Curriculum Vitae

Nama : Dr. Ike Sri Redjeki, dr., SpAnKIC,KMN,M.KesJabatan : Kepala Departemen Anestesiologi & Terapi Intensif Fakultas

Kedokteran Universitas Padjadjaran BandungKetua Program Studi Pendidikan Konsultan Intensive Care (KIC) Fakultas Kedokteran Universitas Padjadjaran Bandung

Alamat : Departemen Anestesiologi & Terapi Intensif Fakultas Kedokteran Universitas Padjadjaran/RS. Hasan Sadikin Jalan Pasteur no. 38 Bandung 40161Telp : 022-2038285/0811230514Fax : 022-2038306E-mail : ikesriredjeki@yahoo.co.id

Update on Opioid Pharmacology

Ike Sri RedjekiDepartment of Anesthesiology and Intensive Care UnitHasan Sadikin Hospital/Medical Faculty of Padjadjaran

UniversityBANDUNG

IntroductionOpioid

• The most effective analgesics are the opioid analgesics

• The opioids interact with opioid receptors in the nervous system

• These receptors are the sites of action for the endorphins, compounds that already exist in the body also site of action for the external opioid drugs

• Pharmakokinetics of this specific drugs also influence its efficacy

Ascending fast -Ascending slow –Descending

* Opioid Receptor

↓Site of action of Endorphine and other mediator

Opioid

**

*

*

*

*

FSC MO P MID DI

C

SC Spinal Cord

MO Medulla (oblongata)

P Pons

C Cerebellum

MID Midbrain (Mesencephalon)

DI Diencephalon (Thalamus + Hypothalamus)

FNRPGRVM

Forebrain (Cerebral Cortex + Deep nuclei, e.g. amygdala) nucleus reticularis paragigantocellularis Rostral Ventral Medulla

PAGRVM

NRPG

Amygdala

ThalamusHypothalamus

Nociceptive Input

Example of physiological control of descending inhibition

Stress produced analgesia (SPA)• Many accounts of people ignoring injuries when

stressed, e.g. during sports contests, in battle• Animal studies show at least partly due to

activation of PAG/RVM system • Possible role for amygdala, hypothalamus,

some cortical regions (insula) that are also involved in other aspects of stress responses (hormonal, cardiovascular)

• Note that PAG/RVM system is also part of cardiovascular control system for stress responses

Enkephalins are derived from pro-enkephalinrelatively selective δ ligands

Endorphins are derived from pro-opiomelanocortin (also the precursor for ACTH and MSH) bind to the µ receptor

Dynorphins are derived from pro-dynorphins and arehighly selective at the µ receptor

Presynaptic

Postsynaptic Opioid

Nociceptins (nociceptin/orphaninFQ [N/OFQ]) (orphanin),have potent hyperalgesic effectsLittle affinity for the µ, d, κ receptors,(“opioid-receptor-like”)Nociceptin antagonists may be antidepressants and analgesics

Kappa receptor only analgesia

and sedation no other side effect

The ORL-1 receptor • the ORL-1 receptor or the “orphan”

receptor was very recently discovered

• The natural opioid peptide that is a ligand for this receptor is nociceptin which is also called orphanin

• The ORL-1 receptor is associated with many different biological effects such as memory processes, cardiovascular function, and renal function

• It is thought to have effects on dopamine levels and is associated with neurotransmitter release during anxiety

Opioid Receptor

Primary afferent nociceptor terminal

Secondary ascending neuron

Ca2+ Ca2+

K+ K+

Neurotransmitter glutamate

opioid receptor

opioid receptor

Noxious stimulus

ATP cAMP

Opioid Receptor placed by opioid

Secondary ascending neuron

Primary afferent nociceptor terminal

Ca2+ Ca2+

K+ K+

Neurotransmitter glutamate

opioid receptor

opioid receptor

Opioid

Opioid

x x

Noxious stimulus

ATP cAMPX

Classification based on degree of affinity and efficacy at various receptor

• Opioid Agonist • Opioid Partial Agonist ( high affinity but

low efficacy at the μ receptor)• Opioid Agonist / Antagonist ( poor μ

opioid receptor efficacy or μ opioid receptor antagonist and have κ agonist )

• Opioid Antagonist

Analgesic effects at opioid receptors.

in the brainstem and medial thalamus

in the limbic and other diencephalic areas, brain stem, and spinal cord

Future of Opioid Analgesics

• The future of Opioid Analgesics seems to be linked to the study of the Kappa Receptor– The kappa receptor induces analgesia

without the dangerous and unwanted side effects that the mu and delta receptors are associated with

– However there are not any selectively strong agonists to this receptor as of now

• As similar as endogenous morphine non toxic metabolite

Chemical Structure of OpioidMorphine

Phenolic hydroxyl

group

Alcohol hydroxyl

group> Nausea and hallucination

Nitrogen Atom

Changes to the methyl group will decrease analgesia

and creating antagonists

( nalorphine )

