Ch.14 Local Anesthetics

1. Ch.14 Local Anesthetics R1. 김영석

2. Theories of Local Anesthtic Action • Resting membrane potential of Neurons - active transprot (by Na+-K+ pump) : 세포 밖으로 세 개의 Na+의 이동 : 세포 안으로 두 개의 K+ 의 이동 - passive diffusion (by concentration gradient) : K+의 세포밖으로의 확산 : Na+의 세포안으로의 확산 - more permeable to K+ than to Na+ : negative resting membrane potential (-70mV)

3. Theories of Local Anesthtic Action • Action potential : threshold (-55mV) 이상의 자극 : voltage-gated Na+- K+ channel 의 activation - sudden influx of Na+ : Na+의 permeability의 증가 : membrane potential to +35mV - voltage-gated Na+ channel의 inactivation - outflux of K+ : return to resting potential - nerve axon을 따라 전도

4. Theories of Local Anesthtic Action • Local anesthetics - Sodium channel은 한 개의 α-subunit 과 하나 혹은 두 개의 β-subunit 으로 구성 - local anesthetics는 세포안에서 α-subunit 과 결합 : Na channel의 activation을 block : impulse conduction의 느려짐 : action potential의 rise 와 magnitude의 감소 : excitation을 위한 threshold의 증가 - action potential과 자극의 전도가 차단

5. Theories of Local Anesthtic Action • Local anesthetics - block Calcium and Potassium channels - block N-methyl-D-aspartate receptors - nerve fiver의 sensitivity : small diameter, lack of myelin 일수록 증가

6. Structure-Activity Relationships • Local anesthetics의 structure - lipohphilic group(benzene ring) - hydrophilic group(tertiary amine) - intermediate chain(ester or amide linkage) : classification의 기준 - physicochemical properties를 결정

7. Structure-Activity Relationships • Local anesthetics - Potency는 lipid solubility가 클수록 증가 : hydrophobic environment에서 membrane permeability가 증가 - Onset of action : lipid solubility가 작을 수록 faster onset : pKa 가 physiologic pH(7.40)에 가까울 수록 faster onset (pKa : drug의 ionized(water-soluble) 와 nonionized(lipid-soluble) form의 양이 같아지는 pH) : commercial local anesthetics의 pKa = 6-7 : epinephrine-containing local anesthetic solutions의 pKa = 4-5 → slower onset : addition of sodium bicarbonate (alkalinization) → onset을 빠르게, blockade를 연장, subcutaneous infiltration동안 pain을 감소 : infected tissue는 more acidic → onset is delayed - Duration of action : lipid solubility가 클수록 duration은 증가 (∵ α1-acid glycoprotein과 결합하여 blood flow에 의한 clearance가 지연)

8. Clinical Pharmacology • Absorption - most mucous membrane : weak barrier로 작용 - intact skin : analgesia를 위해 더 많은 농도의 local anesthetic가 필요 - EMLA cream(a Eutectic Mixture of Local Anesthetic cream) : 1:1 mixture of 5% lidocaine and 5% prilocaine in an oil-in-water emulsion : for split-thickness skin-graft harvesting, laser removal of portwine stains,lithotripsy,circumcision - systemic absorption은 blood flow와 관련 : injection site의 vascularity가 클수록 증가 (intravenous>tracheal>intercostal>caudal>paracervical>epidural>brachial plexus>sciatic>subcutaneous) : vasoconstrictor(eg. Epinephrine) 의 사용 → local anesthetics의 effects를증가, duration을 연장, systemic toxic side effects를 감소 : highly tissue bound agent일수록 느리게 흡수

9. Clinical Pharmacology • Distribution - highly perfused organ(eg, brain,lung,liver,kidney and heart)일수록 빠르게 uptake - plasma protein과 결합력이 클수록 blood에 오래 남아있음 - muscle은 large mass로 인하여 greatest reservoir로 작용 • Metabolism and Excretion a. Esters - pseudocholinesterase에 의해 빠르게 대사 - urine으로 배설 - procaine과 benzocaine의 대사물인 p-aminobenzoic acid(PABA) : allergic reaction과 관련 b. Amides - liver의 microsomal P-450에 의해 대사 (ester hydrolysis보다 느림) - prilocaine의 대사물의 축적은 methemoglobinemia의 원인 → treatment : methylene blue의 intravenous administration ( 1-2mg/kg of a 1% solution over 5min)

