第三次课的内容

1. 第三次课的内容 1、肾上腺素能神经系统 （2）肾上腺素受体拮抗药 2、镇静催眠药

2. Adrenergic Receptor Antagonists • antagonists of NE at either a or b receptors. • - competitiveantagonists (reversible), blocking endogenous norepinephrine • - irreversible antagonists • Antagonist characteristics: • receptor occupancy (binding affinity) • no receptor activation (no efficacy) • nonselective and selective drugs available for both the a or b receptors.

3. Drug actions and classification Adrenoceptor antagonists （1） receptor antagonists • 12 receptor antagonists: short-acting: phentolamine（酚妥拉明） long-acting: phenoxybenzamine（酚苄明） • 1 receptor antagonists:prazosin（哌唑嗪） • 2 receptor antagonists:yohimbine（育亨宾）

4. Drug actions and classification Adrenoceptor antagonists （2） receptor antagonists • 12 receptor antagonists:propranolol （普萘洛尔） • 1 receptor antagonists:atenolol（阿替洛尔） • 2 receptor antagonists:butoxamine（布他沙明） （3）,  receptor antagonists • labetalol（拉贝洛尔）

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

7. Phentolamine （酚妥拉明） • competitive, nonselective(1, 2 receptor antagonists) Pharmacological effects (1) Vasodilatation Blocking 1 receptor: vasodilation 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 

8. Phentolamine Clinical uses (1) • Hypertension from pheochromocytoma (short term use). • pre- and post-operation of pheochromocytoma • Diagnostic test for pheochromocytoma (2) Peripheral vascular diseases • Acrocyanosis, Raynaud’s disease (3) Local vasoconstrictor extravasation Major Adverse effects– postural hypotension, reflex tachycardia, arrhythmia, angina pectoris, GI reactions

9. 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 (a1 & ±b)

10. Pheochromocytoma

11. Phenoxybenzamine (酚苄明) • Irreversible, nonselective ( 1 and 2 antagonists ) • Long-acting • Similar to phentolamine in actions and clinical uses

12. 1 receptor antagonists • prazosin（哌唑嗪） • treatment for hypertension • 2 receptor antagonists • yohimbine（育亨宾） • for research use only

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

14. Effects of an b AR Antagonist

15.  receptor antagonists • Pharmacological effects • (1)  receptor blockade • A. Cardiovascular effects： • Depressing heart: reduction in HR, A-V conduction, automaticity, cardiac output, oxygen consumption • Hypotension: peripheral blood flow , hypotensive effects in hypertensive patients

16.  receptor antagonists • (1)  receptor blockade • B. Bronchial smooth muscles • induces bronchial smooth muscle contraction in asthmatic patients • C. Metabolism • lipolysis  , glycogenolysis  , potentiating insulin effects ~ hypoglycemia • D. Renin secretion • decreasing secretion of renin

17.  receptor antagonists • (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 • (4) Others • Lowering intraocular pressure; • Inhibiting platelet aggregation

18. Circulation of Aqueous humor

19.  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 headache, glaucoma（timolol）...

20.  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 the receptors (4) Worsening of peripheral vascular constriction (5) Others：central depression, hypoglycemia,etc.

21. Propranolol （普萘洛尔） • 1, 2 receptor blocking • no intrinsic activity • first-elimination after oral administration, individual variation of bioavailability Timolol （噻吗洛尔） • For treatment of glaucoma (wide-angle)

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

23. NO, 2 agonist, 1 blocker Ca2+ blocker Antioxidation 1 blocker NO 受体阻断剂的药理学特性

24. α,  receptor antagonists Labetalol （拉贝洛尔） • α, β receptor blocking, β> α • usually used for treatment of hypertension

26. Therapeutic Uses of a1 (±b) AR Agonists 1. Hypotension -To preserve adequate blood perfusion to heart, brain or kidneys in cases of hemorrhage, overdose of antihypertensive drugs or spinal cord injuries. -Short duration of treatment: NE, phenylephrine, methoxamine, ephedrine (a1 AR agonists). 2. Shock -Inadequate perfusion to tissues as a consequence of hypovolemia, cardiac failure, or altered vascular resistance. -Usually associated with hypotension. -Use of a1-adrenergic agonists to increase peripheral vascular resistance, and b1-adrenergic agonists to improve cardiac function. 3. Cardiogenic Shock -Massive myocardial infarction. -Stimulation of cardiac b1-adrenergic receptors is needed: isoproterenol, norepinephrine, epinephrine, dobutamine, dopamine.

27. Therapeutic Uses of a1 (±b) AR Agonists 4. Local Vascular Effects -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 -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 -Epinephrine (s.c.) is used in acute hypersensitivity reactions. -Activation of b-adrenergic receptors on mast cells suppresses the release of histamine and leukotrienes.

