Adrenergic Pharmacology. Adrenergic receptor agonists Adrenergic recpeotr antagonists. 张纬萍 浙江大学医学院药理 2012.12.3. Brain stem or spinal cord. Pre-ganglionic neuron. Ganglionic transmitter. Post-ganglionic neuron. Neuroeffector transmitter. Effector organ. Efferent neurons of ANS.
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Efferent neurons of ANS
tyrosine hydroxylase (TH)*
dopamine beta-hydroxylase (DBH)
and release of NE
Synthesis in the Adrenal Medulla
EPI disposition: metabolism by COMT, MAO,
sulfation, uptake into NE terminals
- Within the same cells where the amines are synthesized, and in liver
- Extraneuronal O-methylation of norepinephrine and epinephrine to metanephrines represent minor pathways of metabolism.
Act on adrenergic receptors/adrenoceptors
low affinity for binding NE
G-Protein Coupled Receptors
& G-Protein Coupled Mechanisms
a1 Adrenergic Receptors:
G protein termed Gqphospholipase C activation, IP3
mechanism: mobilizes and increases intracellular free Ca2+
effects: primarily smooth muscle contraction
2 Adrenergic Receptors:
Inhibition of adenylyl cyclase (AC)through Gi proteins
mechanism: decreases intracellular cAMP levels
effects: decreased protein phosphorylation, decreased cellular
b Adrenergic Receptors:
Activation of adenylyl cyclase through Gs proteins
mechanism: increases intracellular cAMP levels
effects: phosphorylation of intracellular proteins smooth
muscle relaxation (b2), cardiac muscle contraction (b1)
These are receptors activated by NE, EPI, or drugs with similar actions
The SNS Plays a Very Important Role in the Regulation of the Cardiovascular System, which, except for the Heart, is not Innervated by the PSNS
1.1 Direct actions on the receptors
1.2 Indirect actions via affecting transmitters
1.3 Mimetics and antagonists
direct-acting: receptor agonists
indirect-acting: increasing amounts and/or
effects of transmitters
direct-acting: receptor antagonists
indirect-acting: decreasing amounts and/or
effects of transmitters
(2) receptor agonists
(3) receptor agonists：
catecholamines and related compounds
(orally active, a prolonged duration of action)
of sympathomimetic drugs
1, 2 , 1 , 2 receptor agonists
(1) Cardiac effects
HR (positive chronotropic),
cardiac output ,
oxygen consumption ,
(2) Vascular effects (cerebral and renal circulation)
especially at larger doses
and coronary vessels
Concentration-dependent response in vascular smooth muscle to epinephrine
low [EPI] β2 > α
high [EPI] α > β2
(3) Blood pressure
(5) Metabolic effects
free fatty acids (lipolysis)
systolic pressure due to increased cardiac contractile force and a rise in cardiac output .
diastolic pressure usually falls due to the decrease of peripheral resistance decreasing.
1 in heart, 1 in many microvessels, 2 in the vessels of skeletal muscle
(6) Smooth muscle
Acute bronchial asthma
Adjuvant of local anesthesia
(1) Cardiac arrhythmias
(2) Hemorrhage (cerebral or subarachnoid):
reason: a marked elevation of BP
(3) Central excitation：anxiety, headache...
(4) Contraindications: heart diseases, hypertension, coronary arterial disease, arteriosclerosis, hyperthyroidism. Esp. patients receiving nonselective blockers.