10. Effects on Organ Systems • Neurological - CNS는 local anesthetics toxicity에 특히 취약 - overdose시 premonitory signs이 나타나는 site - early symptoms : circumoral numbness : tongue paresthesia : dizziness : tinnitus and blurred vision - excitatoy signs(eg, restlessness,agitation,nervousness,paranoia)가 CNS depression(eg, slurred speech,drowsiness,unconsciousness)전에 나타날 수 있음 - Benzodiazepines and hyperventilation는 cerebral blood flow를 감소시켜 local anesthetic-induced seizures의 발생을 감소 - Thiopental(1-2 mg/kg) 은 seizure를 terminate

11. Effects on Organ Systems • Neurological - Intravenous lidocaine(1.5mg/kg) : cerebral blood flow를 감소 : intubation시 수반되는 intracranial pressure의 증가를 약화 : 흡입마취제의 MAC을 40%까지 감소시킴 - 다량의chloroprocaine의 epidural space가 아닌 subarachnoid로의 주입은 prolonged neurological deficit을 발생시킬 수 있음

12. Effects on Organ Systems • Respiratory - Lidocaine : hypoxic drive를 억제 (low PaO2에 대한 호흡반응) : bronchial smooth muscle을 이완 : intravenous lidocaine(1.5mg/kg) → intubation시 bronchoconstriction을 차단

13. Effects on Organ Systems • Cardiovascular - myocardial auomaticity를 억제 - duration of the refractory period를 감소 - 고농도에서는 myocardial contractility와 coduction속도를 억제 - arteriolar vasodilation을 보임 - bradycardia, heart block, hypotention → cardiac arrest - major cardiovascular toxicity를 위해서는 seziures발생의 3배의 농도가 필요 - lower concentrations of lidocaine은 ventricular arrhythmias에 효과적 치료 - intravenous lidocaine(1.5mg/kg,intubation 1-3min전) → laryngoscopy로 인한 hypertension을 감소

14. Effects on Organ Systems • Cardiovascular - Bupivacaine의 unintentional intravascular injection (during regional anesthesia) : hypotension, atrioventricular heart block, idioventricular rhythms, life-threatening arrhythmias : risk factors – pregnancy, hypoxemia, respiratory acidosis, young children : resuscitation from bupivacaine-induced cardiac toxicity → high doses of vasopressors의 prolonged therapy - Ropivacaine : bupivacaine과 유사한 physiochemical 특징 : half lipid solubility : severe cardiac arrhythmias의 발생빈도 70% 감소 - Cocaine : adrenergic nerve terminal에서 norepinephrine의 재흡수를 억제 : hypertension과 ventricular ectopy를 일으킴 : adrenergic and calcium channel antagonists로 치료

15. Effects on Organ Systems • Musculoskeletal - skeletal muscle에 직접 injection(eg, triggerpoint injection)시 myotoxic : lytic degeneration, edema, and necrosis : bupivacaine > lidocaine > procaine : 3-4주 후 regeneration • Hematological - lidocaine : coagulation의 감소, fibrinolysis를 강화

16. Drug Interactions • Local anesthetics : nondepolarizing muscle relaxant blockade를 강화 : succinylcholine과 ester local anesthetics는 서로 작용을 강화 • Pseudocholinesterase inhibitors : ester local anesthetics의 metabolism을감소 • Cimetidine과 propranolol : hepatic blood flow와 lidocaine clearance를 감소 • Opioids(eg, fentanyl,morphine) and α2-adrenergic agonists(eg, epinephrine, clonidine) : local anesthetic pain relief를 증가

17. Ch.15 Adjuncts to Anesthesia R1 김영석

18. Histamine-Receptor Antagonists • Histamine Physiology - central nervous system, gastric mucosa, peripheral tissues 에서 발견 - amino acid histidine의 decarboxylation에 의해 합성 - H1-receptor : phospholipase C를 활성화 - H2-receptor : intracellular cAMP를 증가 - H3-receptor : additional histamine의 합성과 분비를 억제(negative feedback) - Histamine-N-methyltransferase에 의해 대사되어 urine으로 배설

