1 chapter 11 adrenoceptor antagonist drugs cao yongxiao 曹永孝 department of pharmacology

1

Chapter 11 Adrenoceptor Antagonist Drugs

Cao Yongxiao 曹永孝Department of Pharmacology yxy

@xjtu.edu.cn;029-82655140 http://pharmacology.xjtu.edu.cn

http://pharmacology.xjtu.edu.cn/

http://pharmacology.xjtu.edu.cn/

2

receptors and prevent their activation by catecholamines and related agonists.

Drugs blocking adrenoceptors vary dramatically acc

ording to the drug’s selectivity for αand βreceptors.

Their major effect is to occupy eitherα, or β

西安交大医学院药理学系曹永孝 [email protected]; 029-82655140

mailto:[email protected]

3

Nonselectiveαantagonists can treat pheochromocytoma (secrete catecholamines).

α1-selective antagonists are used in hypertension and benign prostatic hyperplasia (BPH).



4

Beta-receptor antagonist drugs are firmly established in the treatment of hypertension, ischemic heart disease, arrhythmias, endocrinologic and neurologic disorders, and other conditions.



5

I BASIC PHARMACOLOGY OF THE ALPHA- RECEPTOR ANTAGONIST DRUGS

Mechanism of ActionAlpha-receptor antagonists may be reversible or irreversible. Reversible antagonists can dissociate from receptors. Phentolamine, tolazoline, prazosin and labetalol are reversible.

Phenoxybenzamine is irreversible. 西安交大医学院药理学系曹永孝 [email protected]; 029-82655140


6

Cardiovascular Effects

In the case of epinephrine with both αand β2 effects, αreceptor antagonism may convert a pressor to a depressor response which is called epinephrine reversal.

α- antagonist drugs block α receptors, dilate vascular smooth muscle, lower peripheral resistance and BP; can prevent the pressor effects of αagonists.



7

Alpha-receptor antagonists may cause postural hypotension and reflex tachycardia.

Postural hypotension is due to antagonism of sympathetic nervous system stimulation of α1 receptors in venous smooth muscle.



Minor effects in other tissues

miosis and nasal stuffiness.


The radial muscle is innervated by alpha receptor. Its blockade by antagonists results in miosis.

The smooth muscles of the iris

stuffiness


9

Alpha 1-receptor blockade

of base of the bladder and

the prostate is associated

with decreased resistance

to the flow of urine.

Benign Prostatic Hyperplasia (BPH).



10

SPECIFIC AGENTS

Phentolamine is a potent competitive antagonist at bothα1 and α2 receptors.

It reduces peripheral resistance through blockade of α.

It can stimulate the heart due to baroreflex mechanisms resulting in sympathetic stimulation.

It blocks α2 receptors, enhance release of NE from sympathetic nerves, contributing to cardiac stimulation via β receptors.



11

Phentolamine also inhibits responses to serotonin (5-HT) and activate M and histamine (H) receptors, has multiple potential actions,

The principal adverse effects are cardiac stimulation, such as tachycardia, arrhythmias, myocardial ischemia and nasal congestion as well as headache.

Phentolamine has been used in pheochromocytoma.



12

Tolazoline is similar to phentolamine.

It has limited clinical application in the treatment

of pulmonary hypertension in newborn infants wit

h respiratory distress syndrome.

Ergot derivatives, eg ，Ergotamine, dihydroergotamine

cause reversible α-receptor blockade.



13

Phenoxybenzamine binds covalently to αreceptors, causing irreversible blockade of long duration (2 d).

It is somewhat selective for α1 receptors.

It reduces BP when sympathetic tone is high and little fall in BP in normal supine individuals.

It inhibits reuptake of NE by blocking α2 on presynaptic terminals and increase cardiac output.

It also blocks histamine (H1), ACh, and serotonin receptors as well as αreceptors.



14

The adverse effects of phenoxybenzamine derive from its α-receptor –blocking action.

The most important are postural hypotension, tachycardia and nasal stuffiness.

Since phenoxybenzamine enters the CNS, it may cause less specific effects, including fatigue, sedation, and nausea.



15

Prazosin is highly selective for α1 receptors, leads to v

asodilation.

It is effective in the management of hypertension.

It has relatively low affinity for α2 receptors (1/ 1000). Thi

s may explain the relative absence of tachycardia.

Terazosin is another reversible α1-selective antagonist th

at is effective in hypertension.

Terazosin has high bioavailability but is extensively meta

bolized in the liver. Its half-life is 9-12 h.

16

II. Clinical Pharmacology of the Alpha-Receptor-Blocking Drugs

PheochromocytomaPhenoxybenzamine and phentolamine

are most useful in the pre-operative m

anagement of pheochromocytoma. Th

ey can control hypertension and rever

se chronic changes resulting from cate

cholamine secretion such as plasma v

olume contraction.

