Local Anaesthetic Drugs

Question 1

What is nociception?

Answer 1

Pain awareness
Mediated by nerve endings receptors in peripheral tissues and transmitted to the CNS
Transmission can be disrupted by drugs acting on neurotransmitter receptors or by blocking the sodium channels

Question 2

What is the action of local anaesthetics?

Answer 2

Reversibly block the generation and propagation of electrical impulses in the excitable tissues.
Block the propagation of the action potential—> lose of sensation in that local area
Disrupt voltage dependent Na+ ion channel function within neural membrane preventing the transmission of the neuronal action potential

Question 3

What are the properties of anaesthetics?

Answer 3

Aromatic ring: lipophilic
Intermediate linkage
Terminal amine: Hydrophilic (blocks the channel)

Question 4

What are the 2 classes of local anaesthetics?

Answer 4

1. Aminoamide most commonly used clinically
   2.Aminoester more likely to cause allergic reaction

Question 5

Give an example of ester agent?

Answer 5

Cocaine, Procaine

Question 6

Give and example of an amide agent?

Answer 6

Lidocaine

Question 7

What is pKa?

Answer 7

pKa is the acid dissociation constant, which tells us how easily an acid gives up a proton (H⁺).

The reaction shown, HCl → H⁺ + Cl⁻, illustrates the dissociation of hydrochloric acid, a strong acid.

Question 8

What is the relationship between pKa and acid strength?

Answer 8

Lower pKa (~2 or lower) → Strong acid (dissociates easily in water).

Higher pKa (~2-12) → Weak acid (less dissociation in water).

Question 9

Why does pKa matter for local anesthetics?

Answer 9

Local anesthetics are weak bases, and their effectiveness depends on their pKa.

The closer the pKa of the drug is to physiological pH (~7.4), the more of the drug will be in its uncharged (lipid-soluble) form, allowing it to penetrate nerve membranes and exert its effect.

Question 10

Which compounds are more stable: Ester-containing or amides?

Answer 10

Ester containing compounds are inactivated in the plasma and tissue by esterase enzymes
Amides are morestable and thus have a longer plasma half life

Question 11

All LAs are weak bases with pKa between 8 to 9. Why is this good?

Answer 11

At physiological pH, there are mainly ionised but not completely.
This is essential for te penetration of the nerve sheath and axon membrane since compounds that are totally ionised cannot penetrate.
LAs with lower pKa have a more rapid onset of action

Question 12

What is topical surface anesthesia?

Answer 12

Local anesthesia applied by spray or ointment to areas like the nose, mouth, bronchial tree, cornea, and urinary tract.

Question 13

What is a risk of topical surface anesthesia?

Answer 13

Systemic toxicity at high concentrations.

Question 14

What is infiltration anesthesia?

Answer 14

Local anesthesia injected subcutaneously directly into tissue or around nerves, commonly used in minor surgeries.

Question 15

What is a risk of infiltration anesthesia?

Answer 15

Suitable only for small areas or risk of systemic toxicity.

Question 16

What is intravenous regional anesthesia?

Answer 16

Local anesthesia injected intravenously distal to a pressure cuff to stop blood flow, used in limb surgeries.

Question 17

What is a risk of intravenous regional anesthesia?

Answer 17

Systemic toxicity if the cuff is removed too soon.

Question 18

What is a nerve block?

Answer 18

Local anesthesia injected close to a nerve trunk to block sensation, commonly used in dental procedures.

Question 19

What is a risk of a nerve block?

Answer 19

Requires accurate needle placement.

Question 20

What is spinal anesthesia?

Answer 20

Local anesthesia applied into the subarachnoid space to block spinal roots, used when general anesthesia is not an option.

Question 21

What is a risk of spinal anesthesia?

Answer 21

Bradycardia and hypotension due to sympathetic block.

Question 22

What is epidural anesthesia?

Answer 22

Local anesthesia applied into the epidural space to block spinal roots, commonly used during childbirth.

Question 23

What is a risk of epidural anesthesia?

Answer 23

Similar to spinal anesthesia but less probable.

Question 24

What factors determine the absorption (uptake) of local anesthetics?

Answer 24

Dosage, site of injection, physical properties of the drug, and local tissue blood flow.

Question 25

How are amides distributed in the body after intravenous administration?

Answer 25

They are widely distributed, with rapid distribution in highly perfused organs like the brain, liver, kidney, and heart.

Question 26

Where do local anesthetics distribute more slowly?

Answer 26

In less perfused tissues such as muscles and the gastrointestinal (GI) tract.

Question 27

What is sequestration in fat, and why is it important?

Answer 27

It refers to the accumulation of lipid-soluble drugs in fat tissue, which can prolong drug effects and elimination.

Question 28

How are local anesthetics metabolized and excreted?

Answer 28

Amides are metabolized in the liver, while esters are broken down in plasma. Both are converted to water-soluble metabolites and excreted in urine.

Question 29

What are the pharmacokinetic parameters of Bupivacaine?

Answer 29

Half-time distribution: 28 minutes Elimination half-life (T₁/₂): 3.5 hours Volume of distribution at steady state: 72 L Clearance: 0.47 L/min

Question 30

Duration of action of LAs depends on what?

Answer 30

Depends on their affinity for proteins- plasma proteins, sodium channels Depends on the time a local anaesthetics remains in close proximity to neural fibre- sequestration, Constriction of neighbouring vasculature

Question 31

Small nerve fibres are more sensitive than large nerve fibres thus...

Answer 31

Motor axons being large in diameter are relatively resistance to actions of local anaesthestics. Myelinated fibres are blocked before non-myelinatedd fibres of the same diameter Thus the sequence of loss of nerve function proceeds as loss of pain, temperature, touch, proprioception, and then skeletal muscle tone. This is why people may still fell touch but not pain when using LA NOCICEPTIVE AND SYMPATHETIC TRANSMISSION ARE BLOCKED FIRST

Question 32

What is the action of LAs?

Answer 32

Block the initiation and propagation of APs by preventing the voltage-dependent increase in NA+ conductance This is achieved by physically plugging the pore of voltage gated Na+ channels LAs must reach their site of action by penetrating the nerve sheath and axonal membrane as unionised species SO THEY HAVE TO BE WEAK BASES

Question 33

What is the relationship between pH and the activity of local anesthetics (LAs)?

Answer 33

LA activity is strongly pH dependent and increases at alkaline pH while decreasing at acidic pH.

Question 34

Why is LA activity increased at alkaline pH?

Answer 34

Because at alkaline pH, the proportion of ionised molecules is low.

Question 35

In what form must LAs penetrate the nerve sheath and axon membrane?

Answer 35

LAs must penetrate as their non-ionised form.

Question 36

Why is penetration of LAs poor at acidic pH?

Answer 36

Because the ionised form is not membrane permeant.

Question 37

What is the clinical implication of inflamed tissue on LAs?

Answer 37

Inflamed tissue is acidic and resistant to LAs.

Question 38

How is the blocking site of the Na+ channel reached via the hydrophilic pathway?

Answer 38

Through the open channel on the inner surface of the membrane by the ion version of the LA.

Question 39

How is the blocking site of the Na+ channel reached via the hydrophobic pathway?

Answer 39

Through the outer pore of the membrane by the non-ion version of the LA.

Question 40

What are the unwanted side effcets of LAs in ester agents?

Answer 40

They can produce allergic reactions. Due to the sensitivity to theit metabolite produced para-aminobenzoic acid PABA.

Question 41

What are the unwanted side effects of LAs in amides?

Answer 41

They are metabolised in the liver (problem with patients with liver failure), may induce liver injuries