Local anaesthetics & Anti-dysrhythmics

Local anaesthetics &
Anti-dysrhythmics

Local Anaesthetics

clinical use

produce a reversible regional loss of sensation or pain

mechanism of action

reversibly block the generation and conduction of AP,
by affecting voltage-gated Na+ channels

common general structure

Aromatic group

Intermediate chain
(ester or amide bond)

Tertiary or Secondary amino group

LA agents

cocaine - 1st LA

procaine

lidocaine

teracaine

bupivacaine

Administration
& Action

most LAs are weak bases

they are administers as water soluble hydrochlorides (B.HCL)

after injection, the tertiary amine base is
dissociates in alkaline pH of tissue fluids

In tissue LA will be in both ionised and unionised forms
B + H+ <=> BH+

unionized base (B) diffuses through the nerve sheath, perineuronal tissues and neuronal membrane to reach axoplasm and partially ionise again

Hydrophilic pathway: when NA+ channels open ionised form of BH+ enters the channel and combines with subunit IV (especially segment 6) resulting in channel blockade

Potency

determined by lipid solubility (ease of cell membrane penetration)

Duration of action

correlated with the capacity to bind plasma and tissue proteins

Onset of action

lower pKa - more unionised form - easier penetration of nerve membrane - faster onset

Physiology of action

thin fibres are more easily blocked than thick ones
myelinated fibres are more easily blocked than thick ones

C and Asigma pain fibres are thin and unmyelinated

pain > cold > warmth > touch > pressure > motor

Metabolism

Amino esters

Amino amides

relatively unstable in solution and are rapidly hydrolysed by plasma cholinesterase ( and other esterases)

Procaine

Tetracaine

stable in solution and are slowly metabolised by hepatic amidases

Lidocaine

Prilocaine

Toxicity & side effects

CNS effects

low concentrations

High concentrations

tinnitus, numbness of the tongue, blurring of vision, drowsiness

agitation with hyperactivity (occasionally convulsions, followed by profound CNS depression and respiratory depression)

Cardiovascular effects

vasodilation, depression of myocaridum and cardiac slowing, leading to hypotension, cardiac block

Allergic reactions

one of the main breakdown products of ester types is PABA, which is associated with allergic phenomena and hypersensitivity reactions

Hydrophobic pathway: when Na+ channels are closed the unionized form diffuses to the membrane and from the membrane to the channel, where it combines with a proton to block the channel in the same way.

Methods of administration

Topical application - surface anaesthesia

Subdermal application - infiltration anaesthesia

IInjection to a peripheral nerve - nerve block anaesthesia

Injection into subarachnoid space - spinal anaesthesia

Injection into epidural space - epidural anaesthesia

Injection into a vein, distal to a cuff on the limb - intravenous regional anaesthesia

Anti-dysrhythmics

Dysrhythmia

alteration in the rythm of the heart

arrhytmia - no rythm, dysrythmia - abnormal rythm

cause

disruption of the normal electrical conduction system of the heart

can be life-threatening if it causes a sever decrease in the pumping efficacy of the heart

Heart rate
conduction system

SA node => Atrium => AV node => Purkinje fibre => Ventricle

classification

site of origin

heart rate

Process/substrate

atrial/nodal/ventricular

tachycardia - increased

bradycardia - decreased

fibrillation, heart block, ectopic

factors responsible
for dysrhythmias

delayed after-depolarisation

due to stimulation of Na+/Ca2+ echanger (NCX) => [Na+]i rises => depolarisation => can trigger early ectopic (out of pace) beat

disordered conduction (re-entry)

damage to atrial muscle can cause a unidirectional block
(in normal cardia rhythm the atrial AP dies out as impulses converge on AV node) => this allows a slowly moving AP to re-excite tissue that is no longer refractory => re-entrant dysrhythmia with impulse circulating indefinitely

abnormal pacemaker activity

damage can induce abnormal pacemaker activity => this can beat out of synchrony with the normal rythm

Heart block

failure of impulse generation in SA node or failure of propagation through AV node. Ventricular beating is maintained by abnormal pacemaker (e.g. Purkinje system) which is usually slow and unreliable

Anti-dysrhythmics

class 1

class 2

class 3

class 4

Disopyramide

Lidocaine

Flecainide

v.g. Na+ channel block on SA node cells => fever Na+ channels available => threshold increase => slower rate of depolarisation => slower and more regular heart rate

Metoprolol

Antagonism of β1 adrenoceptors on the sympathetic innervation on SA node => slow SA pacemaker activity

Moderate Na+ channel block, prolonged repolarisation

Mild Na+ channel block, shortened repolarisation

Marked Na+ channel block, no change in repolarisation

Amiodarone

v.g. K+ channel block on SA node cells => delay repolarisation => prolongation of cardiac AP => reduce the window in cardiac cycle when dysrhythmias can occur

Verapamil

v.g. Ca2+ channel block  decrease Ca2+ influx  decrease SA excitability and slow AV conduction

Long QT syndrome (LQTS)

prolongation of the QT interval (reflects the duration of ventricular depolarisation) on electrocardiograms

can initiate dysrhythmias

inherited

loss-of-function mutations to v.g. K+ channels ( underlying repolarisation phase)

acquired

certain drugs or electrolyte disturbance => hypokalaemia

lower [K+]o reduces K+ current prolonging the ventricular AP, by increasing the K+ driving force, but paradoxically reduceing Ikr (hERG channel current. It does so by increasing its inactivation, enhancing block of the channel by [Na+]o and channel blocking drugs

this is why anti-dysrhythmics need to be administered with caution for drugs that interact with this system