NEUROMUSCULAR BLOCKING AGENTS & NARCOTICS

Steven SmithDomini CrandonDuncan Jackson

SEPTEMBER 3, 2015

WHAT ARE NEUROMUSCULAR BLOCKING AGENTS?

NEUROMUSCULAR BLOCKING AGENTSNeuromuscular blocking agents (NMBAs) interrupt transmission of nerve impulses at the neuromuscular junction (NMJ) and thereby produce paresis or paralysis of skeletal muscles.

IF THE PATIENT IS ANAESTHETIZED, WHY PROVIDE AGENTS TO PREVENT MOVEMENT?

BRIEF HISTORY OF NEUROMUSCULAR BLOCKING AGENTS IN ANAESTHESIAThey were first administered in 1942, when Griffith and Johnson used Intocostrin to a patient undergoing an appendectomy.

By 1946, it was appreciated that using drugs such as curare in larger doses allowed the depth of the anaesthesia to be lightened.

The use of NMBAs to improve conditions of tracheal intubation, to provide immobility during surgery and to facilitate mechanical ventilation evolved over time.

HOW DO NMBAs WORK?

THE NEUROMUSCULAR JUNCTION1. An Action Potential (AP) is conducted down the somatic motorneuron down to the synaptic knob.

2. The reversal in electrical polarity at the synaptic knob causes an opening of voltage-gated Ca2+ channels (Voltage gated calcium ion channels open and allow calcium ions to flow inside due to the voltage change). Calcium ions are very important for the release of neurotransmitters and secretion of hormones by endocrine cells.

3. Calcium flows into the synaptic knob and its this influx that causes these vesicles to form and release/secrete neurotransmitters. In other words, the entry of Ca2+ into the synaptic knob causes the exocytosis (secretion) of the nerotransmitter Acetylcholine (ACh).

4. The ACh diffuses across the synaptic cleft and binds to nicotinic ACh Receptor Site Proteins on the membrane of the Skeletal Muscle Cell (Fiber). The first chemical they discovered that affects this receptor site, happened to be nicotine so thats why it got the name, nicotinic cholinergic receptor.

THE NEUROMUSCULAR JUNCTION5. Activation of the ACh Receptor Sites causes an opening of ligand-gated Sodium Ion Channels.

6. Influx of sodium ions through channels result in end-plate potential (EPP), and if this is large enough then the AP is developed in the membrane, stimulating voltage sensitive sodium channels

7. As the action potential spreads along the cell, it causes the muscle cell to contract.

8. The ACh which is attached to the receptor site, is split into acetate and choline by acetylcholinesterase (ACHase), an enzyme of the skeletal muscle cell membrane.

9. The ligand-gated sodium ion channels close, permitting the skeletal muscle cell to relax.

ACTION POTENTIAL PROPAGATION

WHAT ARE FEATURES OF THE IDEAL NMBA?

THE IDEAL NMBANon-depolarizing actionRapid onset (within one circulation time)Short duration, suitable for infusionRapid metabolism to inactive productsAntagonized by cholinesterase inhibitorsActions confined to the NMJNot transferred across the placenta or blood-brain barrierNo local or systemic side effectsCompatibility with other drugs and solutionsLong shelf life without refrigerationCheapMade by chemical synthesisSterilizable

WHAT ARE THE TYPES OF NMBAs?

TYPES OF NMBAsNON-DEPOLARIZING AGENTSDEPOLARIZING AGENTSSUCCINYLCHOLINE/SUXAMETHONIUM CHLORIDEd-TUBOCURARINE, PANCURONIUM, ATRACURIUM, ROCURONIUM, VECURONIUM, MIVACURIUM

DEPOLARIZING AGENTS Depolarizing NMBAs work by depolarizing the plasma membrane of the muscle fiber, similar to acetylcholine. However, these agents are more resistant to degradation by acetylcholinesterase, the enzyme responsible for degrading acetylcholine, and can thus more persistently depolarize the muscle fibers.

There are two phases to the depolarizing block. During phase I (depolarizing phase), they cause muscular fasciculations (muscle twitches) while they are depolarizing the muscle fibers. Eventually, after sufficient depolarization has occurred, phase II (desensitizing phase) sets in and the muscle is no longer responsive to acetylcholine released by the motoneurons. At this point, full neuromuscular block has been achieved.

