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Part 4 Adrenoceptor agonists

Part 4 Adrenoceptor agonists. 1. ,  receptor agonists 2.  receptor agonists 3.  receptor agonists. Overview of catecholamine actions on CVS & respiratory systems. Bronchial smooth muscle. Adrenal medulla. Overview of catecholamine actions on blood presure.

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Part 4 Adrenoceptor agonists

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

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

  3. Overview of catecholamine actions on blood presure

  4. Action site of catecholamines

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

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

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

  8. 1，2

  9. Metabolism of catecholamines

  10. Effect patterns of sympathomimetics

  11. Subtypes of adrenoceptors

  12. Effects of catecholamines（therapeutic doses）

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

  14. Epinephrine reversal (adrenaline reversal)

  15. The -adrenoceptor action of epinephrine on cardiovascular system

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

  17. 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

  18. 1. ,  receptor agonists • (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 

  19. 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

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

  21. 1. ,  receptor agonists • 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

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

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

  24. 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

  25. 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

  26. 1. ,  receptor agonists Dopamine 多巴胺

  27. 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

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

  29. 1. ,  receptor agonists • 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

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

  31. -adrenoceptor-mediated signal transduction

  32. 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

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

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

  35. 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

  36. 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

  37. 2.  receptor agonists • 2.3 Adverse effects • (1) Ischemia and necrosis at the site of iv administrationrelieved by filtration with procaine or phentolamine • (2) Acute renal failureavoiding larger doses and longer duration; monitoring urinary volume • (3) Withdrawal hypotension • (4) Contraindicationhypertension, arteriosclerosis, heart diseases, severe urinary volume , microcirculation disorders

  38. 2.  receptor agonists Metaraminol 间羟胺, Aramine • 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

  39. 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 Methoxamien 甲氧明

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

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

  42. 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 

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

  44. Effects of isoproterenol

  45. 3.  receptor agonists 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

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

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

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

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