Local anesthetics. Adrenergic transmission. Anaphylactic shock

1. Local anesthetics. Adrenergic transmission. Anaphylactic shock

2. LOCAL ANESTHETICS

3. Local anesthetics (LA) Are substances inducing local desenzitisation, it means they reversibly inhibit generation and propagation of excitement in nervous fibers D. Ježová

4. D. Ježová

5. Chemical aspects Aromatic part Ester (amid) part Basic side chain D. Ježová

6. All LA are weak basis with values of pK 8-9, so at physiologic pH are partlially, but not absolutely ionisied. The more acid surrounding (inflammation), the more they are ionisied. EFFECT – ionisied form PENETRATION TO THE SITE OF EFFECT – nonionised form D. Ježová

7. [H+] concentration of protons 100 80 60 40 20 0 value of pH 6 7 8 9 10 effective form amphiphilic cation transport form lipophilic R´ R-N H R“ R´ R-N R“ + Ability to penetrate through lipophilic barriers and cell membranes small good kreslila: N. Hlavacova D. Ježová

8. Influx of Na+odvedenie vzruchu LA MECHANISM OF ACTION Block generation of action potential through blocking Voltage dependend Na+channels D. Ježová

9. MECHANISM OF ACTION D. Ježová

10. Na+ ionic channels can be in state : • Steady, not permeable • Activated, open • Inactive • automatically traverse to it from open state, also if depolarisation still remains D. Ježová

11. LA block initiation and propagation of action potential: 1. Non specific effect on membranes ( surface potential, similarity with inhalational anestetics) 2. Specific effect on Na+ channels - “use-dependence“ – the higher frequency of AP, the stronger blockade - LA influence state 2. and 3. - importance for antidysrrhytmic effect D. Ježová

12. OLDER SUBSTANCES COCAINE - history PROCAINE, NOVOCAIN TETRACAINE, AMETHOCAINE LIDOCAINE, LIGNOCAINE, XYLOCAINE TRIMECAINE, MESOCAIN CINCHOCAINE – not used BENZOCAINE – only surface anesthesia D. Ježová

13. Local anesthetic Start of effect Maximal dose(without epinephrine) Lasting of effect(with epinephrine) Lidocaine fast 4.5 mg/kg (7 mg/kg) 120 min (240 min) Mepivacaine fast 5 mg/kg (7 mg/kg) 180 min (360 min) Bupivacaine slow 2.5 mg/kg (3 mg/kg) 4 h (8 h) Procaine slow 8 mg/kg (10 mg/kg) 45 min (90 min) Chloroprocaine fast 10 mg/kg (15 mg/kg) 30 min (90 min) Etidocaine fast 2.5 mg/kg (4 mg/kg) 4 h (8 h) Prilocaine middle 5 mg/kg (7.5 mg/kg) 90 min (360 min) Tetracaine slow 1.5 mg/kg (2.5 mg/kg) 3 h (10 h) D. Ježová

14. EFFECTS OF LA • dependence from thickness and myelinisation of nerve fibers • SEQUENCE OF DESENSITIZATION • pain → cold → heat → touch → deep pressure D. Ježová

15. RISK OF TOXIC EFFECTS mainly if they get to blood (purposely; accidentaly) – heart – slowing down of excitement propagation, stopping – CNS – restlessness, spasms, at last breathing depression – (allergic reactions) Therapy: thiopental, diazepam, i.v., assisted breathing D. Ježová

16. Important role play: speed of administration concentration of solution Effect and toxicity raises with LA concentration faster, than corresponds to total dose. At low concentration can be exceeded maximal doses. On the other hane, at high concentrations are administered lower doses. D. Ježová

17. VAZOKONSTRICTOR ADDITIVES LA slower reaches circulation, result: longer effect lower toxicity epinephrine, corbadrine, norepinephrine If epinephrine is contraindicated - felypressin, derivate of VP - a little toxic LA without additive No at anesthesia of acral parts – ischaemia! D. Ježová

18. Types of Local Anesthesia • Surface anesthesia • Infiltration anesthesia • Conduction anesthesia • Spinal (subdural) anesthesia D. Ježová

19. Surface anesthesia • mucosa, no skin • but: not crystalic (eutectic) mixtures of LA • can be used at skin (e.g. lidocaine + prilocaine) • Infiltration anesthesia • injection to the region to be desensitized • special type at limbs interventions: • intravenous regional anesthesia – cuff D. Ježová