Prototype of opioid

Pentazocine High incidence of

dysporia

Fentanyl, Meperidine

Hihgest affinity for the mu receptor

Include propoxyphene and metadone

Tramadol does not fit in the standard opioid classes unique analgesic , an

atypical opioid 4-phenyl – piperidine analogue of

codeinHas partial μ agonist, in

addition to central GABA catecholamine

and serotonergic activity

Pharmacology of opioidSide effect of opioid

Drug interaction

Morphine ( prototype μ receptor, phenanthrene deriative )

• After oral administration only 40 – 50% reaches the CNS within 30 minute other extended release 90 min

• Poor penetration poor lipid solubility• Respiratory acidosis increase brain concentration of

morphine caused by increase in CBF• Elimination half life 120 min• Drug inhibit morphine degradation : tamoxifen,

diclofenac, naloxone, carbamazepin, tryciclic and heterocyclic antidepressants, benzodiazepine

Side Effect : • Decrease sympathetic nervous

system tone• Decreased intestinal motility• Spasm of biliary smooth muscle

and sphincter Oddi spasm • Induce nausea and vomiting

direct stimulation of CTZ in the floor of 4th ventricle

• Skin sign urticaria ( histamine release)

Pharmacology of opioidSide effect of opioid

Drug interaction

Codein • Weak affinity to μ receptor• Potency 50% of morphine• Half life 2.5 – 3 hours• Analgesic activity occurs from metabolism of codein to

morphine• Inhibitor metabolit : celecoxib, cimetidine, cocaine• Inducers : dexamethasone, rifampin• Doses > 65 mg not well tolerated• Low dose paradoxically more emetic than higher dose

competing effect in CTZ

Side effect :A very rare but serious side

effectin nursing infants whose

mothers are taking codeine,and are apparent ultra-rapid

metabolizers of codeine,resulting in rapid and higher

levels of morphine inthe breast milk, and the

subsequent potentially fatal

neonate respiratory depression

Pharmacology of opioidSide effect of opioid

Drug interaction

Meperidine • Relatively weak opioid μ agonist only 10% of morphine• Have a significant anticholinergic and local anesthetic properties• Half life 3 hours half life the metabolite normeperidine 15

– 30 hour• Must not be given with MAO inhibitor may produce severe

respiratory depression, hyperpyrexia, CNS excitation, delirium, and seizures

• side effect : anxiety, tremors, multifocal myoclonus, seizures especially in patients with renal disease, following repeated administration

Pharmacology of opioidSide effect of opioid

Drug interaction

Fentanyl• Strong opioid agonist• Available in parenteral, transdermal, transbuccal

preparation• Synthetic piperidine opioid agonist• 80x more potent than morphine• Highly lipophylic• Binds strongly to plasma protetin• Transdermal formulation a lag time 6 – 12 hour

to onset of action, reach 3 – 6 days steady state

Notes about the Fentanyl patch

• Takes 12 hours for onset of analgesia

• Need adequate subcutaneous tissue for absorption

• Takes 24 hours to reach maximum effect

• Change patch every 72 hours• Dosage change after six days on

patch• Suitable for stable pain only

Pharmacology of opioidSide effect of opioid

Drug interaction

Tramadol• Unique analgesic • An atypical opioid, has a higher affinity to

μ receptor than the parent compound• Max doses 400 mg/day• Toxic dose cause CNS excitation• Oral tramadol absorbed rapidly analgesic potency

the same with codein

Addiction• A single exposure to morphine could

induce tolerance and dependence • Recent study shows that prolonged

ventral tegmental area (VTA), dopamine neuron activities (DA) and opiate receptor desensitization followed single morphine exposure

• Cause the development of dependence and tolerance cause acute analgesic tolerance and acute addiction of morphine

Withdrawal Sign ( after Physiological Dependence )

Acute Action• Analgesia• Respiratory Depression• Euphoria• Relaxation and sleep• Tranquilization• Decreased blood pressure• Constipation• Pupillary constriction• Hypothermia• Drying of secretions• Reduced sex drive• Flushed and warm skin

Withdrawl Sign• Pain and irritability• Hyperventilation• Dysphoria and depression• Restlessness and insomnia• Fearfulness and hostility• Increased blood pressure• Diarrhea• Pupillary dilation• Hyperthermia• Lacrimation, runny nose• Spontaneous ejaculation• Chilliness and “gooseflesh”

Potential problem in Opioid Therapy

• Opioid induced hyperalgesia : hyperalgesia syndrome occur following effective opioid administration the phenomenon of pharmacological tolerance or may be mediated through mechanism : – Central glutamatergic mechanism– Increase in the synthesis of excitatory

neuropeptides such as dynorphine– Descending facilitatory mechanism arising in the

medula• Medication overuse headache

Pharmakokinetics Aspect of opioid

Percent of peak effectSite Concentration after bolus injection

Minutes since bolus injection0 5 10 15 20

Percent of peak effect

site concentration

0

20

40

60

80

100Methadone

Remifentanil

Fentanyl

Sufentanil

Alfentanil

Hydromorphone

Morphine

Meperidine

Pharmacokinetic of opioid

Therapeutic Window

Blood levels in Therapeutic WindowPCA

Conclusions

• Opioid are important drugs used in the pain management

• Employ appropriate pharmacological choice by knowing the pharmacology of the drugs both pharmaco dynamic and pharmaco kinetics

• Provide optimal effect and minimize side effects

Thank You