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Adrenergic Pharmacology Shi-Hong Zhang (张世红), PhD Dept. of Pharmacology, School of Medicine, Zhejiang University [email protected] 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 1 Adrenergic Receptors: Phospholipase C activation, IP3 increase through Gq mechanism: mobilizes and increases intracellular free calcium effects: primarily smooth muscle contraction 2 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 1 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 1 stimulation • Both glycogenolysis & gluconeogenesis are indirectly stimulated by facilitating release of glucagon (b2) & inhibiting release of insulin (2) 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 receptors • 1 receptors: vasoconstriction: increased peripheral resistance, BP↑; contraction of radial muscle of iris: mydriasis • 2 receptors: CNS, presynaptic membranes of adrenergic nerves: vasodilatation, inhibition of NE release; inhibition of insulin release Summary: Adrenoceptors b receptors • b1 receptors: contractility↑, automaticity↑, conduction↑, oxygen-consumption↑, cardiac output↑: heart stimulation; increased lipolysis • b2 receptors: relaxation of bronchial smooth muscles: 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 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 Adrenomimetic Agents • Adrenomimetic; sympathomimetic; adrenergic agonist • The mode of action: DIRECT; INDIRECT; MIXED • DIRECT: direct interaction with adrenergic receptors. • INDIRECT: causes response indirectly by provoking release of intraneuronal NE into synaptic cleft or interfering with NE reuptake. • MIXED: combination of DIRECT and INDIRECT mechanisms. Adrenergic agonists Norepinephrine, Noradrenaline Pharmacological effect 1, 2 receptor agonists (1) Vascular effects: 1:vasoconstriction (skin, renal, brain, hepatic, mesenteric, etc.), blood flow 2: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, αagonist 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 • 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, 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 1 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) 2 receptor agonists • Clonidine: 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 2 receptor agonists • Clonidine Adverse effects: iv administration may result in transient increase in blood pressure (activation of post-synaptic receptors); dry mouth, sedation 2 receptor agonists Oxymetazoline (羟甲唑啉): a nasal decongestant Apraclonidine (阿可乐定): decreases intraocular pressure. Epinephrine, Adrenaline Pharmacological effects : 1, 2, b1, b2 receptor agonists (1) Cardiac effects b1: contractility (positive inotropic), HR (positive chronotropic), cardiac output , oxygen consumption , induces arrhythmia Epinephrine, Adrenaline Pharmacological effects : 1, 2, b1, b2 receptor agonists (2) Vascular effects 1: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 1:reducing congestion and edema of bronchial mucosa (5) Gastric and bladder smooth muscles: relaxation (b2) (6) Eye: intraocular pressure ↓ (α2) (7) Metabolic effects blood glucose (b2 and 1,2, 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 1、2、 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: , b receptor, dopaminergic receptor agonists (1) Cardiac effects:b1 receptor, weak (2) Vascular effects: DA receptor: vasodilatation of renal, mesenteric arteries (small doses); 1 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 : & b1 effects EPI : b1, b 2 then at higher concentrations 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) Adrenergic Receptor Antagonists receptor antagonists: nonselective: short acting (phentolamine 酚妥拉明) long acting (phenoxybenzamine 酚苄明) selective: 1 antagonists (prazosin 哌唑嗪) 2 antagonists (yohimbine 育亨宾) β receptors antagonists: nonselective: with ISA (pindolol 吲哚洛尔) without ISA (propranolol普萘洛尔) β1 antagonists: with ISA (acebutolol 醋丁洛尔) without ISA (atenolol 阿替洛尔) /β receptor antagonists: labetalol 拉贝洛尔, carvedilol 卡维 地洛 receptor antagonists Phentolamine 酚妥拉明 Competitive, nonselective Pharmacological effects CH 3 N N CH2 N H HO (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 Phentolamine Clinical uses (1) Decrease blood pressure • Hypertension from pheochromocytoma (short term use). • Pre- and post-operation