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    Figure 105

    Classification of adrenergic receptor antagonists.

    Drugs marked by an asterisk (*) also block receptors. 1

I. Alpha Adrenergic Receptor Antagonists

    A. Introduction

    1. Alpha receptors mediate many important actions of endogenous catecholamines. These include: a. alpha 1 mediated vasoconstriction,

b. alpha 2 receptor mediated inhibition of the release of NE and ACh,

    c. alpha 2 mediated inhibition of insulin secretion and inhibition of lipolysis,

    d. alpha 2 mediated contraction of blood vessels in skin and mucosa (these receptors are preferentially activated by circulating catecholamines, whereas alpha 1 receptors are activated by NE released at sympathetic nerve terminals).

    e. alpha 2 mediated central inhibition of sympathetic tone.

    2. Correspondingly therefore it should be evident that "A detailed knowledge of the autonomic nervous system and the sites of action of drugs that act on adrenergic receptors is essential for understanding the pharmacology and therapeutic uses of ..." adrenergic receptor blocking drugs (G & G, 1990,p221).

    B. The most important effects of alpha 1 & 2 adrenergic antagonists are on the cardiovascular system. These cardiovascular effects are mediated in large part by the effects of the antagonists on sympathetic nerve endings, and by effects on the CNS. The antagonism which is observed in most cases is competitive. C. Cardiovascular Effects of Alpha 1 Antagonists

    1. Alpha 1 antagonists block vasoconstriction induced by endogenous catecholamines. The resulting fall in

    peripheral resistance leads to a fall in mean blood pressure. The magnitude of this effect is dependent upon the degree of sympathetic tone at the time the antagonist is administered. Thus there is less hypotension in the supine than in the standing patient. The decrease in blood pressure leads to a reflex tachycardia. The reflex effects are exaggerated if the drug also has alpha 2 antagonist effects, because antagonism of alpha 2

    receptors facilitates release of NE presynaptically to cause a further tachycardic effect.

    2. They block the vasoconstriction and hypertensive effects of exogenous sympathomimetics. For example,

    pressor responses to phenylephrine (a pure alpha 1 agonist) are completely blocked. Pressor responses to EPI can be transformed to depressor responses (EPI reversal) because of stimulation of beta 2 receptors by EPI.

    D. Cardiovascular Effects of Alpha 2 Antagonists

    1. Alpha 2 antagonists increase sympathetic outflow by an action on the CNS. This potentiates the release of NE from sympathetic nerve endings leading to activation of alpha 1 receptors in vascular smooth muscle, and beta 1 receptors in the heart among others. The net result is an increase in mean blood pressure, and a reflex bradycardia.

    E. Other Actions of Alpha Adrenergic Antagonists

    1. Alpha antagonists can block alpha 1 receptors that mediate contraction of nonvascular smooth muscle such as the trigone and sphincter muscles of the bladder, leading to decreased resistance to urinary outflow.

    2. Activation of alpha 2 receptors causes inhibition of insulin secretion. Blockade of these receptors facilitates insulin release.

F. Pharmacology of Phenoxybenzamine

    1. Phenoxybenzamine is an irreversible alpha blocker that blocks both alpha 1 and alpha 2 receptors with a slight preference for alpha 1 receptors. It causes a decrease in peripheral resistance, and a reflex tachycardia due to hypotension mediated baroreceptor effects, and also because it blocks alpha 2 receptors, resulting in increased release of NE. Hypotension is particularly prevalent when sympathetic reflexes are active, such as in the standing patient, or during stress. A major side effect therefore is postural hypotension. Also seen are cardiac arrhythmias. Phenoxybenzamine blocks pressor responses to exogenous catecholamines, and in fact

    causes reversal of the pressor response to EPI into a depressor response. Phenoxybenzamine also inhibits the uptake of catecholamines into nerve terminals and extraneuronal uptake sites, and irreversibly inhibits 5-HT, and histamine receptors in higher doses than those required for alpha receptor blockade. Duration of effect of this drug is many days. A major use of this drug is in the management of hypertension in pheochromocytoma prior to surgery.

    G. Pharmacology of Phentolamine and Tolazoline

    1. Phentolamine and tolazoline are competitive antagonists of both alpha 1 and alpha 2 receptors. As such their effects on the cardiovascular system are similar to those of phenoxybenzamine just discussed. These drugs also have a parasympathomimetic effect on GI smooth muscle and gastric secretions. Toxicity is like that of

    phenoxybenzamine. Phentolamine is no longer marketed in the U.S.A.