SUCCINYLCHOLINE/SUXAMETHONIUM CHLORIDE

StructurePreparation2 acetylcholine molecules joined by a methyl group (diacetylcholine)Clear solution containing 50 mg/ml. Should be stored at 4 degrees C AdministrationMetabolismIV= 1-2mg/kg (1.5 if precruarized)IM=3mg/kg (emergency) Plasma cholinesterasesContraindications Recent burn (OK within 24 hours) 10-100 days after Spinal cord trauma causing paraplegia Severe muscle trauma h/o malignant hyperthermia Hyperkalemia Atypical cholinesterase activity/muscle diseaseOnset30-60sDuration5-10minIndications Rapid intubation of trachea Modification of fits after electroconvulsive therapy

SUCCINYLCHOLINE/SUXAMETHONIUM CHLORIDE

FasciculationMuscarinic action Myalgia Masseter spasm (esp children 8-12) Intragastric pressure ICP IOP serum potassiumN.B. Precurarization can help (not so much with K) Bradycardia (only in children) SalivationN.B. Pre-treat with atropine to avoid Others Allergic reaction Phase II block Prolonged paralysis (atypical cholinesterase activity) Malignant hyperthermia

NON-DEPOLARIZING AGENTS MOA:Competitive antagonists at nicotinic ACh receptors on the motor endplateDo not produce initial fasciculationBlock pre-synaptic autoreceptorsInhibits further ACh release during repetitive stimulationCauses tetanic fade>75% blockade for failure of muscle contraction

NON-DEPOLARIZING AGENTS Indications:Optimize intubating conditions (midline vocal cords and facilitate mouth opening; reduce coughing, gagging) Prevent fasciculations and other complications from succinylcholine when a small amount is administered prior (precurarization) Optimize surgical conditions Optimize conditions for mechanical ventilation (reduce bucking, coughing, breath stacking) Types of adverse effects:Histamine releaseCardiovascular effects (muscarinic blockade)Autonomic ganglion blockadeAnaphylaxis

Classification of Non-Depolarizing AgentsBy structure:Isoquinoline derivatives:d-TubocurarineAtracuriumCisatracuriumMivacuriumSteroid derivatives:PancuroniumVecuroniumRocuronium

By duration of action:Short-acting:MivacuriumIntermediate-acting:AtracuriumCisatracuriumRocuroniumVecuroniumLong-acting:d-TubocurarinePancuronium

Long-Acting Non-Depolarizing Agentsd-Tubocurarine:

StructureEliminationNaturally occuring monoquaternary alkaloidDerived from Chondrodendron tomentosum bark Kidneys (80%) Bile (20%)AdministrationSide EffectsIntubating dose = 0.50.6 mg/kg Hypotension +/- compensatory tachycardia Bronchoconstriction Increased salivary secretionsOnset23 min Duration12 hrs Notes Prototype No longer used (histamine release and ganglion blockade)

Long-Acting Non-Depolarizing AgentsPancuronium:

StructureEliminationBisquaternary steroid derivative Kidneys (85%) Hepatic deacetylation (15%)AdministrationSide Effects and InteractionsIntubating dose = 0.1 mg/kg Moderate tachycardia Slightly inhibits plasma cholinesterases (potentiates succinylcholine and mivacurium)Onset35 min Duration1.52 hrs Notes Longest duration of action Does not stimulate histamine release Suitable for asthmatics

Intermediate-Acting Non-Depolarizing AgentsAtracurium:

StructureEliminationBisquaternary isoquinoline derivative Hoffman elimination Ester hydrolysis in plasmaAdministrationSide EffectsIntubating dose = 0.5 mg/kg Transient hypotension (histamine release) Bronchospasm Cutaneous flushing AnaphylaxisOnset23 min Duration2035 min Notes Not metabolized by liver or kidneys Suitable for hepatic and renal disease

Intermediate-Acting Non-Depolarizing AgentsRocuronium:

StructureEliminationMonoquaternary steroid derivative Bile (>70%) Kidneys (

Intermediate-Acting Non-Depolarizing AgentsVecuronium:

StructureEliminationMonoquaternary steroid derivative Hepatic deacetylation (75%) Kidneys (25%)AdministrationSide EffectsIntubating dose = 0.1 mg/kg Prolonged paralysis (active metabolites)Onset23 min Duration4560 min Notes No significant histamine release or CV effects Metabolism in liver produces active metabolites Accumulates after repeat doses in renal disease

Short-Acting Non-Depolarizing AgentsMivacurium:

StructureEliminationBisquaternary isoquinoline derivative Plasma cholinesterasesAdministrationSide EffectsIntubating dose = 0.2 mg/kg Transient hypotension (histamine release) Bronchospasm Cutaneous flushing Prolonged paralysis (plasma cholinesterase deficiency)

Onset23 minDuration1025 min Notes Potentiated by atypical cholinesterase gene and hepatic and renal disease

Factors Increasing Duration of ActionDrug interactions: Prior administration of succinylcholine Co-administration of inhalational agents (desflurane > sevoflurane > isoflurane > halothane)pH: Metabolic and respiratory acidosis Body temperature: HypothermiaAge: Immature neonates and elderlyElectrolyte disturbance: Hypokalemia and decreased ionized Ca2+Myasthenia gravisHepatic and renal disease

Reversal Agents Given post-op to recover muscle contraction Types: Anticholinesterases (e.g. neostigmine, edrophonium) Increase ACh by inhibiting acetylcholinesterase at the NMJ Cyclodextrins (e.g. sugammadex) Binds steroidal drug to form an inactive complex in plasma Atropine may be co-administered to prevent muscarinic side effects