28. Therapeutic Uses of b2 AR Agonists 1. Asthma -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 -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.

29. Therapeutic Uses of a1 & b AR Antagonists 1. Pheochromocytoma 2. Hypertension -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 -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.

30. Other Important Catecholamine Drugs • TH Inhibitor –a-methyl-p-tyrosine • DBH Inhibitors – (no good selective ones) • VMAT Inhibitors – reserpine & amphetamine • False Transmitters – tyramine & a-methyl-DOPA ( a-methyl-NE) • MAO Inhibitors – pargyline (nonselective), chlorgyline (MAOA), deprenyl (MAOB) • NET Inhibitors – desipramine, reboxetine • Neurotoxin – 6-hydroxydopamine, DSP-4

31. Classification of CNS drugs Sedative-hypnotics Epilepsy and convulsion Parkinson disease Analgesics Central stimulants Neurological（general and special） Antipsychotic drugs depression－mania Dementia Psychological

32. Sedative-Hypnotic Drugs

33. Sedatives （镇静药）： 能缓和激动，消除躁动，恢复安静情绪的药物 -----prescribed to cause sedation (for patients with anxiety) Hypnotics （催眠药）： 能促进和维持近似生理睡眠的药物 -----prescribed to encourage sleep (for patients with insomnia) 中枢抑制药多数随剂量增加而出现镇静、催眠等中枢抑制作用，故合称为镇静催眠药（sedative-hypnotics）

34. Stage 3 & 4, 统称为慢波睡眠 Molecular Neuropharmacology

35. Sleep histogram shows a normal pattern of sleep in a young adult.

37. A schematic drawing showing key components of the ascending reticular activating system (ARAS)

38. Circadian rhythm & Circadian control SCN: suprachiasmatic nucleus 视交叉上核

39. Sedative-Hypnotic Drugs • Benzodiazepines (BZ / BDZ, 苯二氮卓类) • Barbiturates (巴比妥类) • Others

40. A. Benzodiazepines Diazepam 地西泮（安定） R1 R2 R3 R7 R4

41. A. Benzodiazepines 1. Pharmacological effects and clinical uses (1) Antianxiety at small doses acting on limbic system（边缘系统，杏仁核、海马） (2) Sedative-hypnotic effects（作用于脑干） at relatively larger doses, no anesthetic effect; not remarkably affect on REM used forinsomnia（失眠）andpreanesthetic medication

42. A. Benzodiazepines (3) Antiepileptic and anticonvulsant effects Convulsion due various causes; status epilepticus(i.v.) (4) Centrally acting muscle relaxant effect Relaxing the spasticity of skeletal muscle, probably by increasing presynaptic inhibition in the spinal cord. Used for the treatment of skeletal muscle spasms caused by central or peripheral diseases. (5) Others Amnesia (短暂性记忆缺失, i.v.） Respiratory and CVS effects

43. A. Benzodiazepines 2. Mechanisms of actions (1) Sites of action:mainly acts on limbic system and midbrain reticular formation. (2) Interaction with GABAA receptor Benzodiazepines bind to specific, high affinity sites on the cell membrane, which are separate from but adjacent to the receptor for -aminobutyric acid (GABA). The binding of benzodiazepinesenhances the affinity of GABA receptor for this neurotransmitter, resulting in a more frequent opening of adjacent chloride channels.- coagonist This in turn results inenhanced hyperpolarization（超极化）and further inhibition of neuronal firing.

44. Modulation mode of the central inhibitory transmitter GABA and the action sites of drugs

45. Action of the central inhibitory transmitter GABA on Cl- influx and the action sites of benzodiazepines (BDZs)

46. ACh NE DA 5-HT

47. Centrally acting muscle relaxant effect:increasing presynaptic inhibition in the spinal cord

48. A. Benzodiazepines 3. Adverse effects (1) Central depression Most common: drowsiness and confusion (potentiated by ethanol or other central depressants). Ataxia (共济失调); cognitive impairment Antagonized by BZ receptor antagonist flumazenil（氟马西尼） (2) Tolerance and dependence Withdrawal syndrome: central excitation

49. A. Benzodiazepines (3) Others local pain, respiratory and CVS reactions (i.v.) teratogenic effects（致畸效应） (4) Contraindications Myasthenia gravis Infants < 6 months Pregnancy and lactation mothers Elderly, heart/lung/liver/kidney dysfunction

50. A. Benzodiazepines Other benzodiazepines According to the metabolisms • Long-acting： diazepam, chlordiazepoxide (氯氮卓), flurazepam (氟西泮) • Intermediate-acting： Nitrozepam (硝西泮), flunitrozepam (氯硝西泮), oxazepam (奥沙西泮), estazolam (艾司唑仑） • Short-acting：triazolam (三唑仑) 艹