Download 2 receptor antagonists

Adrenergic Pharmacology
Shi-Hong Zhang (张世红), PhD
Dept. of Pharmacology,
School of Medicine,
Zhejiang University
[email protected]
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Biosynthesis of Catecholamines
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Norepinephrine synthesis in nerve terminals and turnover
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Norepinephrine and Epinephrine Synthesis in the Adrenal Medulla
Chromaffin cell
PNMT
- PNMT苯氨基乙醇N-甲基转移酶 is located in the cytosol
- EPI (~80%) and NE (~20%) are released into blood
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Norepinephrine and Epinephrine Metabolism
MOPGAL (3-甲氧-4-羟苯乙二醇),
VMA(香草扁桃酸) and their sulfate
or MHPG
conjugates: used as indices of NE
turnover
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Adrenergic Receptor Subtypes & G-Protein
Coupled Mechanisms
1 Adrenergic Receptors:
Phospholipase C (PLC) activation, IP3 increase through Gq
Mechanism: mobilize and increase intracellular free calcium
Effects: primarily smooth muscle contraction
2 Adrenergic Receptors:
Inhibition of adenyl cyclase (AC) through Gi proteins
Mechanism: decrease intracellular cAMP levels
Effects: decrease protein phosphorylation
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Adrenergic Receptor Subtypes & G-Protein
Coupled Mechanisms
β Adrenergic Receptors:
Activation of adenyl cyclase (AC) through Gs proteins
Mechanism: increase intracellular cAMP levels
Effects: phosphorylation of intracellular proteins
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Adrenoceptors
 receptors
• 1 receptors: vasoconstriction (BP↑),
contraction of radial muscle of iris (mydriasis)
• 2 receptors: vasoconstriction, inhibition of NE
release; inhibition of insulin release
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Adrenoceptors
 Receptors
• 1 receptors: heart stimulation: contractility↑,
automaticity↑, conduction↑, oxygen-consumption↑, cardiac
output↑; increased lipolysis脂肪分解
• 2 receptors: bronchodilation; slight vasodilation;
increased muscle and liver glycogenolysis肝糖分解;
increased release of glucagon胰高血糖素
• 3 receptors: lipolysis, thermogenesis产热
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Four Major Activators of the Adrenergic System
•
Hypoxia - response is mainly cardiovascular: increase in
heart rate & contractility (1); vasodilation of blood vessels in
muscle (2).
•
Hypoglycemia - response is mainly metabolic (glycogenolysis
2 and 1, gluconeogenesis 2 and 1,2, lypolysis  esp. 3,
2), 2-mediated vasodilation in muscle increases glucose
delivery.
•
Hypothermia - piloerection (1), peripheral vasocontraction
(1), thermogenesis ()
•
Hypotension – baroreceptor reflex
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Drug classification
1. Direct actions on the receptors
Agonists (NE, EPI, ISO, dopamine, ephedrine 麻黄碱,etc)
Antagonists (phentolamine, propranolol, etc)
2. Indirect actions via affecting transmitters
Synthesis (L-dopa)
Transport and storage (imipramine丙咪嗪, reserpine 利舍平)
Release (ephedrine 麻黄碱, amphetamine 安非他明)
Inactivation (MAOI)
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Adrenergic agonists
2
1
3
4 5 6
β
Structure-activity relationship of
catecholamines and related compounds

• CNS entry
Phenethylamine 苯乙胺
•Resistant to MAO
Dopamine
• Strong efficacy
• COMT sensitive
• Short duration
• No entry to CNS
Ephedrine麻黄碱
Methamphetamine甲基苯丙胺
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Norepinephrine, Noradrenaline
Pharmacological effects:
1, 2 receptor agonist
(1) Vascular effects：
1: Vasoconstriction (skin, renal, brain,
hepatic, mesenteric, etc.), blood flow ,
systolic BP , Diastolic BP (especially at
larger doses
2: inhibits NE release
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Norepinephrine
(2) Cardiac effects：
Weak direct stimulation (1); inhibition via reflex (in vivo)
Net effect: little cardiac excitation
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Norepinephrine
Clinical uses (limited therapeutic value)
(1) Shock
• used in early phase of neurogenic shock: small doses
and short duration
(dopamine is better; replaced by metaraminol 间羟胺，α
agonist and NE releaser, with weaker but longer effect)
(2) Hypotension due to drug poisoning
