adrenoceptor agonist and antagonist drugs-2014.10.7ppt
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Adrenoceptor Agonist and Antagonist Drugs-2014.10.7pptTRANSCRIPT
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
82
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