NARCOTIC ANALGESICS

NARCOTIC ANALGESICSOpiatesNatural alkaloid (&/or semi-synthetic derivative) Obtained from opium poppy (Papaver somniferum)Bind to opioid receptors & produce psychoactive effects

OpioidsNatural or syntheticExogenous (and/or Endogenous)

NARCOTIC ANALGESICS

NARCOTIC / OPIOID ANALGESICS1 - Receptors are not true opioid receptors but are the site of action of certain psychotomimetic drugs, with which some opioids also interact.Treatment of moderate to severe pain

Mimic the actions of endogenous ligands resulting in the activation of pain-modulating (anti-nociceptive) systems

Analgesic effect mediated via opioid receptors located throughout CNS (esp. substantia gelatinosa and peri-aqueductal grey) (mu) (kappa) (delta)ORL1(, sigma)1

Evidence suggests that PCA may be superior to conventional methods (analgesic need determined by clinicians) of treating pain in acute care setting

Classification of Opioid Receptors AnalgesiaSupraspinal / spinal (1)Spinal only (2)Respiratory depression (2)EuphoriaMiosis, constipation (marked)Physical dependence (2)Spinal analgesiaMiosis Sedation Dysphoria & hallucinationsspinal / supraspinal analgesiaConstipation (minimal)Can also be proconvulsant

ORL1Unlike other receptors naloxone is not an antagonistDysphoriaHallucinationsCardiac stimulation

Classification of Opioid Receptors (International Union of Pharmacology, IUPHAR)

Receptor (new terminology)Classical terminologyEndogenous LigandSiteMOPMu; OP3Endomorphin 1 and 2; met-enkephalin; dynorphin A & BPeripheral inflammation, pre- and post-synaptic neurons in spinal cord, periaqueductal grey matter, limbic system, caudate putamen, thalamus, cerebral cortexKOPKappa; OP1Dynorphin A & B;-endorphinNucleus raphe magnus (midbrain), hypothalamus, spinal cordDOPDelta; OP2Leu- and met-enkephalins; -endorphin Olf centres, cerebral cortex, nucleus accumbens, caudate putamen, spinal cordNOPOrphan; ORL-1Nucleus raphe magnus, spinal cord, afferent neurones

MOA OpioidsAnalgesia is achieved predominantly by receptor:

K+ conductance (hyperpolarization of post-synaptic neurones) Presynaptic inhibition of neurotransmitter release (substance P, dopamine, NE, & ACh)Ca2+ channel inactivation ( presynaptic neurotransmitter release)Inhibition of adenylate cyclase

Pain impulse transmission is interrupted at the level of dorsal horn

Descending inhibitory impulses are accentuated

Pharmacodynamic Effects of OpioidsCNSSedation & SleepMood (Euphoria, Dysphoria)MiosisToleranceAddiction

RespiratoryVentilatory depression (esp. elderly, neonates)May cause increase in Cerebral blood flow (if hypercapnic)

GITNausea, vomitingBiliary Colic

CVSNo significant effect if normotensiveHistamine-releasing opioids HR, SVR, Partery central sympathetic outflow

Other effectsDependence & toleranceMyoclonic jerks sedation & hallucinationsUrinary retention & urgencyPruritus (esp. around nose)Muscle rigidityThermoregulation impairmentDepression of immune system (long-term use)Endocrine problemsOpioid-induced hyperalgesia*

Classification of Opioid AnalgesicsChemical StructurePhenanthrenes, Phenylpiperidine, Diphenylpropylamines, Benzomorphans

AGONISTSmorphine , meperidine (pethidine), methadone, fentanyl, heroin, hydromorphone, oxymorphone, pethidine, levorphanol,

MODERATE / WEAK AGONISTScodeine, propoxyphene, oxycodone, hydrocodone, buprenorphine

MIXED AGONIST-ANTAGONISTSpentazocine , nalbuphine , butorphanol

Strong Opioid Agonists: Prototype - Morphine

StructureEliminationPhenanthrene derivativeExcretion; urine (90% in 24h), CAUTON in renal failureAdministrationClinical UsesMultiple routes of administrationAdjunct to induction = 0.1 0.25 mg/kg IVAnalgesia for severe visceral painAdjunct to GAHigh dose as primary agent (cardiac pt)Should not be used as total anesthetics due to ceiling effectPost surgical painAcute pulmonary oedemaVenodilation preload; perception of SOBDiarrhoea Relief of coughOnset5 minDuration1-4 hrs Notes Administer IV in perioperative period, thus eliminating the unpredictable influence of drug absorption Crosses BBB slowly 5 min onset, but peak in 10-40 min Metabolized in the liver by CYP3A4 glucoronidation to M-6-G (inactive, 75-85%) and M-3-G (active, 5-10%) Can decrease MAC to ~65% Drug InteractionsPhenothiazines, TCAs & MAOIs potentiate CNS effects of morphineResp. depression, sedation & hyperpyrexic comaContraindications / Cautions of Strong Opioid AgonistHead injuryCNS depressionHepatic diseaseRenal diseasePregnancyHypersensitivity (asthma)COPD

