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Pharmacology of the nervous system Shi-Hong Zhang (张世红), PhD Dept. of Pharmacology, School of Medicine, Zhejiang University [email protected] Peripheral Nervous System (PNS) Efferent Division Autonomic System (ANS) Afferent Division Somatic System Parasympathetic Sympathetic Enteric The Enteric Nervous System (+SNS/PSNS) Sympathetic stimulation causes: • • • • • • stimulates heartbeat raises blood pressure dilates the pupils dilates the trachea and bronchi stimulates the conversion of liver glycogen into glucose shunts blood away from the skin and viscera to the skeletal muscles, brain, and heart • inhibits peristalsis (蠕动) in the gastrointestinal (GI) tract • inhibits contraction of the bladder and rectum Parasympathetic stimulation causes: • slowing down of the heartbeat • lowering of blood pressure • constriction of the pupils • increased blood flow to the skin and viscera • peristalsis of the GI tract Nervous System Drugs that produce their Peripheral Nervous System (PNS) Efferent Division Autonomic System (ANS) Central Nervous System (CNS) Afferent Division Somatic System Parasympathetic Sympathetic Enteric Organization of the nervous system primary therapeutic effect by mimicking or altering the functions of autonomic nervous system are called autonomic drugs. Neurotransmitters • Synthesis • Storage • Release • Degradation Receptors • Activation • Blockade Drug actions and classification (1) Mimetics - direct-acting: receptor agonists - indirect-acting: increasing amounts and/or effects of transmitters (2) Antagonists - direct-acting: receptor antagonists - indirect-acting: decreasing amounts and/or effects of transmitters Pharmacology of efferent nervous system • Cholinergic Pharmacology • Adrenergic Pharmacology CASE STUDY • In mid-afternoon, a coworker brings 43-year-old JM to the emergency department because he is unable to continue picking vegetables. His gait is unsteady and he walks with support from his colleague. JM has difficulty speaking and swallowing, his vision is blurred, and his eyes are filled with tears. His coworker notes that JM was working in a field that had been sprayed early in the morning with a material that had the odor of sulfur. Within 3 hours after starting his work, JM complained of tightness in his chest that made breathing difficult, and he called for help before becoming disoriented. Cholinergic Terminal • Choline Uptake→ • ACh Synthesis Choline + AcCoA → ACh ChAT • ACh Storage • ACh Release • ACh Effects - Postsynaptic - Presynaptic • ACh inactivation ACh → Choline + Acetate AChE Acetylcholine Release Regulation - by autoreceptors ACh acting on presynaptic M2-cholinergic receptors - by heteroreceptors NE acting on presynaptic alpha2-adrenergic receptors - by metabolism (extraneuronal) ACh inactivation Cholinesterases Acetylcholinesterase is located at cholinergic synapses and in erythrocytes (does not hydrolyze succinylcholine) Pseudocholinesterase (synonyms: plasmacholinesterase or butyrylcholinesterase丁酰胆碱脂酶 ) occurs mainly in plasma, liver and in glia (hydrolyzes succinylcholine) Cholinergic Receptors • Muscarinic receptors (M receptors) M1, 3, 5 (smooth muscles); M2, 4(heart) G-protein Coupled End Organs • Nicotinic receptors (N receptors) NN (N1) receptors; NM(N2 ) receptors Ligand-gated Ion Channels NMJ & Ganglia M receptors : G-protein Coupled Muscarinic Receptor Signaling Pathways M receptors: • Depression of the heart (heart rate, conduction) • Contraction of smooth muscles (sensitive: GI tract, bronchial, urinary bladder; insensitive: uterine, blood vascular) • Exocrine glands (sensitive: sweat, tear, salivary; insensitive: GI tract); • Eye (contraction of sphincter muscle of iris: miosis; contraction of ciliary muscle睫状肌: contraction for near vision) Cholinergic Vasodilation • The response of an isolated blood vessel to ACh depends on whether the endothelium is intact (unrubbed) or missing • When the endothelium is present, ACh causes smooth muscle relaxation by stimulating the production of nitric oxide (NO) in the endothelium • In the absence of the endothelium, a small amount of vasoconstriction is observed N receptors • NN receptors( N1 receptors ) - Sympathetic and parasympathetic ganglia - Adrenal medulla • NM receptors (N2 receptors ) - The Neuromuscular Junction (NMJ) (Contraction of skeletal muscles) N receptors : Ligand-gated Ion Channels • At the NMJ, N receptors pentameric with four types of subunits, two a subunits bind ACh for ligand gating • All other nAChRs, including those at the peripheral ganglia, have 2 a’s and 3 b’s Ganglionic Neurotransmission N = Nicotinic AChR M = Muscarinic AChR EPSP = Excitatory Postsynaptic Potential IPSP = Inhibitory Postsynaptic Potential The Neuromuscular Junction (NMJ) A B Myasthenia Gravis • This means “serious disorder the NMJ” • This is an autoimmune disease • Antibodies against the a subunit of the nAChR • The ability of ACh to activate the nAChRs is blocked by the antibodies • As many autoimmune diseases, stress can make the symptoms worse • Treatment is to potentiate cholinergic signaling and to remove the antibodies (blood dialysis) Drug classification 1. Cholinomimetics (1) Direct-acting drugs: Cholinoceptor agonists M, N receptor agonists: acetylcholine M receptor agonists: pilocarpine N receptor agonists: nicotine (2) Indirect-acting drugs: Cholinesterase inhibitors (Anticholinesterases) Reversible: neostigmine新斯的明 Irreversible: organophosphates 有机磷酸酯类 Cholinesterase reactivators: pralidoxime iodide 碘解磷定 Drug classification 2 Cholinergic antagonists (1) Cholinoceptor antagonists M cholinoceptor antagonists atropine (Antimuscarinic drugs) N cholinoceptor antagonists NN cholinoceptor antagonists: mecamylamine (Ganglionic blocking drugs, rarely used) NM cholinoceptor antagonists: succinylcholine (Neuromuscular blocking drugs ) (2) Botulinum Toxin (Botox, blocks ACh release) Cholinomimetics Direct-acting drugs Ach derivatives (胆碱酯类) Natural muscarinic agonists (生物碱类M 受体激动剂) Nicotinic receptor agonists (N受体激动剂) ACh Derivatives Bond cleaved by AChE 乙酰胆碱 醋甲胆碱 卡巴胆碱 氯贝胆碱 AChE resistant ACh Derivatives Bethanechol 氯贝胆碱is most commonly used, particularly post-op for the treatment of paralytic ileus and urinary retention Natural Muscarinic Agonists 槟榔碱 毛果芸香碱 毒蕈碱 Nicotinic potency • Arecoline: areca or betal nuts (India,E. Indies) • Pilocarpine: pilocarpus (S. Amer. shrub) • Muscarine: amanita muscaria (mushroom) “Food” Poisoning • Poisoning causes muscarinic overstimulation: - salivation, lacrimation, visual disturbances; Amanita muscaria - abdominal colic and diarrhea 伞形毒蕈 - bronchospasm and bradycardia - hypotension; shock • Atropa belladonna 颠茄 Treatment is with atropine Pilocarpine (1) Eyes • Miosis (缩瞳): contraction of sphincter muscle of iris • Lowing intraocular pressure: enlarging angle of anterior chamber, increasing drainage of aqueous humor • Spasm of accommodation (调节痉挛): contraction of ciliary muscle, contraction for near vision • Ophthalmological 眼科 uses Glaucoma 青光眼: narrow (closed)- or wide (open)-angles used for the emergency, lowering intraocular pressure Iritis: miotics缩瞳药/mydriatics扩瞳药 Ciliary muscle (dilation) Canal of Schlemm mydriasis zonule Posterior chamber Anterior chamber lens iris paralysis of accommodation far sight atropine spasm of accommodation miosis zonule Anterior chamber Ciliary muscle (contraction) near sight pilocarpine Circulation of aqueous humor Glaucoma • Open-angle glaucoma: disease of the aging eye increased intraocular pressure, degeneration of the optic head, and restricted visual field • Obstruction of the aqueous drainage leads to elevated intraocular pressure (IOP), and may result in glaucomatous damage to the optic nerve Glaucoma • Glaucoma management involves lowering IOP by - Decreasing aqueous production by the ciliary body - Increasing aqueous outflow through the trabecular meshwork and uveal outflow paths • Pilocarpine: increase aqueous outflow by contraction of the ciliary muscle to increase tone and alignment of the trabecular network Pilocarpine (2) Promoting secretion of exocrine glands, especially in sweat, salivary and tear glands • Systemic use Antidote解毒剂 for atropine poisoning • Adverse effects M-like syndrome N receptor agonists: Nicotine Actions at ganglia, NMJ, brain are complex and frequently unpredictable, because of the variety of neuroeffector sites and because nicotine both stimulates and desensitizes effectors. Periphery: HR, BP, GI tone & motility CNS: stimulation, tremors, respiration, emetic effects The addictive power of