Local anesthetics. Adrenergic transmission. Anaphylactic shock

1. Local anesthetics. Adrenergic transmission. Anaphylactic shock

2. LOCAL ANESTHETICS

3. Local anesthetics (LA) Are substances inducing local desensitisation, they reversibly inhibit the generation and propagation of action potential in nerve fibers D. Ježová

4. D. Ježová

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

6. All LA are weak bases with values of pK 8-9, so at physiologic pH, they are partially, but not absolutely ionisied. The more acidic the surrounding is (inflammation), the more they are ionisied. EFFECT in the cell – ionisied form PENETRATION TO THE SITE OF EFFECT (into the nerve fiber) – non-ionised 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+ LA MECHANISM OF ACTION Block the generation of action potential through blocking Voltage dependend Na+channels D. Ježová

9. MECHANISM OF ACTION D. Ježová

10. Na+ ion channels can be in state : • Steady (not permeable) • Activated (open) • Inactive D. Ježová

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

12. OLDER SUBSTANCES Esters: COCAINE - history PROCAINE, NOVOCAIN TETRACAINE, AMETHOCAINE BENZOCAINE – only surface anesthesia Amides: LIDOCAINE, LIGNOCAINE, XYLOCAINE TRIMECAINE, MESOCAIN CINCHOCAINE – not used 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 the blood (purposely; accidentally) – heart – slow propagation of action potential, asystolia – CNS – restlessness, spasms, at the end breathing depression and death – (allergic reactions) Therapy: thiopental, diazepam, i.v., assisted breathing D. Ježová

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

17. VASOCONSTRICTOR ADDITIVES LA reach the circulation slower: longer effect lower toxicity epinephrine, corbadrine, norepinephrine If epinephrine is contraindicated - felypressin, derivate of ADH Not at anesthesia of acral parts – ischemia! D. Ježová

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

19. Surface anesthesia • mucosa, skin • Infiltration anesthesia • injection to the region to be desensitized D. Ježová

20. Conductionanesthesia • higherconcentrationsof LA with more vasoconstrictoradditive • Near a nerve branch • highconductionanesthesia – paravertebral and epidural D. Ježová

21. D. Ježová

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

23. D. Ježová

24. Use of Local Anesthetics D. Ježová

25. D. Ježová

26. Other Indications of Local Anesthetics prevention and therapy of some arrhythmias - lidocaine and trimecaine, i.v. administration, usually 50 – 100 mg analgesia – postherpetic neuralgias - lidocaine patches (concentration 5 %)

29. Sympathic Nervous System (Thoracolumbal system) • Main mediator is norepinephrine (NE) (in vegetative ganglions acetylcholine) • Receptors α: α1 vessels – vasoconstriction; mydriasis, ejaculation α2 GIT - ↓ motility and secretion; CNS – decreased sympathic activity- negative feedback • Receptors β: β1 heart – increased frequency, contractility, conductivity and excitability; kidneys - ↑ excretion of renin β2 bronchi – dilation, arteries (mostly in skeletal muscles – vasodilation, uterus – tocolysis β3 adipocytes – lipolysis

30. Sympathomimetics Direct (act directly on the sympath. receptors) endogenous catecholamines and their derivates (NE, epinephrine etc.) α1 phenylephrine, nafazoline, oxymetazoline (mydriasis, decongestion of mucosa) α2 clonidine, α-metyldopa (hypertension) β1dopamine, dobutamine (acute heart failure- cardiogenic shock) β2short lasting effect – salbutamol, fenoterol, terbutaline long lasting effect – salmeterol, formoterol, clenbuterol indications: asthma bronchiale, tocolysis Indirect (increase the release of sympath. mediators) amphetamine, metamphetamine (penetration to CNS, abuse)

31. Selectedsympathomimetics norepinephrine – effects on αare dominating˃β1-effect;˃β2-effect → effects on CVS: ↑↑ peripheralvascularresistance (arteries), ↑↑ systolicbloodpressure, ↑↑ diastolicbloodpressure, ↑ contractilityofthemyocardium - reactionoftheorganism to theincreased BP → reflexbradycardia ! epineprine – strongagonistofβ1 and β2, in higherdosesalsoα1, α2, β2 → vasodilation in somepartsofthe body: skeletalmuscles, liver, brain → effects on CVS : ↓↑ peripheralvascularresistance (arteries), ↑↑ systolicbloodpressure, ↓↑ diastolicbloodpressure, ↑↑↑ contractilityofthemyocardium - ++ chronotropiceffect → tachykardia - in smalldosesmostlyßeffects, in higheralsostrongαeffects

32. dopamine – α, ßreceptors and dopaminereceptors - stimulationof D1 → vasodilatation (kidney, GIT) - importantfrom a clinicalstandpoint – increasedperfusionofthekidneys- in caseofshock→ protectsagainstkidneyfailure! - smalldoses – activationofmainlyD1 - middledoses – activationofD1 and ß - largedoses - activationofD1, ßandα dobutamine – syntheticcatecholamine; fairlyselectiveß1 agonist, - cardiogenicshock; acuteheartfailure

33. Sympatholytics Direct- actdirectly on thesympath. receptors (blockade) α: non-selective (α1+α2): phentolamine, phenoxybenzamine (pheochromocytoma) selectiveα1: prazosin, doxazosin, terazosin (hypertension + benignprostatichyperplasia) specificallyagainst BPH: tamsulosin β: indications: hypertension, IHD, tachyarrhythmias, glaucoma non-selective (β1+ β2): propranolol, metipranolol, ... selectiveβ1: metoprolol, bisoprolol, atenolol, ... hybrid (+ vasodilatativeeffect): carvedilol, labetalol, nebivolol, celiprolol Indirect decreasethereleaseofsympath. mediators guanethidine, rezerpine – obsoleteantihypertensives

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

35. Anaphylactic shock = anaphylactic reaction + ↓ BP +/- unconsciousness - symptom of anaphylactic reaction to exposition to a specific antigen Hypotension, shock bronchoconstriction acute respiratory insuficiency Quincke´s edema, edema - +1 mm skin fold = +1 liter in IST dermal symptoms – urticaria, pruritus GIT = nausea, vomiting, 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

36. H1-antihistaminics (bisulepine – Dithiaden), Calcium gluconicum • epinephrine – physiologic antagonist of chemical mediators, effect on smooth muscles, vessels,... • shock – dose 0,5-1,0 mg i.v. in bolus doses by 0,1 mg, then repeat according to the patient´s condition and it´s reaction to therapy • continual infusion in saline solution at a speed of 2-4 µg/min • alternative routes of administration: intratracheal, sublingual • persistance of bronchospasm → aminophyline 6 mg/kg (Syntophyllin inj.) • after an anaphylactic episode, patients should be examined by an allergologist! • Prevention in case of high risk: antihistaminics and glucocorticoids for example before RTG investigation with contrast substance