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INTRAVENOUS OPIOIDS
Co-ordinator : Dr.SugandhaModerators : Dr.Shobha, Dr.Anzar
Presenter : Dr.Sheeja Krishnan
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Opioid Receptors
Mechanism of action of Opioids
Effects of Opioids
Anaesthetic Techniques using opioids
Agonist Antagonist opioid compounds Opioid Antagonist
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Opioid Receptors
Theory of Receptor Dualism 3 Major types - , ,
Receptor sub types
Other opioid receptors, Opioid receptor like1(ORL1)
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Endogenous opioid peptides
Endogenous peptidesReceptor types
Enkephalins ++ +++
Beta-Endorphin +++ +++
Dynorphin A ++ +++
Dynorphin B + + +++
Alpha-neoendorphin + + +++
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Rational IUPHAR recommendations and currentnomenclatures of opioid receptors
PreferentialEndogenousLigands
OPIOID RECEPTORS
IUPHARPharmacologicnomenclature
Molecular biologyname
Enkephalins OP1 DOR
Dynorphins OP2 KOR
Beta endorphins OP3 MOR
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Stereoselective
Levorotatory(-) isomer is the active enantiomer at
opioid receptors
Effects are reversible by Naloxone
receptors shows preference for dextro rotatorycompounds and is not sensitive to Naloxone
Structure Activity Relation
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Classification of Opioid receptors
Effect 1 2
AnalgesiaSupra spinal
Spinal
Spinal Supra spinal
Spinal
Supra spinal
Spinal
Respiratory -Depression ofventilation
-Depression ofventilation
CNS
Euphoria &
Sedation -
Dysphoria &Sedation
HallucinationDelirium
-
CVS Bradycardia - - -
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Classification of Opioid receptors Contd.
Effect 1 2
GITUrinaryretention
Constipation
(Marked)-
Urinaryretention &Constipation
EndocrineProlactinrelease
-
DecreaseADH release
? GHsecretion
Dopamineturnover
Other Effects
Pruritus
Biliary spasm
SkeletalMuscle rigidity
FeedingLearning &
Memorythermo
regulation
Immunefunction
OlfactionCognitivefunction
Immunefunctions
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Classification of Opioid receptors Contd.
Effect 1 2
Agonist
Endorphin
Morphine
Synthetic Opioids
Endorphin
Morphine
Synthetic
Opioids
Dynorphin
SyntheticOpioids
Enkephalin
SyntheticOpioids
Antagonist
Naloxone
Naltrexone
Nalmefene
Naloxone
Naltrexone
Nalmefene
Naloxone
Naltrexone
Nalmefene
Naloxone
Naltrexone
Nalmefene
DistributionPutamen,Neocortex Thalamus,Hippocampus, Amygdala, Nucleus
accumbens, Dorsal Horn of spinalcord
Cerebral cortex
SubstantiaNigra,
InterpeduncularNucleus
Olfactory bulbNeo cortex
Nucleusaccumbens
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Actions and selectivity of some opioids at opioid receptors
DrugsReceptor types
Morphine +++ +
Fentanyl +++
Methadone +++
Sufentanil +++ + +
Butorphanol p +++
Buprenorphine p --
Naloxone --- --
Nalorphine --- +
Pentazocine p +++
Nalbuphine -- ++
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INTRA CELLULAR SIGNAL TRANSDUCTION MECHANISM
OF OPIOID RECEPTORS
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Mechanism of Analgesia
Opioid receptors are expressed in various areas of CNS
Amygdala, Mesencephalic reticular formation,
Periaqueductal grey matter, rostral ventral medulla Substantia gelatinosa of spinal cord
Analgesic effects
1. Direct inhibition of ascending transmission of pain2. Modulation of descending pain control circuits
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Effects of Opioids
1. Analgesic action
2. Anaesthetic action
3. EEG
4. Sensory evoked potential
5. Cerebral Blood Flow(CBF) &Cerebral Metabolic rate(CMR)
6. Intracranial Pressure
7. Neuroprotection
8. Muscle Rigidity
9. NeuroexcitatoryPhenomenon
10. Pupil size
11. Thermo regulation andshivering
12. Pruritus
Neurophysiologic Effects
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Analgesia
Not assosciated with loss of consciousnes
Nociceptive pain responds better than neuropathic pain
Opioids as anaesthetics
Reduce MAC of volatile Anaesthetcs
Potency ratio for MAC reduction Fentanyl : Sufentanil:Alfentanil:remifentanilare 1:12:1/16:1.2
Midazolam is potentiated
Propofol action is enhanced
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EEG
Sensory Evoked Potential
Modest decrease in CMRDecrease CBF when combined with N2O
CBF & CMR
ICP
Isoflurane N2O opioid Anaesthesia donot increse ICP during craniotomy
Opioid sedation donot alter ICP in head injured patients
Neuroprotection
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Muscle Rigidity
Factors Affecting
Dose and speed of drug administration
Concomitant use of N2O
Presence/Absence of Muscle relaxants
Patients age
Problems Associated
System Problem
Hemodynamic Increase CVP,PAP, PVR
Respiratory Decrease compliance, FRC,ventilation.
