opioid pharmacology - a comprehensive subject seminar on opioids
DESCRIPTION
Opioid pharmacology - A comprehensive subject seminar on Opioids for postgraduates and beyond.TRANSCRIPT
![Page 1: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/1.jpg)
OPIOID PHARMACOLOGYPG Seminar
Dr. Rohan Kolla,PG in MD PHARMACOLOGY,
JNMC, BELGAUM
![Page 2: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/2.jpg)
Outline
• Definitions• History• Endogenous Opioids• Opioid Receptors• Pharmacokinetics• Pharmacological Effect Profile• Classification of Opioids– Pure AGONISTS– Agonist-antagonists– Antagonists
![Page 3: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/3.jpg)
Outline (contd.)
• Clinical Pharmacology– Therapeutic use of Opiates in Pain control– Guidelines for Opiate Dosing– Non analgesic therapeutic uses– Acute Opioid toxicity
• Screening Methods
![Page 4: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/4.jpg)
Etymology
• OPIOIDS ( from Greek opos, ‘juice’): is any substance regardless of its origin or structure that produces morphine-like effects that are blocked by antagonists such as nalaxone.
• OPIATES: includes the natural alkaloids derived from the resin of the opium poppy; – some authors also include the semisynthetic
substances derived directly from these alkaloids.
![Page 5: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/5.jpg)
• Narcotic (from Greek narkos, ‘I benumb’): – any substance which induces sleep– any substance which acts on opioid receptors– any illicit substance– legally - opium, opium derivatives & their
semisynthetic derivatives
![Page 6: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/6.jpg)
Papaver somniferum
![Page 7: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/7.jpg)
History
• Oldest drug known to mankind• Sumer – 4000 BC• Greeks; Theophrastus – 3rd century BC• Arab Physicians• Used for – asthma, bad eyesight, diarrhoea
and as a euphoriant.
![Page 8: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/8.jpg)
History (contd.)
• Opium Addiction – a lifestyle statement in 17th – 18th century
• It was the source of an important "social problem", one of the first "public health" concerns, known as "baby-doping" (giving a child opium to keep them quiet).
![Page 9: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/9.jpg)
• East India company• Opium Wars: 1/3rd of adult chinese population
was addicted• India is a major produces of legal opium• Taliban & the Afghan War
![Page 10: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/10.jpg)
History (contd.)
• Frederick Sertuner 1806: isolated the crystalline pure substance from opium that he named morphine ( after morpheus, the Greek god of dreams.
• Arnold Beckett in 1950: Proposed that morphine like compounds act by binding to specific receptors in the brain
![Page 11: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/11.jpg)
Mapping of the morphinoids
•Huda Akil•John Leibeskind, UCLA
•Stimulus Produced Analgesia•Periaqueductal Grey matter
•Reversed by antagonists
![Page 12: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/12.jpg)
Mapping of the morphinoids
•Avram Goldstein, Stanford
•Grind and Bind technique
•Radiolabelled opioids
![Page 13: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/13.jpg)
Receptors
•Solomon Snyder &•Candace Pert, John Hopkins
•Grind and Bind technique•Improved radiolabelling techniques
•Discovery of Mu receptors in 1973
![Page 14: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/14.jpg)
Substance X
•Hans Kosterlitz &•John Hughes, Aberdeen University, Scotland
•Pig brain soup•Guinea Pig Ileum
•Discovery of ENKEPHALINS in 1973
![Page 15: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/15.jpg)
Endogenous Opioid Systems
• An agent found within the brain that acts through an opioid receptor is called as an endogenous opioid.
• Principally three classes – enkephalins, endorphins, dynorphins
• All are peptides derived from distinct large precursor proteins - POMC, preproenkephalin, preprodynorphin
• Common amino terminal sequence: TYR-GLY-GLY-PHE-(MET OR LEU)
![Page 16: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/16.jpg)
Endogenous Opioid Systems
• The distribution of cells producing these three different types of endogenous opioids varies: – limited to arcuate nucleus and hippocampus in case of
POMC– in the areas of brain related to pain producing
pathways in case of preproenkephalins– Wider distribution in case of preprodynorphins
• ENDOMORPHINS – newly discovered endogenous opioids with atypical structures and selectivity towards μ receptors
![Page 17: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/17.jpg)
Functions of Endogenous Opioids
• Modulation of pain perception
• Modulation of Motor activity for sustained periods – “runners high”
• Autonomic regulation
“When I’m tired, I go for a run and feel I have more energy when I’m done.”