    H. Pharmacology of Prazosin and Related Drugs

    1. Prazosin is the prototype of a family of potent and very selective alpha 1 receptor antagonists. It has 1000X greater affinity for alpha 1 vs alpha 2 receptors. It blocks all alpha one receptor subtypes equipotently. It is a short acting drug with a duration of action of about 7 to 10 hours. Prazosin causes a decrease in total peripheral resistance, but not an increase in heart rate (since alpha 2 receptors are not inhibited). Terazosin is a close

    structural analogue of prazosin with similar pharmacological effects, but an intermediate duration of action, ie approximately 18 hours. Doxazosin is another structural analogue with similar pharmacological effects to

    prazosin, but with a long duration of action, ie 36 hours. Adverse effects of these drugs include the so-called "first dose phenomenon". That is marked postural hypotension and fainting 30-90 minutes after the first dose, or with the addition of a second antihypertensive drug to a patient already taking one of these agents. Postural hypotension is another side effect. A major use of these drugs is in the treatment of hypertension. Alpha 1 receptors in the trigone muscle of the bladder and in the urethra contribute to the resistance to outflow of urine. Alpha 1 receptor blockers reduce this resistance especially when impaired bladder emptying is the result of benign prostatic hyperplasia. Tamsulosin is another alpha 1 blocker, with little effect on alpha 1-B receptors

    and considerable efficacy at the alpha 1-A receptor which is believed to be predominant in human bladder and prostate.. It is used in the treatment of benign prostatic hyperplasia because it decreases the resistance to urinary flow, with less hypotensive effects on blood pressure (although all the alpha blockers have been tested and are relatively effective in BPH). Alfuzosin is another related compound used in the treatment of benign

    prostatic hypertrophy.

    I. Miscellaneous drugs with alpha adrenergic blocking activity

    1. The ergot alkaloids were the first adrenergic blocking agents to be discovered.Ergot is a fungus which grows on rye which contains many biologically active components. Ergotism is a disease characterized by profound

    vasoconstriction , ischemia, and gangrene of the affected limb. In the Middle Ages it was known as St. Anthony's Fire, and was relieved by visiting the shrine of St. Anthony which was located in an area of France where bread was seldom contaminated with the fungus. Both ergotamine, and dihydroergotamine are

    structural derivatives of a compound isolated from ergot which have potent competitive alpha antagonist effects. These drugs are sometimes used in the treatment of migraine headache. However, 5HT-1 receptor agonists (ie sumatriptan) appear to be more effective and safer for migraine.

    2. Phenothiazines, which are antipsychotic drugs, have potent alpha blocking actions.

    J. Therapeutic Uses of Alpha Adrenergic Receptor Blockers

    1. Hypertension

    2. Pheochromocytoma

    3. Sometimes used in treatment of peripheral vasospastic disease ie Raynauds disease to improve perfusion

    4. To enhance urinary flow in benign prostatic hyperplasia. Major therapy is surgery.

    5. Treatment of local excess concentration of a vasoconstrictor in order to prevent necrosis.

    K. Toxicity of Alpha Blockers

    1. Postural hypotension

    a. First dose phenomenon with prazosin and analogues

    2. Reflex tachycardia, especially with agents that also block alpha 2 receptors.

    3. Other arrhythmias

    4. Parasympathomimetic effects of phentolamine and tolazoline.


    II. Beta Adrenergic Receptor Blockers

    A. Introduction

    1. Cardiovascular effects of Beta Blockers

    a. Since catecholamines have positive inotropic and chronotropic effects on the heart, beta blockers slow the heart rate, and decrease myocardial contractility. When sympathetic activation is low, these drugs have modest effects. However, when sympathetic activation is high, such as during exercise and stress, beta

    blockers attenuate the expected increase in heart rate, and diminish cardiac output. Blockade of vascular Beta 2 receptors results in increased total peripheral resistance. Blood flow to most organs other than the brain is reduced. With long term use total peripheral resistance returns toward normal by unclear mechanisms. Beta blockers tend to decrease the capacity to work. Exercise performance is impaired less by selective Beta 1 blockers. Beta blockers have important effects on cardiac rhythm and automaticity. They reduce the sinus rate, decrease the rate of depolarization of ectopic pacemakers, and slow conduction in the atria and AV node. Lots more on this topic during lectures on antiarrhythmic drugs. Beta blockers do not

    lower blood pressure in normal man, however they do reduce blood pressure in hypertensive man. The

    mechanism of this effect has not been satisfactorily explained.Some beta blockers have peripheral vasodilating effects via different mechanisms which may contribute to their capacity to lower blood pressure. These include celiprolol and nebivolol. Chronic prophylactic therapy with a beta blocker in patients who have had a myocardial infarct appears to help prevent the recurrence of a second fatal myocardial infarct. 2. Pulmonary effects of Beta Blockers

    a. Beta blockade usually has little effect on pulmonary function in normal man, however in asthmatics they can cause life threatening bronchoconstriction. Although Beta 1 selective blockers may be less likely to cause respiratory problems in asthmatics, these drugs should be used with great caution, if at all in patients with bronchospastic disease since even relatively selective blockers have some affinity for the beta 2 receptor.

