Local anesthetics. Adrenergic
transmission. Anaphylactic
shock
LOCAL ANESTHETICS
Local anesthetics (LA)
Are substances inducing local
desensitisation, they reversibly inhibit the
generation and propagation of action
potential in nerve fibers
D. Ježová
Local Anesthetics- History
• 1860 - cocaine isolated from erythroxylum coca
• Koller - 1884 uses cocaine for topical anesthesia
• Halsted - 1885 performs peripheral nerve block
with local an.
• Bier - 1899 first spinal anesthesis
D. Ježová
Chemical aspects
Aromatic
part
Ester
(amide)
Basic side-chain
part
D. Ježová
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
[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
D. Ježová
MECHANISM OF ACTION
Block the generation of action potential through blocking
Voltage dependend Na+ channels
Influx of Na+
LA
D. Ježová
MECHANISM OF ACTION
D. Ježová
Na+ ion channels can be in state :
1. Steady (not permeable)
2. Activated (open)
3. Inactive
D. Ježová
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
OLDER SUBSTANCES
Esters:
COCAINE - history
PROCAINE, NOVOCAIN
TETRACAINE, AMETHOCAINE
BENZOCAINE – only surface anesthesia
Amides:
LIDOCAINE, LIGNOCAINE, XYLOCAINE
TRIMECAINE, MESOCAIN
CINCHOCAINE – not used
D. Ježová
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)
D. Ježová
EFFECTS OF LA
- dependence from thickness and myelinisation of nerve
fibers
SEQUENCE OF DESENSITIZATION
pain → cold → heat → touch → deep pressure
D. Ježová
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
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
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
Types of Local Anesthesia
1. Surface anesthesia
2. Infiltration anesthesia
3. Conduction anesthesia
4. Spinal (subdural) anesthesia
D. Ježová
1. Surface anesthesia
mucosa, skin
2. Infiltration anesthesia
injection to the region to be desensitized
D. Ježová
3. Conduction anesthesia
higher concentrations of LA with more vasoconstrictor additive
Near a nerve branch
high conduction anesthesia – paravertebral and epidural
D. Ježová
D. Ježová
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
D. Ježová
Use of Local Anesthetics
D. Ježová
D. Ježová
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 %)
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
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)
β1 dopamine, dobutamine (acute heart failure-
cardiogenic shock)
β short lasting effect – salbutamol, fenoterol,
terbutaline
long lasting effect – salmeterol, formoterol,
clenbuterol
indications: asthma bronchiale, tocolysis
2
Indirect (increase the release of sympath. mediators)
amphetamine, metamphetamine (penetration to CNS, abuse)
Selected sympathomimetics
 norepinephrine – effects on α are dominating ˃ β1-účinky; ˃ β2-účinok
→ 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
 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
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
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
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
-
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