19. Histamine-Receptor Antagonists • Histamine Physiology a. Cardiovascular - H1-receptor: capillary permeability와 ventricular irritability를 증가 - H2-receptor: heart rate와 myocardial contractility를 증가 - Both types of receptors : peripheral artery와 coronary artery를 확장 → arterial blood pressure를 감소 b. Respiratory - H1-receptor : bronchiolar smooth muscle의 수축, pulmonary vasodilation - H2-receptor : mild bronchodilation, pulmonary vasoconstriction c. Gastrointestinal - H1-receptor : intestinal smooth muscle의 수축 - H2-receptor : parietal cells에서 gastric acid의 secretion을 증가

20. Histamine-Receptor Antagonists • Histamine Physiology a. Dermal - H1-receptor : capillary permeability의 증가, vasodilation → classic wheal-and-flare response b. Immunological - H1-receptor : leukocyte를 유인, prostaglandin을 합성 → Type I hypersensitivity와 관련 - H2-receptor : suppressor T lymphocytes를 활성화

21. H1-Receptor Antagonists • Mechanism of Action - Competitively blocks H1-receptors • Properties - considerable antimuscarinic - atropine-like (eg, dry mouth) - antiserotonergic (antiemetic)

22. H1-Receptor Antagonists • Clinical Uses - Therapeutic Uses : suppression of allergic symptoms (eg, urticaria, rhinitis, conjunctivitis) : vertigo, nausea, and vomiting (eg, motion sickness, Meniere’s disease) : sedation : suppression of cough : dyskinesia (eg, parkinsonism) - Bronchial asthma에 ineffective - Acute anaphylactic reaction에 대한 효용성도 제한적 - Antiemetic and mild hypnotic effect : premedication으로 사용 : significant sedation을 보이지만 ventilatory drive에는 영향을 주지 않음 - Newer (2nd generation) antihistamines : little or no sedation (∵ limited penetration across the blood-brain barrier) : only in oral preparations : for allergic rhinitis and urticaria

23. H1-Receptor Antagonists • Dosage

24. H2-Receptor Antagonists • Mechanism of Action - competitively inhibit histamine binding to H2-receptors • Clinical Usese - Therapeutic Uses : peptic duodenal and gastric ulcers : Zollinger-Ellison syndrome : GERD : stress ulceration (by intravenous preparations) - perioperative risk of aspiration pneumonia를 감소 : gastric fluid의 volume과 hydrogen ion content를 감소시킴으로써

25. H2-Receptor Antagonists • Side Effects - Rapid intravenous injection of cimetidine and ranitidine : 드물게 hypotension,bradycardia,arrhythmias, and cardiac arrest 유발 - Long-term cimetidine therapy의 Complications : hepatotoxicity (serum transaminases 증가) : interstitial nephritis (serum creatinine 증가) : granulocytopenia : thrombocytopenia : gynecomastia : impotence • Drug Interactions - Cimetidine : hepatic blood flow를 감소 : cytochrome P-450 mixed-function oxidases와 결합 : drugs의 metabolism을 지연

26. H2-Receptor Antagonists • Dosage

27. Antacids • Mechanism of Action - gastric fluid 의 acidity에 base를 제공하여 hydrogen ions을 water로 중화 • Clinical Uses - Therapeutic Uses : gastric and duodenal ulcers : GERD : Zollinger-Ellison syndrome - aspiration pneumonia의 예방 (gastric contents의 pH를 증가) - immediate effect (unlike H2-receptor antagonists) - but, increase intragastric volume - particulate antacid(aluminum or magnesium)의 aspiration → lung function의 abnormailities를 일으킴 - nonparticulate antacid(sodium citrate or sodium bicarbonate) → less damaging to lung alveoli

28. Antacids • Dosage - usual adult dose : 0.3 M solution of sodium citrate를 15-30mL orally ( induction 15-30분 전 ) • Drug Interactions - digoxin, cimetidine, and ranitidine의 흡수율 감소 - phenobarbital의 elimination은 빨라짐

