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Part 5 Adrenoceptor Antagonists

Part 5 Adrenoceptor Antagonists. 1.  receptor antagonists 2.  receptor antagonists 3.  ,  receptor antagonists. Epinephrine reversal （ 肾上腺素作用的翻转 ）. 1.  receptor antagonists. 1-1  1 ,  2 receptor antagonists Short-acting. Phentolamine 酚妥拉明.

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Part 5 Adrenoceptor Antagonists

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  1. Part 5Adrenoceptor Antagonists 1.  receptor antagonists 2.  receptor antagonists 3. ,  receptor antagonists

  2. Epinephrine reversal（肾上腺素作用的翻转）

  3. 1.  receptor antagonists • 1-1 1, 2 receptor antagonists • Short-acting Phentolamine 酚妥拉明

  4. 1.  receptor antagonists • 1.1 Pharmacology • (1) Vasodilatation • Blocking 1 receptor; direct action • (2) Stimulating heart • Reflex；blocking 2 receptor ～NE release  • (3) Cholinergic and histamine-like effects • Contraction of GI smooth muscles, • Gastric acid secretion 

  5. 1.  receptor antagonists • 1.2 Clinical uses • (1) Peripheral vascular diseases • Acrocyanosis, Raynaud’s disease • (2) Local vasoconstrictor extravasation

  6. 1.  receptor antagonists • (3) Shock • cardiac output ; • redistribution of blood flow; • shift of fluid from interstitial compartment to vascular compartment; • pulmonary pressure ; • should be used after fully adequate replacement of intravascular fluid

  7. 1.  receptor antagonists • (4) Acute myocardial infarction and congestive heart failure • after-load ； cardiac output 

  8. 1.  receptor antagonists • (5) Pheochromocytoma • pre- and post-operation uses • diagnosis • (6) Others: impotency (阳痿)

  9. 1.  receptor antagonists • 1.3 Adverse effects • (1) Postural hypotension • (2) Reflex heart stimulation • tachycardia, arrhythmia, angina pectoris • (3) G.I. reactions • (4) Other • central depression

  10. 1.  receptor antagonists • Tolazoline妥拉唑啉 • weak effects • more severe adverse effects

  11. 1.  receptor antagonists • Long-acting • Longer action duration • used for peripheral vasculardiseases • anti-shock • pheochromocytoma • improving urinary flow in patients with benign prostatic hypertrophy Phenoxybenzamine 酚苄明

  12. 1.  receptor antagonists • 1-2 1 receptor antagonists • prazosin（哌唑嗪）, for hypertension treatment • tamsulosin（坦洛新）, for benign prostatic hypertrophy • 1-3 2 receptor antagonists • yohimbine（育亨宾）

  13. 2.  receptor antagonists • 2.1 ADME • First-pass elimination, • lower bioavailability: propranolol • Hepatic metabolism and renal excretion, hepatic and renal functions alter the effects of the drugs and result in large individual variation • Thus, dose individualization is necessary.

  14. 2.  receptor antagonists • 2.2 Pharmacological effects • (1)  receptor blockade • A. Cardiovascular effects： • Depressing heart: reduction in HR, A-V conduction, automaticity, cardiac output, oxygen consumption • Hypotension: hypotensive effects only in hypertensive patients; peripheral blood flow , BP in normal subjects.

  15. Blockade of –adrenoceptor cardial responses by propranolol

  16. 2.  receptor antagonists • B. Bronchial smooth muscles • inducing bronchial smooth muscle contraction in asthmatic patients • C. Metabolism • lipolysis , glycogenolysis , potentiating insulin effects ~ hypoglycemia • D. Renin secretion • decreasing secretion of renin

  17. 2.  receptor antagonists • (2) Intrinsic sympathomimetic effects • Some drugs: HR , output  • (3) Membrane-stabilizing effects • Larger doses of some drugs: quinidine-like effects due to Na+ channel block • (4) Others • Lowering intraocular pressure; • Inhibiting platelet aggregation

  18. 2.  receptor antagonists • 2.3 Clinical uses • (1) Arrhythmia：supraventricular, sympathetic activity  • (2) Hypertension • (3) Angina pectoris and myocardial infarction • (4) Chronic heart failure • (5) Others: hyperthyroidism, migraine headache, glaucoma（timolol）, etc.

