E PIDURAL AND CSF P HARMACOKINETICS OF D RUGS Ioanna Siafaka Dept of Anaesthesiology Pain Therapy and Palliative Care Aretaieion University Hospital Athens – Greece
What is Pharmacokinetics Part of Pharmacology The term pharmacokinetics comes from the Greek words: - pharmakon - drug or medicine - kinitiki / kinisi – procedure of “movement” What the body does to the drug Relationship between drug dose & its concentration of effector sites
Pharmacokinetics Hypothesis Drug Action: requires presence of a certain concentration in the fluid bathing the target tissue. The magnitude of response (good or bad) depends on concentration of the drug at the site of action
HISTORICAL PERSPECTIVE Brill S et al. A history of neuraxial administration of local analgesics and opioids. Eur J Anaesth 2003; 20: 682 – 689
Analgesics – LA 1900 1800 1850 1950 2000 Techniques & Management
Neuraxial Drug Administration Local Anaesthetics Vasoconstrictors Opioids a2 – adrenergic agonists NMDA receptor antagonists (ketamine) Midazolam Calcitonin Baclofen Somatostatin Anticholinesterase drugs, Octreotide cholinergic agonists Antioxidants Adenosine Steroids Ziconotide
Epidural & CSF Pharmacokinetics Pharmacology of spinal drug delivery: subject of innumerable clinical and animal studies Pharmacokinetics of spinal drugs: - many studies in literature - animal models - very few data for humans Up to now: Indirect Study Approach - inability to sample epidural space - Measurement of drug C: plasma & CSF (occasionally) - not direct experimental evidence - questionable validity of knowledge Bernards CM et al. Anesthesiology 2003; 99: 455 – 465
Spinal Drugs Administration SPINAL DRUGS Epidurally Intrathecally • Single – Shot / Bolus • Single – Shot / Bolus • Continuous Infusion • Continuous Infusion
INJECTION - INFUSION Epidural Epidural Spinal Cerebral Meninges Fat Space CSF CSF Epidural Venous Spinal Brain Drainage Cord Systemic Systemic Central Distribution Distribution Compartment Compartment Compartment ELIMINATION Chrubasik J et al. Eur J Anaesth 1993; 10: 79 – 100
Spinal Drugs Pharmacokinetics Changes in drug concentration over time in various compartments - Blood - Epidural Space - CSF - Effector Site: Spinal Cord DETERMINED physicochemical properties of drug multitude of biologic functions
SPINAL OPIOIDS Pharmacokinetics ?
Spinal Drugs Administration Aim: Intense Spinal Analgesia Spinally Mediated Analgesia without dose limiting side – effects associated with systemic administration Misconception: any drug - epidurally - intrathecally Resultant analgesia not always mediated by a spinally selective mechanism Bernards CM et al. Anesthesiology 2003; 99: 455 – 465
Spinal Opioids Commonality of mechanism of action Differences in pharmacokinetics & pharmacodynamics Opioids differ in their ability to reach opioid receptors Net Analgesic Effect: The result of numerous processes prior to G – protein activation Bernards CM, ASA Refresh Course Lectures, Seattle, 2002
Epidural - Intrathecal Drugs
Mechanism of Action - Bioavailability Effect depends on: affinity ability to reach receptors Penetration of neural tissue: The rate limiting step Factors affecting transmembrane movements pKa (the lower pK, the greater fraction of uncharged form at pH of 7.4) Molecular Weight Protein Binding Lipid Solubility
Bioavailability of spinally administered drug The fraction of the dose of a drug (F) given spinally (epidural / intrathecal space) that reaches the intended site of action F= amt. of drug that reaches site of action Dose administered F = AUC/Dose
Pharmacokinetics - A dministration - A bsorption - D istribution - B inding - B ioavailability - I nactivation - M etabolism (Biotransformation) - E limination - E xcretion
Pharmacokinetics Key Terms -Onset of Action -Peak Effect -Duration of Action
EPIDURAL DRUGS – ROUTES OF UPTAKE POTENTIAL FATES EPIDURAL ADMINISTRATION Vascular Uptake by Paraspinous Epidural Vessels Muscle Space through intervertabral Diffusion into foramina Diffusion to Diffusion ligaments that lipophilic tissues in across border epidural epidural space meninges space (epidural fat) (CSF mixture)
Target of Action: Reaching Receptors Epidurally administered drugs must travel through: dura matter arachnoid matter CSF pia matter white matter gray matter dorsal horn Competing pathways Uptake into epidural fat Uptake into systemic circulation
Target of Action: Reaching Receptors Intrathecally administered drugs must travel through: CSF pia matter white matter gray matter dorsal horn Competing pathways Diffusion into epidural space Uptake into systemic circulation
Absorption Absorption Mechanics Absorption Principles Absorption Barriers
Distribution Generalized distribution of a drug controls the movement of a drug by its effect on ionization ratios how long a drug acts how intense are its effects side effects produced Is there a magic bullet?