29. Metoclopramide • Mechanism of Action - peripherally : as a cholinomimetic (ie, acetylcholine의 transmission을 증가) - centrally : as a dopamine antagonist • Clinical Uses - lower esophageal sphincter tone을 증가 - gastric emptying time을 빠르게 - gastric fluid volume을 감소 - diabetic gastroparesis, GERD, aspiration pneumonia의 예방에 효과적 - antiemetic effect (during cancer chemotherapy) : blocking dopamine receptors - some degree of analgesia effect : smooth muscle spasm과 관련된 renal or biliary colic, uterine cramping : prostaglandin-induced termination of pregnancy

30. Metoclopramide • Side effects - rapid intravenous injection : abdominal cramping - contraindicated : complete intestinal obstruction - hypertensive crisis : pheochromocytoma환자에서 tumor로부터 catecholamines의 release - Parkinson’s disease에서는 절대적 금기 • Dosage - adult dose : 10-20mg(0.25mg/kg,over 5min) orally, intramusculary, or intravenously : Higher doses(1-2mg/kg) for chemotherapy동안의 emesis 예방 : urine으로 배설되므로 renal dysfunction환자에서는 용량을 줄여야 • Drug interactions - antimuscarinic drugs(eg, atropine,glycopyrrolate) : block the GI effects of metoclopromide - cimetidine의 흡수를 감소시킴 - phenothiazines or butyrophenones와 같이 사용시 extrapyramidal side effects 증가 - thiopental의 induction 용량을 감소시킴

31. Proton Pump Inhibitors • Mechanism of Action - gastric mucosa의 parietal cells의 proton pump와 결합 hydrogen ions의 분비 억제 • Clinical Uses - Therapeutic uses : duodenal ulcer : GERD : Zollinger-Ellison syndrome - H2-receptor blockers보다 빠른 작용 - aspiration의 예방에 사용은 제한적 : omeprazole은 H2-receptor보다 less reliable : lansoprazole은 H2-receptor와 비슷한 효과 : lansoprazole은 two doses(수술전날 저녁,수술당일 아침)가 single dose보다 more effective

32. Proton Pump Inhibitors • Side Effects - few side effects - 주로 GI (nausea, abdominal pain, constipation, and diarrhea) - long term treatment시 gastric enterochromaffin-like cell hyperplasia • Dosage - omeprazole : 20mg - lansoprazole : 15mg - pantoprazole : 40mg - 주로 liver에서 배설되므로 severe liver impairment환자에서는 반복투여시 감량 • Drug Interactions - omeprazole : hepatic P-450 enzymes의 작용을 방해 → diazepam, warfarin, and phenytoin의 배설을 지연

33. 5-HT3 Receptor Antagonists • Serotonin Physiology - Serotonin : tryptophan의 hydroxylation과 decarboxylation에 의해 형성 : monamine oxidase에 의해 5-HIAA로 inactivation - 5HT3 receptors : vomiting - 5HT2A receptors : smooth muscle contraction, platelet aggregation - 5HT4 receptors : GI secretion and peristalsis - 5HT6 and 5HT7 receptors : depression - heart 와 skeletal muscle을 제외한 arterioles과 vein에 powerful vasoconstrictor로 작용 - smooth m. contraction → airway resistance를 증가 → bronchoconstriction

34. 5-HT3 Receptor Antagonists • Mechanism of Action - ondansetron : selectively block serotonin 5-HT3 receptors (vomiting reflex) with little or no effect on dopamine receptors • Clinical Uses - postoperative antiemetics로 효과적 - 예방적 사용이 고려되는 경우 : prior history of postoperative nausea : nausea의 가능성이 높은 prosedures (eg, laparoscopy) : nausea와 vomiting을 피해야하는 경우 (eg, neurosurgery)

35. 5-HT3 Receptor Antagonists • Side Effects - serious side effects는 거의 없음 - most common side effect : headache • Dosage - ondansetron : 4mg (every 4-8h 반복적 사용 가능) : liver의 cytochrome P-450에 의해 대사 → liver failure시 용량을 감량 - dolasetron : 12.5mg - granisetron : 1mg