cigarettes is directly related to their nicotine content. Drug classification 1. Cholinomimetics (1) Direct-acting drugs: Cholinoceptor agonists M, N receptor agonists: acetylcholine M receptor agonists: pilocarpine N receptor agonists: nicotine (2) Indirect-acting drugs: Cholinesterase inhibitors (Anticholinesterases) Reversible: neostigmine 新斯的明 Irreversible: organophosphates 有机磷酸酯类 Cholinesterase reactivators: pralidoxime iodide 碘解磷定 Acetylcholinesterase (AChE) Activity AChE Inhibitors A. Competitive (reversible) B. Carbamates (氨甲酰类slowly reversible) C. Organophosphates (irreversible) 依酚氯铵 These agents are reversible and are used medically (glaucoma or MG) 新斯的明 neostigmine 毒扁豆碱 These agents are irreversible and are used as pesticides or for glaucoma Acetylcholinesterase Inhibitors: Reversible Edrophonium (依酚氯铵) Rapidly absorbed; A short duration of action (5-15min); Competitive (reversible) Used in diagnosis of myasthenia gravis. Excess drug may provoke a cholinergic crisis, atropine is the antidote. Other reversible ACHEI: tacrine 他克林, donepezil 多奈哌齐 Acetylcholinesterase Inhibitors: Carbamates Inhibitory Effects are slowly reversible Representative Drugs neostigmine (quaternary amine 季铵) pyridostigmine (quaternary amine) physiostigmine (tertiary amine 叔胺) quaternary amines effective in periphery only tertiary amines effective in periphery and CNS (fat-soluble) Neostigmine 新斯的明 Pharmacological effects • AChE(-), ACh release↑, stimulating NMR • stronger effect on skeletal muscles • effective on GI tract and urinary bladder • more polar and can not enter CNS • relatively ineffective on CVS, glands, eye Neostigmine Clinical uses 1. Myasthenia gravis: symptomatic treatment overdose: cholinergic crisis 胆碱能危象:大量出汗,大小便失禁,瞳孔缩小,睫状肌痉挛, 心动过缓,低血压,肌无力,呼吸困难 2. Paralytic ileus 麻痹性肠梗阻urinary retention: post operative abdominal distension and urinary retention 3. Paroxysmal supraventricular tachycardia(rarely use) 4. Antidote for tubocurarine ( 筒 箭 毒 碱 ) and related drug poisoning 5. Glaucoma Neostigmine Adverse effects • Cholinergic effects: muscarinic and nicotinic effects, treated with atropine (muscarinic) • Contraindications: mechanical ileus(机械性肠梗阻) urinary obstruction bronchial asthma poisoning of depolarizing skeletal muscle relaxants (e.g. succinylcholine, 琥珀酰胆碱) Acetylcholinesterase Inhibitors: Irreversible Bond is hydrolyzed in binding to the enzyme 乙磷硫胆碱 For ophthalmic use 梭曼 Dichlorvos 敌敌畏 对硫磷 对氧磷 Dimethoate 乐果 马拉硫磷 马拉氧磷 Organophosphates (1) Toxic symptoms Acute intoxication • Muscarinic symptom: eye, exocrine glands, respiration, GI tract, urinary tract, CVS • Nicotinic symptoms: NN: elevation of BP, increase of HR; NM: tremor of skeletal muscles • CNS symptoms: excitation, convulsion; depression (advanced phase) CASE STUDY • In mid-afternoon, a coworker brings 43-year-old JM to the emergency department because he is unable to continue picking vegetables. His gait is unsteady and he walks with support from his colleague. JM has difficulty speaking and swallowing, his vision is blurred, and his eyes are filled with tears. His coworker notes that JM was working in a field that had been sprayed early in the morning with a material that had the odor of sulfur. Within 3 hours after starting his work, JM complained of tightness in his chest that made breathing difficult, and he called for help before becoming disoriented. Organophosphates (1) Toxic symptoms Chronic intoxication • usually occupational poisoning • plasma ChE activity ↓, • weakness, restlessness, anxiety, tremor, miosis, …… Organophosphates (2) Detoxication • Elimination of poison; Supportive therapy • Antidotes Atropine-antagonizing muscarinic effects; early, large dose, and repeated use Cholinesterase reactivators-reactivation of phosphated AChE; moderate-severe patients, early use (More effective on tremor), combined with atropine – Pyraloxime methoiodide (PAM,碘解磷定) – Pralidoxime chloride (氯解磷定): safer than PAM – Obidoxime chloride(双复磷): two active oxime groups Organophosphates Pralidoxime (解磷 定)can restore AChE activity if administered soon after toxin exposure. • Conjugating with organophosphate by oxime group; • Conjugating with free organophasphates Why isn’t this ACHEI pesticide neurotoxic to humans? Malathion马拉硫磷 Insects and mammals metabolize the ‘prodrug’ differently