Strong Opioid Agonists: Prototype - MorphineOpioid tolerance and dependenceAcquired tolerance develops after 2-3 weeksTolerance to analgesia, euphoria, sedation, ventilatory depression, but often NOT constipationAddiction (physical and psychological dependence): usually takes ~ 25 days to developSome degree occurs within 48 hours

Withdrawal symptoms:Occurs 8-12 hours after last dosePeaks at 36-72 hours, lasts up to 7-10 days

Symptoms (Severe Flu-like illness; Super flu) include:Loss of sedation:insomnia, yawning, hyperactivity, tremorsLoss of stimulation: diarrhea, abdominal crampsOthers:Vomiting, chills, fever, lacrimation, sweating, rhinorrhea, sneezing

Opioid Agonists Used in AnaesthesiaAdapted from Gwinnutt, C. L., & Gwinnutt, M. (2012). Lecture notes: Clinical Anaesthesia. Chichester, West Sussex, UK: Wiley-Blackwell.

Opioid Agonists Used in AnaesthesiaAdapted from Vacanti, C. A. (2011). Essential Clinical Anesthesia. Cambridge: Cambridge University Press.

Opioid Agonists Used in AnaesthesiaAdapted from Stoelting, R. K., & Hillier, S. C. (2015). Handbook of Pharmacology and Physiology in Anesthetic Practice. 3rd Edition. Philadelphia: Wolters Kluwer Health.

Moderate / Weak Agonists Prototype: Codeine

StructureEliminationPhenathrene derivativeRenal excretion, fecesAdministrationClinical Uses15-60 mg PO/SC/IM q4-6hr PRNOften combined with non-opioid analgesic (e.g. acetaminophen, paracetamol) to reduce dose of opioid required to achieve adequate pain reliefGood antitussive & anti-diarrhoeal properties Onset30-60 min PO; 10 30 min IMDuration4 6 hrsNotesSide EffectsOral analgesic that is less potent than morphine (mild-moderate pain)Up to 10% of a codeine dose is metabolized by the hepatic CYP2D6 to morphine, which contributes significantly to its analgesic effectAround 8% western Europeans are CYP2D6 deficient10% of Caucasians and 30% of Asian & Blacks are super metabolizers opioid toxicityHas little S/E on mental state, pupil size and respirationConstipationDrowsiness

MIXED AGONIST-ANTAGONISTS Prototype - Pentazocine

StructureEliminationBenzomorphan derivativeUrine (mainly), fecesAdministrationClinical Uses30mg IV/IM/SC moderate-severe pain relief30 mg IV/IM/SC q3-4hr supplement to preoperative surgical anaesthesiaUsed for post-operative pain and chronic pain, esp. when there is a risk of physical dependenceOften combined with non-opioid analgesic (e.g. acetaminophen) to reduce dose of opioid required to achieve adequate pain reliefGood antitussive & anti-diarrhoeal properties OnsetIM 15-20 min; IV 2-3 min DurationIM 2 hr; IV 1 hrNotesSide EffectsAgonist at receptors, and weak antagonist at & receptorsLow potential for dependence40mg pentazocine has analgesic potency of 10mg morphineSedationN/V less common than morphineDysphoria (high doses)Ceiling effect of respiratory depression (30-70mg IM, 30mg IV)

Atypical Analgesic Prototype: Tramadol

StructureEliminationNon-opioid-derived synthetic opioidUrine (90%)AdministrationClinical UsesOral: 50 mg tablets; 100, 200, 300 mg extended-release tabletsEffective analgesic (moderate pain; adjunct to opioids in chronic pain syndromes)Onset~1 hrDuration9 hrsNotesSide EffectsAgonism mediated by metabolites stimulatory activity at & receptorsO-desmethyltramadol, has 200-fold higher affinity for over Enhances descending inhibitory system by inhibiting 5-HT & NE reuptakeLess likely than pure opioids analgesics to depress respiration and cause dependenceEffects not completely reversed by opioid antagonistsNo histamine release (cf. morphine)Constipation, nausea, vomitingSedation, headache, dizziness, tirednessSweating, rash

Contraindications risk of seizures with MAOIs, SSRIs, TCAsUse with caution in pts with hepatic impairment

Naloxone (Narcan )

Opioid Antagonists:Naloxone & Naltrexone

NaltrexoneIn contrast to naloxone, is highly effective orallySustained antagonism of opioid agonist effects for up to 24 hrs

StructureEliminationPhenanthrene derivativeHepatic metabolism to naloxone-3-glucuronide; renal excretionAdministrationClinical Uses1 4 g/kg IV. Repeat q2-3 min PRNNot to exceed 10 mg (0.01 mg/kg)Mx of acute opioid overdose reverses opioid-induced resp. depression

Onset1 2 minsDuration30 45 minsNotesSide EffectsNon-selective antagonist affecting all 3 opioid receptor types (, , )Continuous infusion of naloxone, 5 g/kg/hr, prevents recurrence of respiratory depression (renarcotization) without altering analgesia produced by neuraxial opioidsTachycardia & ArrhythmiasPrecipitate full blown withdrawal in dependent patientsN.B. titration of dose may acceptably antagonize while maintaining partial analgesia (i.e. titrate to achieve desired effect)

REFERENCESSmith, G., Aitkenhead, A. R., Moppett, I. K., & Thompson, J. P. (2013). Smith and Aitkenhead's textbook of anaesthesia. New York: Churchill Livingstone/Elsevier.