of pheochromocytoma • Diagnostic test for pheochromocytoma (2) Peripheral vascular diseases • Acrocyanosis (手足发绀), Raynaud’s disease (3) Local vasoconstrictor extravasations (4) Improve microcirculation: shock with pulmonary edema (5) Acute myocardial infarction and obstinate congestive heart failure Major Adverse effects – postural hypotension, reflex tachycardia, arrhythmia, angina pectoris, GI reactions Pheochromocytoma is a rare catecholaminesecreting 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 (1 & ±b) Pheochromocytoma Phenoxybenzamine 酚苄明 • Irreversible, nonselective ( 1 and 2 antagonists ) • Long-acting • Similar to phentolamine in actions and clinical uses 1 receptor antagonists • Prazosin: treatment for hypertension • Tamsulasin: 1A blocker, for benign prostate hypertrophy 2 receptor antagonists • Yohimbine: for research use, ED, diabetic neuropathy Adrenergic Receptor Antagonists receptor antagonists: nonselective: short acting (phentolamine 酚妥拉明) long acting (phenoxybenzamine 酚苄明) selective: 1 antagonists (prazosin 哌唑嗪) 2 antagonists (yohimbine 育亨宾) β receptors antagonists: nonselective: with ISA (pindolol 吲哚洛尔) without ISA (propranolol 普萘洛尔) β1 antagonists: with ISA (acebutolol 醋丁洛尔) without ISA (atenolol 阿替洛尔) /β receptor antagonists: labetalol 拉贝洛尔, carvedilol 卡维 地洛 b receptor antagonists General properties: ADME • First-pass elimination, especially for those with high lipid solubility (eg普萘洛尔). • lower bioavailability: propranolol • Hepatic metabolism and renal excretion hepatic and renal functions alter the effects of the drugs and result in large individual variation • Dose individualization is necessary. b receptor antagonists Pharmacological effects (1) b 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 b receptor antagonists (1) b 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 b receptor antagonists (2) Intrinsic sympathomimetic effects Partial agonists: e.g. pindolol, acebutolol (weaker cardiac inhibition and bronchoconstriction; cardiac stimulation in larger doses) (3) Membrane-stabilizing effects Larger doses of some drugs: quinidine-like effects, Na+ channel blockade (4) Others • Lowering intraocular pressure; • Inhibiting platelet aggregation Circulation of Aqueous humor b 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)... b 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, sexual dysfunction, etc. Propranolol • b1, b2 receptor blocking • no intrinsic activity • first-elimination after oral administration, individual variation of bioavailability Timolol • For the treatment of glaucoma (wide-angle) Atenolol, Metoprolol • b1receptor antagonists, no intrinsic activity • • atenolol : longer t1/2, once daily • usually used for the treatment of hypertension α, b receptor antagonists Labetalol • α, β receptor blocking, β> α • usually used for treatment of hypertension Summary Agonist Receptor specificity Therapeutic uses epinephrine 1,2 b1,b2 • Acute asthma, • Anaphylactic(过敏性) shock, • in local anesthetics to increase duration of action norepinephrine 1,2 (b1) • shock isoproterenol b1,b2 • Asthma • As cardiac stimulant dopamine Dopaminergic , b • Shock, • Congestive heart failure dobutamine b1 • Heart failure Summary Agonist Receptor specificity Therapeutic uses Ephedrine(麻黄碱) , b •asthma •as a nasal decongestant Metaraminol (间羟 胺) •Shock •hypotension Phenylephrine (苯 肾上腺素) 1 •supraventricular tachycardia •glaucoma •as a nasal decongestant Methoxamine (甲 氧胺) 1 •supraventricular tachycardia Clonidine 2 •hypertension Salbutemol Terbutaline Ritodrine b2 •Asthma •Premature labor Summary Antagonist Receptor specificity Therapeutic uses Phentolamine Phenoxybenzamine (酚苄 明) 1, 2 • pheochromocytoma • Peripheral vascular diseases • Local vasoconstrictor extravasation prazosin 1 • hypertension propranolol b1, b2 • • • • • • timolol b1, b2 • Glaucoma • hypertension Atenolol Metoprolol b1 • hypertension labetalol , b • hypertension Hypertension Glaucoma Migraine Hyperthyroidism Angina pectoris Myocardial infarction Pharmacology for Pain and Analgesia What is pain An unpleasant sensory or emotional experience associated with actual or potential tissue damage, or described in terms of such damage. Pain is always subjective. Each individual learns the application of the word through experiences related to injury in early life. It