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Local anesthetics. Adrenergic transmission. Anaphylactic shock

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Presentation on theme: "Local anesthetics. Adrenergic transmission. Anaphylactic shock"— Presentation transcript:

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 EFFECT in the cell – ionisied form
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
value of pH [H+] concentration of protons 100 80 60 40 20 transport form lipophilic good R-N R“ effective form amphiphilic cation H R“ + small Ability to penetrate through lipophilic barriers and cell membranes kreslila: N. Hlavacova D. Ježová

8 Block the generation of action potential through blocking
MECHANISM OF ACTION Block the generation of action potential through blocking Voltage dependend Na+ channels Influx of Na+ LA 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 Maximal dose (without epinephrine) Lasting of effect (with
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 5 mg/kg (7 mg/kg) 180 min (360 min) Bupivacaine slow 2.5 mg/kg (3 mg/kg) 4 h (8 h) Procaine 8 mg/kg (10 mg/kg) 45 min (90 min) Chloroprocaine 10 mg/kg (15 mg/kg) 30 min (90 min) Etidocaine 2.5 mg/kg (4 mg/kg) Prilocaine middle 5 mg/kg (7.5 mg/kg) 90 min (360 min) Tetracaine 1.5 mg/kg (2.5 mg/kg) 3 h (10 h) D. Ježová

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

15 mainly if they get to the blood (purposely; accidentally)
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 speed of administration concentration of the administered solution
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 Infiltration anesthesia injection to the region to be desensitized
Surface anesthesia mucosa, skin Infiltration anesthesia injection to the region to be desensitized D. Ježová

20 Conduction anesthesia
higher concentrations of LA with more vasoconstrictor additive Near a nerve branch high conduction anesthesia – 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 %)

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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 β2 short lasting effect – salbutamol, fenoterol, terbutaline
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) β dopamine, dobutamine (acute heart failure- cardiogenic shock) β2 short 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 Selected sympathomimetics
 norepinephrine – effects on α are dominating ˃ β1-effect; ˃ β2-effect → effects on CVS: ↑↑ peripheral vascular resistance (arteries), ↑↑ systolic blood pressure, ↑↑ diastolic blood pressure, ↑ contractility of the myocardium - reaction of the organism to the increased BP → reflex bradycardia !  epineprine – strong agonist of β1 and β2, in higher doses also α1, α2, β2 → vasodilation in some parts of the body: skeletal muscles, liver, brain → effects on CVS : ↓↑ peripheral vascular resistance (arteries), ↑↑ systolic blood pressure, ↓↑ diastolic blood pressure, ↑↑↑ contractility of the myocardium - ++ chronotropic effect → tachykardia - in small doses mostly ß effects, in higher also strong α effects

32  dopamine – α, ß receptors and dopamine receptors
- stimulation of D1 → vasodilatation (kidney, GIT) - important from a clinical standpoint – increased perfusionof the kidneys - in case of shock → protects against kidney failure! - small doses – activation of mainly D1 - middle doses – activation of D1 and ß - large doses - activation of D1, ß and α  dobutamine – synthetic catecholamine; fairly selective ß1 agonist, - cardiogenic shock; acute heart failure

33 Sympatholytics Direct - act directly on the sympath. receptors (blockade) α: non-selective (α1+α2): phentolamine, phenoxybenzamine (pheochromocytoma) selective α1: prazosin, doxazosin, terazosin (hypertension + benign prostatic hyperplasia) specifically against BPH: tamsulosin β: indications: hypertension, IHD, tachyarrhythmias, glaucoma non-selective (β1+ β2): propranolol, metipranolol, ... selective β1: metoprolol, bisoprolol, atenolol, ... hybrid (+ vasodilatative effect): carvedilol, labetalol, nebivolol, celiprolol Indirect  decrease the release of sympath. mediators guanethidine, rezerpine – obsolete antihypertensives

34 Anaphylactoid reaction
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 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


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