Phenoxybenzamine is useful in the chronic treatment of inoperable or metastatic pheochromocytoma.Beta-receptor antagonists may be required to reverse the cardiac effects of excessive catecholamines.



17

HYPERTENSIVE EMERGENCIES

Labetalol has been used in hypertensive emergency.

The α-adrenoceptor antagonists are most useful when increased BP reflects excess of αagonists.

In this circumstance, which may result from overdosage of sympathomimetic drugs, pheochromocytoma, phentolamine can be used to control high BP.



18

Chronic Hypertension

Prazosin family of α1-selective antagonists are efficacious in the treatment of hypertension. However, their efficacy in preventing heart failure for hypertension has been questioned.

The adverse effect is postural hypotension, which may be severe after the first dose.

Nonselective α antagonists are not used in primary hypertension.



19

Peripheral Vascular Disease

Theα-receptor-blocking drugs have been tired in the treatment of peripheral vascular occlusive disease.

Local Vasoconstrictor Excess Phentolamine has been used to reverse the vasoconstriction caused by infiltration of αagonists (NE)into subcutis during intravenous administration.

The αantagonist is administered by local infiltration into the ischemic tissue.

http://images.google.com/imgres?imgurl=http://www.zcbj.com/images/wenxian_10.jpg&imgrefurl=http://www.zcbj.com/anuice/anlezhi-wenxian.htm&h=270&w=448&sz=19&hl=zh-CN&start=7&tbnid=D3K7YTYn6KppnM:&tbnh=77&tbnw=127&prev=/images%3Fq%3D%25E6%25AF%259B%25E7%25BB%2586%25E8%25A1%2580%25E7%25AE%25A1%26svnum%3D10%26hl%3Dzh-CN%26lr%3D%26newwindow%3D1%26sa%3DG

http://www.sinoas.com/tutorial/tutorial10/200505/1668.html

20

Urinary Obstruction Alpha-receptor blockade ca

n improve urine flow in BPH. The mechanism involves reversal of smooth muscle contraction in the enlarged prostate and in the bladder base.

Phenoxybenzamine, prazosin, doxazocin, and terazosin are efficacious, particularly in patients with hypertension.



21

III. Basic Pharmacology of the Beta-Receptor- Antagonist Drugs

Beta-blocking drugs occupy βreceptors and reduce receptor occupy by catecholamines and other βagonists.

Most β-blocking drugs are pure antagonists; ie, after being occupied, βreceptor causes no activation.

Some are partial agonists; ie, they cause partial activation of the receptor, less than that caused by the full agonist.

Partial agonists inhibit the activation of receptors in the presence of high catecholamine concentrations but moderately activate the receptors in the absence of endogenous agonists.



The partial agonist in this example has high affinity for the receptor, so it remains bound for a long time once it reaches the binding site. As a result, when the partial agonist is present at high concentration, most of the receptors are occupied most of the time. However, because it has lower "efficacy" than the full agonist, only a fraction of the bound receptors can activate effector molecule. Therefore, the maximum response produced by the partial agonist is less than 100% of the maximum response of the system.



Partial agonist AffinityLow intrinsic activityLow efficacy

对激动剂：小剂量激动大剂量拮抗



24

Another major difference among the β-receptor-blocking drugs concerns their relative affinities forβ1 and β2 receptors.

Some of these antagonists have a higher affinity for β1 than forβ2 receptors

The selectivity is dose-related, ie, it tends to diminish at higher concentrations.

Other major differences among β antagonists relate to their pharmacokinetics.



25

Pharmacodynamics of theβ-Receptor- Antagonist Drugs

However, some actions may be due to partial agonist activity at βreceptors and local anesthetic action, which differ among the β-blockers.

Most of the effects of these drugs are due to occupancy and blockade of βreceptors.



Effects on the Cardiovascular System Beta-adrenoceptor-blocking drugs are of major clinical importance in the treatment of hypertension.

.

Conventional doses do not cause hypotension in healthy individuals with normal BP.

The mechanisms include effects on the heart and blood vessels, the rennin-angiotensin system, and the CNS


HeartBeta-receptor antagonists

have prominent effects on

the heart.

The negative inotropic and chronotropic effects.

Slowed atrioventricular conduction with an increased PR

interval is a related result of adrenoceptor blockade in the

atrioventricular node. 西安交大医学院药理学系曹永孝 [email protected]; 029-82655140

Vascular System

Theβ-antagonists

blockade β2-receptors, contracting vessel,

antagonize the release of rennin, dilating vessel.

In any event, while the acute effects of these drugs may include a rise in peripheral resistance.

Chronic drug administration leads to a fall in peripheral resistance in patients with hypertension.

Effects on the Respiratory Tract

Beta 1 antagonists have advantage over nonselective βantagonists when blockade of β1 in the heart is desired and β2 blockade is undesirable .

