Part 4 Adrenoceptor agonists §1. ,  receptor agonists §2.  receptor agonists §3.  receptor agonists

Bronchial smooth muscle Overview of catecholamine actions on CVS & respiratory systems Adrenal medulla

Overview of catecholamine actions on blood presure

Action site of catecholamines

Tyrosine Dopa Dopamine Norepinephrine Epinephrine Tyrosine hydroxylase Dopa decarboxylase Dopamine  -hydroxylase Phenylethanolamine N-methyltransferase Catecholamine biosynthesis

Catecholamines ( 儿茶酚胺 ) 去甲肾上腺素 肾上腺素 异丙肾上腺素 多巴胺

Structure-activity relationship of catecholamines and related compounds Substitution on the aromatic nucleus Substitution on the aromatic nucleus COMT, central activity COMT, central activity Substitution on the  -carbon atom Substitution on the  -carbon atom MAO, uptake-1, NE release MAO, uptake-1, NE release Substitution on the amino group Substitution on the amino group sensitivity to the subunits of receptors sensitivity to the subunits of receptors

1，21，2

Metabolism of catecholamines

Effect patterns of sympathomimetics

Subtypes of adrenoceptors

Effects of catecholamines （ therapeutic doses ）

BP  antagonist  antagonist epinephrine Epinephrine reversal （ adrenaline reversal ） epinephrine

Epinephrine reversal (adrenaline reversal)

The  -adrenoceptor action of epinephrine on cardiovascular system

1. ,  receptor agonists Epinephrine 肾上腺素, Adrenaline Short action because of rapid metabolism

1. ,  receptor agonists §1.1 Pharmacological effects §(1) Cardiac effects §  1 : HR , output , § oxygen consumption , inducing arrhythmia §(2) Vascular effects §  1 ： vasoconstriction, especially at larger doses §  2 ： vasodilatation of skeletal muscles and coronary vessels

§(3) Blood pressure § SP , DP  (at therapeutic doses) §(4) Bronchodilatation §  2 ： dilatation of bronchial smooth muscles §  1 ： reducing congestion and edema of bronchial mucosa §(5) Metabolic effects § blood glucose  ; free fatty acids  1. ,  receptor agonists

§1.2 Clinical uses §(1) Cardiac arrest §(2) Anaphylactic shock & other sever allergy §(3) Acute bronchial asthma §(4) Local uses adjuvant for local anesthetics; control of bleeding § adjuvant for local anesthetics; control of bleeding 1. ,  receptor agonists

Clinical uses of epinephrine Systmatic uses: Cardiac arrest Anaphylactic shock Acute bronchial asthma Topical uses: Adjuvant of local anesthesia Bleeding

§1.3 Adverse effects §(1) Cardiac arrhythmia: BP , arrhythmia §(2) Excessive rise of BP: cerebral or subarachnoid hemorrhage §(3) Central excitation ： anxiety §(4) Contraindications: heart diseases, hypertension, coronary arterial disease, arteriosclerosis, hyperthyroidism 1. ,  receptor agonists

Ephedrine 麻黄碱 Ephedrine麻黄碱 Epinephrine肾上腺素 1. ,  receptor agonists

§1.1 Pharmacological effects §Promoting release of NE, weak agonist effects on  1,  2,  1,  2 receptors §Properties ： § chemically stable, orally effective ； § central stimulating ； § less potent and longer action duration; § tachyphylaxis. 1. ,  receptor agonists

§1.2 Clinical uses §(1) Prevention of hypotension: anesthetics §(2) Nasal decongestion: nasal drop §(3) Bronchial asthma: mild, chronic cases §(4) Relieving allergic disorders: urticaria, angioneurotic edema 1. ,  receptor agonists

§1.3 Adverse effects §(1) Central stimulation §(2) CVS effects §(3) Dependence §Pseudoephedrine ( 伪麻黄碱 ） §usually used in the compounds for treatment of cold 1. ,  receptor agonists

Dopamine 多巴胺 1. ,  receptor agonists

§1.1 Pharmacological effects §(1) Cardiac effects ：  1 receptor, weak §(2) Vascular effects and blood pressure ： § DA receptor ： dilatation 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. ,  receptor agonists

