 2) drug. It also strongly releases insulin by activating Beta 2 receptors.

D. Metabolism

1. Primarily by COMT, not MAO. Mainly in the liver.

E. Toxicity

1. Like EPI, but much less pronounced. Cardiac arrhythmias can occur readily.

F. Therapeutic uses

1. Used in emergencies to stimulate heart rate in patients with bradycardia or heart block. Its use in asthma and shock has been discontinued due to development of more selective sympathomimetics.

VI. Pharmacology of Dobutamine

B. Cardiovascular effects

C. Toxicity is like isoproterenol, esp. arrhythmias

E. Therapeutic Uses

VII Pharmacology of Selective Beta 2 Agonists

C. Formoterol is a selective Beta 2 agonist with similarities to the above agents, however it has the advantages a rapid onset of action (minutes) and a long duration (12 hours).

D. Salmeterol is another long acting Beta 2 agonist however it has a slow onset of action, therefore it is not useful for acute asthmatic attacks. It may also have anti-inflammatory activity.

E. Adverse effects of Beta 2 agonists

2. Restlessness, apprehension, anxiety

3. Tachycardia may occur possibly secondary to beta 2 receptor mediated vasodilation. In patients with heart disease particularly, can see arrhythmias.

4. Increased glycogenolysis

VIII. Pharmacology of Alpha 1 Agonists

A. Phenylephrine and Methoxamine

B. Mephentermine and Metaraminol

IX. Pharmacology of Alpha 2 Agonists

A. Introduction

B. Pharmacology of Clonidine

1. Pharmacological effects

2. Pharmacokinetics

3. Adverse effects

4. Therapeutic uses

a. The major use of clonidine is in the treatment of hypertension.

C. Pharmacology of Guanfacine and Guanabenz

X. Miscellaneous Adrenergic Agonist Drugs A. Amphetamine

2. Cardiovascular effects of amphetamine include increased blood pressure, and reflex bradycardia. In larger doses see cardiac arrhythmias.

6. Therapeutic uses include treatment of narcolepsy, obesity, and attention-deficit hyperactivity disorder.

B. Ephedrine

C. Ethylnorepinephrine

D. Oral sympathomimetics used primarily for relief of nasal congestion include phenylephrine, pseudoephedrine, and phenylpropanolamine.

E. Topical sympathomimetics used primarily as nasal decongestants or mydriatics include naphazoline, tetrahydrozoline, oxymetazoline.,and xylometazoline

XI. A Summary of Therapeutic Uses of Sympathomimetics A. Uses that relate to vascular effects of sympathomimetics

1. Control of superficial hemmorhage, ie in facial, oropharyngeal, and nasopharyngeal surgery. EPI

2. Decongestion of mucous membranes.

a. Usually get temporary relief, but it is often followed by a rebound swelling.

3. To prolong the duration of action of local anesthetics: EPI

4. In the treatment of hypotension and shock.

a. Use controversial because autoregulatory phenomena usually cause intense sympathetic activation, and sympathomimetics may compromise perfusion of vital organs. DA!

B. Uses that relate to CNS effects of sympathomimetics

1. Narcolepsy (amphetamines)

2. Weight Reduction (amphetamines)

3. Attention deficit-hyperactivity disorder (amphetamines, methylphenidate)

C. Uses for cardiac effects

1. Phenylephrine and methoxamine used in PAT by causing a reflex bradycardia.

2. Epinephrine used in emergency treatment of cardiac arrest.

3. DA is useful in the treatment of cardiogenic or septicemic shock especially in patients with compromised renal function.

D. Uses in allergic reactions

1. Epinephrine is the drug of choice to reverse the manifestations of serious acute hypersensitivity reactions due both to its cardiovascular effects and its ability to suppress release of histamine.

2. Asthma is preferentially treated with selective beta 2 agonists (Metaproterenol, terbutaline, albuterol).

E. Uses in ophthalmology

1. Sympathomimetics cause mydriasis ie phenylephrine and epi. These two drugs also cause a reduction in intraocular pressure in wide angle glaucoma.

F. Uses in obstetrics

1. Beta 2 agonist (Ritodrine) blocks onset of premature labor by inhibiting contractility of uterus

G. Nasal decongestion

Beta-blockers

History: Ahlquist hypothesized in 1948 that the physiologic effects of catecholamines were mediated by the activation or inhibition of specific receptors, which he termed alpha and beta. This finding led to the development of antagonists at these receptors that would interfere with the effects of catecholamines. Although alpha-receptor-specific antagonists were available in the early 1950s (e.g., phentolamine and phenoxybenzamine), the first pure beta-blocker, propranolol, was not marketed until 1967. Subsequent to the discovery of propranolol, beta₁– and beta₂-selective agents, as well as drugs with intrinsic sympathomimetic activity within each subset, were developed. Today, no fewer than 15 beta-blockers have been marketed.