Butterworth, J. F., Mackey, D. C., Wasnick, J. D., Morgan, G. E., Mikhail, M. S., & Morgan, G. E. (2013). Morgan & Mikhail's clinical anesthesiology. 5th Edition. New York: McGraw-Hill.

Rang, H. P., Dale, M. M., Flower, R. J., & Henderson, G. (2016). Rang and Dale's pharmacology. 8th Edition. 6th Edition. United Kingdom: Churchill Livingstone/Elsevier.

Katzung, B. G., Masters, S. B., & Trevor, A. J. (2012). Basic & clinical pharmacology. 12th Edition. New York: McGraw-Hill Medical

Campbell, J. (2014, February). Analgesics 1 & 2. Neuroscience 2. University of the West Indies (Mona), Kingston, Jamaica.

Stoelting, R. K., & Hillier, S. C. (2015). Handbook of Pharmacology and Physiology in Anesthetic Practice. 3rd Edition. Philadelphia: Wolters Kluwer Health.

Vacanti, C. A. (2011). Essential clinical anesthesia. Cambridge: Cambridge University Press.

Gwinnutt, C. L., & Gwinnutt, M. (2012). Lecture notes: Clinical Anaesthesia. Chichester, West Sussex, UK: Wiley-Blackwell.

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********Benzylisoquinoliniums tend to be more potent, slower in onset, are eliminated by the kidneys or Hofmann elimination, and can promote histamine releaseSteroidal compounds are less potent with faster onset, are eliminated by the liver, and are less associated with histamine releaseDivided into short-acting (1520 min), intermediate acting (2050 min), and long-acting (>50 min) Recovery from blockade occurs initially through redistribution, but later via metabolism and elimination of the drug (may be prolonged in renal failure)

*blocked autonomic ganglia, reducing the ability of the sympathetic nervous system to increase heart contractility and rate in response to hypotension and other intraoperative stresses.

It has a marked propensity to produce histamine release via a direct effect on mast cells and thus hypotension, with possibly a compensatory tachycardia. In large doses, it may also produce ganglion blockade, which potentiates these cardiovascular effects.

*Pancuronium-induced tachycardia has been attributed to:(1) Vagolytic action, probably as a result of M2 inhibition(2) Sympathetic stimulation involving both direct (blockade of neuronal uNE uptake) and indirect (NE release from adrenergic nerve endings) mechanisms

*Hoffman elimination: spontaneous degradation in plasma and tissue at normal body pH and temperature

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Prior administration of succinylcholine potentiates the effect and lengthens the duration of action of non-depolarizing drugs. Concomitant administration of a potent inhalation agent increases the duration of block. This is most marked with the ether anaesthetic agents such as isoflurane, enflurane and sevoflu- rane, but occurs to a lesser extent with halothane. pH changes.Metabolic and, to a lesser extent, respiratory acido- sis extend the duration of block. With monoquaternary amines such as tubocurarine and vecuronium, this effect is produced probably by the ionization, under acidic conditions, of a second nitrogen atom in the molecule, making the drug more potent. Body temperature. Hypothermia potentiates block as impair- ment of organ function delays metabolism and excretion of these drugs. This may occur in patients undergoing cardiac surgery; reduced doses of muscle relaxants are required during cardiopul- monary bypass. Age. Non-depolarizing muscle relaxants which depend on organ metabolism and excretion may be expected to have a prolonged effect in old age, as organ function deteriorates. In healthy neonates, who have a higher extracellular volume than adults, resistance may occur, but if the baby is sick or immature then, because of underdevelopment of the neuromuscular junction and other organ function, increased sensitivity may be encountered. Children of school age tend to be relatively resistant to non-depo- larizing muscle relaxants, when given on a weight basis. Electrolyte changes. A low serum potassium concentration potentiates neuromuscular block by changing the value of the rest- ing membrane potential of the postsynaptic membrane. A reduced ionized calcium concentration also potentiates block by impairing presynaptic acetylcholine release. Myasthenia gravis. In this disease, the number and half-life of the postsynaptic receptors are reduced by autoantibodies produced in the thymus gland. Thus, the patient is more sensitive to the effects of non-depolarizing muscle relaxants. Resistance to succinyl- choline may be encountered. Other disease states. Because of the altered pharmacokinetics of muscle relaxants in hepatic and renal disease, prolongation of action may be found in these conditions, especially if excretion of the drug is dependent upon these organs.

