LA - pharmacology

Question 1

Analgesia definition

Answer 1

Loss of pain alone

Question 2

Anaesthesia definition

Answer 2

Loss of all forms of sensation

Question 3

Local anaesthesia definition

Answer 3

Loss of sensation in a circumscribed areas of the body by a depression of excitation in nerve endings or an inhibition of conduction process in peripheral nerves

Question 4

LA uses

Answer 4

Controlling operative pain
Control post-operative pain
Controlling operative haemorrhage
Diagnosis of pain
Relief of orofacial pain - topical and injection

Question 5

History of LA drugs

Answer 5

1855 - Gardeke - extracted cocaine = leaves chewed with lime by natives of Bolivia and Peru
1884 - Carl Koeller - synthesised procaine
1943 - Nils Lofgren - synthesised lignocaine
1963 - Prilocaine

Question 6

History of LA administration

Answer 6

1827 - Nov Neuner - seveloped syringe for vet use
1884 - Zophar Jayne - used syringe in man through incision
Nov 1884 - William Halstead - blocked IAN by injection of 4% cocaine
1917 - Harvey COok - devised cartridge system

Question 7

Chemistry of LAs

Answer 7

All weak bases with general formula
Aromatic group - intermediate chain - 2. or 3. amine
-aromatic group is lipophilic i.e. dissolve in lipid sheath around nerve
-intermediate chain are esters or now amides
-amino terminal is hydrophilic (1. soluble and 2 transfer through interstitial fluids)

Question 8

Ester or amide

Answer 8

Early: cocaine, procaine and amethocaine aromatic and intermediate groups were ester
-disadvantages: unstable in soln, not autoclavable, antigenic/ allergy
Lignocaine, prilocaine and all other are amides
-advantages: more stable, autoclavable and very rarely antigenic

Question 9

Example of long acting LA

Answer 9

Bupivocaine

Question 10

Example of short acting LA

Answer 10

Procaine (ester, don’t use it anymore)

Question 11

How is drug administered so it dissolves

Answer 11

LAs are weak organic bases - poorly soluble in H2O
Drug combined with strong acid to form water soluble salt (usually hydrochloride)
Therefore ionises to cationic form (pH in cartridge approx 2-6)
Active form is non-ionised base formed in tissues and is lipid soluble (therefore penetrates lipid membranes and tissue barriers)
Therefore, at physiological pH (extra-cellular fluid = 7.4), need reasonable conc. of non-ionised form (lignocaine approx 25%, procaine approx 2.5%, therefore lignocaine better)

Question 12

Mode of action

Answer 12

Nerve conduction
Depolarisation by receptor potential/ chemical etc. –> a.p.
At rest nerve cell membrane largely impermeable to sodium ions
If stimulus reduces electro- charge to around -55mV (firing level) then membrane becomes highly permeable to sodium ions - a.p.
LA binding site is inside nerve cell - hence need for LA to be non-charged
Once inside nerve it re-equilibrates into mixed charged and non-charged forms. Charged form binds to specific receptor (specific receptor theory)
Non-specific action of LA is lipophilic portion of molecule may cause swelling of membrane (non-specific theory)
Initially high threshold for excitation, then conduction block

Question 13

Henderson-Hasselbach equation

Answer 13

Look at graphs on slides

Question 14

Anaesthetic drug - non-ionised form penetrates

Answer 14

Epineurium
Perineurium
Endoneurium

Question 15

Two theories of mode of action

Answer 15

Once inside nerve it re-equilibrates into mixed charged and non-charged forms. Charged form binds to specific receptor (specific receptor theory)
Non-specific action of LA is lipophilic portion of molecule may cause swelling of membrane (non-specific theory)

Question 16

What does LA effect

Answer 16

Affects all fibre types (not function specific), but small (pain and T) first and large (motor, proprioceptive) last
Vasomotor (BV wall) effects:
-blocks sympathetic vasoconstrictors (therefore dilation)
-direct effect on smooth muscle of vessels is variable (cocaine constricts, lignocaine dilates)

Question 17

Detoxification of esters

Answer 17

Esters - esterases in blood and liver –> benzoic acids and alcohol –> urine
1:2800 of pop. lack peudocholineserase (plasma) - problems with suxamethonium (GA) but OK with amide LAs

Question 18

Detoxofication of amides

Answer 18

Mainly broken down in liver, oxidised, some conjugated with glucuronic acid, all –> urine
Therefore if severe liver disease
Lignocaine half life 90 mins
Articaine (amide) undergoes initial breakdown by esterases in the plasma. Rapid breakdown - half life 20 minutes

Question 19

Ideal characteristics

Answer 19

Produce complete LA without damaging or other local tissues
Rapid onset with predictable and appropriate duration
Isotonic
Non-toxic sytemically
Readily soluble and stable in soln. (adequate shelf-life - usually 2-2 1/2 years)
Sterilisable (esters not autoclavable)
Non-addictive (not cocaine)

