《基础医学各论3》资料：神经系统药理2

1、各论3：神经系统药理2,1、胆碱能神经系统 （3）胆碱受体拮抗药 2、肾上腺素能神经系统 （1）肾上腺素受体激动药,2013.10.16,Muscurinic receptor antagonists,M cholinoceptor antagonists Atropine阿托品 (Antimuscarinic drugs) N cholinoceptor antagonists NN cholinoceptor antagonists: mecamylamine美加明 (Ganglionic Blocking drugs, rarely used ) NM cholinoceptor ant

2、agonists: succinylcholine琥珀胆碱 (Neuromuscular Blocking drugs ) Botulinum Toxin肉毒毒素 (blocks ACh release),Drug classification of cholinergic antagonists,Muscarinic Antagonists (Antimuscarinic drugs),Tertiary amines叔胺类,Quaternary amines季胺类,阿托品,东莨菪碱,异丙托溴铵,噻托溴铵,甲硝阿托品,1. Pharmacological effects,Atropine,li

3、ght,调节麻痹,1. Pharmacological effects (2) Antispasmodic action on smooth muscle sensitive: GI, urinary bladder (spasmodic state) relatively insensitive: bile duct, urinary tract, bronchial tract insensitive: uterus (3) Inhibition of exocrine gland secretion salivary, sweat glands tear, respiratory tra

4、ct glands relatively ineffective: GI tract,Atropine,Pharmacological effects (4) Cardiovascular System: dose dependent Lower therapeutic doses: HR(bradycardia); Blood vessels and blood pressure: no effect Moderate to high therapeutic doses / high vagal tone: HR (tachycardia); A-V conduction Larger do

5、ses: cutaneous vasodilatation (5) CNS stimulation sedation, memory loss, psychosis (high dose),Atropine,Lower therapeutic doses: Block Pre-synaptic M1 receptor ACh release activate Post-synaptic M2 receptor HR,Regulation of K+ Channels Heart rate ,Moderate to high therapeutic doses : Block Post-syna

6、ptic M2 receptor HR,2. Clinical uses (1) Ophthalmology Measurement of the refractive errors(验光): children Acute iritis or iridocyclitis: mydriatics/miotics （to prevent synechia/adhesion） (2) Antispasmodic agent GI, biliary or renal colic, enuresis(遗尿) (3) Inhibiting exocrine gland secretion Preanest

7、hetic medication (4) Bradyarrhythmia sinus or nodal bradycardia, A-V block (5) Antidote for organophosphate poisoning,Atropine,3. Adverse effects (1) Side effects dry mouth, blurred vision, “sandy eyes” (2) toxicity Lethal dose: 80130 mg (adult), 10 mg (child) Low: xerostomia (dry mouth); anhidrosis

8、 (dry skin), tachycardiad Moderate: above plus mydriasis (扩瞳), cycloplegia(睫状肌麻痹); difficulty on speaking, swallowing coma (昏迷) (i.e. CNS symptoms) (3) Detoxication Symptomatic treatment: e.g. diazepam. Physostigmine 毒扁豆碱 or pilocarpine 匹鲁卡品 (4) Contraindications glaucoma, prostatauxe (前列腺肥大), fever

9、,Atropine,Actions and clinical uses Peripheral effects are similar to atropine; but has stronger central effects (depression) Pre-anesthetic medication, prevention of motion sickness, Parkinsons disease,Scopolamine (东莨菪碱),Actions and clinical uses 654, 654-2 Weaker action than atropine, lower toxici

10、ty,Anisodamine (山莨菪碱),Synthetic or semi-synthetic Homatropine 后马托品 Tropicamide 托吡卡胺 Cyclopentolate 环喷托酯 Eucatropine 尤卡托品 Lower side effect and shorter duration for mydriasis,others,Synthetic anti-spasm agents Ipratropium (异丙托溴胺): asthma Scopolamine methylbromide (溴甲东莨菪碱): GI Homatropine methylbromid

11、e (溴甲后马托品): GI and cough Mepenzolate bromide (溴化甲哌佐酯): GI Propantheline (普鲁本辛) poor absorption (po) and BBB penetration antispasmodic effects in GI, treatment of peptic ulcer disease,others,Selective M-receptor antagonists Pirenzepine 哌仑西平：M1 and M4 Telenzepine 替仑西平：more selective to M1 ulcer Tripit

