Adrenoceptor Agonist and Antagonist Drugs-2014.10.7ppt

1

Adrenoceptor agonists

Jiang Junlin 江俊麟

Department of Pharmacology,

School of Pharmaceutical Science, Central South University

Adrenergic Nervous System: Overview

HO

HO

NHMe

OH

Epinephrine(Adrenaline)

HO

HO

NH2

OH

Norepinephrine(Noradrenaline)

Types of -adrenergic receptor

They are subdivided into two types:

1 adrenergic Receptor-Located on postsynaptic effector cells

in vessel, eye, heart, and liver, with effects including

vasoconstriction, uterine contraction and pupillary dilation,

2-adrenergic receptor-Located on presynaptic nerve terminals, with

effects controlling the release of neurotransmitters (negative

feedback-inhibition of norepinephrine release.)

Predominant -adrenergic agonist responses---Vasoconstriction

-receptor types

They are subdivided into three types:

β1-Adrenergic receptors are located mainly in heart and kidney.

β2-Adrenergic receptors are located mainly in bronchial tract,

liver, uterus, vascular smooth muscle in skeletal muscle.

β3-receptors are located in fat cells.

Adrenergic Drugs

Drugs that stimulate the sympathetic nervous system (SNS)

Adrenergic agonists

Sympathomimetics

Mimic the effects of the SNS neurotransmitters: norepinephrine (NE)

epinephrine (EP)

Basic Pharmacology of Sympathomimetics

Phenylethylamine is the parent compound for sympathomimetic drugs.

This compound consists of a benzene ring with an ethylamine side chain.

Substitutions may be made (1) on the terminal amino

group, (2) on the benzene ring, (3) on the α or β-carbons.

Substitution by -OH group at the 3 and 4 positions yield

catecholamines.

The modification of phenylethylamine change the affinity of the drugs for receptors, the intrinsic

ability and pharmacokinetics.

Structure-Activity Relationship (SAR) of Adrenomimetics

Responsible for

different receptor selecitvity of sympathomimetics --> different actions

different distribution of drugs --> different actions

different duration

Catechol amine

OH

OH

phenylethylamine

CH CH NH

R1 R2 R3

1

65

4

3 2

According to the chemical structure

catecholamines

non-catecholamines

Catecholamine drugs

Catecholamines-high polarity ①poor oral absorption ② easy to be inactivated by COMT, shorter duration not easily cross the blood brain barrier ( weak role in the central , ③strong role in peripheral )

Non-catecholamines-high lipophila Go to a hydroxyl group (metaraminol) - increased oral ①bioavailability, prolonged duration of action, reduced role in peripheral

To two hydroxyl (ephedrine) - reduced role in peripheral, strong ②role in central

Structure-Activity Relationship1) different chemical groups on the

benzene ring

2) the hydrogen atom of the amino group (-NH-) is substituted by various groups:Substituted groups from methyl, tertiary and butyl, the role of α weakened, role of β receptor enhanced (epinephrine isoproterenol, salbutamol).

CH CH NH

R1 R2 R3

1

65

4

3 2

norepinephrine epinephrine isoproterenol salbutamol

3 ） α-H replaced by methyl (-CH3):Not easily be MAO destruction, prolonged duration of action, and promote norepinephrine (ephedrine, metaraminol, etc.).

4) -H replaced by hydroxy (-OH):The central role is weak, peripheral effect is obvious.

CH CH NH

R1 R2 R3

1

65

4

3 2

ClassificationAccording to the affinity for different

groups of receptor:

α-adrenoceptor agonists

β-adrenoceptor agonists

α, β-adrenoceptor agonists

α-adrenoceptor agonists

Norepinephrine

Metaraminol

α 1 -adrenoceptor agonists

phenylephrine and methoxamine

Potent effect of α receptor

Relative little effect on β1 receptor

weak effect on β2 receptor

α receptor agonist

norepinephrin

1. Cardiovascular system

Pharmacodynamics

Vessel : α receptor

constrict vessels of skin, cutaneous, visceral(splanchn

ic), lung, kidney

a rise in BP and an increase in peripheral vascular r

esistance (PVR)

Heart : receptor

an increase in heart rate, contractions and conduction

velocity

a reflex increase in vagal outflow (BP increase) --> reflex bradycardia

Net effect: BP ， heart rate？Net effect: BP ， heart rate？

2. Metabolism (high dose)

Blood glucose increased (glycogenolysis and

gluconeogenesis, α2, β1)

Free fatty acids increased (α2, β1, β3)

1) early shock: Drug induced hypotension Pheochromocytoma resection Resection of sympathetic nerve

Clinical uses:

Application of the principles

early, low-dose, short-term use (long-term heavy use: vasoconstriction, increased peripheral resistance, increased the burden on the heart, decreased cardiac output, reduced pressure, decreased in perfusion of heart, brain, kidney and lung.

