Opioids - Anaesthetics

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CME - May 2012

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Presentation Transcript

Opioids:

Opioids Continuing Medical Education Modbury Hospital Dr Ravi Sandhu 3 rd May 2012

Outline:

Outline Pain Analgesia Opioids - Pharmacology Morphine Fentanyl Alfentanil Remifentanil

Terminology:

Terminology Opiate All naturally occurring substances with morphine like properties Opioid General term including natural and synthetic compounds with an affinity for opioid receptors

Pain:

Pain An unpleasant sensory and emotional experience associated with actual of potential tissue damage

Pain - Transmission:

Pain - Transmission Stimulus Nociceptors Ascending afferent pathways Fast A delta fibres Sharp, well-localised pain Slow C fibres Dull, poorly localised pain Spinothalamic and spinoreticular tracts ascend to brain

Pain - Inhibition:

Pain - Inhibition Inhibitory interneurons are present in the dorsal horn of the spinal cord Activation by descending pathways can prevent transmission of pain Gate theory of pain

Analgesia:

Analgesia Pain can be modified by altering the neural pathway From its origin at the nociceptor to the interpretation within the CNS Consider the WHO Analgesic Ladder for every patient Multimodal analgesia

Opioid Receptors:

Opioid Receptors Serpentine, linked to inhibitory G-proteins Stimulation by an opioid agonist Closure of voltage sensitive Ca 2+ channels Efflux of K + Hyperpolarisation Inhibition of adenylase cyclase Decreased cAMP Results in inhibition of transmitter release between nerve cells μ , κ , δ and NOP subtypes

µ Opioid Receptor:

µ Opioid Receptor Sites Cerebral cortex Basal ganglia Spinal cord Pre- synaptically on primary afferent neurons in the dorsal horn Effects Analgesia Respiratory depression Constipation Cardiovascular depression Meiosis Euphoria

Morphine:

Morphine Naturally occurring phenanthrene derivative µ- and κ -receptor agonist Papaver somniferum

Morphine - Pharmacokinetics:

Morphine - Pharmacokinetics Weak base, pKa 8.0 23% un-ionised at pH 7.4 Protein binding 35% Plasma levels do not correlate with clinical effect Low lipid solubility – slow equilibration across BBB

Morphine – Pharmacokinetics (cont.):

Morphine – Pharmacokinetics (cont.) Oral 5-20 mg q4hr Acidic gastric environment Mostly ionised Poor absorption until it reaches relatively alkaline small bowel environment Un-ionised Bioavailability 30% Hepatic first pass metabolism Intramuscular 0.1-0.2 mg.kg -1 q4hr

Morphine – Pharmacokinetics (cont.):

Morphine – Pharmacokinetics (cont.) Intravenous 0.05-0.1 mg.kg -1 q4hr, titrated to effect Peak effect 10-30 mins Duration 3-4 hrs Subcutaneous Slow absorption Relative low lipid solubility Intrathecal, epidural Slow absorption Can get delayed respiratory depression

Morphine - Metabolism:

Morphine - Metabolism Liver - Conjugation Morphine-3-glucuronide – 80% Morphine-6-glucuronide – 10% Active - 13x potency of morphine Metabolites are renally excreted Chronic Kidney Disease is a relative contraindication to use

Morphine - Effects:

Morphine - Effects Analgesia Respiratory depression Reduced chemoreceptor sensitivity to CO2 Nausea and vomiting Stimulates chemoreceptor trigger zone via 5-HT3 and dopamine receptors CNS Sedation, euphoria and dysphoria CVS Mild bradycardia and hypotension due to histamine release and decreased sympathetic tone GIT Constricts sphincters Constipation due to spastic immobility of the bowel

Morphine – Effects (cont.):

Morphine – Effects (cont.) Histamine release Can cause bronchospasm and hypotension Rash, pruritus Muscle rigidity Chest wall rigidity ? Due to interaction with dopaminergic and GABA pathways in substantia nigra and striatum Meiosis Stimulation of Edinger-Westphal nucleus Endocrine Inhibits release of ACTH, prolactin and gonadotrophic hormones Increased ADH – impaired water excretion and hyponatremia Urinary Increased tone of bladder detrusor and vesical sphincter – urinary retention