Insects - P450 metabolism: P-S bond converted to P-O bond: now, the molecule, malaoxon, is an active inhibitor Mammals – esterase activity: hydrolyzes the molecule into inactive metabolites Summary: ACHEI Applications Pharmacological Actions: Increases ACh concentrations at cholinergic synapses, thereby increasing cholinergic activity. glaucoma (e.g. physiostigmine毒扁豆碱, echothiophate乙磷硫胆碱 ) myasthenia gravis (e.g. Edrophonium, neostigmine, pyridostigmine ) reverse neuromuscular blockade from competitive antagonists (neostigmine) Alzheimer’s disease (tacrine & donepezil, galanthamine) chemical warfare agents insecticides Drug classification 2 Cholinergic antagonists (1) Cholinoceptor antagonists • M cholinoceptor antagonists – atropine (Antimuscarinic drugs) • N cholinoceptor antagonists – NN cholinoceptor antagonists: mecamylamine (Ganglionic blocking drugs, rarely used) – NM cholinoceptor antagonists: succinylcholine (Neuromuscular blocking drugs ) • Botulinum Toxin (botox, blocks ACh release) Muscarinic Antagonists (Antimuscarinic drugs) Tertiary amines(叔铵) Quaternary amines(季铵) 东莨菪碱 异丙托铵 噻托溴铵 Atropa belladonna 颠茄 Datura sp. 洋金花 Datura stramonium 曼陀罗 Henbane Seed 山莨菪 Atropine 1. Pharmacological effects (1) Inhibition of exocrine gland secretion salivary, sweat glands tear, respiratory tract glands relatively ineffective: GI tract (2) Eye mydriasis 瞳孔散大 rise in intraocular pressure paralysis of accommodation调节麻痹 Ciliary muscle (dilation) Canal of Schlemm mydriasis zonule Posterior chamber Anterior chamber lens iris paralysis of accommodation far sight atropine miosis spasm of accommodation zonule Anterior chamber Ciliary muscle (contraction) near sight pilocarpine Atropine 1. Pharmacological effects (3) Antispasmodic action on smooth muscle • sensitive: GI, urinary bladder (spasmodic state) • relatively insensitive: bile duct, urinary tract, bronchial tract • insensitive: uterus Atropine 1. 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 doses: cutaneous vasodilatation (5) CNS stimulation: • sedation, memory loss, psychosis (high dose) Atropine 2. Clinical uses (1) Ophthalmology Measurement of the refractive errors (屈光不正): children Acute iritis or iridocyclitis: mydriatics/miotics (2) Antispasmodic agent GI, biliary or renal colic, enuresis (3) Inhibiting exocrine gland secretion Preanesthetic medication麻醉前用药 (4) Bradycardia sinus or nodal bradycardia, A-V block (5) Antidote for organophosphate poisoning (6) Septic shock 感染性休克 Atropine 3. Adverse effects (1) Side effects dry mouth, blurred vision, “sandy eyes” (2) toxicity Lethal dose: 80~130 mg (adult), 10 mg (child) • Low: xerostomia (dry mouth); anhidrosis (dry skin), tachycardia • Moderate: above plus mydriasis, cycloplegia (睫状肌麻 痹); difficulty in speaking, swallowing & urinating; and hot, red, dry skin • High: above plus ataxia, hallucinations幻觉 & delirium 谵妄; coma Atropine 3. Adverse effects (3) Detoxication Supportive treatment Symptomatic treatment: e.g. diazepam for CNS symptoms. Antidote: Physostigmine or pilocarpine (4) Contraindications glaucoma, prostatauxe 前列腺肥大, fever Scopolamine东莨菪碱 • Actions and clinical uses – Peripheral effects are similar to atropine; but has stronger central effects (depression) – Pre-anesthetic medication, prevention of motion sickness, Parkinson’s disease Anisodamine (654-1,2) • Actions and clinical uses – Peripheral effects, similar to atropine; lower toxicity – Septic shock and visceral colic (relieve spasm of vascular smooth muscles) Synthesized surrogates • Tropicamide 托吡卡胺: mydriatic, cycloplegic shorter duration (1/4 day) • Propantheline 丙胺太林,普鲁本辛 poor absorption (po) and BBB penetration • • • • antispasmodic effects in GI, treatment of peptic ulcer Ipratropium 异丙托铵: asthma Benztropine 苯托品: Parkinson’s disease Trihexyphenidyl 苯海索 Pirenzepine 哌仑西平:M1 selective, peptic ulcer, asthma CASE STUDY JH, a 63-year-old architect, complains of urinary symptoms to his family physician. He has hypertension and the last 8 years, he has been adequately managed with a thiazide diuretic and an angiotensin-converting enzyme inhibitor. During the same period, JH developed the signs of benign prostatic hypertrophy, which eventually required prostatectomy to relieve symptoms. He now complains that he has an increased urge to urinate as well