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Local anesthetics. Adrenergic
transmission. Anaphylactic
shock
LOCAL ANESTHETICS
Local anesthetics (LA)
Are substances inducing local
desenzitisation, it means they reversibly
inhibit generation and propagation of
excitement in nervous fibers
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Local Anesthetics- History
• 1860 - cocaine isolated from erythroxylum coca
• Koller - 1884 uses cocaine for topical anesthesia
• Halsted - 1885 performs peripheral nerve block
with local
• Bier - 1899 first spinal anesthetic
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Chemical aspects
Aromatic
part
Ester
(amid)
Basic side chain
part
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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
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[H+] concentration of protons
100
80
60
40
20
0
6
7
8
9
10
value of pH
effective form
amphiphilic
cation
transport form
lipophilic
R´
R´
+
R-N
H
R-N
R“
small
kreslila: N. Hlavacova
Ability to penetrate
through lipophilic
barriers and cell
membranes
R“
good
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MECHANISM OF ACTION
Block generation of action potential through blocking
Voltage dependend Na+ channels
Influx of Na+
odvedenie vzruchu
LA
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MECHANISM OF ACTION
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Na+ ionic channels can be in state :
1. Steady, not permeable
2. Activated, open
3. Inactive
automatically traverse to it from open state, also if
depolarisation still remains
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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
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OLDER SUBSTANCES
COCAINE - history
PROCAINE, NOVOCAIN
TETRACAINE, AMETHOCAINE
LIDOCAINE, LIGNOCAINE, XYLOCAINE
TRIMECAINE, MESOCAIN
CINCHOCAINE – not used
BENZOCAINE – only surface anesthesia
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Local
anesthetic
Start of
Maximal dose
effect (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)
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EFFECTS OF LA
- dependence from thickness and myelinisation of nerve
fibers
SEQUENCE OF DESENSITIZATION
pain → cold → heat → touch → deep pressure
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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
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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.
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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!
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Types of Local Anesthesia
1. Surface anesthesia
2. Infiltration anesthesia
3. Conduction anesthesia
4. Spinal (subdural) anesthesia
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1. Surface anesthesia
mucosa, no skin
but: not crystalic (eutectic) mixtures of LA
can be used at skin (e.g. lidocaine + prilocaine)
2. Infiltration anesthesia
injection to the region to be desensitized
special type at limbs interventions:
intravenous regional anesthesia – cuff
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3. Conduction anesthesia
higher concentrations of LA with higher addition of vasoconstrictor
substance
near nerve branch
high conduction anesthesia – paravertebral and epidural
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4. Spinal (subdural) anesthesia
Difference between subdural and epidural (sometimes listed as spinal)
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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
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Use of Local Anesthetics
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Other Indications of Local Anesthetics
5. prevention and therapy of some arrhytmias
- lidocaine and trimecaine, i.v. administration, usually 50
– 100 mg
6.
Višnevský´s blockade
7. analgesia – postherpetic neuralgias
- lidocaine patches (concentration 5 %)
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
Indirect
amphetamine, metamphetamine – budivé amines (penetration to CNS,
abuse)
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
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
-
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

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