However, no available β1-selective antagonist is sufficiently specific to completely avoid interactions with β2 adrenoceptors.

They should be avoided in patients with asthma.

Blockade of the β2 receptors in bronchus increases airwayresistance, particularly in asthma.

C. Effects on the Eye

Several β-blocking agents reduce intraocular

pressure, especially in glaucomatous eyes.


The mechanism usually is decreased aqueous humor production



D. Metabolic and Endocrine Effects Beta-receptor antagonists such as propranolol inhibit lipolysis.

The effects on carbohydrate metabolism are less clear, but they should be used with caution in insulin-dependent diabetic patients.

The chronic use of β-adrenoceptor antagonists has been associated with increased plasma VLDL and decreased concentrations of HDL cholesterol.


E. Effects not Related to Beta-BlockadeLocal anesthetic action, also known as “membrane-stabilizing” action, is a prominent effect of several β-blockers.

This action is the result of local anesthetic blockade of sodium channels.

However, this effect is not important, since the concentration in plasma usually achieved by these routes is too low for the anesthesia.


Clinical Application

HypertensionThe β-adrenoceptor-blocking

drugs are effective and well

tolerated in hypertension.

While many hypertensive patients will respond to a β-blocker used alone, the drugs is often used with either a diuretic or a vasodilator.


Ischemic Heart DiseaseBeta-adrenoceptor blockers reduce t

he frequency of anginal episodes an

d improve exercise tolerance in patie

nts with angina.

These actions relate to the blockade of cardiac βreceptors, resulting in decreased cardiac work and reduction in oxygen demand. Slowing of the heart rate may contribute to clinical benefits.


Cardiac ArrhythmiasBeta antagonists are effective in both supraventricular and ventricular arrhythmias. By increasing the atrioventricular nodal refractory period, β antagonists slow ventricular rates in atrial flutter and fibrillation.

They can also reduce ventricular ectopic beats, particularly precipitated by catecholamines.


http://www.nda.ox.ac.uk/wfsa/html/u11/u1105f14.htm

Other Cardiovascular Disorders Beta-receptor antagonists can increase stroke volume in some patients with obstructive cardiomyopathy.

This is due to the slowing of ventricular ejection and decreased outflow resistance.

Beta-antagonists are useful in dissecting aortic aneurysm to decrease the rate of dev

elopment of systolic pressure. 西安交大医学院药理学系曹永孝 [email protected]; 029-82655140

Glaucoma

Timolol and related βantagonists are suitable for local use in the eye because they lack local anesthetic properties.

Betaxolol, carteolol, levobunolol, and metipranolol are newer β-receptor antagonists for the glaucoma.

β-blocking drugs can reduce production of aqueous humor and decrease intraocular pressure in glaucoma.


Hyperthyroidism

These beneficial effects relate to blockade of adrenoceptors and to the inhibition of peripheral conversion of thyroxine to triiodothyronine.

Propranolol has been used extensively in patients with thyroid storm.

Excessive catecholamine action is an

important aspect of hyperthyroidism.

The β antagonists have salutary effects

in this condition.


Neurologic Diseases

Propranolol reduce the frequency and intensity of migraine headache.

Other β-receptor antagonists with preventive efficacy include metoprolol and probably also atenolol, timolol, and nadolol.

The mechanism is not known.


CHOIC OF A BETA-ADRENOCEPTOR ANTAGONIST DRUG

Propranolol is the standard against.

It is a safe and effective drug for many indications布莱克 (1924 ～ ) 英国药理学家1964 年研制出治疗冠心病的代表药—心得安。1988 年获 Nobel Prize 。 Sir James W. BlackThe Nobel Prize in Physiology or Medicine 1988


CLINICAL TOXICITY OF THE BETA-RECEPTOR ANTAGONIST DRUGS

A variety of minor toxic effects have been reported.

Beta 2-receptor blockade by nonselective agents commonly causes worsening of preexisting asthma and airway obstruction in normal individuals.

Beta-receptor blockade depresses myocardial contractility and excitability.

Caution must be exercised in using β-receptor antagonists in compensated heart failure.


Beta-blockers may interact with the calcium antagonist; hypotension, bradycardia, heart failure, conduction abnormalities have all been described.

These adverse effects may even arise in susceptible patients taking a topical (ophthalmic) β-blocker and oral verapamil.

Patients with ischemic heart disease may be at increased risk if β-blockade is suddenly interrupted, which might involve up-regulation of the β-receptors.


I am glad to share my knowledge with you,

and I want you to become a master of the subject, pharmacology

Thanks a million

for your co-operation西安交大医学院药理学系曹永孝 [email protected]; 029-82655140


1 chapter 11 adrenoceptor antagonist drugs cao yongxiao 曹永孝 department of pharmacology

Documents