Shock

is a complex acute cardiovascular syndrome that

results in a critical reduction in perfusion of vital

tissues, and usually associated with hypotension,

oliguria.

The major mechanisms are hypovolemia, cardiac

insufficiency, and altered vascular resistance.

sympathomimetic drugs have been used in the

treatment of all forms of shock.

2)cardiac arrest adjuvant therapy (to help cardiac

resuscitation)

3) upper gastrointestinal bleeding: oral (local effects)

Side effects

1) local tissue necrosis

2) Acute renal failure: renal vasoconstriction, oliguria,

anuria, renal damage

Hypertension, arteriosclerosis

Contraindication

Metaraminol

Characteristics: non-catecholamine, stable, maintaining for a long time, not easily damaged by COMT and MAO.Effects:(1) a direct role: mainly act on α1 receptors, beta receptors weak.

indirect role: promoting the release of NA.②

Clinical uses:

1) replace NA for shock in the early

2) Hypotension or shock induced by

operation or spinal anesthesia

Phenylephrine

α 1receptor agonist

1) shock, or anesthesia-induced hypotension

2) paroxysmal supraventricular tachycardia

3) Examining the retina is facilitated by

mydriasis.

increase peripheral resistance and venous capacitance and rise the

BP. The rise in BP increases baroreceptor-mediated vagal tone with

slowing of the heart rate.

increase peripheral resistance and venous capacitance and rise the

BP. The rise in BP increases baroreceptor-mediated vagal tone with

slowing of the heart rate.

α and β agonist

Epinephrine

Dopamine

ephedrine

adrenal medulla ： EP85% ， NA 15%

At low concentration, β effects predominate ;

at high concentration, α effects predominate.

β-R are more sensitive to EP than the α-R.

Epinephrine

Cardiovascular System Pharmacological propertiesPharmacological properties

The heart are determined

largely by β1 receptors.

β-receptor activation increase

calcium influx in cardiac cells.

Contractility is increased, heart rate is

accelerated.

A. Heart

B. Blood Vessels

Regulate vascular tone.

Alpha receptors increase arterial resistance,

B1recptors in kidney induce the release of renin, β2 receptors relax smooth muscle.

There are differences in receptor types in the various vascular beds.

Blood PressureThe effects of sympathomimetic drugs on BP is based on their effects on the heart, the peripheral vascular resistance, and the venous return

Cummulative effect is

an increase in systolic BP,

a slight decrease diastolic BP

Epinephrine (E)

Vasoconstriction in systemic arteries (α)

Vasodilation in skeletal muscle arteries (β2);

The overall response

At low concentrations, epinephrine decreases BP. 

At high concentrations, epinephrine increases BP because vasoconstriction of α-receptors offsets the β2-receptor mediated vasodilation.

Respiratory Tract Bronchial smooth muscle contains β2

receptors that cause bronchodilation.

The blood vessels of the respiratory tract

mucosa contains α receptors;

The decongestant action of adrenoceptor

stimulants is clinically useful.

Blocks the release of histamine (β2 in mast

cell of bronchial tract)

snuffle

Metabolic effects

increase in glucoses and lactate production via

glycogenolysis (β-R)

inhibition of insulin secretion (α-R)

increase in free fatty acid and oxygen

consumption .

1 ） cardiac arrest ：cardiac arrest due to electric shock, severe electrolyte

imbalance, drug allergies, drug toxicity, acute asthma,

drowning, anesthesia accidents, infectious diseases

2) Anaphylactic shock —will usually lead to

death in minutes if left untreated.

Therapeutic uses

Characteristics: ① dilated small blood vessels, increased peripheral

resistance, increased capillary permeability, and decreased

blood pressure.

② bronchial smooth muscle spasm, mucosal edema,

laryngeal edema, difficulty in breathing

③ Cardiac function depression

Adrenaline is a first choice drug for treatment of anaphylactic shock. Why?

Effect of Adrenaline

• Constrict blood vessels, increase blood pressure ;

• Stimulate heart, dilate coronary artery, improve heart

function

• Dilate bronchial, constrict bronchial mucosa, reduce

bronchial mucosal edema, relieve breathing difficulties;

• Inhibit the release of allergic mediators (histamine),

improve breathing difficulties.

3) Bronchial asthma-Control acute bronchial asthma, subcutaneous or intramuscular injection can work within minutes.

① stimulate β2 receptor in bronchial smooth muscle, relax

bronchial smooth muscle.