as urinary frequency, and this has disrupted the pattern of his daily life. What do you suspect is the cause of JH’s problem? What information would you gather to confirm your diagnosis? What treatment steps would you initiate? Nicotinic receptor antagonists NN receptor antagonists (Ganglionic blocking drugs) • 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; tachyphylaxis (快速抗药反应) • Used for treatment of hypertension ─ Trimethaphan(咪噻芬) – Mecamylamine (美加明) NM receptor antagonists (Neuromuscular blocking drugs ) • Two classes: Depolarizing: succinylcholine 琥珀酰胆碱 Non-depolarizing: drugs act as competitive antagonists d-tubocurarine 筒箭毒碱 Note: Belong to Skeletal Muscle Relaxants. It is important to 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 the depolarized membranes remain depolarized and unresponsive to subsequent impulses (ie, they are in a state of depolarizing block). not metabolized by AChE - diffuse away from the neuromuscular junction and are hydrolyzed in the plasma and liver by pseudocholinesterase (nonspecific cholinesterase, plasma cholinesterase, or butyrylcholinesterase) and elimination by kidney Succinylcholine (Scoline司可林) acetylcholine succinylcholine Succinylcholine is the only depolarizing agent used clinically (t1/2= 2-4 min). Properties of actions: • • • • • • initially transient fasciculations (肌束震颤) anti-AChE potentiates their effects tachyphylaxis 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 Succinylcholine (Scoline) • Main pharmacological effects – Transient excitation (fasciculations), and then inhibition (relaxation) – Relax Skeletal Muscles in neck, limbs > face, tongue, throat; less effective on breath muscles at therapeutic doses Succinylcholine (Scoline) • Clinical uses – An adjuvant in anesthesia or operation – Intubation of trachea, esophagus, etc. – Prevention of trauma during electroshock therapy (无抽 搐电休克疗法) – Contraindicated in awake patients, should be used under anesthesia Succinylcholine (Scoline) • Adverse effects (1) Apnea (respiratory paralysis) overdose or hypersensitive patients; neostigmine potentiates the toxic effects (2) Muscle spasm muscular pain after operation Succinylcholine (Scoline) (3) Elevation of K+ in plasma contraindicated in patients with a tendency of hyperkalemia (4) Malignant hyperthermia genetic abnormality, treated by dantrolene (Ca2+ release inhibitor) (5) Others rise in intraocular pressure (glaucoma); histamine release Genetic Variation: Effects on Duration of Action of Succinylcholine • Duration of action is prolonged by high doses or by abnormal metabolism. The latter may result from hypothermia (decreases the rate of hydrolysis), low pseudocholinesterase levels, or a genetically aberrant enzyme. • Low pseudocholinesterase levels generally produce only modest prolongation of succinylcholine's actions (2-20 min). • One in 50 patients has one normal and one abnormal (atypical) pseudocholinesterase gene, resulting in a slightly prolonged block (20-30 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., 4-8 h) following administration of succinylcholine. • Scoline apnea Succinylcholine (Scoline) • Drug interactions - Thiopental (强碱性,可分解scoline) - ChE inhibitors: AChE inhibitors, cyclophosphamide, procaine, etc. - Some antibiotics: kanamycin, polymyxins, etc. (synergism in neuromuscular blocking) NM receptor antagonists (Neuromuscular blocking drugs) 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) Tubocurarine • Effects: competitive blockade of NM receptors • Uses: adjuvant medication for anesthesia or operations, eg. tracheal intubation • Adverse effects: Respiratory paralysis: can be reversed by neostigmine Enhancing histamine release: BP , bronchoconstriction, salivary secretion Blocking ganglion: BP Contraindications: myasthenia gravis, bronchial asthma, shock, child (< 10 y) Other nondepolarizing neuromuscular blockers • Benzylisoquinolines(苄基异喹啉类) atracurium (阿曲库铵) doxacurium(多撒库铵) mivacurium(米库铵) • Ammonio steroids(类固醇铵类) pancuronium (潘库铵) vecuronium(维库铵) pipecuronium(哌库铵) rocuronium(罗库铵) Botulinum Toxin 肉毒杆菌毒素 - Skeletal muscle relaxants - blocks ACh release from cholinergic terminals - selective for ACh terminals - results in irreversible flaccid paralysis (松弛性瘫痪) in muscles Acts by cleaving SNAP proteins → inhibits ACh