Although initially it was believed that beta-receptors on myocardial tissue were of the beta₁ subtype, it is now accepted that beta₂-receptors are also located on myocardial cells and are also important regulators of cardiac activity. In addition to cardiac tissue, beta-receptors are located on smooth muscle of the bronchioles, uterus, within the eye, on many blood vessels, in the liver, and in various organ and regulatory systems throughout the body.

Further, it is increasingly being recognized that administration of beta-blockers following myocardial infarction exerts a beneficial effect on mortality. Beta-blockers have been beneficial for both primary and secondary myocardial infarction prophylaxis to prevent sudden death and also are beneficial for the acute treatment of myocardial infarction.

Beta-blocking drugs have many non-cardiovascular applications including treatment of essential tremor, treatment of thyrotoxicosis, prevention of anxiety, prevention of migraine headache, prevention of bleeding associated with esophageal varicies and, administered ophthalmically, beta-blockers are useful for the treatment of glaucoma. The use of beta-blockers for the prevention of GI bleeding or rebleeding due to esophageal varices is controversial. A meta-analysis of 4 trials of patients with esophageal varices without previous bleeding found that patients receiving nadolol or propranolol had a significantly lower incidence of GI bleeding or fatal bleeding compared to the control group, however, overall survival after 2 years was not different between the groups.

Ophthalmic beta-blockers are the most commonly used agents in the treatment of glaucoma. They reduce IOP and treat ocular hypertension. Beta-blockers provide an alternative mechanism for the treatment of glaucoma over the more traditional agents (e.g., pilocarpine, physostigmine). Some ophthalmically-administered beta-blockers are also available for systemic administration (e.g., betaxolol, carteolol, timolol), whereas other beta-blockers are only available as ophthalmic preparations (levobunolol, metipranolol).

Mechanism of Action: In general, all beta-adrenergic antagonists compete with adrenergic neurotransmitters (i.e., catecholamines) for binding at sympathetic receptor sites. These drugs block sympathetic stimulation mediated by beta₁-adrenergic receptors in the heart and vascular smooth muscle. Blockade of beta₁-receptors decreases both resting and exercise heart rate and cardiac output, decreases both systolic and diastolic blood pressure, and inhibits the reflex response to orthostatic hypotension. The fall in cardiac output induced by beta₁ antagonism is often countered by a moderate reflex increase in peripheral vascular resistance that can be magnified by beta₂ blockade (unopposed alpha stimulation). As a result, nonselective beta-blocking agents can produce a more modest decrease in diastolic blood pressure compared with selective beta₁ antagonists. In addition, nonselective agents can competitively block beta₂-adrenergic responses in the bronchial muscles, potentially inducing bronchospasm.

Therapeutic actions of beta-blockers in the treatment of hypertension include a negative chronotropic effect that decreases heart rate at rest and after exercise; a negative inotropic effect; reduction of sympathetic outflow from the CNS; and suppression of renin release from the kidneys. Thus, beta-blockers affect blood pressure via multiple mechanisms.

Actions that make beta-receptor antagonists useful in treating hypertension also apply to managing chronic stable angina. The reduction in myocardial oxygen demand induced by these agents decreases the frequency of anginal attacks, decreases nitrate requirements, and increases exercise tolerance. Other postulated anti-anginal actions include an increase in oxygen delivery to tissues as a result of beta-receptor antagonist’s lowering of hemoglobin’s affinity for oxygen; reduction of platelet aggregation is postulated to be related to interference with calcium ion flux.

A critical result of beta blockade is a reduction in myocardial ischemia. Beta-blockers can limit the severity and recurrence of infarction, as well as a decrease in mortality secondary to myocardial infarction. In addition to a decrease in myocardial oxygen demand, beta-blockers also possess antiarrhythmic properties at the nodal level of pacemaker control. Although beta blockade is most beneficial when initiated within the first few days following acute myocardial infarction, especially in the highest risk subgroup of patients, relative reductions in infarct size secondary to the use of beta-blockers can approach 10-30% per year. As a result, beta-blockers should be considered standard therapy for secondary prevention of reinfarction and reduction of late mortality in all patients who do not have a clear contraindication to beta blockade.