*Atropine (crosses BBB) and glycopyrrolate (doesnt cross BBB; neither does neostigmine) co-administered to minimize muscarince effects of reversal agents*The term narcotic is derived from the Greek word for stupor and traditionally has been used to refer to potent morphine-like analgesics with the potential to produce physical dependence.

The development of synthetic drugs with morphine-like properties has led to the use of the term opioid to refer to all exogenous substances, natural and synthetic, that bind specifically to any of several subpopulations of opioid receptors and produce at least some agonist (morphine-like) effects

Sometimes terms opiates and opioids used interchangeably but strictly speaking not the same

*Nociceptive afferent neurons and the spinothalamic tract (Spinothalamic and Spinoreticular Nociceptive Processing in the Spinal Cord)Primary afferents (C and A delta fibers) conveying fast, localized pain and temperature sensation terminate in laminae I and V of the dorsal horn of the spinal cord, from which the crossed spinothalamic axons originate. Unmyelinated primary afferents (C fibers) also terminate on neurons in the dorsal horn, from which a cascading system involving recruitment, convergence, and polysynaptic interconnections originates. This system contributes to the spinoreticular tract (mainly crossed, but some are uncrossed), which projects into the RF and continues polysynaptically to nonspecific, medial dorsal and anterior thalamic nuclei. This system contributes to perception of excruciating pain and its emotional connotation via cortical regions such as the cingulate, insular, and prefrontal cortices. The gating mechanism, shown on the left, allows primary DC axon collaterals to dampen pain processing in the dorsal horn via inhibitory interneuronal connections that inhibit the flow of information through the cascading dorsal horn system that contributes to the spinoreticular pathway.

Visceral pain Responds to opioidsSomatic pain Responds to NSAIDsNeuropathic pain Respond better to adjuvant analgesics (anticonvulsants gabapentin, pregabalin; or low dose TCA)Neuropathic pain is pain caused by peripheral or central system injury, often described as burning, lancinating, shooting or tinglingResults in allodynia or hyperalgesiaBreakthrough pain is defined as a transient increase in pain of moderate-to-severe intensity, which occurs against a background of persistent pain of mild-to-moderate intensity that has been controlled. It must be differentiated from uncontrolled persistent pain, acute episodic pain, and end-of-dose failure

* Receptors are not true opioid receptors but are the site of action of certain psychotomimetic drugs, with which some opioids also interact.

ORL1 = Nociceptin/orphanin FQ peptide receptor / orphanin opioid-receptor-like subtype 1 PCA patient-controlled analgesia

Endogenous Opioid Peptides (Physiologic Conditions)Endorphins have highest affinity for receptors, Enkephalins for receptorsDynorphins for receptors

*Caption to image Spinal sites of opioid action. The , , and agonists reduce excitatory transmitter release from presynaptic terminals of nociceptive primary afferents. The agonists also hyperpolarize second-order pain transmission neurons by increasing K+ conductance, evoking an inhibitory postsynaptic potential (IPSP).

All opioid receptors are linked through Gi/Go proteins and thus open potassium channels (causing hyperpolarisation) and inhibit the opening of calcium channels (inhibiting transmitter release). In addition they inhibit adenylyl cyclase and activate the MAP kinase (ERK) pathway.

*The ubiquitous nature of opioid receptors implies that agents acting at them have wide-ranging effects, some of which may be problematic. Some opioids or their metabolites also have activity at other receptors, e.g. methadone acts at the N-methyl-D-aspartate (NMDA) receptor.

Opioids exert their analgesic effect by:supraspinal effects in the brainstem, thalamus and cortex, in addition to modulating descending systems in the midbrain, periaqueductal grey matter, nucleus raphe magnus and the rostral ventral medullainhibitory effects within the dorsal horn of the spinal cord both pre- and postsynapticallya peripheral action in inflammatory states, where MOP receptors modulate immune function and nociceptors are important in regulating peripheral sensitization.

*Intrathecal opiates bind to opioid receptors at the substantia gelatinasa in the spinal cord.All can he given intravenously. Morphine and meperidine are absorbed reliably via the IM route. Fentanyl can he administered transdermally via patch, which provides reservoir of drug in the upper dermis. Higher lipid solubility results in a faster onset of action.Lower fat solubility of morphine slows passage through blood-brain barrier.Alfentanil has a rapid onset of action due to its high nonionized fraction.Many lipid-soluble drugs can undergo first-pass uptake by the lungs and then diffuse hack to systemic circulation later. Biotransformation primarily depends on hepatic metabolism.Morphine 6-glucuronide is pharmacologically active.Normeperidine (metabolite of meperidine) is associated with seizure activity. The effects are more pronounced in renal failure patients.Remifentanil has a unique ester structure that allows for hydrolysis by nonspecific esterases in the blood. Context-sensitive half time is approximately 3 min, regardless of duration of infusion.