release Botulinum Toxin - an anaerobic bacillus, clostridium botulinum can multiply in preserved food - it synthesizes a protein that can be absorbed (pinocytosis or transport?) from the GI tract to reach the systemic circulation - penetrates tissues to reach cholinergic nerve terminals - then, it is uptaken (pinocytosis) and internalized in vesicles whose lumen becomes acidified - the low pH of the vesicles splits the inactive molecule into 2 active enzymes that have proteolysis functions Botulinum Toxin Applications • Strabismus (lack of parallelism of eyes 斜视), blepharospasm (eyelid spasm), dystonia (abnormal tonicity). • Excessive sweating • Cosmetic procedures ( “frown lines” or “crow’s feet”鱼尾纹) Note: effects can last for ~3-6 months. Pharmacology of efferent nervous system • Cholinergic Pharmacology • Adrenergic Pharmacology Noradrenergic Nerve: Synthesis, storage and release of NE Tyrosine tyrosine hydroxylase (TH) L-DOPA DOPA decarboxylase dopamine (DA) dopamine beta-hydroxylase (DBH) norepinephrine (NE) • Uptake neurotransmitter transporters – uptake 1: neuronal uptake – uptake 2: non-neuronal uptake • Enzymatic degradation – monoamine oxidase (MAO) – catechol-O-methyltransferease (COMT) Regulation of NE Synthesis and Turnover Tyrosine hydroxylase (TH) activity is rate limiting TH activity is inhibited by NE product TH activity is modulated by presynaptic autoreceptors - alpha2 receptors can reduce NE release - beta2 receptors can increase NE release Presynaptic heteroreceptors can modulate NE release - ACh can reduce NE release Tyrosine hydroxylase activity increases or decreases to maintain steady-state levels of norepinephrine. The above processes contribute to regulation of steady-state NE levels (rate of synthesis = rate of output) Catecholamine Biosynthetic Pathway Norepinephrine and Epinephrine Synthesis in the Adrenal Medulla - PNMT is located in the cytosol - DBH is located in vesicles - EPI is stored in vesicles. - EPI (~80%) and NE (~20%) released into blood NE NE PNMT EPI Chromaffin cell EPI NE Metabolism - takes place within the same cells where the amines are synthesized, and in liver - Extraneuronal O-methylation of norepinephrine and epinephrine to metanephrines represent minor pathways of metabolism. MHPG(3-甲氧4-羟苯乙二醇): was used as an index of CNS NE turnover but generated mostly from periphery VMA(香草扁桃酸): sometimes used as an index of NE turnover Sulfate conjugates also prevalent or MHPG Adrenergic Receptor Subtypes & G-Protein Coupled Mechanisms a1 Adrenergic Receptors: Phospholipase C activation, IP3 increase through Gq mechanism: mobilizes and increases intracellular free calcium effects: primarily smooth muscle contraction a2 Adrenergic Receptors: Inhibition of adenyl cyclase through Gi proteins mechanism: decreases intracellular cAMP levels effects: decreased protein phosphorylation, decreased cellular function Adrenergic Receptor Subtypes & G-Protein Coupled Mechanisms β Adrenergic Receptors: Activation of adenyl cyclase through Gs proteins mechanism: increases intracellular cAMP levels effects: phosphorylation of intracellular proteins smooth muscle relaxation, cardiac muscle contraction 可乐定 去氧肾上腺素 异丙肾上腺素 q Four Major Activators of the Adrenergic System 1 Hypoglycemia 2 Hypothermia 3 Hypoxia 4 Hypotension • • Hypoxia - response is mainly cardiovascular: b1 receptors via SNS NE increase heart rate & contractility, resulting in greater cardiac output; b2 receptors via adrenal Epi vasodilate blood vessels in muscle, increasing oxygen delivery, and mediate bronchodilation to facilitate oxygen intake. Hypoglycemia - response is mainly metabolic, but b2 vasodilation in muscle increases glucose (as well as oxygen) delivery. Response to Hypoglycemia The release of E (and to a lesser extent NE) by the adrenal is in direct response to falling blood glucose levels Insulin injection (insulin injection) Glycogenolysis • • • • The brain and muscle must have glucose The main sites of glycogenolysis are the liver and muscle Glycogen is broken down by glycogen phosphorylase This enzyme is activated by both PKA and PKC through stimulation of b2 and a1 adrenergic receptors, respectively Gluconeogenesis • The liver and kidney are the key sites • Substrates: lactate (from muscle) and glycerol (from fat) • Several