Intravenous Opioids1

8/3/2019 Intravenous Opioids1

1/41

INTRAVENOUS OPIOIDS

Co-ordinator : Dr.SugandhaModerators : Dr.Shobha, Dr.Anzar

Presenter : Dr.Sheeja Krishnan


2/41

Opioid Receptors

Mechanism of action of Opioids

Effects of Opioids

Anaesthetic Techniques using opioids

Agonist Antagonist opioid compounds Opioid Antagonist


3/41

Opioid Receptors

Theory of Receptor Dualism 3 Major types - , ,

Receptor sub types

Other opioid receptors, Opioid receptor like1(ORL1)


4/41

Endogenous opioid peptides

Endogenous peptidesReceptor types

Enkephalins ++ +++

Beta-Endorphin +++ +++

Dynorphin A ++ +++

Dynorphin B + + +++

Alpha-neoendorphin + + +++


5/41

Rational IUPHAR recommendations and currentnomenclatures of opioid receptors

PreferentialEndogenousLigands

OPIOID RECEPTORS

IUPHARPharmacologicnomenclature

Molecular biologyname

Enkephalins OP1 DOR

Dynorphins OP2 KOR

Beta endorphins OP3 MOR


6/41

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


7/41

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 - - -


8/41

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


9/41

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


10/41

Actions and selectivity of some opioids at opioid receptors

DrugsReceptor types

Morphine +++ +

Fentanyl +++

Methadone +++

Sufentanil +++ + +

Butorphanol p +++

Buprenorphine p --

Naloxone --- --

Nalorphine --- +

Pentazocine p +++

Nalbuphine -- ++


11/41

INTRA CELLULAR SIGNAL TRANSDUCTION MECHANISM

OF OPIOID RECEPTORS


12/41

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


13/41

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


14/41

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


15/41

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


16/41

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


17/41

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


18/41

1. Therapeutic Effects

2. Non Therapeutic Effects

Therapeutic Effects

Prevents hyper ventilation

Attenuates stress response

Antitussive action

Antimuscarinic, Antihistaminergic, Antiserotoninergic actions

Respiratory Effects


19/41

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


20/41

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


21/41

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


22/41

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


23/41

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


24/41

Renal and urodynamic Effects

Urinary retention occurs especially after intrathecal opioids

Receptor mediates antidiuresis

Receptor mediates diuresis

Morphine is most potent


25/41

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


26/41

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


27/41

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


28/41

ANAESTHETIC TECHNIQUES USING OPIOIDS

Sedation and analgesia

Balanced anaesthesia

High dose opioid anaesthesia

Neurolept analgesia anaesthesia

Total intravenous anaesthesia


29/41

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


30/41

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


31/41

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


32/41

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


33/41

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


34/41

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


35/41

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


36/41

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


37/41

Hemodynamic effect of agonist antagonist compoundscompared with morphine

Cardiac workload Blood pressure HR PAP

Morphine = =

Buprenorphine ?

Butorphanol = =

Nalbuphine = = =

Pentazocine


38/41

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


39/41

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


40/41

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


41/41

THANK YOU

Intravenous Opioids1

Documents

Transcript of Intravenous Opioids1