*Opioids should be titrated against pain; if higher than necessary doses are given, respiratory depression and excessive sedation may result. If the pain is incompletely opioid-responsive, as may occur with neuropathic pain, then care must be taken with dose titration and a detailed reassessment of analgesic response is essential

Coadministration of ketamine abolishes the hyperalgesia induced by remifentanyl, implying an underlying NMDA-receptor (N-methyl-d-aspartate) mechanism

Opioids, given at sufficient dose, are effective at suppressing the stress response to laryngoscopy and airway manipulation. They may reduce the plasma concentrations of catecholamines, cortisol and other stress hormones by inhibiting the pituitary-adrenal axis, reducing central sympathetic outflow and influencing central neuroendocrine responses. Opioids also suppress cough activity and mucociliary function. This may cause inadequate clearing of secretions and hypostatic pneumonia, especially if there is associated sedation and respiratory depression. This antitussive activity is, at least in part, mediated peripherally.

Histamine-releasing opioids meperidine, morphine, codeine, fentanyl

Opioid lipid solubility least to mostMorphine (least) Meperidine methadone alfentanil fentanyl Sufentanil (most)

*Classification based on opioid structurePhenanthrenesmorphine, hydromorphone, buprenorphine, nalbuphine, and butorphanolPhenylpiperidine fentanyl, meperidine, alfentanil, and sufentanil.DiphenylpropylaminesMethadoneBenzomorphansPentazocine

*Morphine-3-glucuronide (75-85%) pharmacologically inactiveMorphine-6-glucuronide (5-10%) produce analgesia and respiratory depression ()

Ceiling effect- max dose after which increasing dosage does not decrease MAC (minimum alveolar concentration) of inhalational anesthetics.

(loperamide slows intestinal motility through opiod receptor via direct activity on longitudinal and circular muscle; reduces fecal volume & increases viscosity)

The cause of pain persists, but even low doses of morphine increase the threshold to pain and modify the perception of noxious stimulation such that it is no longer experienced as pain (continuous, dull pain is relieved by morphine more effectively than is sharp, intermittent pain).

Can decrease MAC to ~65%Crosses BBB slowly 5 min onset, but peak in 10-40 minutes35% protein-bound (albumin)Rapid redistribution; elimination half-life 1.7 3.3hAge-dependent: 7-8 hrs in neonates; 4.5 hours for ages 61-80High hepatic extraction elimination affected by decreased hepatic flowNeuroaxial route: diffusion to opioid receptors in spinal cordCompared to local anaesthetics, no sympathectomy, motor blockade, or loss of propioceptionSpecific visceral > somatic analgesiaMorphine: 10 mg IV = 1 mg epidural = 100 mcg intrathecal (spinal)Less true with lipid soluble (fentanyl)Primarily due to systemic absorptionReversed by naloxone (narcan)***Dependence drug cessation or administration of an opioid antagonist results in withdrawal symptoms (appear 8-12 hrs, peaking 36 72hrs, last up to 7-10 days): Opioid withdrawal is not life-threatening; seizures, altered mental status, hallucinations are all rareSevere Flu-like illness (super flu)Rhinorrheapilo erection (gooseflesh)SneezingNausea & VomittingYawningDiarrheaLacrimationDilated pupilsAbdominal cramping, leg crampinOpioid tolerance and dependenceAcquired tolerance develops after 2-3 weeksTolerance to analgesia, euphoria, sedation, ventilatory depression, but often NOT constipationAddiction (physical and psychological dependence): usually takes ~ 25 days to developSome degree occurs within 48 hours*Hydromorphone, oxymorphone: Like morphine in efficacy, but higher potency 1.5mg hydromorphone (Dilaudid) IV = 10 mg morphine IV Meperidine: Strong agonist with anticholinergic effects; used in labour & post-op pain managementOxycodone: Dose-dependent analgesiaSufentanil, alfentanil, remifentanil: Like fentanyl but shorter durations of action

Meperidine shares several structural features that are present in local anesthetics and structurally is similar to atropine (possesses a mild atropine-like antispasmodic eff ect on smooth muscle).

Although there is cross-tolerance between different opioid agonists, it is not complete. This provides the basis for opioid rotation, whereby analgesia is maintained (eg, in cancer patients) by changing from one drug to another.

Pethidine / Meperidinesynthetic opioid agonist at and Only opioid with some local anaesthetic propertiesLess constipation, no miosis, cardiac depression- HRAtropine-like effects may cause a tachycardia, in addition to direct myocardial depression at high dosesLess potent; shorter action & more rapidIts metabolism is decreased by the oral contraceptive pill.Used in labour & post-op pain MxInteraction with MAOIs - resp depression, convulsions, death