enzymes in the pathway are activated by PKC through a1 stimulation • Both glycogenolysis & gluconeogenesis are indirectly stimulated by facilitating release of glucagon (b2) & inhibiting release of insulin (a2) Lypolysis • Lipases are stimulated by b (esp. b3) receptors Energy Mobilization by Epinephrine Response to Hypothermia: 1 - Piloerection 2 - Peripheral vasoconstriction 3 - Thermogenesis -Brown fat a) activation b) proliferation Summary: Adrenoceptors a receptors • a1 receptors: vasoconstriction: increased peripheral resistance, BP↑; contraction of radial muscle of iris: mydriasis • a2 receptors: CNS, presynaptic membranes of adrenergic nerves: vasodilatation, inhibition of NE release; inhibition of insulin release Summary: Adrenoceptors b receptors • b1 receptors: heart stimulation: contractility↑, automaticity↑, conduction↑, oxygen-consumption↑, cardiac output↑; increased lipolysis • b2 receptors: bronchodilation; slight vasodilation; increased muscle and liver glycogenolysis; increased release of glucagon • b3 receptors: lipolysis, thermogenesis Drug classification 1. Direct actions on the receptors Agonists Antagonists 2 Indirect actions via affecting transmitters Synthesis (L-dopa) Transport and storage (imipramine丙咪嗪, reserpine 利舍平) Release (ephedrine 麻黄碱, amphetamine 安非他明) Inactivation (MAOI) Drug classification 3. Mimetics and antagonists (1) Mimetics direct-acting: receptor agonists indirect-acting: increasing amounts and/or effects of transmitters (2) Antagonists direct-acting: receptor antagonists indirect-acting: decreasing amounts and/or effects of transmitters Structure-activity relationship of catecholamines and related compounds •Strong efficacy •Short duration •No entry to CNS • Receptor activation 苯乙胺 •Resistant to MAO 麻黄碱 Methamphetamine 甲基苯丙胺 • Catecholamine • Non-catecholamine 苯乙胺 – Indirect-acting by – High potency in causing the release of activating a or b stored catecholamine. receptors – Not inactivated by COMT; some are poor – Rapid inactivation by substrate for MAO COMT and by MAO (orally active, a – Poor penetration into the prolonged duration of CNS action) – Greater access to the CNS Adrenergic agonists Norepinephrine, Noradrenaline Pharmacological effect a1, a2 receptor agonists (1) Vascular effects: a1:vasoconstriction (skin, renal, brain, hepatic, mesenteric, etc.), blood flow a2:inhibiting NE release (2) Blood pressure: Systolic BP , Diastolic BP (especially at larger doses) Norepinephrine (3) Cardiac effects: weak direct stimulation (b1); inhibition via reflex (in vivo) Net result: little cardiac stimulates Effects of Norepinephrine on BP and HR Norepinephrine Clinical uses (limited therapeutic value) (1) Shock • used in early phase of neurogenic shock: small doses and shorter duration (dopamine is better; replaced by Metaraminol 间羟胺,α agonist and NE releaser, weaker but longer effect) (2) Hypotension due to drug poisoning • especially for chlorpromazine (氯丙嗪) (3) Hemorrhage in upper alimentary tract (上消化道) • orally given after dilution Norepinephrine Adverse effects (1) Ischemia and necrosis at the site of iv administration - relieved by filtrating the area with phentolamine (酚妥拉明, a receptor antagonist) (2) Acute renal failure - avoiding larger doses and longer duration; monitoring urinary volume (3) Contraindication - hypertension, arteriosclerosis, heart diseases, severe urinary volume , microcirculation disorders a1 receptor agonists Phenylephrine (去氧肾上腺素) Methoxamine (甲氧明) • Induces reflex bradycardia, used in hypotension under anesthesia and drug poisoning, paroxysmal supraventricular tachycardia ; • Phenylephrine: Mydriasis: pupillary dilator muscles, no or less effect on intraocular pressure, short-acting (for several hours); act as a nasal decongestant (鼻血管收缩药) a2 receptor agonists • Clonidine可乐定: Uses: antihypertensive drug; can be administered as transdermal patch (permits continuous administration) Mechanism of action: a2 - adrenergic partial agonist; actions predominantly in CNS lowers blood pressure by inhibiting sympathetic vasomotor tone a2 receptor agonists • Clonidine Adverse effects: iv administration may result in transient increase in blood pressure (activation of post-synaptic receptors); dry mouth, sedation a2 receptor agonists Oxymetazoline (羟甲唑啉): a nasal decongestant