• especially for chlorpromazine氯丙嗪 overdose
(3) Hemorrhage in upper alimentary tract (上消化道)
• orally given after dilution
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Norepinephrine
Adverse effects
(1) Ischemia and necrosis at the site of iv infusion
- relieved by phentolamine (酚妥拉明， receptor antagonist)
(2) Acute renal failure
- avoid larger doses and longer duration; monitor urinary
volume
(3) Contraindication
- hypertension, arteriosclerosis, heart diseases, severe
urinary volume , microcirculation disorders
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1 receptor agonists
Phenylephrine (去氧肾上腺素)
Methoxamine (甲氧明)
• Induce reflex bradycardia, used in hypotension under
anesthesia and drug poisoning, paroxysmal supraventricular
tachycardia;
• Phenylephrine: Mydriasis扩瞳, no or little effect on
intraocular pressure, short-acting (for several hours); act as a
nasal decongestant (鼻血管收缩药)
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2 receptor agonists
• Clonidine可乐定
Uses: antihypertensive drug; can be administered as
transdermal patch (permits continuous administration)
Mechanism of action:
2 adrenergic partial agonist; actions predominantly in CNS,
lowers blood pressure by inhibiting sympathetic vasomotor
tone
Adverse effects: iv administration may result in transient
increase in blood pressure (activation of post-synaptic α2b
receptors); dry mouth (α2 inhibit saliva secretion), sedation
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2 receptor agonists
Oxymetazoline (羟甲唑啉): a nasal decongestant
Apraclonidine (阿可乐定): decreases intraocular
pressure.
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Epinephrine, Adrenaline
Pharmacological effects: 1, 2, 1, 2 agonist
(1) Cardiac effects
1: contractility  (positive inotropic), HR  (positive
chronotropic), cardiac output , oxygen consumption ,
induces arrhythmia
(2) Vascular effects
: vasoconstriction (skin, mucous, viscera), especially
at large doses
2: vasodilatation, especially in skeletal muscle and
coronary vessels
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Concentration-dependent response in
vascular smooth muscle to epinephrine
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Epinephrine
(3) Blood pressure- two phases, dose dependent
Systolic BP, diastolic BP↓(slight) , pulse pressure 
Epinephrine
Epinephrine
reversal
10 g/min
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Epinephrine
(4) Respiratory
2: dilates bronchial smooth muscles
inhibits degranulation of mast cells
1: reduces congestion and edema of bronchial mucosa
(5) Gastric and bladder smooth muscles: relaxation (2)
(6) Eye: intraocular pressure ↓ (β desensitization, α1,2)
(7) Metabolic effects
blood glucose  (2 and 1,2, hyperglycemia);
free fatty acids  (, lipolysis)
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Epinephrine
Clinical uses:
Topical uses:
• Adjuvant of local anesthesia
• Bleeding
• Glaucoma
Systematic uses:
• Cardiac arrest
• Anaphylactic shock (过敏性休克)
• Acute bronchial asthma
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Epinephrine
Adverse effects
(1) Cardiac arrhythmias
(2) Hemorrhage (cerebral or subarachnoid): due to a
marked elevation of BP
(3) Anxiety, headache
(4) Contraindications: heart diseases, hypertension,
coronary arterial disease, arteriosclerosis （动脉硬化）,
hyperthyroidism （甲亢）
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Dopamine
Pharmacological effects:
, , DA receptor agonist
(1) Cardiac effects：1 receptor, weak
(2) Vascular effects：
DA receptor: vasodilatation of renal,
mesenteric arteries (small doses);
1 receptor: vasoconstriction of
skin, mesenteric/renal vessels (large
doses)
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Dopamine
Clinical uses
(1) Shock
cardiac and septic (感染性) shock
(2) Acute renal failure
combined with furosemide呋塞米
Adverse effects
Tachycardia, arrhythmia, reduction in urine
flow (renal vasoconstriction)
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Ephedrine 麻黄碱
NH
CH
CH
OH
CH3 CH3
Ephedrine
CH2
CH
NH
CH3 CH3
Methamphetamine
Properties：
- promotes release of NE, weak agonist effects on 1、2、
1、2 receptors
- chemically stable, orally effective；
- less potent but longer action duration than Epi;
- central stimulating: alertness , fatigue ↓, sleeplessness
- tachyphylaxis (快速耐受).