20. Conduction anesthesia • higher concentrations of LA with higher addition of vasoconstrictor • substance • near nerve branch • high conduction anesthesia – paravertebral and epidural D. Ježová

21. D. Ježová

22. Spinal (subdural) anesthesia • Difference between subdural and epidural (sometimes listed as spinal) D. Ježová

23. D. Ježová

24. Subdural anesthesia Solution lighter than liquor (hypobaric) in liquor goes up, hyperbaric goes down – can be influenced with NaCl and glucosa, important for the region of desensitization By paralysis of vasomotoric nervs occurs vasodilation in anesthetised region; blood pressure goes down No vasoconstrictor additives D. Ježová

25. Use of Local Anesthetics D. Ježová

26. D. Ježová

27. Other Indications of Local Anesthetics 5. prevention and therapy of some arrhytmias - lidocaine and trimecaine, i.v. administration, usually 50 – 100 mg • Višnevský´s blockade 7. analgesia – postherpetic neuralgias - lidocaine patches (concentration 5 %)

28. Sympathic Nervous System (Thoracolumbal) • Mediator is norepinephrine (NE); in ganglions acetylcholine • Receptors α: α1 vessels – vasoconstriction; mydriasis, ejaculation α2 GIT - ↓ motility and secretion, CNS – central hypotension • Receptors β: β1 heart – increases frequency, contractility, conductivity and excitability; kidneys - ↑ excretion of renin β2 bronchi – dilation, skeletal muscle – vasodilation, uterus – tocolysis β3 adipocyts – lipolysis Sympathomimetics Direct endogenous catecholamines and their derivates (NE more α1,α2, β1; epinephrine α1, α2, β1, β2; isoprenaline only β1, β2) α1 phenylephrine, nafazoline, oxymetazoline (mydriasis, decongestion of mucosa) α2 clonidine, corbadrine (← α-metyldopa), guanfacin (hypertension) β1 nonglycoside cardiotonics – dopamine, dobutamine (heart failure) β2 short lasting effect – salbutamol, fenoterol, terbutalin long lasting effect – salmeterol, formoterol, klenbuterol indications: asthma bronchiale, tocolysis

29. Indirect amphetamine, metamphetamine – budivé amines (penetration to CNS, abuse)

30. Anaphylaxis = acute generalised allergic reaction with simultaneous affection of more organ systems, usually CVS, resp. GIT - sensibilizing antigen, repeated exposition to Ag Ag + IgE → histamine, leucotriens → bronchoconstriction, vasodilation - foreign proteins; often bee, gad-bee, snake - hormones, enzymes, fine dust, polysacharids, dg preparations, blood derivates, drugs (antibiotics) – low-molecular substances → haptens → bond to blood plasma proteinst occurrence – seconds to minutes after allergen penetration – usually in parenteral form Anaphylactoid reaction = missing reaction Ag+Ab - toxically-idiosyncratical mechanisms - after first application of Ag! - opioid analgetics, polymyxine, RTG contrast substances

31. Anaphylactic shock = anaphylactic reaction + ↓ BP +/- unconsciousness - symptom of anaphylactic reaction to esposition of specific antigen shock condition bronchoconstriction acute respiratory insuficiency Quincke´s edema, edema +1 mm skin fold = +1 liter in IST dermal symptoms – urticaria, pruritus GIT = nausea, vommiting, abdominal spasms, diarrhoea Treatment - stop penetration of Ag to organism • vein cannulation • ensure breathing • immediate administration of epinephrine • i.v. glucocorticoides – hydrocortisone 200 mg and more, methylprednisolone 40-80 mg and more

32. H1-antihistaminics (bisulepine – Dithiaden), Calcium gluconicum • epinephrine – fysiologic antagonist of chemical mediators effects of an. reaction on smooth muscles, vessels,... • shock – dose 0,5-1,0 mg i.v. in bolus doses by 0,1 mg, than repeat according to patient´s condition and its reaction to therapy • continual infusion in saline solution at speed 2-4 µg/min • alternative routes of administration: intratracheal, sublingual • if persistance of bronchospasm → aminophyline 6 mg/kg (Syntophyllin inj.) • patient should be after anaphylactic episode examined by allergologist! • prevention: before RTG investigation antihistaminic substance and glucocorticoid according to risk category