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

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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 an.

• Bier - 1899 first spinal anesthesis

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Aromatic part

Ester

(amide)

part

Basic side-chain

Chemical aspects

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EFFECT in the cell – ionisied form

PENETRATION TO THE SITE OF EFFECT (into the nerve fiber) – non-ionised 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.

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value of pH

[H+] concentration of protons 100

80

60

40

20

06 7 8 9 10

transport form lipophilic

good

R´

R-N

R“

effective form amphiphilic

cation

R´

R-N

H R“

+

small

Ability to penetrate through lipophilic barriers and cell

membranes

kreslila: N. Hlavacova D. Ježová

MECHANISM OF ACTION

Influx of Na+

LA

Block the generation of action potential through blocking

Voltage dependend Na+ channels

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MECHANISM OF ACTION

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Na+ ion channels can be in state :

1. Steady (not permeable)

2. Activated (open)

3. Inactive

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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.

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Esters:

COCAINE - history

PROCAINE, NOVOCAIN

TETRACAINE, AMETHOCAINE

BENZOCAINE – only surface anesthesia

Amides:

LIDOCAINE, LIGNOCAINE, XYLOCAINE

TRIMECAINE, MESOCAIN

CINCHOCAINE – not used

OLDER SUBSTANCES

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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)

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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 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

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Important role: speed of administrationconcentration 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 .

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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!

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1. Surface anesthesia

2. Infiltration anesthesia

3. Conduction anesthesia

4. Spinal (subdural) anesthesia

Types of Local Anesthesia

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1. Surface anesthesia mucosa, skin

2. Infiltration anesthesiainjection to the region to be desensitized

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3. Conduction anesthesia

higher concentrations of LA with more vasoconstrictor additive

Near a nerve branch

high conduction anesthesia – paravertebral and epidural

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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

4. Subdural anesthesia

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Use of Local Anesthetics

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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

SympathomimeticsDirect (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) β2 short lasting effect – salbutamol, fenoterol,

terbutaline long lasting effect – salmeterol, formoterol,

clenbuterol indications: asthma bronchiale, tocolysisIndirect (increase the release of sympath. mediators)

amphetamine, metamphetamine (penetration to CNS, abuse)

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

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

SympatholyticsDirect - 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, shockbronchoconstrictionacute respiratory insuficiencyQuincke´s edema, edema - +1 mm skin fold = +1 liter in ISTdermal symptoms – urticaria, pruritusGIT = 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