1, 2 receptor agonists
NE and Epi are similar potent on 1
NE has little action of 2
(1) Vascular effects：
1：vasoconstriction (skin, renal, brain,
hepatic, mesenteric, etc.), blood flow
2：inhibiting NE release
Actions of norepinephrine on post-synaptic (1) and pre-synaptic (2 ) receptors
(2) Blood pressure：
(3) Cardiac effects：
Clinical uses (limited therapeutic value)
(dopamine is better; replaced by Metaraminol，间羟胺)
(2) Hypotension due to drug poisoning
(3) Hemorrhage in upper alimentary tract，上消化道出血
(1) Ischemia and necrosis at the site of iv administrationrelieved by filtrating the area with phentolamine (receptor antagonist)
(2) Acute renal failureavoiding larger doses and longer duration; monitoring urinary volume
(3) Contraindicationhypertension, arteriosclerosis, heart diseases, severe urinary volume , microcirculation disorders
Pharmacological effects :
, receptor, dopaminergic receptor agonists
(1) Cardiac effects：1 receptor, weak
(2) Vascular effects：
DA receptor：vasodilatation of renal and mesenteric arteries , blood flow (small doses);
1 receptor：vasoconstriction of skin, mesenteric vessels (larger doses)
(3) Renal effects：renal vasodilatation; natriuretic effects
(1) Shock, sever congestive failure
(2) Acute renal failure
Adverse effects – short-lived
L-DOPA but not dopamine can enter brain.
1 , 2 receptor agonists
(1) Cardiac effects (1 receptor)
(2) Vascular effects
2 receptor:dilatation of skeletal muscles and coronary vessels；
SP ，DP or ，pulse pressure
(3) Bronchodilatation (2 receptor)
Promoting effects as epinephrine
Predominant Effects: HR, systolic BP, distolic BP, peripheral resistance
1, myocardial contraction
2, vascular dialization
, at higher concentrations
(1) Cardiac arrest / A-V block: in emergencies
(2) Shock / Bronchial asthma: replaced by
(1) Heart stimulation, arrhythmia
(2) Contraindications:coronary heart
disease, myocarditis, hyperthyroidism,
(-) isomer of dobutamine is a potent agonist at 1 receptors
(+)-dobutamine is a potent 1 receptor antagonist
Dilation of bronchial smooth muscle; 2 > 1 agonist (partially selective): preferential activation of pulmonary 2 receptors by inhalation.
Premature Labor (combine with ritodrine，羟苄羟麻黄碱).
headache, cardiac stimulation and skeletal muscle fine tremor (2 receptors on presynaptic motor terminals; their activation enhances ACh release).
(1) Prevention of hypotension:anesthetics
(2) Nasal decongestion:nasal drop，如感冒
(3) Bronchial asthma:mild, chronic cases
(4) Relieving allergic disorders:urticaria（荨麻
疹）, angioneurotic edema
(2) receptor agonists
(3) receptor agonists：
（1） receptor antagonists
（2） receptor antagonists
（3）, receptor antagonists
Blocking 1 receptor: vasodilatation in both arteriolar
resistance vessels and veins
(2) Cardiac Stimulation
Reflex；blocking 2 receptor ～NE release
(3) Cholinergic and histamine-like effects
Contraction of GI smooth muscles,
Gastric acid secretion
(1) Hypertension from pheochromocytoma (short term use).
• Diagnostic test for pheochromocytoma
(2) Peripheral vascular diseases
(3) Local vasoconstrictor extravasation
Major Adverse effects– postural hypotension, reflex tachycardia, arrhythmia, angina pectoris, GI reactions
-adrenergic antagonists (a1 & ±b)
Prazosin（哌唑嗪）: treatment for hypertension
Tamsulosin (坦索罗辛): treatment for benign prostatauxe (to relief the difficulty of urination)
Terazosin (特拉唑嗪): less potent than prazosin, but retains high specificity for 1
Doxazosin (多沙唑嗪): similar as prazosin, but has longer duration of action.
Alfuzosin (阿夫唑嗪): structure not related.