is unquestionably a sensation in a part of the body, but it is also unpleasant, and therefore also an emotional experience. Many people report pain in the absence of tissue damage or any likely pathophysiological cause; usually this happens for psychological reasons. There is no way to distinguish their experience from that due to tissue damage, if we take this subjective report. IASP. Pain 1979(6)249-252 Physiology of Pain Pain sensation Acute Pain - First pain:sharp, pricking, well defined,A fibers - Second pain:dull, aching, poorly localized, C fibers Chronic Pain - Inflammatory - Neuropathic - Diabetic - Bone cancer pain - Fibromyalgia - Migraine - Psychogenic pain Milligan et al, 2009 Clinical relief of acute pain • General anesthetics and barbiturates for anesthesia (麻醉) • Local anesthetics and opioids for both anesthesia and analgesia (镇痛) What is anesthesia? • Definition – “induced, reversible insensibility to surgical stimulation” • Anesthesia is necessary for some diagnostic, therapeutic, and surgical intervention • Anesthetics are a class of drugs that produce anesthesia, not all induce unconsciousness Anesthetics • General anesthetics: Some administered as gases or “vapors”, others can be given intravenously • Local anesthetics: local application Before October 16, 1846 "Suffering so great as I underwent cannot be expressed in words . . . but the blank whirlwind of emotion, the horror of great darkness, and the sense of desertion by God and man, which swept through my mind, and overwhelmed my heart, I can never forget.” -Ashhurst J Jr , Surgery before the days of anesthesia, 1997 http://content.nejm.org/cgi/reprint/348/21/2110.pdf On October 16, 1846, William Morton, a dentist at Massachusetts General Hospital, employed ether in the surgical removal of a tumor with no signs or reports of pain in the patient. History • • • • • • • 1846, Ether 1860, Cocaine 1884, N2O 1905, Procaine 1934, Thiopental 1943, Lidocaine …… Pharmacology of Local Anesthetics (LAs) Local Anesthetics (LAs) • Reversibly block nerve conduction • Act on every type of nerve fibers: non/thin myelinated sensory fibers myelinated sensory fibers autonomic fibers motor fibers • Also act on cardiac muscle, skeletal muscle and the brain • No structural damage to the nerve cell 酯类 可卡因 普鲁卡因 丁卡因 苯佐卡因 酰胺类 利多卡因 甲哌卡因 布比卡因 依替卡因 丙胺卡因 Action site: voltage-gated Na+ channels Actions of LAs • Ionic gradient and resting membrane potential are unchanged • Only bind in the inactivated state: use dependent • Decrease the amplitude of the action potential • Slow the rate of depolarization • Increase the firing threshold • Slow impulse conduction • Prolong the refractory period Types of local anesthesia Topical local (surface) anesthesia: for eye, ear, nose, and throat procedures and for cosmetic surgery Infiltration anesthesia: local injection around the region to be operated. Conduction anesthesia: local injection around the peripheral nerve trunk Epidural anesthesia: local injection into the epidural space Subarachnoid anesthesia or Spinal anesthesia: local injection into the cerebrospinal fluid in subarachnoid cavity Infiltration anesthesia Conduction anesthesia (cervical plexus) Pharmacokinetics • LAs bind in the blood to a1-glycoprotein and albumin • There is considerable first-pass uptake of LAs by the liver • LAs enter the blood stream by: – Direct injection – Absorption • Epinephrine decreases this via vasoconstriction • Peak concentrations vary by site of injection Metabolism of LAs • Esters (rapid) – Hydrolyzed in the plasma by pseudocholinesterase • Break down product – para-aminobenzoic acid (对苯 氨甲酸) • Amides (slower) – Occurs in the endoplasmic reticulum of hepatocytes • Tertiary amines are metabolized into secondary amines that are then hydrolyzed by amidases Allergic Reactions • Metabolite of ester LAs – Para-aminobenzoic acid – Allergen • Allergy to amide LAs is extremely rare CNS Toxicity • Correlation between potency and seizure threshold – Bupivacaine • 2 ug/ml – Lidocaine • 10 ug/ml Cardiovascular Toxicity • Attributable to their direct effect on cardiac muscle • Contractility – Negative inotropic effect that is dose-related and correlates with potency – Interference with calcium signaling mechanisms • Automaticity – Negative chronotropic effect • Rhythmicity and Conductivity – Ventricular