FentanylPhenylpiperidine-derivativeHigh potency, more rapid onset and shorter duration of action from rapid redistribution to inactive tissues (N.B. lipophilic thus crosses BBB)However, after continuous infusions, or even multiple consecutive intravenous boluses, a saturation of these inactive tissue sites may lead to a "sink" phenomena, where the depot of fentanyl leaches back into the systemic circulation after the initial intravenous doses are stopped.As such the effects of fentanyl are often prolonged in the elderlyFentanyl is metabolized primarily in the liver to the inactive metabolites norfentanyl, hydroxyproprionyl-fentanyl, and hydroxyproprionyl- norfentanyl, which are all excreted in the urine2 50 g/kg (intraoperative anaesthesia)0.5 1.5 g/kg (Postoperative analgesia)ADRs Truncal rigidity, less histamine release, bradycardia more prominentGiven that fentanyl has been shown to produce fewer side effects (e.g. sedation, nausea/vomiting, urinary retention, pruritus) than morphine and hydromorphone, it may actually be a preferable drug for patient controlled analgesia in the acute care setting*Most commonly, an opioid is combined with another drug more likely to provide hypnosis and amnesia. For example, the combination of alfentanil and propofol produces excellent TIVA. Alfentanil provides analgesia and hemodynamic stability while blunting responses to noxious stimuli. Conversely, propofol provides hypnosis and amnesia and is antiemetic. Profound synergism also exists when more than two agents, such as propofol, alfentanil, and midazolam, are combined.

Methadone -receptor agonist + NMDA antagonistTx of opioid withdrawal and chronic pain

Remifentanil (Ultiva)Ultrashort-acting opioidEster hydrolysis by blood and tissue (plasma) esterases not pseudocholinesterasesMetabolism >> redistributionInfusion (rigidity with bolus)Can decrease MAC by up to 90% at high dosesDose:Induction: 0.5 1.0 mcg/kg over 30 seconds (with propofol)Infusion: 0.1 mcg/kg/min low propofol infusion (TIVA)MAC: 0.05 0.25 mcg/kg/minEven less if midazolam or propofol are also usedPost-operative hyperalgesia, acute opioid tolerance, some nauseaExpensive

*FENTANYL, SUFENTANIL, ALFENTANIL STRONG OPIOID AGONISTSVery high analgesic potency (fentanyl 100x more potent than morphine. Sufentanil 5x more potent than fentanyl).Duration of action by injection significantly shorter than that of morphineAdministered primarily as component of balanced anesthesiaFentanyl transdermal system (Duragesic) 72 hr continuous relief of pain Fentanyl is highly protein bound compared to 35% protein bound of morphinepH dependent: acidosis unbinding more free drugFentanyl side effects Chest wall rigidity difficult to ventilateRespiratory depression, especially when given with midazolam

*These characteristics make partial agonists a reasonable choice for opioid abuse deterrence and maintenance therapy

The rest is metabolized in the liver to norcodeine and then conjugated to produce glucuronide conjugates of codeine, norcodeine and morphine. Codeine is considerably less potent than morphine. Around 8% of Western Europeans are deficient in the CYP2D6 enzyme due to genetic polymorphism and such individuals may not experience adequate analgesia with codeine. Similarly, with super-metabolizers, there may be problems with opioid toxicity

Buprenorphine (Buprenex): partial -receptor agonist -receptor antagonistOften given sublingually to avoid 1st pass effect50 times greater affinity for -receptor compared to morphineProlonged duration of action due to slow dissociation from receptorsResistance to antagonism with naloxoneUsed in management of chronic pain as well as opioid dependenceBinds more strongly to receptors than other opioids doMore difficult for opioids to react when beprenorphine is in the systemCaution: in surgical patients uncontrolled post-op pain!Suboxone = Beprenorphine + naloxoneMixed with a pure -receptor antagonist to prevent diversion for illicit IV use*Advantages of opioid agonistantagonists are the ability to produce analgesia with limited depression of ventilation and a low potential to produce physical dependence. In general, agonistantagonist drugs should be reserved for patients who are unable to tolerate a pure agonist.

Nalbuphine (Nubain): Strong receptor agonist and -receptor antagonistSimilar analgesia to morphineRespiratory depression with ceiling effect similar 30mg morphineCould reverse morphine-induced respiratory depression without compromise of analgesiaAntagonism of pruritis with intrathecal/epidural morphine or fentanylCan precipitate withdrawal in opioid-dependent patientsLow abuse potentialElimination half-life = 3-6 hours

*available in immediate- and sustained-release oral preparations and for parenteral administration. Its use is contraindicated in patients receiving monoamine oxidase inhibitors (MAOIs). Caution must also be exercised in hepatic impairment as its clearance is reduced to a much greater extent than morphine and related agents.

No histamine release as with morphine

*A pure opioid antagonist has high affinity but no efficacy at opioid receptors. These agents function to reverse the undesirable effects of opioids, and are often combined with full or partial opioid agonists for opioid abuse deterrence and long-term maintenance therapy

Naloxone is clinically used to treat the adverse effects associated with opioids, most commonly respiratory depression, but also pruritus and gastrointestinal effects (constipation and/or opioid-induced ileus). Unfortunately, naloxone also reverses the most desired effect of opioids, i.e. analgesia.

Naloxone Dose: Dilute 1 vial (0.4mg) in 10 mLTitrate 20-40 mcg (0.02-0.04 mg) every 1-2 minutesShort duration of action; infusion may be required*