36. Ketorolac • Mechanism of Action - prostaglandin 합성을 억제하는 비경구 투여 NSAID • Clinical Uses - postoperative period의 short-term(5일이하) pain management에 효과적 - standard dose 사용시 morphine 6-12mg과 비슷한 효과 - but, longer duration of action(6-8h) than morphine - CNS side effect(eg, respiratory depression, sedation, nausea, vomiting)가 거의 없음 - intraabdominal surgery보다 정형외과,부인과 수술에 더 효과적

37. Ketorolac • Side Effects - platelet aggregation을 억제, bleeding time을 연장 : postoerative hemorrhage가능성이 있는 환자에서 주의해서 사용 - long term 사용시 : renal toxicity : renal failure환자에서 금기 - GI tract ulceration with bleeding and perforation - aspirin or NSAIDs에 allergic 환자에서는 금기 • Dosage - intramuscular : 60mg - intravenous : 30mg - maintenance dose : 15-30mg every 6h • Drug Interactions - aspirin : ketolorac의 protein binding을 감소시켜 효과를 증가시킴

38. Clonidine • Mechanism of Action - α2-adrenergic agonist 로 작용 - sympathetic activity를 감소 - parasympathetic tone을 증가 - circulatingcatecholamines를 감소 • Clinical Uses - 주로 antihypertensive agent로 사용 (nonadrenergic receptor와 결합) - epidural infusion시 pain management위해사용 (pre- and postsynaptic α2-adrenergic receptor에 작용) - control of withdrawal syndrome (nicotine, opioids, alcohol, and vasomotor symptoms of menopause) - treatment of glaucoma

39. Clonidine • Side Effects - sedation,dizziness,bradycardia, and dry mouth are common • Dosage - epidural : 30μg/h in a mixture with an opioid and/or local anesthetic - treatment of acute hypertension : 0.1mg/h orally (maximum of 0.6mg) : maintenance dose is 0.1-0.3mg twice a day • Drug Interactions - epidural local anesthetics의 sensory and motor blockade를 증가

40. Dexmedetomidine • Mechanism of Action - more selective α2-adrenergic agonist than clonidine • Clinical Uses - opioid sparing effect - but, no significant respiratory drive depression, excessive sedation • Side Effects - bradycardia, heart block, hypotension • Dosage - initial loading dose : 1μg/kg intravenously over 10min - maintenance infusion rate : 0.2-0.7μg/kg/h • Drug Interactions - vasodilators, cardiac depressants와 사용시 주의

41. Doxapram • Mechanism of Action - peripheral and central nervous system stimulant - low doses : carotid chemoreceptors를 활성화 (hypoxic drive를 자극, tidal volume을 증가, respiratory rate를 증가) - high doses : medulla의 central respiratory centers를 자극 • Clinical Uses - COPD환자에서 유용 - drug-induced respiratory depression에서도 일시적으로 유용 - but, airway obstruction에는 효과없음 • Side Effects - mental change (confusion, dizziness, seizures) - cardiac abnormalities (tachycardia, dysrhythmias, hypertension) - pulmonary dysfunction (wheezing, tachypnea) - vomiting and laryngospasm • Dosage - Bolus intravenous administration : 0.5-1 mg/kg - continuous intravenous infusion : 1-3mg/min

42. Naloxone • Mechanism of Action - competitive antagonist at opioid receptors • Clinical Uses - opioid overdose로 인한 unconsciousness와 respiratory depression을 reverse • Side Effects - pain perception으로 인한 sympathetic stimulation (tachycardia, ventricular irritability, hypertension, pulmonary edema) - opioid dependent 환자에서 acute withdrawal syndrome - vomiting • Dosage - 0.5-1μg/kg every 3-5min (intravenous maximum dose is 0.2mg)

43. Flumazenil • Mechanism of Action - benzodiazepines의 specific and competitive antagonist • Clinical Uses - benzodiazepine sedation의 reverse -benzodiazepine overdose의 treatment • Side Effects - rapid administration시 anxiety reaction과 withdrawal symptoms - intracranial pressure의 증가 • Dosage - 0.2mg/min intravenously (total dose is 0.6-1.0mg)