Local Anaesthetics Flashcards
Where does local anaesthetic bind?
What is the difference between inactivated and resting Na channels?
- the drug binds to Na channel between region 5 and 6. There are 6 regions in total within 1 Na channel subunit. 4 subunits form a Na channel.
- resting and inactivated Na channels both achieve the same effect,ie no Na can enter. But the actual configuration of channel differs.
What is local anaesthetics? And how it works?
- local, reversible loss of sensations without losing consciousness
- mechanism: block fast Na channels from opening or enhance the inactivated state of Na channels.
Ultimately, to prevent further entering of Na ions into cells and prevent triggering of AP
What is the difference regarding to effects of local anaesthetics between big diameter neurones and small diameter neurones?
- small diameter neurone fibres bind more readily to LA than large diameter neurone fibres
- if LA is being over-administered, it could block other nerve fibres, eg cardiac cells
- nociceptive stimuli are carried by A delta or C fibres= small diameter
Types and trend of different fibres.
- as the diameter of fibre reduces, the speed of conductance reduces but the sensitivity to LA increases
- A mu = propriception of muscles, motor
- A beta = skin touch
- A gamma = motor to muscle spindles
- A delta = sharp, pricking pain, temp
- B = sympathetic preganglionic
- C = slow, burning pain; temp, itch, sympathetic postganglionic
General chemical structure of LA
- aromatic group + ester/ amide group + amino group
- aromatic= hydrophobic, lipophilic
- amino= water soluble when protonated
- many LA can interact with specific receptors at lower concentrations. Ie only at high conc, they have anaesthetics effects e.g. Propranolol, morphine
How do the charged and uncharged forms of local anaesthetics?
- uncharged LA: important for penetration of neural sheath (which determines the rate of onset) and crosses the plasma membrane ( which determines access to site of action)
- charged LA: interact with Na channel so can produces anaesthetic effect. Protonation of LA ( at the amino group) makes LA more soluble in blood
What determines % of LA molecules are ionised?
- determines by pH and the pKa of the LA.
- pKa is defined at which pH- 50% of LA are ionised and 50% of LA are unionised.
- most LA has pKa of 8-9( as most LA are weak bases)
- % of ionised/ unionised LA molecules at a given pH by using Henderson- Hasselbach equation
- as pH decreases, conc of unionised LA decreases while ionised LAH increases. This means it takes more time for LA to enter plasma membrane because unionised LA decreases
Two pathways in which LA produces effects. (Hydrophilic pathway is commonest)
1- hydrophobic pathway: LA doesn’t need to be charged at all to block Na channels
2- hydrophilic pathway: LA has to be unionised initially to penetrate the neural sheath and crosses the plasma membrane then LA becomes ionised to binds to NA channels, either blocks it from opening or maintains it at the inactivated state
What are the atypical LAs? (2)
-benzocaine: ester group and no amine group so can’t be protonated as there’s no nitrogen present.
= hydrophobic pathway only
-QX-314: permanently charged, ie 100% ionised at the nitrogen group.
What is use-dependence?
- more often of the neurone fires an AP, the greater the degree of the neural block by the local LA
- this mechanism is generally not a major route for LA to act as the nociceptive fibres fire high frequency of AP. And use-dependence mechanism is more short lasting
- it only becomes more important when LA is affecting sites other than the nociceptive fibres, ie cardiac cells for anti-dysthymia or anti-epileptic drugs (only affect the over active cells)
- otherwise generally, LA binds to the inactivated state of Na channel as higher conc of drug usually present = more likely to go down that route
How are LA being metabolised?
- ester linked: LA are hydrolysed by plasma esterases so have a shorter plasma half life
- amide linked: LA are metabolised in the liver so has a longer half life as it takes time for liver to process
- for both routes, movement of drug from tissue to blood is important for anaesthesia to wear off, ie the longer the LA stay in the tissues, it can’t be processed by esterases or liver
How does LA’s intrinsic vasodilator property can affect its function?
- vasodilation means increases vascular uptake and shorter duration of LA activity as the rate of removal is sped up
- this means often a vasoconstrictor is given along side LA so slow blood flow and prolong LA stay in tissue
- usually adrenaline is used: max conc 1 in 200 000 (5 microgram/ml) so generate local anaesthetics effects but not activating masses of receptors
Procaine
- short plasma half life and is readily hydrolysed by non-specific esterases in plasma
- rarely used because of poor penetration
Lidocaine (lignocaine)
- 2 hours of plasma half life and is metabolised by liver by N-dealkylation
- most widely used LA
- rapid onset, moderate duration and extremely stable, ie long shelf life
Mepivacine
- rapid onset, medium duration
- doesn’t produce a big vasodilate effect so can be administered without a vasoconstrictor