Question 20

Citonest

Answer 20

Trade name of prilocaine

Question 21

Intermediate duration LAs

Answer 21

Lignocaine
Prilocaine
Mepivacaine
Articaine

Question 22

Vasoconstrictors advantages

Answer 22

Delay removal from site
More rapid onset of anaesthesia
Prolongs and enhances effect
Reduces operative bleeding

Question 23

Vasoconstrictors disadvantages

Answer 23

Prolonged soft tissue anaesthesia unpopular with pxs e.g. dentala analgesia from lignocaine 2% with 1:80,000 adrenaline = approx 1/3 - 1 hour; soft tissue approx 3 hours
Without adrenaline, analgesia = 5-20 mins; soft tissue = approx 1 hour
Potential systemic effects (e.g. heart palputations) with intravascular injection

Question 24

Adrenaline

Answer 24

Usually used as 1:80,000 (12.5µg/ml) with lignocaine
Systemically, affects α and beta receptors, with +ve inotropic (force) and chronotropic (rate) effects and > potential for arrythmias
In practice, these effects are usually insignificant

Question 25

Adrenaline with affect

Answer 25

``` Blood pressure -vasodilation of muscles -vasoconstriction of skin Heart rate ->rate and force of contractions Blood glucose -> glucose Plasma potassium -< potassium ```

Question 26

Noradrenaline

Answer 26

Can cause > BP and lead to CVA (stroke) | Never used in UK

Question 27

Felypressin (octapressin)

Answer 27

Synthetic polypeptide. similar to vasopressin Usually used as 0.03 i.u. with prilocaine (citanest) Less likely to produce CV effects than adrenaline Action on uterus - beware preganncy

Question 28

Why do we avoid esters

Answer 28

Can cause allergies

Question 29

Reducing agent

Answer 29

Sodium metabisulphate to prevent oxidisation of vasoconstrictors (brown discolouration)

Question 30

Preservative

Answer 30

e.g. Methyl paraben | May be responsible for allergic reactions (no longer used by Dentsply)

Question 31

Fungicide

Answer 31

e.g. thymol or fungi, may cause cloudiness

Question 32

Modified Ringer's solution

Answer 32

Isotonic

Question 33

Cocaine

Answer 33

Rarely used May cause idiosyncratic reactions in some people Sometimes used by anaesthetists to aid nasal intubation (vasoconstrictor effet) Systemically causes exhiliration and overcomes fatigue but is addictive and toxic with overdose Can lead to tremors, convulsions, hallucinations, etc Categorised as a dangerous drug

Question 34

Procaine

Answer 34

1905-1940s Ester, slow onset, short duration, poor penetration of tissues Superseded

Question 35

Amethocaine

Answer 35

Ester, potent and long-acting and highly effective as a surface anaesthetic Not used routinely

Question 36

Lignocaine trade names

Answer 36

Lidocaine, xylocaine, xytolox, lignostab

Question 37

Lignocaine

Answer 37

Most widely used LA drug 2% soln usually with 1:80,000 adrenaline Max total dose approx. 4.4mg/kg in healthy adult (approx 7 cartridges) Rapid onset - good penetration

Question 38

Other application %s of lignocaine

Answer 38

5% ointment, 4% or 10% spray or 2% gel, for topical use (ulcers etc.)

Question 39

Mepivacaine (Carbocaine)

Answer 39

Similar to lignocaine 3% plain (without vasoconstrictor) is better than plain lignocaine and so good for short procedures 2% with 1:80,000 adrenaline is indistinguishable from lignocaine

Question 40

Bupivacaine (Marcain)

Answer 40

0.5% solution, 1:200,000 adrenaline Slow onset but very long duration (approx 2x lignocaine) Used for major surgery or short term relief for trigeminal neuralgia

Question 41

Prilocaine (Citonest)

Answer 41

4% plain or 3% with felypressin Rapid onset, good penetration Used if avoiding adrenaline Used with lignocaine as EMLA (Eutectic Mixture of LAs) for venepuncture in children

Question 42

Articaine (Ultracaine)

Answer 42

4% with adrenaline Claimed to diffuse widely Not yet in routine use and may cause > incidence of nerve damage Avoid use for nerve blocks

Question 43

Ropivacaine (naropin)

Answer 43

Long acting agent, recently launched in UK | Not yet in routine use

Question 44

Maximum recommended dose - lignocaine

Answer 44

Lignocaine 4.4mg/kg - healthy px 2% lignocaine will contain 20mg/ml 65kg man may have total of 65x4.4mg = 286mg 14.3ml of 2% 6.5 x 2.2ml cartridges One tenth of a cartridge per kg in weight