Absorption – Distribution Rate & Extent depend upon Chemical structure of drug Rate of blood flow Ease of transport through membrane Binding of drug to proteins in blood Elimination processes THE ONLY MECHANISM BY WHICH DRUGS REDISTRIBUTE FROM ES TO SC: Bernards CM et al. Diffusion through spinal meninges Anesthesiology 1994; 80: 872 – 878 Curr Opin Anesthesiol 2003; 17: 441 - 447
Drug Physicochemical properties Pk a Partition coefficient - Lipid Solubility - Octanol:Buffer distribution coefficient Permeability coefficient
Relative Solubilities Solution pH: < 7 (Acid) > 7 (Base) Drug pH : < 7 (Acid) Un-ionized, Ionized, Fat soluble Water soluble > 7 (Base) Ionized, Un-ionized, Water soluble Fat soluble
OPIOID Partition Coefficient Octanol:Buffer Coefficient Lipid Solubility Morphine 1.0 Hydrophilic Drugs Meperidine 38.8 Lidocaine 110 Alfentanyl 129 Butorphanol 180 Lipophilic Drugs Bupivacaine 560 Fentanyl 813
• Quantification of Redistribution • Well characterized in vivo pig model • Concentrations measured • Microdialysis Technique - Epidural Space • Continuous Samples - Intrathecal Space • Bolus Epidural: - Systemic Venous Plasma morphine, alfentanyl, fentanyl, sufentanil - Epidural Venous Plasma
Lipid Solubility & Mean Residence Time (MRT) in epidural space LINEAR RELATIONSHIP Bernards CM et al. Anesthesiology 2003; 99: 455 – 465 Curr Opin Anesthesiol 2003; 17: 441 - 447
Lipid Solubility & Terminal Elimination Half – Life in epidural space LINEAR RELATIONSHIP Bernards CM et al. Anesthesiology 2003; 99: 455 – 465 Curr Opin Anesthesiol 2003; 17: 441 - 447
Lipid Solubility & Dose – Normalized C in epidural fat (lumbar ES) LINEAR RELATIONSHIP Bernards CM et al. Anesthesiology 2003; 99: 455 – 465 Curr Opin Anesthesiol 2003; 17: 441 - 447
Epidural Administration of Drugs Lipid Solubility Lipid Soluble Drugs Spend a significantly longer time in epidural space Require a significantly longer time to be eliminated from epidural space Greater Partitioning in epidural fat Ongoing Slow Release back into the epidural space Bernards CM et al. Anesthesiology 2003; 99: 455 – 465
Lipid Soluble Opioids Lower C in CSF Low CSF Bioavailability A larger proportion of morphine reaches CSF in comparison with other more lipid soluble opioids Rapid clearance from Epidural Space to circulation - Decreased amount of drug available at the spinal level - Systemic effects Bernards CM et al. Anesthesiology 2003; 99: 455 – 465 Curr Opin Anesthesiol 2003; 17: 441 - 447
Epinephrine Action In Lumbar ES Increased MRT morphine Decreased MRT fentanyl sufentanil No effect on elimination of morphine in ES Decreased terminal elimination half life of fentanyl sufentanil
Increased AUC concentration time in the intrathecal space of morphine No effects in pharmacokinetics of other opioids in lumbar intrathecal space
Absorption & Distribution Principles Opioids from Epidural Space to CSF & SC General principle: Simple Diffusion Concentration Gradient But in Epidural Space Additionally Pulsation with systole Kinetic Energy to opioids molecules Motion production Bernards CM et al. Curr Opin Anesthesiol 2003; 17: 441 - 447
Absorption Principles Opioids from Epidural Space to CSF & SC Preferential Diffusion - arachnoid granulations of spinal nerve root cuff Uptake - radicular arteries traversing epidural space - vascular distribution to SC Absorption influenced amount of blood flow at the site of administration Diffusion through spinal meninges Bernards CM et al. Curr Opin Anesthesiol 2003; 17: 441 - 447
Absorption Principles Opioids from Epidural Space to CSF & SC Differential Permeability through Meninges Meningeal Permeability Significant Differences of clinically available opioids Not important role in absorption Bernards CM et al. Anesthesiology 1994; 80: 872 – 878
Meninges INFLECTION POINT = 129
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