    3. Metabolic effects of Beta Blockers

    a. Catecholamines promote glycogenolysis and mobilize glucose in response to hypoglycemia. Non-selective Beta blockers adversely effect recovery from hypoglycemia in insulin dependent diabetics. Nonselective Beta blockers must therefore be used with great caution in diabetics. A selective Beta 1 blocker is usually preferable in this case. Beta blockers (Beta 3 receptor) attenuate the lipolytic response to sympathetic nervous system activation which is an important energy source for exercising muscle. Selective beta 1 antagonists may cause these effects less fequently than non-selective antagonists.

    B. Pharmacology of Nonselective Beta Blockers

    1. Propranolol

    a. After oral administration, propranolol is almost completely absorbed, but undergoes extensive first pass metabolism in the liver. The extent of clearance by the liver varies radically across patients however and results in as much as a 20 fold difference in plasma concentration of the drug after oral administration to different persons. This has obvious significance in patients with liver disease. 90% of the drug in the circulation is bound to plasma proteins. When used as an antihypertensive agent, the full response on the blood pressure may not develop until after several weeks of administration. Abrupt withdrawal of propranolol after chronic therapy can lead to the develpment of withdrawal symptoms. Side effects include GI distress (relatively unopposed parasympathetic nervous system), and CNS effects such as nightmares, insomnia, and depression.

    2. Nadolol

    a. Nadolol is a nonselective beta blocker with a long duration of action. Nadolol is poorly lipid soluble, and incompletely absorbed from the GI tract. Interindividual variability in its bioavailability is less than with propranolol. It is not extensively metabolized, and is excreted intact in the urine. As such kidney disease is a cause for concern, and may result in an accumulation of nadolol. Because nadolol is poorly lipid soluble, it is thought that there will be lower concentrations of nadolol in the brain, and this may contribute to a lower incidence of CNS side effects seen with this drug.

    3. Timolol

    a. It is a nonselective blocker with a short duration of action. It is well absorbed from the gut and is subject to moderate first pass metabolism. It is metabolized by the liver and only a small fraction is excreted by the kidney in unchanged form. Timolol is an example of a beta blocker which is used in glaucoma to reduce the rate of synthesis of aqueous humor. The ocular form of timolol is well absorbed into the circulation and adverse effects can occur in patients with asthma or congestive heart failure.

    b. Other new drugs with similar mechanisms of action include Penbutolol, and Pindolol

    4. Labetolol

    a. It is an example of a nonselective beta blocker which also blocks alpha 1 receptors. It also inhibits uptake

    of NE from the synaptic cleft (a cocaine-like effect). Its pharmacokinetics are like those of Propranolol discussed above, ie well absorbed, highly metabolized and very variably so on first pass through liver, mainly metabolized by liver. It is used in the treatment of pheochromocytoma and hypertensive emergency, where its alpha 1 effects promote vasodilation and hypotension, while its beta 1 effect helps reduce reflex tachycardia.

    b. Other new drugs with a similar mechanism of action include Carvedilol, and Bucindolol

    C. Pharmacology of Selective Beta Blockers

    1. Metaprolol

    a. It is a selective Beta 1 antagonist, whose pharmacokinetics are like propranolol which is also devoid of intrinsic sympathomimetic activity and membrane-stabilizing activity.

    2. Atenolol

    a. It is also a selective Beta 1 antagonist which is also devoid of intrinsic sympathomimetic activity and membrane-stabilizing activity. It is a poorly lipid soluble drug. About half of an oral dose is absorbed, but most of this reaches the systemic circulation ie there is no first pass metabolism in the liver. As a result, peak concentrations of this drug in the plasma are not so variable across patients. It is excreted unchanged in the urine. It has a somewhat longer duration of action than metaprolol.

    3. Esmolol

a. it is a selective Beta 1 antagonist with a very very short duration of action which is also devoid of intrinsic

    sympathomimetic activity and membrane-stabilizing activity.

     It is given by iv infusion. It has a half life of about 8 minutes in plasma, and is metabolized by plasma

    esterases. It is used only for the treatment of atrial tachycardia.