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Ephedrine
Clinical uses
(1) Prevention of hypotension during anesthesia
(2) Nasal decongestion: nasal drop
(3) Bronchial asthma: mild, chronic cases
(4) Relief of allergic disorders: urticaria 风疹,
angioneurotic edema 血管神经性水肿
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Isoproterenol, Isoprenaline
Pharmacological effects:
1 , 2 receptor agonist
(1) Cardiac effects (1 receptor)
(2) Vascular effects and blood pressure
2 receptor: dilatation of skeletal
muscles and coronary vessels；
SP , DP  or , pulse pressure 
(3) Bronchodilatation (2 receptor)
(4) Metabolism
Promoting effects as epinephrine
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Effects of NE, EPI, ISO and DA (therapeutic doses) on
cardiovascular indices
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Isoproterenol
Clinical uses
(1) Cardiac arrest / A-V block: in emergencies
(2) Shock: replaced by other sympathomimetics (due to
muscular vasodilatation)
(3) Bronchial asthma
Adverse effects
(1) Heart stimulation, arrhythmia
(2) Contraindications: coronary heart disease,
myocarditis 心肌炎, hyperthyroidism
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1 receptor agonists
Dobutamine （多巴酚丁胺）
• Cardiac stimulation
• Heart failure (after cardiac surgery or
congestive HF or acute myocardial
infarction; short-term treatment)
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2 receptor agonists
Salbutamol (沙丁胺醇)
• Uses:
Bronchial asthma: dilation of bronchial smooth muscle; 2 >
1 agonist (partially selective, preferential activation of
pulmonary 2 receptors by inhalation.
• Adverse effects:
headache, cardiac stimulation and skeletal muscle fine
tremor (2 receptors on presynaptic motor terminals; their
activation enhances ACh release).
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Adrenergic Receptor Antagonists
 receptor antagonists:
nonselective: short-acting (phentolamine 酚妥拉明)
long-acting (phenoxybenzamine 酚苄明)
selective: 1 antagonists (prazosin 哌唑嗪)
2 antagonists (yohimbine 育亨宾)
β receptors antagonists:
nonselective: with ISA (pindolol 吲哚洛尔)
without ISA (propranolol普萘洛尔)
β1 antagonists: with ISA (acebutolol 醋丁洛尔)
without ISA (atenolol 阿替洛尔)
/β receptor antagonists: labetalol 拉贝洛尔, carvedilol 卡维地洛
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 receptor
antagonists
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Phentolamine 酚妥拉明
Competitive, nonselective
Pharmacological effects
CH 3
N
N
CH2
N
H
HO
(1) Vasodilatation
Blocking 1 receptor: vasodilation in both arteriolar
resistance vessels and veins
(2) Cardiac stimulation
Reflex; blockade of 2 receptor promotes NE release
(3) Cholinergic and histamine-like effects
Contraction of GI smooth muscles,
Gastric acid secretion 
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Phentolamine
Clinical uses
(1) Decrease blood pressure
- Hypertension from drugs
- Pheochromocytoma嗜铬细胞瘤 (short term use) : diagnostic test,
peri-surgery uses
(2) Peripheral vascular diseases
- Acrocyanosis (手足发绀), Raynaud’s disease雷诺氏病
(3) Local NE extravasations
(4) Shock: improves microcirculation
(5) Acute myocardial infarction and obstinate congestive heart failure
Major Adverse effects
Postural hypotension, reflex tachycardia, arrhythmia, angina pectoris,
GI reactions
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Pheochromocytoma is a rare
catecholamine-secreting tumor
derived from chromaffin cells of
the adrenal medulla that
produces excess epinephrine.