  19. Effect of a  receptor antagonist on the mortality of chronic heart failure

  20. 2.  receptor antagonists • 2.4 Adverse effects • (1) Worsening of asthma: contraindicated in bronchial asthmatic patients • (2) Heart depression: contraindicated in heart failure, severe A-V block, sinus bradycardia • (3) Worsening of peripheral vascular constriction • (4) Withdrawal syndrome：up-regulation of  receptors • (5) Others：central depression, hypoglycemia, etc.

  21. 2.  receptor antagonists • 2.5 Representative drugs Propranolol 普萘洛尔

  22. 2.  receptor antagonists • 1, 2 receptor blocking • no intrinsic activity • first-elimination after oral administration, individual variation of bioavailability Propranolol 普萘洛尔

  23. 2.  receptor antagonists Timolol 噻马洛尔 • For treatment of glaucoma (wide-angle)

  24. 2.  receptor antagonists Atenolol 阿替洛尔 Metoprolol 美托洛尔 • 1 receptor antagonists, no intrinsic activity • atenolol : longer t1/2, once daily • usually used for treatment of hypertension

  25. 3. α,  receptor antagonists Labetolol 拉贝洛尔 • blockingα, β receptors, β> α • usually used for treatment of hypertension

  26. 3. α,  receptor antagonists Carvedilol 卡维地洛 • α, β receptor blocking, β> α • S(-) isomer: βand α receptor blocking • R(+) isomer: α receptor blocking • usually used for treatment of hypertension and chronic heart failure

  27. Part 6Local Anesthetics

  28. procaine 普鲁卡因 lidocaine 利多卡因 tetracaine 丁 卡 因

  29. Local anesthetics • 1. Pharmacological effects • (1) Local anesthetic effects • inhibiting Na+ inward flow and the conduction of nerve fibers • sensory (fine – thick)  CNS(inhibiting - excitatory)  ANS  motor nerves  muscles

  30. The mechanism of local anesthetics Blocking Na+ channels on the nerve fibers

  31. The mechanism of local anesthetics Intracellular blockade of Na+ channel

  32. Local anesthetics • (2) Systemic effects（Adverse effects） • Depressing CNS：excitation - depression • Cardiovascular effects：heart depression; vasodilatation; lowering BP • combined with epinephrine:reducing absorption and systemic effects • ( but contraindicated in: terminal tissues; epinephrine contraindications )

  33. Local anesthetics • 2. Clinical uses • (1) Surface anesthesia (表面麻醉） • penetration • (2) Infiltration anesthesia （浸润麻醉） • (3) Conduction anesthesia （传导麻醉）

  34. Local anesthetics • (4) Epidural anesthesia (硬脊膜外麻醉) • Avoiding misdirection into cerebrospinal fluid • (5) Subarachnoid anesthesia (蛛网膜下腔麻 • 醉 , 腰麻） • head-up position; • hyperbaric solution; • hypotension: prevention with ephedrine

  35. Local anesthetics • 3. Adverse effects • (1) Systemic effects • depression of CNS: excitation – depression – respiratory depression • cardiovascular effects: hypotension; arrhythmia • (2) Allergic reactions • urticaria, bronchoconstriction; anaphylactic shock

  36. Local anesthetics • 4. Special agents Efffect Toxicity Pene-Uses tration procaineweak weak weak can not be used 普鲁卡因(allergic) for surface skin allergic test lidocainestronger lower stronger for various uses； 利多卡因anti-arrhythmia tetracainestronger stronger stronger mainly for surface 丁卡因

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