First-dose effect, marked hypotension,
Clinically，these drug are used for the patient with hypertentsion and benign prostatic hyperplasia (良性前列腺肥大)
2 receptor antagonists
Yohimbine: for research use only
low bioavailability: propranolol（普萘洛尔）
(1) receptor blockade
A. Cardiovascular effects：
Depressing heart: reduction in HR, A-V conduction, automaticity, cardiac output, oxygen consumption
Hypotension: peripheral blood flow , hypertensive effects in hypertensive patients
(1) receptor blockade
B. Bronchial smooth muscles (2)
Induces bronchial smooth muscle contraction in asthmatic patients
C. Metabolism (2 and 3)
Lipolysis(脂解作用) , glycogenolysis(糖原分解) , classical blockers decreasing while novel blockers potentiating insulin effects ~ hypoglycemia(低血糖)。
D. Renin secretion (1)
Decreasing secretion of rennin
(2) Intrinsic sympathomimetic effects
Partial agonists: e.g. pindolol,acebutolol
(3) Membrane-stabilizing effects
Larger doses of some drugs: quinidine-like
effects, Na+ channel block
Lowering intraocular pressure;
Inhibiting platelet aggregation
(1) Arrhythmia：supraventricular, sympathetic activity
(3) Angina pectoris and myocardial infarction
(4) Chronic heart failure
(5) Others: hyperthyroidism, migraine, glaucoma（timolol）
LVEF % change
Initial hemodynamic deterioration followed by reverse remodeling (decrease in EDV and ESV) with improved ventricular function over time (increased LVEF
Not well studied
1CIBIS II Investigators and Committees. Lancet. 1999;353:9-13. 2The BEST Investigators. N Engl J Med 2001; 344:1659-1667. 3Colucci WS, et al. Circulation 1996;94:2800-2806. 4Packer M, et al. N Engl J Med 2001;344:1651-1658. 5The CAPRICORN Investigators. Lancet. 2001;357:1385-1390. 6Waagstein F, et al. Lancet. 1993;342:1441-1446. 7MERIT-HF Study Group. Lancet. 1999;353:2001-2007. 8SENIORS Study Group. Eur Heart J. 2005; 26:215-225. 9The Xamoterol in Severe heart Failure Study Group. Lancet. 1990;336:1-6.
(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 the receptors
(4) Worsening of peripheral vascular constriction
(5) Others：central depression, hypoglycemia,etc.
1 blocker Ca2+ blocker Antioxidation
3. Cardiogenic Shock（心源性休克）
4. Local Vascular Effects（局部的血管变化）
- Reduction of regional blood flow in surgery (nose, throat, larynx) to improve visualization by limiting hemorrhage.
- Epinephrine retards the absorption of local anesthetics and increases the duration of anesthesia (vasoconstrictor effect of epinephrine)
5. Nasal Decongestion（鼻腔充血）
- a1-Adrenergic agonists are used as nasal decongestants.
- These drugs decrease the volume of the nasal mucosa and therefore reduce the resistance to airflow.
- Oxymetazoline, phenylephrine and ephedrine are commonly used.
6. Allergic Reactions（过敏反应）
- Epinephrine (s.c.) is used in acute hypersensitivity reactions.
- Activation of b-adrenergic receptors on mast cells suppresses the release of histamine and leukotrienes.
- Asthma is a condition of overreactive airways. Asthma attacks can make it very difficult to breath because of excess bronchoconstriction.
- b2 AR agonists such as albuterol, metaproterenol and terbutaline are used.
- The drugs are administered by inhalation and are absorbed slowly, limiting their systemic side effects, and b2 selectivity reduces cardiac stimulation.
2. Premature Labor（早产）
- When labor occurs prematurely (before 37 weeks), it is a risk to the fetus.
- b2 AR agonists relax the smooth muscle of the uterus and help prevent premature delivery. The goal is to reach at least 37 weeks when the fetal lungs have matured.
- While not commonly used anymore, a1 blockers can be use to treat hypertension.
- Somewhat more common is the use of b blockers. These work centrally (the most important effect – the mechanism is not completely understood) and peripherally (decrease heart rate some).
3. Heart Failure（心功能衰竭）
- After a myocardial infarction, the SNS will be activated to increase the cardiac output from the remaining good heart tissue. This is good in the short-term, but long-term changes lead to cardiac hypertrophy and failure.
- Ironically, b blockers reduce the incidence of sudden death from heart failure.