Hypercarbia, Hypoxemia
Miscellaneous Increase oxygen consumption, ICP,
Fentanyl plasma levels
Clinical Manifestations
Mechanism for Muscle rigidity
Measures to Prevent
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Neuroexcitatory Phenomena
Ranges from Delirium to grandmal seizure like activity
Meperidine is more potent
Pupil size
Thermo regulation and shivering
Reduces thermoregulatory threshold
Meperidine 0.5mg/Kg
Tramadol is useful
Pruritus
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1. Therapeutic Effects
2. Non Therapeutic Effects
Therapeutic Effects
Prevents hyper ventilation
Attenuates stress response
Antitussive action
Antimuscarinic, Antihistaminergic, Antiserotoninergic actions
Respiratory Effects
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Non Therapeutic Effects
Dose dependent depression of respiration by direct action onbrain stem respiratory centers
Receptor mediated
Ventilatory response to CO2 is reduced
Decrease hypoxic ventilatory drive
Respiratory rate is reduced with prolonged expiratory time
Tidal volume is decreased
High dose eliminates respiration without loss of consciousness
Treatment - Naloxone
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High dose
Sleep
Old age & neonates
CNS depressants
Renal insufficiency
Hyper ventilation & Hypocapnia
Respiratory acidosis
Decreased clearance
Secondary peaks in plasma opioid levels
Factors affecting opioid induced respiratory depression
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1. Neurologic Mechanism
2. Cardiac Mechanism
Cardio vascular EffectsOpioids maintains hemodynamic stability
Neurologic Mechanism
Modulates stress response through receptor mediatedaction on HPA axis.
Produces hypotension and bradycardia by stimulation
of central vagal nucleus
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Cardiac Mechanism
Contractility
Heart rate and rhythm
- vagal mediated
- asystole especially in premedication with blocker and CCB
- Treatment atropine
Cardiac conduction - Direct membrane action
Ischemia
Coronary circulation
Baro receptor
Cardiogenic reflex
Vascular Mechanism
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Main components of stress response are
Paraventricular hypothalamic nucleus which releasecortico tropin releasing hormone
Locus caerulus nor epinephrine secreting areas of
ANS
Endocrinologic Effects
Mechanism of action
Modulates nociception
inhibits HPA axis
Effects
Decrease plasma glucose, ADH, Renin, Aldosterone,
cortisol, Growth Hormone
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Renal and urodynamic Effects
Urinary retention occurs especially after intrathecal opioids
Receptor mediates antidiuresis
Receptor mediates diuresis
Morphine is most potent
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Gastro intestinal Effects
Decreased gastro intestinal motility & LES tone
Patient considered full stomach
Mediated by and receptor agonist
IV and epidural morphine reduce GIT motility
Tramadol has least effect
Reversal with naloxone
- Metoclopramide
Biliary and Hepatic Effects
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Nausea and Vomiting
Stimulation of CTZ in area postrema of Medulla
Receptor mediated
Fentanyl and sufentanil > alfentanil
Mechanism
Treatment
Dopamine antagonist Metoclopramide
5HT3 antagonist ondansetron
Use of propofol in TIVA
Butyrophenones Phenergan
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Obstetric Effects
Morphine and Meperidine exacerbates aortacavalcompression and hypo tension
Analgesia in vaginal delivery
Decrease IOP during induction of Anaesthesia, succinylcholineadministration and tracheal intubation
Dose : Fentanyl 2.5Mg/Kg , Alfentanil 10Mg/Kg
Sufentanil 0.1Mg/Kg , Remifentanil 1Mg/Kg
Ocular Effects
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ANAESTHETIC TECHNIQUES USING OPIOIDS
Sedation and analgesia
Balanced anaesthesia
High dose opioid anaesthesia
Neurolept analgesia anaesthesia
Total intravenous anaesthesia
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BALANCED ANAESTHESIA
Term introduced by John. S Lundy