Other clinical applications of beta-blockers make use of both the cardiovascular and the nervous system actions. The cardiovascular actions of beta-blockers are useful in the prevention of migraine and the treatment of portal hypertension to prevent bleeding of esophageal varicies. Sympatholytic effects make beta-blockers useful for the treatment of essential tremor, thyrotoxicosis, and to control situational anxiety.

beta-blockers, especially propranolol, have been used for the treatment of thyrotoxicosis. Beta-blockade can ameloriate the symptoms associated with thyrotoxicosis such as tremor, palpitations, anxiety, and heat intolerance. In addition, D-propranolol and nadolol block the conversion of T₄ to T₃, but the therapeutic effect of this action is minimal.

beta-blockers have been used to treat portal hypertension and to prevent bleeding of esophageal varices. Nonselective beta-blockers such as nadolol and propranolol decrease blood flow in the superior portosystemic collateral circulation and blood flow in the splanchnic region, ultimately decreasing portal venous pressure. A decrease in cardiac output may also reduce hepatic arterial and portal venous perfusion. Most trials utilized a therapeutic end point of a reduction in resting heart rate of 20-25% or a decrease in hepatic pressure of 25% (or < 12 mmHg). Activation of unopposed alpha-receptors leads to splanchnic vasoconstriction, thus decreasing portal perfusion. The efficacy of therapy appears to be related to compliance, lack of ascites, and patients with less severe disease.

In the prevention of migraine headaches, beta-blockade can interfere with arterial dilation, inhibit renin secretion, and block catecholamine-induced lipolysis. Blocking lipolysis decreases arachidonic acid synthesis and subsequent prostaglandin production. Inhibition of platelet aggregation is secondary to a decrease in prostaglandins and blockade of catecholamine-induced platelet adhesion. Other actions include increased oxygen delivery to tissues and prevention of coagulation during epinephrine release.

In the management of hereditary of familial essential tremor, beta-blockade controls the involuntary, rhythmic and oscillatory movements. Tremor amplitude is reduced, but not the frequency of tremor.

beta-blockers can dampen the peripheral physiologic symptoms of anxiety. Beta-blockade can attenuate somatic symptoms of anxiety such as palpitations and tremor, but it is less effective in controlling psychologic components, such as intense fear.

Ophthalmic beta-blockers interfer with the production of aqueous humor via inhibition of adrenergically driven processes within the ciliary processes. As a result of their actions, IOP is reduced in patients with either elevated or normal IOP. This reduction occurs irrespective of the presence of glaucoma. Decreased aqueous humor may also be responsible for the ocular antihypertensive effects. Visual acuity, pupil size, and accommodation do not appear to be affected by beta-blockade.

Distinguishing Features: Beta-adrenergic blockers can be divided into five primary categories: nonselective agents with or without intrinsic sympathomimetic activity (ISA) or partial agonist activity (PAA); cardioselective (e.g., beta₁-selective) agents with or without ISA/PAA; and dual-acting (alpha- and beta-antagonist) agents. Nonselective agents without ISA include nadolol, propranolol, sotalol, and timolol. Cardioselective agents without ISA include atenolol, betaxolol, bisoprolol, esmolol, and metoprolol. The primary nonselective beta-adrenergic antagonist with ISA currently available in the United States is pindolol. Acebutolol is the only cardioselective beta-blocker with ISA. Carvedilol and labetalol are beta-adrenergic antagonists with alpha-blocking properties.

Another distinction can be made with respect to lipophilicity of the beta-blockers. The more lipophilic drugs tend to be metabolized to a greater extent, to exhibit greater serum concentration variability, and to have a shorter duration of activity. The most lipophilic beta-blockers are acebutolol, betaxolol, labetalol, metoprolol, propranolol, and timolol. The water-soluble beta-antagonists are atenolol, nadolol, and sotalol. There is some possibility that lipid-soluble beta-blockers may be more effective in prevention sudden cardiac death following myocardial infarction. Because the more lipid-soluble members of the class appear to be more effective for this use, a central mechanism of action is proposed. Atenolol (water-soluble) and metoprolol (lipid-soluble) are currently approved by the FDA for early and late adjunctive treatment of acute myocardial infarction.

Propranolol is the only agent FDA approved for essential tremor, although metoprolol, nadolol and timolol are also effective. Atenolol, nadolol, propranolol, timolol have been used to prevent migraine headaches.

With respect to administration, esmolol is an ultra-short-acting agent with a half-life of 9 minutes that is given only by continuous infusion. When considering indications, most agents, except labetalol, are useful in one or more of the following conditions: angina, hypertension, arrhythmias, mild congestive heart failure, and post-MI adjunctive therapy. Clearly, the beta-adrenergic antagonists are a diverse and extremely important class of pharmacologic agents.