• Hypertension & Crises
• Elevated Metabolic Rate
-heat intolerance
-excessive sweating
-weight loss
• Temporarily manage with
-adrenergic antagonists (1 & ±)
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Phenoxybenzamine 酚苄明
• Irreversible, nonselective (1 and 2)
• Strong effect, slow but long action (up to
3~4 days)
• Similar to phentolamine in actions and
clinical uses
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Other α antagonists
1 receptor antagonists
• Prazosin (哌唑嗪): treatment for hypertension, CHF
• Tamsulosin (坦洛新): 1A blocker, for benign
prostate hypertrophy
2 receptor antagonists
• Yohimbine (育亨宾): for research use, ED, diabetic
neuropathy
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Adrenergic Receptor Antagonists
 receptor antagonists:
nonselective: short acting (phentolamine 酚妥拉明)
long acting (phenoxybenzamine 酚苄明)
selective: 1 antagonists (prazosin 哌唑嗪)
2 antagonists (yohimbine 育亨宾)
β receptors antagonists:
nonselective: with ISA (pindolol 吲哚洛尔)
without ISA (propranolol 普萘洛尔)
β1 antagonists: with ISA (acebutolol 醋丁洛尔)
without ISA (atenolol 阿替洛尔)
/β receptor antagonists: labetalol 拉贝洛尔, carvedilol 卡维地洛
ISA: intrinsic sympathomimetic activity
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 receptor antagonists
General properties:
ADME
• First-pass elimination, especially those with
high lipid solubility (eg. propranolol普萘洛尔).
• Hepatic metabolism and renal excretion
hepatic and renal functions alter the effects of
the drugs and result in large individual
variation
• Dose individualization is necessary.
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 receptor antagonists
Pharmacological effects
1.  receptor blockade
1) Cardiovascular effects：
• Depression of the heart: reduction in HR, A-V
conduction, automaticity, cardiac output,
oxygen consumption
• Hypotension: hypotensive effect in
hypertensive patients
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 receptor antagonists
1.  receptor blockade
2) Bronchial smooth muscles
induces bronchial smooth muscle contraction in
asthmatic patients
3) Metabolism
lipolysis , VLDL and TG , HDL
glycogenolysis, potentiating insulin effects –
hypoglycemia, hyperglycemia
T4-T3 turnover, T3 sensitivity
4) Renin secretion: decrease
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 receptor antagonists
2. Intrinsic sympathomimetic effects
Partial agonists: e.g. pindolol, acebutolol (weaker
cardiac inhibition and bronchoconstriction; cardiac
stimulation in larger doses)
3. Membrane-stabilizing effects
Larger doses of some drugs: quinidine-like effects, Na+
channel blockade
4. Other effects
• Lower intraocular pressure
• Inhibit platelet aggregation
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Circulation of Aqueous humor
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 receptor antagonists
Clinical uses
(1) Arrhythmia: supraventricular, sympathetic
activity 
(2) Hypertension
(3) Angina pectoris and myocardial infarction
(4) Chronic heart failure
(5) Others: hyperthyroidism, migraine, glaucoma
(timolol)...
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 receptor antagonists
Adverse effects
(1) Heart depression: contraindicated in heart failure,
severe A-V block, sinus bradycardia
(2) Worsening of asthma: contraindicated in bronchial
asthmatic patients
(3) Withdrawal syndrome：up-regulation of receptors
(4) Worsening of peripheral vascular constriction
(5) Others：central depression, hypoglycemia, sexual
dysfunction, etc.
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 receptor antagonists
Propranolol 普萘洛尔，心得安
• 1, 2 receptor blockade
• no intrinsic activity
• first-elimination after oral administration,
individual variation of bioavailability
Timolol 噻吗洛尔
• For the treatment of glaucoma (wide-angle)
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Atenolol, Metoprolol
• 1receptor antagonists, no intrinsic activity
• atenolol : longer t1/2, once daily
• usually used for the treatment of
hypertension
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α,  receptor antagonists
Labetalol, Carvedilol
• α, β receptor blocking, β> α
• Usually used for treatment of
hypertension, angina pectoris, CHF.
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