Apraclonidine (阿可乐定): decreases intraocular pressure. Epinephrine, Adrenaline Pharmacological effects : a 1, a2, b1, b2 receptor agonists (1) Cardiac effects b1: contractility (positive inotropic), HR (positive chronotropic), cardiac output , oxygen consumption , induces arrhythmia Epinephrine, Adrenaline Pharmacological effects : a 1, a2, b1, b2 receptor agonists (2) Vascular effects a1:vasoconstriction (skin, mucous, viscera), especially at larger doses b2:vasodilatation of skeletal muscles and coronary vessels Concentration-dependent response in vascular smooth muscle to epinephrine Predominant Effects low [EPI] β2 > α high [EPI] α > β2 Epinephrine (3) Blood pressure- two phases Systolic BP, Diastolic BP↓(slight) , pulse pressure Epinephrine (4) Respiratory b2:dilatation of bronchial smooth muscles (Bronchodilatation) inhibition of degranulation of mast cells a1:reducing congestion and edema of bronchial mucosa (5) Gastric and bladder smooth muscles: relaxation (b2) (6) Eye: intraocular pressure ↓ (α1,2) (7) Metabolic effects blood glucose (b2 and a1,2, hyperglycemia); free fatty acids (b, lipolysis) Epinephrine Clinical uses Topical uses: Systematic uses: • Adjuvant of local anesthesia • Cardiac arrest • Bleeding • Glaucoma • Anaphylactic shock (过敏性休克) • Acute bronchial asthma Epinephrine Adverse effects (1) Cardiac arrhythmias (2) Hemorrhage (cerebral or subarachnoid) : reason: a marked elevation of BP (3) Central excitation: anxiety, headache... (4) Contraindications: heart diseases, hypertension, coronary arterial disease, arteriosclerosis (动脉硬化), hyperthyroidism (甲亢) Ephedrine 麻黄碱 HO NH CH CH OH CH3 CH3 HO Ephedrine CH CH OH Epinephrine NH CH3 CH2 CH NH CH3 CH3 Methamphetamine Properties: - Promoting release of NE, weak agonist effects on a1、a2、 b1、b2 receptors - chemically stable, orally effective; - less potent but longer action duration; - central stimulating: alertness , fatigue ↓, prevents sleep (adverse effects) - Tachyphylaxis (快速耐受). Ephedrine Clinical uses (1) Prevention of hypotension: anesthesia (2) Nasal decongestion: nasal drop (3) Bronchial asthma: mild, chronic cases (4) Relieving allergic disorders: urticaria 风疹, angioneurotic edema 血管神经性水肿 Dopamine Pharmacological effects: a, b receptor, dopaminergic receptor agonists (1) Cardiac effects:b1 receptor, weak (2) Vascular effects: DA receptor: vasodilatation of renal, mesenteric arteries (small doses); a1 receptor: vasoconstriction of skin, mesenteric/renal vessels (larger doses) Dopamine Clinical uses (1) Shock cardiac and septic (感染性) shock (2) Acute renal failure combined with furosemide Adverse effects short-lived; tachycardia, arrhythmia, reduction in urine flow (renal vasoconstriction) Isoproterenol, Isoprenaline: Pharmacological effects: b1 , b2 receptor agonists, NE releaser (1) Cardiac effects (b1 receptor) (2) Vascular effects and blood pressure b2 receptor: dilatation of skeletal muscles and coronary vessels; SP , DP or , pulse pressure (3) Bronchodilatation (b2 receptor) (4) Metabolism Promoting effects as epinephrine Effects of catecholamines(therapeutic doses) Predominant Effects: NE : a & b1 effects EPI : b1, b 2 then at higher concentrations a effects predominate ISO: b1 and b 2 Isoproterenol Clinical uses (1) Cardiac arrest / A-V block: in emergencies (2) Shock: replaced by other sympathomimetics (muscular vasodilatation) (3) Bronchial asthma Adverse effects (1) Heart stimulation, arrhythmia (2) Contraindications: coronary heart disease, myocarditis (心肌炎), hyperthyroidism b1 receptor agonists Dobutamine (多巴酚丁胺) • Heart failure (after cardiac surgery or congestive HF or acute myocardial infarction; short-term treatment) • Cardiac stimulation b2 receptor agonists Terbutaline (特布他林) • Uses: Bronchial asthma dilation of bronchial smooth muscle; b2 > b1 agonist (partially selective): preferential activation of pulmonary b2 receptors by inhalation. Use: Premature Labor (ritodrine). • Adverse effects: headache, cardiac stimulation and skeletal muscle fine tremor (b2 receptors on presynaptic motor terminals; their activation enhances ACh release). INDIRECT-acting drugs (summary) 参考书目 • 杨世杰主编《药理学》人民卫生出版社2010 第二版 • Katzung BG, Basic & Clinical Pharmacology (10th edition), 2007. • Lipincott’s illustrated reviews— Pharmocology (2nd edition), 2002