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Local anaesthetics & Anti-dysrhythmics (Local Anaesthetics…
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
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.
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
relatively unstable in solution and are rapidly hydrolysed by plasma cholinesterase ( and other esterases)
Procaine
Tetracaine
Amino amides
stable in solution and are slowly metabolised by hepatic amidases
Lidocaine
Prilocaine
Toxicity & side effects
CNS effects
low concentrations
tinnitus, numbness of the tongue, blurring of vision, drowsiness
High concentrations
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
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
classification
site of origin
atrial/nodal/ventricular
heart rate
tachycardia - increased
bradycardia - decreased
Process/substrate
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
Heart rate
conduction system
SA node => Atrium => AV node => Purkinje fibre => Ventricle
Anti-dysrhythmics
class 1
a
Disopyramide
Moderate Na+ channel block, prolonged repolarisation
b
Lidocaine
Mild Na+ channel block, shortened repolarisation
c
Flecainide
Marked Na+ channel block, no change in repolarisation
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
class 2
Metoprolol
Antagonism of β1 adrenoceptors on the sympathetic innervation on SA node => slow SA pacemaker activity
class 3
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
class 4
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