② stimulate β 2 receptor in mast cell of bronchial mucosa

and submucosa, inhibit the release of allergic mediators

(histamine and other substances )

③constrict bronchial mucosal vascular (α receptor ), reduce

asthma mucosal edema and capillary permeability.

hypertension, diabetic melliusCerebral arteriosclerosis

Palpitations, irritability

Headache, elevated BP

Cerebral hemorrhage

Arrhythmia

Ventricular fibrillation

contradiction

Side effects

DopamineBe metabolized by MAO and COMT quickly

No effect on CNS

activate α 、 β1 and dopa-receptor

Pharmacological properties

heart: act on β1 receptor, positive inotropic effect on the myocardium, increase cardiac output

blood vesselsAt low or intermediate concentration: act on D1 receptor, dilate

At high concentration : act on α-receptor, constrict

Pharmacological Effects

KidneyAt low or intermediate concentration: reduce arterial resistance in the mesentery and kidney At high concentration: cause vasoconstriction with consequent reduction in renal function

The effect on renal blood flow is of clinical value.

Clinical uses

Shock

Acute renal failure

Adverse reaction

Arrhythmia

Reduction in renal function

Ephedrine

Ephedrine occurs in plants and has been used in China for over 2000 years.

Ephedrine can activate both α and βreceptors

Because ephedrine is a noncatechol, it has high bioavailability and a long duration of action –hours rather than minutes.

Clinical Uses

bronchial asthma

nasal decongestant

hypotension without crisis

Adverse reactions: CNS

β-receptor agonist-isoproterenol

A very potent β-receptor

agonist.

It activates β1 and causes

positive chronotropic and

inotropic actions; leading to a

marked increase in cardiac

output and an increase in

systolic BP. It activates β2, results in vasodilation, which associate

with a fall in diastolic and mean arterial pressure.

Cardiac Applications

Isoproterenol and epinephrine have been

utilized in the management of complete heart

block and cardiac arrest.

Heart failure may respond to the positive

inotropic effects of drugs such as dobutamine.

Pulmonary Applications

The most important use is in the therapy of

bronchial asthma.

Nonselective drugs, β agents, and β2-selective

agents are all available for this indication.

β2-selective drugs have less adverse effects.

ANS - Adrenergic DrugsResponses to Stimulation

Location Receptor Response

Cardiovascular:Blood vessels 1 Constriction

2 DilationCardiac muscle 1 Increased contractility

AV Node 1 Increased heart rate

SA Node 1 Increased heart rate

Gastrointestinal: Muscle: 2 Decreased motilitySphincters: 1 Constriction

ANS - Adrenergic DrugsResponses to Stimulation

Location Receptor Response

Genitourinary:Bladder sphincter 1 Constriction

Penis 1 Ejaculation

Uterus 1 Contraction2 Relaxation

Respiratory:Bronchial muscles 2 Dilation

Liver 2 Glycogenolysis

Pupils 1 Dilation

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Adrenoceptor Antagonist Drugs

Jiang Junlin 江俊麟

Department of Pharmacology,

School of Pharmaceutical Science, Central South University

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Drugs blocking adrenoceptors are classified

according to the drug’s selectivity for α and β

receptors.

Their major effect is to occupy either α, or β

receptors and prevent their activation by

catecholamines and

related agonists.

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BASIC PHARMACOLOGY OF THE α- RECEPTOR ANTAGONIST DRUGS

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Cardiovascular Effects

Epinephrine reversal

The fall in blood pressure produced by

epinephrine following the

administration of alpha-blockers. ( due to cancel alpha1 role, retain beta2 role)

Reversal of epinephrine is a phenomenon that is

usually seen in people who are being treated for high blood pressure. Administration of

alpha-blockers helps in inducing the process of epinephrine reversal.

α- antagonist drugs block α receptors, dilate vascular

smooth muscle, lower peripheral resistance and BP; reflex

tachycardia.

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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)

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

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α receptor antagonists-phentolamine

a potent competitive antagonist at both α1 and α2 receptors.

Pharmacological properties1.Vessel-reduces peripheral resistance by blockade of α. 2. heart-stimulate the heart due to baroreflex mechanisms; stimulate the heart by exciting β receptors ; block α2 receptors, enhance release of NE from sympathetic nerves3. multiple potential actions: inhibit responses to serotonin (5-HT) ; activate M and histamine (H) receptors.

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Therapeutic effects

1. Pheochromocytoma

phentolamine is most useful in the

pre-operative management of

pheochromocytoma. it can control

hypertension and reverse cardiac

effects of excessive catecholamines.

