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 : [email protected]
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