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

 

List:

·     PC

·     PK

·     PD

 

Physicochemical:

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

 

Pharmacokinetics:

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

·  VD 0.5L/kg

Metabolism

·  Hepatic CYP450

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

·  t1/2β 120mins

Excretion

·  Metabolites -> urine

Comparison with bupivacaine

·  ↓t1/2β -> ↓duration toxicity

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

 

Pharmacodynamics:

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