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2. Peripheral Vascular Spasm Diseases

3. Local Vasoconstrictor Excess

Phentolamine has been used to

reverse the vasoconstriction caused

by infiltration of NE

into subcutis during intravenous administration.

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Adverse effects:

The principal adverse effects are cardiac

stimulation, such as tachycardia, postural

hypotension, arrhythmias, myocardial ischemia

and nasal congestion as well as headache.

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Prazosin is highly selective for α1 receptors, leads

to vasodilation.

It is effective in the management of hypertension.

Terazosin is another reversible α1-selective

antagonist that is effective in hypertension.

α1-selective antagonist drugs

First-dose effect-orthostatic hypotensive response, faintingFirst-dose effect-orthostatic hypotensive response, fainting

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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.

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Urinary Obstruction Prazosin can improve urine

flow in BPH.

The mechanism involves

reversal of smooth muscle

contraction in the enlarged

prostate and in the bladder

base.

Prazosin is efficacious,

particularly in patients with

hypertension.

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

Beta-blocking drugs occupy β receptors and reduce receptor occupy by catecholamines and other β agonists.

major difference among the β-receptor-blocking drugs is their relative affinities for β1 and β2 receptors.

Some of these antagonists have a higher affinity for β1 than for β2 receptors

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

Other major differences among β antagonists relate to their pharmacokinetics.

1) 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

Pharmacodynamics of the β antagonist Drugs

Vascular System

Blocking β1-mediated contraction of heart decreased

cardiac output

Blocking β1-mediated release of rennin dilating vessel

Blockingβ2-mediated vasodilation contracting vessel

HeartDecreased cardiac output due to negative inotropic

and chronotropic effects.

Cardiac output, work, oxygen consumption are

decreased, which is useful in treating angina.

Attenuating superventricular cardiac arrhythmias, no

useful in ventricular arrhythmias

2)Effects on the Respiratory Tract

β 1 antagonists have advantage over nonselective β

antagonists 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 airway

resistance, particularly in asthma.

3) Effects on the Eye

Several β-blocking agents reduce intraocular

pressure, especially in glaucomatous eyes.

The mechanism usually is due to a decrease in cAMP levels, which results in a reduction of aqueous humor production

4) Metabolic and Endocrine Effects

Beta-receptor antagonists such as propranolol

inhibit lipolysis.

The chronic use of β-adrenoceptor antagonists has

been associated with increased plasma VLDL and

decreased concentrations of HDL cholesterol.

Beta-receptor antagonists lead to decreased

glycogenolysis, and they should be used with

caution in insulin-dependent diabetic patients.

Clinical Application

Hypertension

The β-adrenoceptor-blocking

drugs are effective and well

tolerated in hypertension.

The drug is often used with either a diuretic

or a vasodilator.

Ischemic Heart Disease

Beta-adrenoceptor blockers

reduce the frequency of anginal

episodes and improve exercise

tolerance in patients with angina.

These actions relate to the blockade of cardiac β

receptors, resulting in decreased cardiac work and

reduction in oxygen demand. Slowing of the heart rate

may contribute to clinical benefits.

Cardiac Arrhythmias

Beta antagonists are effective in

supraventricular arrhythmias by

increasing the atrioventricular nodal

refractory period.

Glaucoma

Timolol, Betaxolol, carteolol, levobunolol and metipranolol

are used for treatment of glaucoma.

β-blocking drugs can reduce production

of aqueous humor and decrease

intraocular pressure in glaucoma.

Hyperthyroidism

These beneficial effects is to 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.

Propranolol

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-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.

Thanks a lots

Key points of efferent nervous drugs

1. Pharmacodynamics and therapeutic application of atropine

2. The toxicology and treatment of organophosphorate cholinesterase inhibitor

3. Drugs on eye effects (M-R agonist, M-R antagonist and anticholinesterase inhibitor)

4. Cycloplegia or spasm of accomodation 5. Therapeutic applications of beta receptor blocker6. Adrenaline reversal7. Adrenaline is a first choice drug for treatment of

anaphylactic shock. Why?

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Practice QuestionsWhich of the following drugs does stimulate mainly b receptors

NE

EP

Isoproterenol

Dopamine

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Which of the following drugs, when administrated intravenously, can decrease blood flow to the skin, increase blood flow to skeletal muscle, an increase the force and rate of cardiac contraction?

NE

EP

Phenylephrine

Isoproterenol

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Which of the following catecolamines may cause reflex bradycardia due to stimulation of a1 receptors?

NE

EP

Dopamine

Isoproterenol

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What is the treatment of choice for anaphylactic shock

NE

EP

Isoproterenol

Dobutamine