Balance of agents and techniques to produce differentcomponents of anaesthesia
opioids produce sedation and analgesia
- abolish stress response- lowers requirement of inhaled anaesthetics
- improve hemodynamic stability
- reduce dose of propofol and sedative hypnotic
- post operative pain relief
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HIGH DOSE OPIOID ANAESTHESIA
Fentanyl and sufentanil are recommended
uses - cardiac surgery in adult with CPB
- premature infants for repair of PDA
- Paediatric heart surgery
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Anaesthetic phase Fentanyl Sufentanil Alfentanil RemifentanilPremedication (Mg) 25-50 2-5 250-500
0.5-1.0+
Or 0.25-0.5 Mg/Kg/min
Induction
1. With hypnotic (Mg/Kg) 1.5 2.5 0.1-1 10-50
2. With 60-70 % N2O (Mg/Kg) 8-23 1.3-2.8
3. High dose (Mg/Kg) 5-50 10-30 120 2.5
Infusion 0.1-1.0Mg/Kg/min
Maintenance in Balanced Anaesthesia
Intermittent Bolus (Mg) 25-200 5-20 250-500 25-50
Infusion (Mg/Kg/min) 0.033 0.005-0.015 0.5-1.5 0.25-0.5
MAC
Intermittent Bolus (Mg) 12.5-5.0 2.5-10 125-250 12.5-25
Infusion (Mg/Kg/min) 0.01-0.2
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NEUROLEPT ANALAGESIA ANAESTHESIA
Involves combination of major tranquilizer ButyrophenoneDroperidol and a potent opioid analgesic fentanyl
characterised by
analgesia
suppression of motor activity,suppression of autonomic reflex
maintenance of cardio vascular stability
amnesia
Contra indications
use of concomitant MAO inhibitors
Drug & alcohol abuse
Parkinsons disease
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TOTAL INTRAVENOUS ANAESTHESIA
Provide analgesia component during TIVA
Combined with other drugs
Combination of drug used
Propofol + Alfentanil Excellent TIVA
Midazolam + Sufentanil Major cardiac surgeryPropofol + Remifentanil ENT surgery
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Opioid loading doses; Maintenance infusion rates and
additional bolus dose for TIVA
Drug Loading dose (Mg/Kg)Maintenance Infusion rate
Mg/Kg/MinAdditional Bolus
Alfentanil 25-100 0.5-2 5-10 Mg/Kg
Sufentanil 0.25-2.0 0.5-1.5 2.5-10
Fentanyl 4.0-20 2-10 25-100
Remifentanil 1-2 0.1-1.0 0.1-1.0
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Actions of Nalbuphine, Butorphanol and Buprenorphine at opioid receptors
Drugs Receptor Receptor
Nalbuphine Partial agonist Partial agonist
Butorphanol Partial agonist Partial agonist
Buprenorphine Partial agonist Antagonist
Pentazocine agonist
OPIOID AGONIST ANTAGONIST
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Dosing data for agonist antagonist opioids and morphine
Equi analgesic dose Duration of Analgesia Oral: IM efficacy ratio
Morphine 10 4-5 1:6
Buprenorphine 0.3-0.4 >6 1:2 (sub:IM)
Butorphanol 2 3-4 -
Nalbuphine 10 3-6 1:4-5
Pentazocine 40 3 1:3
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Hemodynamic effect of agonist antagonist compoundscompared with morphine
Cardiac workload Blood pressure HR PAP
Morphine = =
Buprenorphine ?
Butorphanol = =
Nalbuphine = = =
Pentazocine
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Respiratory depressant effect of agonist antagonist compared with morphine
Drug Correlation of Respiratory Depression with dose
Morphine Increases with doses
Buprenorphine Ceiling effect at 0.15-0.12 mg in adults
Butorphanol Ceiling effect at 30-60 Mg/Kg in adults
Nalbuphine Ceiling effect at 30mg in adults
Pentazocine Ceiling effect suggested
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OPIOID ANTAGONIST
Naloxone
Active at , , receptor
Uses
Side effects : Hemodynamic alterations
Sympathetic activation
Increased oxygen consumption and minute ventilation
Dose : Initial dose 0.4 to 0.8 mg-IV/intrathecal
Onset of action : 1 -2 minutes
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OPIOID ANTAGONIST
Naltrexone
Active at , , receptorUses Longer acting
Nalmefene
Active at , , receptor
Longer acting
Route of administration
Oral 0.5 to 3mg/kg
Parenteral- 0.2 to 2 mg/kg
Methyl Naltrexone
First quaternary ammonium opioid receptor antogonist
Doesnot reverse analgesic effects.
Reverses peripheral opioid effects
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