INTRAVENOUS OPIOIDS

Co-ordinator Moderators Presenter : Dr.Sugandha : Dr.Shobha, Dr.Anzar : Dr.Sheeja Krishnan

Opioid Receptors Mechanism of action of Opioids Effects of Opioids Anaesthetic Techniques using opioids Agonist Antagonist opioid compounds Opioid Antagonist

Opioid Receptors
Theory of Receptor Dualism 3 Major types - , , Receptor sub types Other opioid receptors , Opioid receptor like
1(ORL1)

Endogenous opioid peptides

Receptor types

Endogenous peptides

Enkephalins Beta-Endorphin Dynorphin A Dynorphin B Alpha-neoendorphin

++ +++ ++ + +

+++ +++ +++ + + +++ +++

Rational IUPHAR recommendations and current nomenclatures of opioid receptors

OPIOID RECEPTORS Pharmacologic nomenclature Molecular biology name

Preferential Endogenous Ligands

IUPHAR

Enkephalins

OP1

DOR

Dynorphins

OP2

KOR

Beta endorphins

OP3

MOR

Structure Activity Relation

Stereoselective Levorotatory(-) isomer is the active enantiomer at opioid receptors Effects are reversible by Naloxone receptors shows preference for dextro rotatory compounds and is not sensitive to Naloxone

Classification of Opioid receptors

Effect
Analgesia

1
Supra spinal Spinal

2
Spinal

Supra spinal Spinal

Supra spinal Spinal Depression of ventilation

Respiratory

Depression of ventilation

CNS

Euphoria & Sedation

Dysphoria & Sedation Hallucination Delirium

-

CVS

Bradycardia

Classification of Opioid receptors

Effect
GIT

Contd.

1
Urinary retention

2
Constipation (Marked)

Decrease ADH release ? GH secretion

Urinary retention & Constipation

Dopamine turnover Olfaction Cognitive function Immune functions

Endocrine

Prolactin release

Other Effects

Pruritus Biliary spasm Skeletal Muscle rigidity

Feeding Learning & Memory thermo regulation

Immune function

Classification of Opioid receptors

Effect
Agonist

Contd.

1
Endorphin Morphine Synthetic Opioids

2
Endorphin Morphine Synthetic Opioids

Dynorphin Synthetic Opioids

Enkephalin Synthetic Opioids

Antagonist

Naloxone Naltrexone Nalmefene

Naloxone Naltrexone Nalmefene

Naloxone Naltrexone Nalmefene Cerebral cortex Substantia Nigra, Interpeduncular Nucleus

Naloxone Naltrexone Nalmefene

Olfactory bulb Neo cortex Nucleus accumbens

Distribution

Putamen,Neocortex Thalamus, Hippocampus, Amygdala, Nucleus accumbens, Dorsal Horn of spinal cord

Actions and selectivity of some opioids at opioid receptors

Receptor types

Drugs Morphine Fentanyl Methadone Sufentanil Butorphanol Buprenorphine Naloxone Nalorphine Pentazocine Nalbuphine

+++ +++ +++ +++ p p ----p --

+ +++ --+ +++ ++

INTRA CELLULAR SIGNAL TRANSDUCTION MECHANISM

OF OPIOID RECEPTORS

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 pain 2. Modulation of descending pain control circuits

Effects of Opioids
Neurophysiologic Effects
1. 2. 3. 4. 5. Analgesic action Anaesthetic action EEG Sensory evoked potential Cerebral Blood Flow(CBF) & Cerebral Metabolic rate (CMR) Intracranial Pressure 7. Neuroprotection

6.

8. Muscle Rigidity 9. Neuroexcitatory Phenomenon 10. Pupil size 11. Thermo regulation and shivering 12. Pruritus

 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:remifentanil are 1:12:1/16:1.2 Midazolam is potentiated Propofol action is enhanced

 EEG Sensory Evoked Potential

CBF & CMR

Modest decrease in CMR Decrease CBF when combined with N2O

ICP
Isoflurane N2O opioid Anaesthesia donot increse ICP during craniotomy
Opioid sedation donot alter ICP in head injured patients

Neuroprotection

 Muscle Rigidity
Factors Affecting Dose and speed of drug administration

Concomitant use of N2O

Presence/Absence of Muscle relaxants Patients age Problems Associated System Hemodynamic Respiratory Problem Increase CVP,PAP, PVR Decrease compliance, FRC,ventilation.

Hypercarbia, Hypoxemia
Miscellaneous Increase oxygen consumption, ICP, Fentanyl plasma levels Clinical Manifestations Mechanism for Muscle rigidity Measures to Prevent

 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

Respiratory Effects
1. Therapeutic Effects 2. Non Therapeutic Effects
Therapeutic Effects
Prevents hyper ventilation Attenuates stress response Antitussive action Antimuscarinic, Antihistaminergic, Antiserotoninergic actions

Non Therapeutic Effects

Dose dependent depression of respiration by direct action on brain 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

Factors affecting opioid induced respiratory depression

High dose

Sleep
Old age & neonates CNS depressants

Renal insufficiency
Hyper ventilation & Hypocapnia Respiratory acidosis Decreased clearance Secondary peaks in plasma opioid levels

Cardio vascular Effects Opioids maintains hemodynamic stability

1. Neurologic Mechanism 2. Cardiac Mechanism

Neurologic Mechanism

Modulates stress response through receptor mediated action on HPA axis.