    4. Nebivolol

    a. It is the most selective Beta 1 antagonist clinically available which is devoid of intrinsic sympathomimetic

    activity, but has the ability to reduce systemic vascular resistance via a direct vasorelaxant effect mediated

    via release of NO. Nebivolol is effective in treating hypertension and heart failure. b. Other new drugs with a similar mechanism of action include Bisoprolol, Acebutolol,

Table 104 Pharmacological/Pharmacokinetic Properties of Receptor Blocking





    NG T ON (%) s) NG



    Classical non-selective blockers: First generation

     Nadolol 0 0 Low 30 3050 2024 30

    Penbutol0 + High 100 100 5 8098


    Pindolol + +++ Low >95 100 34 40

    Propranol++ 0 High <90 30 35 90


    Timolol 0 0 Low to 90 75 4 <10


    -Selective blockers: Second generation 1

Acebutol+ + Low 90 2060 34 26


    Atenolol 0 0 Low 90 5060 67 616

    Bisoprolol0 0 Low ð90 80 912 30

Esmolol 0 0 Low NA NA 0.15 55

    *Metoprol+ 0 Moderate 100 4050 37 12


    Non-selective blockers with additional actions: Third generation

    Carteolol 0 ++ Low 85 85 6 2330

    Carvedilo++ 0 Moderate >90 30 710 98


    Labetalol + + Low >90 33 34 50

    -selective blockers with additional actions: Third generation 1

Betaxolol+ 0 Moderate >90 80 15 50

Celiprolol0 + Low 74 3070 5 45

     *Detectable only at doses much greater than required for blockade.

    D. Toxic Effects of Beta Blockers

    1. Patients with impaired cardiac function have high levels of sympathetic activation of the heart to provide support for cardiac performance. In these patients, beta blockers may provoke an acute incident of congestive heart failure. In fact use of beta blockers in heart failure was once contraindicated. a. Despite this fact, beta antagonists are currently being used for the treatment of mild to moderate degrees of congestive heart failure. Not all beta blockers are equally efficacious, however metoprolol appears to be

    useful. The mechanisms which underly this beneficial effect are poorly understood at this time. 2. Arrhythmias, especially bradyarrhythmias .

3. Bronchoconstriction, especially in asthmatics

    4. CNS effects include fatigue, sleep disturbances & depression

    5. Beta blockers may blunt recognition of hypoglycemia by patients. Metabolic effects include delayed recovery from insulin induced hypoglycemia. Beta blockers should be used with great caution in patients with diabetes who are prone to hypoglycemic reactions. Beta 1 selective antagonists may be prefereable. E. Drug Interactions

    1. Drugs that induce hepatic drug metabolizing enzymes will reduce the plasma concentrations of beta blockers that are extensively metabolized by the liver. These include barbiturates, many miscellaneous sedative hypnotic drugs, phenytoin (diphenylhydantoin), as well as smoking.

    F. Therapeutic Uses of Beta Blockers

    1. Used as Antihypertensives especially in mild cases where they are less likely than other agents to provoke postural hypotension.

    2. In the treatment of ischemic heart disease

    a. In angina, beta blockers reduce cardiac work and oxygen consumption. This reduces the frequency of anginal episodes.

    b. Long term prophylactic use of nonspecific beta blockers helps prevents the recurrence of a fatal second myocardial infarct in patients who survived an initial attack. The mechanism of this effect is not known, but may derive from decreased myocardial oxygen demand and antiarrhythmic effects of beta blockers. 3. In the treatment of mild to moderate degees of congestive heart failure, chronic treatment with certain beta-1 blockers prolong the life expectancy. Long term use of beta blockers reduces cardiac volume, myocardial hypertrophy, filling pressure, and increases ejection fraction.Beta blockers impact mortality rates however even before these events are seen.

    4. Beta blockers are antiarrhythmics. More in other lectures. Here, only mentioned their ability to block atrial tachycardia.

    5. In glaucoma, beta blockers decrease the rate of synthesis of aqueous humors. Topically administered beta blodkers have little or no effect on pupil size or accommodation and do not cause the blurred vision and night blindness often seen with miotics.

    6. Many of the signs and symptoms of hyperthyroidism are due to sympathetic nervous system activation. Beta blockers reduce these symptoms.

    7. Beta blockers are useful in the prophylaxis of migraine, but not in treatment.

    III. A Summary of the Pharmacology of Alpha and Beta Receptor Agonists and Antagonists

    Table 106 Summary of Adrenergic Agonists and Antagonists




    Direct-Epinephrine (, Increase in Open-angle Palpitation Not given 1

    acting , , , ) heart rate glaucoma orally 2123Cardiac non- Increase in With local arrhythmias Life saving selective blood anesthetics in agonistsCerebral pressure to prolong anaphylaxis hemorrhage action or cardiac Increased arrest Headache contractility Anaphylacti

    c shock Tremor Slight

    decrease in Complete Restlessnes

    PVR heart block s

    or cardiac Increase in arrest cardiac

    output Bronchodilat

    or in Vasoconstriasthma ction





    Increase in


    glucose and

    lactic acid

    Norepinephrine (Increase in Hypotension Similar to Not absorbed orally

    , , , >> ) systolic and Epi 1212

     diastolic Hypertensioblood n pressure



    Increase in



    increase in

    heart rate


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