Few distinctions are available for the ophthalmic beta-blockers. The onset of action is similar for all agents, ranging from 30-60 minutes, with a duration of action ranging between 12-24 hours. Betaxolol is the only beta₁-receptor specific ophthalmic beta-blocker. Levobunolol appears to be the most effective agent when given on a once daily basis.

Adverse Reactions: The adverse effects of beta-blockers are generally mild and temporary; they usually occur at the onset of therapy and diminish over time. Most adverse reactions of beta-blockers are extensions of their therapeutic effects. Bradycardia and hypotension are rarely serious and can be reversed with IV atropine, if necessary. AV block, secondary to depressed conduction at the AV node, might necessitate sympathomimetic and/or pressor therapy or the use of a temporary pacemaker. Congestive heart failure is more likely to occur in patients with preexisting left ventricular dysfunction and usually will respond to discontinuation of beta-blocker therapy.

Adrenoblockers, Sympatholytics agents

All BBs except esmolol and sotalol are approved for treatment of hypertension and one or more of following indications: angina pectoris, myocardial Infarction, ventricular arrhythmia, migraine prophylaxis, heart failure and perioperative hypertension.

Beta-blockers may be classified based on their ancillary pharmacological properties. Cardioselective agents have high affinity for cardiac β ₁ and less affinity for bronchial and vascular β₂ receptors compared with non-selective agents and this reduces (but does not abolish) β₂receptor-mediated side effects. However, with increasing doses cardiac selectivity disappears. Lipid-soluble agents cross the blood-brain barrier more readily and are associated with a higher incidence of central side effects. Some beta-blockers have intrinsic sympathomimetic activity – ISA (i.e., they stimulate β receptors when background sympathetic nervous activity is low and block them when background sympathetic nervous activity is high). Therefore, theoretically BBs with ISA are less likely to cause bradycardia, bronchospasm, peripheral vasoconstriction, to reduce cardiac output, and to increase lipids. BBs with ISA are less frequently used in the treatment of hypertension.

Beta Blocker

Relative

Cardiac

Selectivity

Intrinsic Sympathomimetic

Activity

Daily

Dosing

Frequency

Lipid

Solubility

b₁ + a₁

Acebutolol SECTRAL

Moderate

–

Atenolol TENORMIN

–

Low

–

Betaxolol KERIONE

–

Low

–

Bisoprolol ZEBETA

–

Low

–

Carteolol CARTROL

–

Low

–

Carvedilol COREG

–

High

Esmolol BREVIBLOC

–

i.v.

Moderate

–

Labetalol TRANDATE

NORMODYNE

–

Moderate

Metoprolol LOPRESSOR

–

1 or 2

Mod. / High

–

Nadolol CORGARD

–

Low

–

Penbutol LEVATOL

–

High

–

Pindolol VISKEN

+++

Moderate

–

Propranolol INDERAL

–

High

–

Timolol BLOCADREN

–

Low / Mod.

–

Adverse effects: BBs slow the rate of conduction at the atrio-ventricular node and are contraindicated in patients with second- and third-degree heart block. Sinus bradycardia is common and treatment should be stopped if patient is symptomatic or heart rate falls below 40 b/min. Because of blockade of pulmonary ß₂ receptors, even small doses of BBs can cause bronchospasm (less common with cardioselective agents), and all beta-blockers are contraindicated in asthma. Blockade of ß receptors in the peripheral circulation causes vasoconstriction and may induce particularly in patients with peripheral circulatory insufficiency adverse affects such as cold extremities, Raynaud’s phenomenon, and intermittent claudication. Nevertheless, they are reasonably tolerated in patient with mild peripheral vascular disease. Lipid-soluble agents can cause central nervous system side effects of insomnia, nightmares and fatigue. Exercise capacity may be reduced by BBs and patients may experience tiredness and fatigue. BBs can worsen glucose intolerance and hyperlipidemia and in diabetic patients mask signs of hypoglycemia. However, diabetic hypertensive patients with previous MI should not be denied BB because of concerns about metabolic side effects.

Catecholamines

Drug

Receptors

Epinephrine

alpha1, alpha2 ß1, ß2

Norepinephrine (Levophed)

alpha1, alpha2, ß1

Isoproterenol (Isuprel)

ß1, ß2

Dobutamine (Dobutrex)

ß1 (alpha1)

Dopamine (Intropin)