arrhythmias Comparison of LAs Potency Toxicity Permeability Application Procaine Weak Low (allergic) Weak Not for topical, skin test Tetracaine Strong High Strong Especially topical, Not for infiltration Lidocaine Strong Low Strong All kinds Ropivacaine Strong Low Strong Epidural and conduction Pharmacology of General Anesthetics General Anesthetics • General anesthesia: analgesia, amnesia, loss of consciousness, inhibition of sensory and autonomic reflexes, and skeletal muscle relaxation. • Intravenous anesthetics (barbiturates, etc) • Inhaled anesthetics (gases, or volatile liquids) Intravenous Anesthetics 硫喷妥钠 咪达唑仑 丙泊酚 依托咪酯 氯胺酮 Usually activate GABAA receptors, or block NMDA receptors Induction of iv anesthesia Commonly used for initial anesthesia induction along with inhalation anesthetics Inhaled anesthetics • Many different, apparently unrelated molecules produce general anesthesia – inert gases, simple inorganic & organic compounds, more complex organic compounds • Characteristics – rapid onset (emergence), rapid reversibility, relationship between lipid solubility & potency Stages of anesthesia (ether) • Stage I: analgesia – sensory block in spinal cord, and later amnesia • Stage II: paradoxical excitation (irregular breath, retching, vomiting, struggle) due to loss of some inhibitory tone and direct stimulation of excitatory transmission • Stage III: surgical anesthesia – block of the ascending reticular activating system • Stage IV: failure – cardiovascular and respiratory collapse due to inhibition Signs for anesthetic depth TOO LIGHT • • • • • • Tachycardia Hypertension Eyelid reflex Lacrimation 流泪 Swallowing Laryngospasm 喉痉挛 (involuntary spasm of the laryngeal cords • Movement TOO DEEP • Hypotension • Organ failure Inhaled anesthetic delivery system Vaporizing the anesthetic liquid Gas flowmeters Nitrous Oxide (N2O) O N N Laughing gas Volatile liquids at room temperature Diethyl Ether Isoflurane Halothane Sevoflurane (七氟烷) Induction of anesthesia Blood:gas partition coefficient (an index for solubility): =[blood]/[alveoli] Higher solubility (shown as a larger blood box) means gas rapidly moves into blood, but concentration that reaches brain increases more slowly MAC –minimum alveolar anesthetic concentration MAC: The median concentration that results in immobility in 50% of patients Addition of MAC Factors that alter MAC • Increase MAC – Being young, hyperthermia, chronic ETOH, CNS stimulants, hyperthyroidism (甲状腺功能亢进) • Decrease MAC – Old age, hypothermia, acute ETOH, CNS depressant drugs including narcotics & benzodiazepines General characteristics • Analgesia – weak except for nitrous oxide • Potency – high, except for nitrous oxide • Muscle Relaxation – some, but weak • Airway irritation – desflurane worst, sevoflurane best tolerated • Primary effect on conductive tissue – inhibitory • Primary effect on smooth muscle – relaxation • Primary effect on macrophages -- inhibitory Effects on ventilation Respiratory Rate; Tidal Volume Ventilation; PaCO2; Hypoxia Risk Effects on brain • Transition to unconsciousness 0.4 MAC • O2 consumption but Cerebral Blood Flow means potential injury with brain tumors/head injury (↑ pressure) Liver toxicity • “Halothane Hepatitis” • Incidence post Halothane – 0.003% • Symptoms – fever, anorexia, nausea & vomiting that occur 2 - 5 days post-op • Eosinophilia; altered liver function • Rare – liver failure & death Malignant hyperthermia • Hypermetabolic syndrome – hyperthermia, CO2, tachycardia, cyanosis, muscle rigidity • Triggered by halogenated anesthetics & depolarizing muscle relaxants • Familial relationship, i.e. genetic heterogeneity – mutation in Ca2+ reuptake • Incidence, ~ 1/14,000 anesthesia (0.01%) • Specific Treatment – Dantrolene (inhibit Ca2+ release from the sarcoplasmic reticulum) Nitrous oxide toxicity • Bone Marrow Depression – megaloblastic, inhibition of B12 dependant enzymes • Peripheral neuropathy • Expansion of closed air spaces – bowel obstruction, pneumothorax (气胸), bullous emphysema (大泡性肺气肿), middle ear obstruction, pneumocephalus (颅腔积气) • CNS injury – adults & neonates NITROUS OXIDE KILLS NEURONS IN THE YOUNG AND THE OLD control Early apoptosis • Developing rat brain • Exposure to a combination including nitrous, isoflurane & midazolam exposed • Persistent learning deficits Late apoptosis