Vasodilatation (DA receptor) Vasoconstriction (  -adrenoceptor) Effects of dopamine on CVS

§1.2 Clinical uses §(1) Shock §cardiac and septic shock: low output, urinary volume , to be used after fully adequate replacement of intravascular fluid §(2) Acute renal failure § combined with furosemide （呋塞米） §1.3 Adverse effects § tachycardia, arrhythmia, renal vasoconstriction 1. ,  receptor agonists

2.  receptor agonists § 2-1  1,  2 receptor agonists Norepinephrine 去甲肾上腺素, noradrenaline noradrenaline

 -adrenoceptor-mediated signal transduction

2.  receptor agonists §2.1 Pharmacological effects §(1) Vascular effects ： §  1 ： vasoconstriction (skin, renal, brain, hepatic, mesenteric, etc.) § vasodilatation of coronary arteries  2 ： inhibiting endogenous NE release §  2 ： inhibiting endogenous NE release

Actions of norepinephrine on post-synaptic (  1 ) and pre-synaptic (  2 ) receptors

§(2) Cardiac effects ： weak direct stimulation (  1 ); § weak direct stimulation (  1 ); § inhibition via reflex, HR  §(3) Blood pressure ： § SP , DP  ( especially at larger doses ), larger doses:pulse pressure , tissue blood flow  § larger doses: pulse pressure , tissue blood flow  2.  receptor agonists

§2.2 Clinical uses §(1) Shock § BP , tissue blood flow , tissue damage  § used in early phase of some types of shock or BP rise too slow after treatment: small doses and shorter duration 2.  receptor agonists

§(2) Hypotension due to drug poisoning § for example: chlorpromazine §(3) Hemorrhage in upper alimentary tract § orally given after dilution with cold saline 2.  receptor agonists

§2.3 Adverse effects §(1) Ischemia and necrosis at the site of iv administration relieved by filtration with procaine or phentolamine §(2) Acute renal failure avoiding larger doses and longer duration; monitoring urinary volume §(3) Withdrawal hypotension §(4) Contraindication hypertension, arteriosclerosis, heart diseases, severe urinary volume , microcirculation disorders 2.  receptor agonists

§Acting on  receptors directly, promoting NE release indirectly ； §Weaker effects and longer duration than NE, §weak for renal vessels; §Used in early phase of shock, hypotension Metaraminol 间羟胺, Aramine 2.  receptor agonists

 2-2  1 receptor agonists § §used in hypotension, paroxysmal supraventricular tachycardia (by reflex) ； §Mydriasis (phenylephrine): pupillary dilator muscles, no or less effect on intraocular pressure, short-acting (for several hours) Phenylephrine 去氧肾上腺素 Phenylephrine 去氧肾上腺素 Methoxamien 甲氧明 Methoxamien 甲氧明 2.  receptor agonists

3.  receptor agonists §3-1  1,  2 receptor agonists Isoproterenol 异丙肾上腺素, Isoprenaline Isoprenaline

 -adrenoceptor-mediated signal transduction PKA PKA (cAMP-dependent protein kinase)

3.  receptor agonists §3.1 Pharmacological effects §(1) Cardiac effects §  1 receptor stimulation §(2) Vascular effects and blood pressure §  2 receptor: dilatation of skeletal muscles and coronary vessels ； § SP , DP  or , pulse pressure 

§(3) Bronchodilatation §  2 receptor ， no effect on edema of mucosa §(4) Metabolism § Promoting effects as epinephrine 3.  receptor agonists

Effects of isoproterenol

3.2 Clinical uses §(1) Cardiac arrest §(2) A-V block §(3) Septic shock ： low-output §(4) Acute bronchial asthma ： § generally use  2 receptor agonists 3.  receptor agonists

3.3 Adverse effects §(1) Heart stimulation, arrhythmia §(2) Contraindications: § coronary heart disease, myocarditis, hyperthyroidism 3.  receptor agonists

§3-2  1 receptor agonists § Heart failure § Cardiac stimulation Dobutamine 多巴酚丁胺 3.  receptor agonists

§3-3  2 receptor agonists Bronchial asthma § Bronchial asthma Salbutemol 沙丁胺醇 3.  receptor agonists