Fentanyl:

Fentanyl Synthetic phenylpiperidine derivative µ- and κ -receptor agonist

Fentanyl - Pharmacokinetics:

Fentanyl - Pharmacokinetics pKa 8.4 9% un-ionised at pH 7.4 High lipid solubility, ~600x morphine In small doses Short duration of action, determined by redistribution rather than elimination Plasma levels correlate well with effect Crosses BBB easily

Fentanyl – Pharmacokinetics (cont.):

Fentanyl – Pharmacokinetics (cont.) Intravenous 1-2 mcg.kg -1 for co-induction/sedation 50-100 mcg.kg -1 for opioid-based anaesthetic Onset of action 2-5 minutes High lipid solubility Duration 30-60 minutes Short due to redistribution not elimination Lungs act as a large inactive storage site, up to 75% of initial dose undergoes first-pass pulmonary uptake High/repeated doses may be effective for 4-6 hrs Dependent on elimination half life

Fentanyl – Pharmacokinetics (cont.):

Fentanyl – Pharmacokinetics (cont.) Epidural 10-60 mcg.hr -1 in adults Readily diffuses across dura and also into blood Transdermal High lipid solubility allows for transdermal use 50-100 mcg.hr -1 patches Delay (5-6 hrs) in reaching therapeutic levels

Fentanyl - Metabolism:

Fentanyl - Metabolism Liver Demethylation to norfentanyl and then hydroxylated Inactive metabolites are renally cleared

Context Sensitive Half Time:

Context Sensitive Half Time The time for the plasma concentration to fall to 50% of its value at the cessation of an infusion Time taken for reduction in plasma concentration is dependent on the duration of the infusion

Alfentanil:

Alfentanil Synthetic phenylpiperidine derivative µ-receptor agonist

Alfentanil - Pharmacokinetics:

Alfentanil - Pharmacokinetics pKa 6.5 89% un-ionised at pH 7.4 Lipid solubility ~90x morphine Comparison with fentanyl Less lipid soluble Lower pKa, greater percentage is un-ionised at physiologic pH Faster onset of action

Alfentanil – Pharmacokinetics (cont.):

Alfentanil – Pharmacokinetics (cont.) Intravenous 5-25 mcg.kg -1 boluses for short term analgesia Onset of action 60-90 sec Duration of action 5-10 min

Alfentanil - Metabolism:

Alfentanil - Metabolism Liver Dealkylation to noralfentanil Conjugation to glucuronide (CYP 3A3 & 3A4) Cirrhotic patients can have prolonged effects Decreased clearance Decreased protein binding Higher free fraction of drug available Metabolites excreted in urine Midazolam also metabolised by CYP 3A4 Concurrent administration increases elimination half-lives

Remifentanil:

Remifentanil Synthetic phenylpiperidine derivative Pure µ-receptor agonist

Remifentanil - Pharmacokinetics:

Remifentanil - Pharmacokinetics pKa 7.3 68% un-ionised at pH 7.4 Unique metabolism results in favourable properties for anaesthesia

Remifentanil – Pharmacokinetics (cont.):

Remifentanil – Pharmacokinetics (cont.) Intravenous Bolus 1 mcg.kg -1 Infusion 0.1-2.0 mcg.kg -1 .min -1 Onset of action 1-3 mins Duration of action 5-10 mins Very short due to metabolism

Remifentanil - Metabolism:

Remifentanil - Metabolism Rapidly broken down by non-specific plasma and tissue esterases Inactive carboxylic acid metabolite excreted in urine Elimination half life 3-10 mins Duration of action is determined by metabolism not distribution (c.f. alfentanil and fentanyl)

Remifentanil – Metabolism (cont.):

Remifentanil – Metabolism (cont.) Unique metabolism results in favourable properties Short duration of action Precise and rapidly titratable effect due to rapid onset and offset Noncumulative effects Rapid recovery after discontinuation of its administration Additional analgesia is required once the infusion is ceased

Pharmacokinetics - Comparison:

Pharmacokinetics - Comparison

Thank you.:

Thank you.

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