12、amine： M2 and M3 selective Darifenacin 达非那新,others,Nicotinic receptor antagonists,Acting on sympathetic and parasympathetic ganglionic cells; reducing blood pressure by inhibiting sympathetic ganglia ( have been abandoned for clinical use, due to their lack of selectivity) Short-acting; tachyphylaxi

13、s Used for treatment of hypertension Trimethaphan (樟磺咪芬) Mecamylamine (美卡拉明),NN receptor antagonists(Ganglionic Blocking drugs),Two classes: Non-depolarizing: drugs act as competitive antagonists Depolarizing: succinylcholine (琥珀胆碱, 司可林),Note: Belong to Skeletal Muscle Relaxants. It is important to

14、realize that muscle relaxation does not ensure unconsciousness, amnesia, or analgesia.,NM receptor antagonists (Neuromuscular Blocking drugs ),1. Depolarizing neuromuscular blockers (Non-competitive) (depolarizing skeletal muscle relaxants) act as acetylcholine (ACh) receptor agonists导致肌束颤动 the depo

15、larized membranes remain depolarized and unresponsive to subsequent impulses (ie, they are in a state of depolarizing block). not metabolized by AChE使作用延长，过量不能被新斯的明解救 they diffuse away from the neuromuscular junction and are hydrolyzed in the plasma and liver by pseudocholinesterase (nonspecific cho

16、linesterase, plasma cholinesterase, or butyrylcholinesterase) and elimination by kidney,NM receptor antagonists (Neuromuscular Blocking drugs ),Succinylcholine琥珀胆碱, Scoline,Succinylcholine is the only depolarizing agent used clinically (t1/2= 2-4 min). Properties of actions: initially transient fasc

17、iculations anti-AChE potentiates their effects tachyphylaxis (快速耐受性) after repeated uses no ganglion-blocking effects at therapeutic doses the drugs are highly polar, poor bioavailability; i.v. as quaternary compounds. . .do not enter CNS,acetylcholine,succinylcholine,Main pharmacological effects Tr

18、ansient excitation (fasciculations肌束震颤), and then inhibition (relaxation) Relax Skeletal Muscles in neck, limbs face, tongue, throat; less effective on breath muscles at therapeutic doses,Succinylcholine琥珀胆碱, Scoline,Clinical uses An adjuvant in anesthesia or operation Intubation of trachea, esophag

19、us, etc. Prevention of trauma during electroshock therapy Contraindicated in awake patients, should use under anesthesia,Succinylcholine琥珀胆碱, Scoline,Adverse effects (1) Apnea (respiratory paralysis) overdose or hypersensitive patients; neostigmine potentiates the toxic effects (2) Fasciculations 肌束

20、震颤 muscular pain after operation (because of transient fasciculations) (3) Malignant hyperthermia genetic abnormality,Succinylcholine琥珀胆碱, Scoline,(4) Elevation of K+ in plasma contraindicated in patients with a tendency of hyperkalemia (burn injury, massive trauma, neurological disorders) (5) Cardi

21、ovascular response various arrhythmia (6) Others rise in intraocular pressure (glaucoma); histamine release,Succinylcholine琥珀胆碱, Scoline,Genetic Variation: Effects on Duration of Action of Succinylcholine,The duration of action is prolonged by high doses or by abnormal metabolism. The latter may res

22、ult fromhypothermia, low pseudocholinesterase levels, or a genetically aberrant enzyme. (hypothermia decreases the rate of hydrolysis) Low pseudocholinesterase levels generally produce only modest prolongation of succinylcholines actions (220 min). One in 50 patients has one normal and one abnormal

23、(atypical) pseudocholinesterase gene, resulting in a slightly prolonged block (2030 min). Even fewer (1 in 3000) patients have two abnormal genes (homozygous atypical) that produce an enzyme with little or no affinity for succinylcholine and have a very long blockade (e.g., 48 h) following administr

24、ation of succinylcholine. Scoline Apnea： mechanical ventilation,Drug interactions Thiopental (硫喷妥)，易分解 AChE inhibitors: AChE inhibitors, cyclophosphamide(环磷酰胺), procaine(普鲁卡因), etc. Some antibiotics: kanamycin(卡那霉素), polymyxins(多粘菌素), etc. (synergism in neuromuscular blocking),Succinylcholine琥珀胆碱, S

