2004B02 Write a brief description of the pharmacology of ropivacaine.

Class

·   Mepivacaine series

Structure

·   Lipid soluble modified benzene ring

·   Intermediate chain with amide bond

·   Terminal amine: piperidine ring with propyl (C₃H₇) addition

·   Exhibits optical stereoisomerism:

o S enantiomer more potent and less toxic

o Hence produced as an enantiopure preparation

Behaviour

·   Lipid solubility very high 300x procaine -> ↑potency, ↑toxicity

·   Weak base. pKa 8.1

·   15% unionized at ECF pH (7.4) (cf. 25% lignocaine) -> slower onset

·   90% ionized at ICF pH (6.8)

Formulation

·   Aqueous solution

·   0.2%, 0.75%, 1%

·   No added adrenaline due to intrinsic vasoconstrictor property

Administration

·   Routes: subcut, around peripheral nerve or plexus, epidural, subarachnoid

Time course

·   Dependent upon location

·   Medium onset ~30 mins for large peripheral nerve block

·   Duration long ~12-24 hours for large peripheral nerve block

Absorption

·   Rate: tracheal > intercostal > caudal > paracervical > epidural > plexus > peripheral nerve

Distribution

·   94% plasma protein bound

·   Highly tissue protein bound -> ↑duration of action

·   V_D 0.5L/kg

Metabolism

·   Hepatic CYP450

·   Metabolites: 3-OH and 4-OH-ropivacaine; both have some LA activity

·   t_1/2β 120mins

Excretion

·   Metabolites -> urine

Comparison with bupivacaine

·   ↓t_1/2β -> ↓duration toxicity

·   Vasoconstriction -> ↓rate of systemic absorption -> ↓peak plasma concentration

Target

·  Voltage-dependent Na⁺ channel (VDNaC)

·  (less active at VDKC, VDCaC)

Entry

·  From ICF: unionised form diffuses into axoplasm, ionised form enters active receptor

·  From ECF: ionised form enters active receptor (less common)

Binding

·  Rate ∝ time spent in active state ∝ rate of cycling ∝ nerve activity

·  Affinity ∝ Inactive > resting > activated

Effect

·  ↓Rate of cycling -> no action potential propagation

·  Initial: incomplete blockade, tonic

·  Repeated stimulation: complete blockade, phasic

·  No change to resting potential

Comparison with bupivacaine

·   Motor block slower onset, ↓ density, faster offset than bupivacaine

o Allows differential blockade (i.e. sensory but not motor)

·   ↓ affinity for cardiac VDNaC -> ↓CC:CNS

LAST

Numbers:

·   Toxic concentration: 4mcg/mL (CVS collapse)

·   Max safe subcut dose 3mg/kg

·   CC:CNS ratio 5:1 (cf. 3:1 bupiv, 7:1 ligno)

CNS effects:

·   Initial excitatory (block inhibitory interneurons): peri-oral tingling, vertigo, tinnitus, inattention, slurred speech, twitching, seizure

·   Then inhibitory (block excitatory interneuron): coma, apneoa

·   Hyperventilation -> ↓PaCO₂ -> cerebral vasoconstriction -> ↓toxicity

CVS effects:

·   First phase: ↑HR, ↑mAP

·   Second phase: myocardial depression, ↓mAP

·   Terminal phase: peripheral vasodilatation, severe ↓mAP, arrythmia, arrest

·   Arrhythmias: sinus bradycardia, AV block, ventricular tachyarrhythmia, asystole