Canonical Question
NeuroPharm – LA
Master answer
Classification of Local Anaesthetics
- Esters: Procaine, Cocaine
- Unstable in solution
- Rapid hydrolysis by plasma cholinesterases
- ↑ freq of hypersensitivity reactions due to PABA byproduct
- Amides: Lignocaine, Prilocaine, Bupivacaine, Ropivacaine
- Stable in solution
- Slower hepatic metabolism
- Low rate of hypersensitivity reactions
Factors
| Factors affecting the… | Patient Factors | Drug Factors |
|---|---|---|
| Onset | 1. Tissue pH · infected (acidic tissue) → ↑ ionised portion → ↓ ΔC → slower onset 2. Nerve diameter · ↑ diameter → ↑ surface area → faster onset 3. Nerve firing rate · ↑ firing rate → faster onset (remember mechanism of reaching internal H-gate) 4. Pregnancy · ↑ Progesterone → ↑’d sensitivity to LA | 1. Ionisation factors · PKa · Weak bases (7.6-8.9) · Only ionised fraction transfers · pH < pKa → ↑ ionisation → ↓lipid solubility → ↓ rate of onset · Higher pKa → more effective once inside axon · Alkalinisation · addition of NaHCO3 → ↑ pH of preparation · ↑ pH → ↑ unionised fraction → ↑ rate of onset 2. Lipid solubility · ↑ lipid sol → ↑ potency → ↓dose → ↓’d Δ C · ↓ rate of onset 3. MW · ↓’d MW → ↑ rate of diffusion = ↑ rate of onset 4. Diffusion distance · ↓T → ↑ rate of onset 5. Area of diffusion · ↑ A (eg large nerve axon) → ↑ rate of onset |
| Duration of Action | 1. Site of administration · ↑’d regional blood flow → ↓’d duration 2. Metabolism · Esters metabolised faster than amides → ↓’d duration | 1. Protein binding · ↑ protein binding → longer duration 2. Intrinsic vasodilator/constrictor activity · Ropivicain has intrinsic vasoconstrictor activity · ↑ vasoconstrictor activity → ↑ duration 3. Lipid Solubility · ↑ lipid solubility → ↑ potency → ↓ dose → ↓ ΔC → ↓’d diffusion rate · This ↑’s sequestration into lipid rich compartments → ↑’d duration 4. Presence of Additives · Adrenalin → vasoconstriction → ↓’d systemic absorption → ↑’d ↑duration 5. Dose · ↑ dose → ↑ duration 6. Clearance · ↓ metabolism → ↑ duration · Amides slower metabolised that esters |
| Toxicity | Site of injection ↑tox with ◦ ↑local perfusion/Cardiac output ◦ low plasma cholinesterase activity (esters) ◦ hepatic or renal failure ◦ pregnancy | CC:CNS rato (higher is safer) – Lignocaine 7, ropivacaine 4, bupivacaine 3 ↑tox with ◦ ↑Dose ◦ Type (Amide>Ester) ◦ ↑Protein binding in tissues decreases systemic absorption, ↑protein binding in CNS = ↑toxicity ◦ ↑Na channel affinity (Bupivocaine slower to dissociate than lignocaine) ◦ ↑Conc – higher conc gradient between tissue and plasma, increasing systemic absorption ◦ ↓vasoconst additives ◦ pKa – LA’s are weak bases with high pKa’s; lower pKa = more unionized = ↑systemic absorption. Lignocaine pKa 7.9 (25% unionized at pH 7.4), bupivacaine pKa 8.4, 11% unionized at 7.4 |
Note: CC/CNS ratio was required (the ratio of plasma levels at which CVS Collapse vs. Convulsions occur).
Gladwin 2016
Exam appearances
| Exam | Exact wording | Relationship | Success |
|---|---|---|---|
| 2009A Q03 | Outline the factors which affect the onset, duration of action and toxicity of local anaesthetic agents. | historical_member | — |