Produces hypotension and bradycardia by stimulation of central vagal nucleus

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

Endocrinologic Effects Main components of stress response are

Paraventricular hypothalamic nucleus which release cortico tropin releasing hormone Locus caerulus nor epinephrine secreting areas of ANS

Mechanism of action
Modulates nociception inhibits HPA axis

Effects
Decrease plasma glucose, ADH, Renin, Aldosterone, cortisol, Growth Hormone

Renal and urodynamic Effects

Urinary retention occurs especially after intrathecal opioids

Receptor mediates antidiuresis Receptor mediates diuresis Morphine is most potent

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

Nausea and Vomiting Mechanism

Stimulation of CTZ in area postrema of Medulla Receptor mediated

Fentanyl and sufentanil > alfentanil

Treatment

Dopamine antagonist Metoclopramide

5HT3 antagonist ondansetron Use of propofol in TIVA Butyrophenones Phenergan

Obstetric Effects

Morphine and Meperidine exacerbates aortacaval compression and hypo tension

Analgesia in vaginal delivery

Ocular Effects
Decrease IOP during induction of Anaesthesia, succinylcholine administration and tracheal intubation

Dose : Fentanyl 2.5Mg/Kg , Alfentanil 10Mg/Kg

Sufentanil 0.1Mg/Kg , Remifentanil 1Mg/Kg

ANAESTHETIC TECHNIQUES USING OPIOIDS

Sedation and analgesia

Balanced anaesthesia High dose opioid anaesthesia Neurolept analgesia anaesthesia Total intravenous anaesthesia

BALANCED ANAESTHESIA

Term introduced by John. S Lundy

Balance of agents and techniques to produce different components 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

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

Anaesthetic phase
Premedication (Mg) Induction
1. With hypnotic (Mg/Kg)

Fentanyl
25-50

Sufentanil
2-5

Alfentanil
250-500

Remifentanil

1.5 2.5

0.1-1

10-50 0.5-1.0+ Or 0.25-0.5 Mg/Kg/min 120 2.5

2. With 60-70 % N2O (Mg/Kg)

3. High dose (Mg/Kg)

8-23
5-50 0.1-1.0Mg/Kg/min

1.3-2.8
10-30

Infusion

Maintenance in Balanced Anaesthesia

Intermittent Bolus (Mg) Infusion (Mg/Kg/min) 25-200 0.033 5-20 0.005-0.015 250-500 0.5-1.5 25-50 0.25-0.5

MAC
Intermittent Bolus (Mg) Infusion (Mg/Kg/min) 12.5-5.0 2.5-10 125-250 12.5-25 0.01-0.2

NEUROLEPT ANALAGESIA ANAESTHESIA

Involves combination of major tranquilizer Butyrophenone Droperidol 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

TOTAL INTRAVENOUS ANAESTHESIA

Provide analgesia component during TIVA

Combined with other drugs Combination of drug used Propofol + Alfentanil Excellent TIVA Midazolam + Sufentanil Major cardiac surgery Propofol + Remifentanil ENT surgery

Opioid loading doses; Maintenance infusion rates and additional bolus dose for TIVA

Drug

Loading dose (Mg/Kg)

Maintenance Infusion rate Mg/Kg/Min

Additional Bolus

Alfentanil Sufentanil Fentanyl Remifentanil

25-100 0.25-2.0 4.0-20 1-2

0.5-2 0.5-1.5 2-10 0.1-1.0

5-10 Mg/Kg 2.5-10 25-100 0.1-1.0

OPIOID AGONIST ANTAGONIST Actions of Nalbuphine, Butorphanol and Buprenorphine at opioid receptors
Drugs Receptor Partial agonist Partial agonist Partial agonist Receptor Partial agonist Partial agonist Antagonist agonist

Nalbuphine Butorphanol Buprenorphine Pentazocine

Dosing data for agonist antagonist opioids and morphine

Equi analgesic dose

Duration of Analgesia

Oral: IM efficacy ratio

Morphine Buprenorphine Butorphanol Nalbuphine Pentazocine

10 0.3-0.4 2 10 40

4-5 >6 3-4 3-6 3

1:6 1:2 (sub:IM) 1:4-5 1:3

Hemodynamic effect of agonist antagonist compounds compared with morphine

Cardiac workload

Blood pressure
=

HR

PAP
= ?

Morphine Buprenorphine Butorphanol Nalbuphine Pentazocine

= =

= = =

Respiratory depressant effect of agonist antagonist compared with morphine

Drug

Correlation of Respiratory Depression with dose

Increases with doses Ceiling effect at 0.15-0.12 mg in adults Ceiling effect at 30-60 Mg/Kg in adults Ceiling effect at 30mg in adults Ceiling effect suggested

Morphine Buprenorphine Butorphanol Nalbuphine Pentazocine

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

OPIOID ANTAGONIST
Naltrexone Active at , , receptor

Uses
Nalmefene

Longer acting

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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