25、coline,2. Nondepolarizing neuromuscular blockers (Competitive ) (nondepolarizing skeletal muscle relaxants),Tubocurarine (筒箭毒碱),Reversibly bind to the nicotinic receptor at the neuromuscular junction (competitive antagonists),(note: curare rarely used),Effects: competitive blockade of NM receptors P

26、harmacological effects: Relax Skeletal Muscles in 眼部肌肉，四肢、颈部、躯干、肋间肌、膈肌呼吸抑制 Uses: adjuvant treatment of anesthesia or operations,Tubocurarine (筒箭毒碱),Adverse effects: Respiratory paralysis: can be reversed by neostigmine Enhancing histamine release: BP , hypotension, bronchoconstriction, salivary secr

27、etion Blocking ganglion: BP Contraindications: myasthenia gravis, bronchial asthma, shock, child ( 10 y) Drug interactions Similar to these of scoline,Tubocurarine (筒箭毒碱),Benzylisoquinolines(苄基异喹啉类 ) Atracurium(阿曲库铵) Doxacurium(多库氯铵) Mivacurium(咪库铵) Ammonio steroids Pancuronium(潘库铵) Vecuronium(维库铵)

28、Pipecuronium(派库铵) Rocuronium(罗库铵),Other nondepolarizing neuromuscular blockers,It is important to realize that neuromuscular junction blocking agents produce paralysis, not anesthesia. In other words, muscle relaxation does not ensure unconsciousness, amnesia, or analgesia.,(note: currently used NMJ

29、 blockers differ in time of onset and clinical duration : pancuroniumatracuriumrocuronium),Botulinum Toxin肉毒毒素,Skeletal Muscle Relaxants blocks ACh release from cholinergic terminals selective for ACh terminals - irreversible; Botox acts as a protease that cleaves specific proteins involved in exocy

30、tosis. results in flaccid paralysis （松弛性麻痹） in muscles; (can also be used for excessive sweating, tension/migraine),Acts by cleaving SNARE proteins inhibits ACh release, Strabismus (lack of parallelism of eyes，斜视), blepharospasm (eyelid spasm), dystonia (abnormal tonicity，肌张力障碍). Excessive sweating

31、Cosmetic procedures ( “frown lines” or “crows feet”) Note: effects can last for 3-6 months.,LA Times,Botulinum Toxin Applications,Adrenergic Pharmacology,Parasympathetic NS EYE Contraction of iris sphincter muscle (pupil dilates) Contraction of ciliary muscle (lens accommodates for near vision) Lacr

32、imal gland Stimulates tears Salivary gland Copious, water secretion Trachea and bronchioles Constricts, increase secretion Heart ratecontractility Gastrointestinal Muscle motility some are poor substrate for MAO (orally active, a prolonged duration of action) Greater access to the CNS,Catecholamine

33、High potency in activating a or b receptors Rapid inactivation by COMT and by MAO Poor penetration into the CNS,Sympathomimetic amines,儿茶酚胺,-苯乙胺,Structure-activity relationship of catecholamines and related compounds,b-receptor activity,麻黄碱,苯乙胺,Bioavailability of oral admin.,Duration.,CNS distributi

34、on,Block MAO uptake-1,For activation of receptor,Adrenoceptors,Direct mode e.g. Norepinephrine epinephrine isoproterenol Indirect mode Mixed mode e.g. ephedrine,The mode of action of sympathomimetic drugs,Enhances release of stored catecholamines e.g. amphetamine Inhibition of reuptake of released c

35、atecholamines e.g. cocaine Inhibition of MAO e.g. pargyline,拟交感药,Adrenoceptor agonists , receptor agonists epinephrine (adrenaline)，dopamine, ephedrine (2) receptor agonists 12 receptor agonists: norepinephrine 1 receptor agonists: phenylephrine 2 receptor agonists: clonidine (3) receptor agonists：

36、12 receptor agonists: isoproterenol 1 receptor agonists: dobutamine 2 receptor agonists: salbutenol,Drug actions and classification,Pharmacological effects 1, 2 , 1 , 2 receptor agonists (1) Cardiac effects 1: contractility (positive inotropic), HR (positive chronotropic), cardiac output , oxygen co

37、nsumption , inducing arrhythmia (2) Vascular effects 1：vasoconstriction (skin, mucous, viscera), especially at larger doses 2：vasodilatation of skeletal muscles and coronary vessels,Epinephrine, Adrenaline (肾上腺素): DIRECT,Concentration-dependent response in vascular smooth muscle to epinephrine,Predo

38、minant Effects low EPI 2 high EPI 2,Epinephrine reversal （adrenaline reversal）,(3) Blood pressure Systolic BP , Diastolic BP (slight) (4) Respiratory 2：dilatation of bronchial smooth muscles (Bronchodilatation) 1：reducing congestion and edema of bronchial mucosa (5) Metabolic effects blood glucose (

39、hyperglycemia); free fatty acids (lipolysis),Epinephrine, Adrenaline,Effects of catecholamines（therapeutic doses）,Predominant Effects: NE : 1 receptor：vasoconstriction of skin, mesenteric vessels (larger doses) (3) Renal effects：renal vasodilatation; natriuretic effects,Dopamine (多巴胺): DIRECT Pharma

40、cological effects : , receptor, dopaminergic receptor agonists,Clinical uses (1) Shock cardiac and septic shock (2) Acute renal failure combined with furosemide Adverse effects short-lived tachycardia, arrhythmia, reduction in urine flow (renal vasoconstriction),Dopamine,Promoting release of NE, wea

41、k agonist effects on 1、2、1、2 receptors Properties： chemically stable, orally effective； less potent but longer action duration; central stimulating: alertness , fatigue , prevents sleep (adverse effects) Tachyphylaxis (快速耐受).,Ephedrine (麻黄碱): MIXED,Epinephrine,Ephedrine,Clinical uses (1) Prevention

42、of hypotension: anesthetics (2) Nasal decongestion: nasal drop (3) Bronchial asthma: mild, chronic cases (4) Relieving allergic disorders: urticaria (风疹), angioneurotic edema,Ephedrine,Norepinephrine, Noradrenaline (去甲肾上腺素): DIRECT,Pharmacological effect 1, 2 receptor agonists (1) Vascular effects：

43、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： Systolic BP , Diastolic BP (especially at larger doses) (3) Cardiac effects： Weak direct stimulati

44、on (1); inhibition via reflex (in vivo) Net result: little cardiac stimulates Coronary artery dilation,Norepinephrine, Noradrenaline,Effects of catecholamines（therapeutic doses）,Predominant Effects: NE : replaced by Metaraminol间羟胺) (2) Hypotension due to drug poisoning especially for chlorpromazine

45、(氯丙嗪) (3) Hemorrhage in upper alimentary tract orally given after dilution,Norepinephrine, Noradrenaline,Adverse effects (1) Ischemia and necrosis at the site of iv administration relieved by filtrating the area with phentolamine ( receptor antagonist) (2) Acute renal failure avoiding larger doses a

46、nd longer duration; monitoring urinary volume (3) Contraindication hypertension, arteriosclerosis, heart diseases, severe urinary volume , microcirculation disorders,Norepinephrine, Noradrenaline,Acting on receptors directly, promoting NE release indirectly； Weaker effects and longer duration than N

47、E, Weak effects on renal vessels; Used in early phase of shock, hypotension,Metaraminol 间羟胺,Induces reflex bradycardia, used in hypotension, paroxysmal supraventricular tachycardia ； Activate receptor at normal dose Block receptor at high dose Phenylephrine: Mydriasis, pupillary dilator muscles, no

48、or less effect on intraocular pressure, short-acting (for several hours); 可作为快速扩瞳药,Methoxamine甲氧明: DIRECTINDIRECT Phenylephrine苯肾上腺素: DIRECTINDIRECT,1 receptor agonists,Clonidine: DIRECT Uses: antihypertensive drug; can be administered as transdermal patch (permits continuous administration) Mechanism of action : 2 - adrenergic partial agonist; actions predominantly in CNS lowers blood pressure by inhibiting sympathetic vasomotor tone Adverse effects: (iv administration may result in transient increase in blood pressure (activation of post-synaptic