![Page 18: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/18.jpg)
OPIOID RECEPTORS
• μ, κ and δ; the three opioid receptors • Rhodopsin family of GPCRs• Disributed through the brain & spinal cord; and
also outside the CNS – vascular tissues, cardia, airway/lung, gut and cells of the immune system.
• IUPHAR – MOP, KOP & DOP• Opiate receptor-like protein (ORL1 or NOP) with an
endogenous ligand ‘nociceptin/orphanin(F/Q)’
![Page 19: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/19.jpg)
OPIOID RECEPTORS (contd.)
• Upon activation of the receptors , Gi/Gs coupling occurs leading to a large no. of intracellular events:– Inhibition of adenylyl cyclase activity– Reduced opening of voltage-gated Ca2+ channels– Stimulation of K+ current through GIRKs (G protein-activated inwardly rectifying K+ channels)– Activation of PKC & PLCβ
![Page 20: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/20.jpg)
Pharmacokinetics
![Page 21: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/21.jpg)
Absorption
• Modestly absorbed through GI tract -oral, rectal,
• Depends on lipophilicity• High first pass metabolism• Morphine - ~25% bioavailability by oral route• Codeine & oxycodone – low FPM• Well absorbed through SC & IM routes• Nasal Insufflation – rapid rise in blood levels
![Page 22: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/22.jpg)
Distribution
• 1/3rd of morphine is plasma protein bound• They achieve high concentrations in highly
perfused tissues – brain, liver, kidneys & spleen
• In chronic administration – this buildup can take place & opioids are found in the plasma long after their dosage has been stopped
![Page 23: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/23.jpg)
Metabolism
• In liverMorphine morphine-6-glucuronide, morphine-3-
glucuronideThese have significant activity themselves.
• CYP3A4 & CYP2D6 are involved in biotransformation of morphine congeners like heroin, codeine, fentanyl etcEx: Increased & Decreased activity of CYP2D6
![Page 24: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/24.jpg)
Excretion
• In kidneys,M6G & M3G are excreted by glomerular filtration.CRF can cause elevated levels of these metabolites
& lead to adverse effects – seizures, CNS depression
![Page 25: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/25.jpg)
Pharmacodynamic effect profile of Clinically Used
Opioids
![Page 26: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/26.jpg)
Central Nervous System effects
![Page 27: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/27.jpg)
Analgesia• When given to patients in pain:
less intense, tolerable and they feel more comfortable with relief of distress
• When given to normal patients:frankly unpleasant with drowsiness, difficulty in mentation, lessened physical activity and apathy
![Page 28: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/28.jpg)
Analgesia – Different pain states
• Acute nociception: activation of small high threshhold sensory afferents, Aδ & C fibres Spinothalamic tracts anterior cingulate cortex ( limbic system).
• Examples: hot plates, needle prick, incisions
![Page 29: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/29.jpg)
Analgesia – Different pain states
• Tissue Injury:Ex: Burns,
abrasion, joint inflammation, musculoskeletal injury
![Page 30: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/30.jpg)
Analgesia – Different pain states
• Nerve Injury:Activation of Aβ Ex: Nerve
compression, chemotherapy,
diabetes, etc
![Page 31: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/31.jpg)
Analgesia – Mechanism
• Supraspinal Action
![Page 32: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/32.jpg)
Analgesia – Mechanism
• Spinal Opiate Action
![Page 33: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/33.jpg)
Analgesia - Mechanism
Peripheral Mechanism:• Basic tenet of Opiate pharmacology has been
that these drugs act centrally• Recently, in conditions of inflammation it has
been found that opioids act directly even on the peripheral terminals of small primary afferents.
![Page 34: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/34.jpg)
Mood alterations & Rewarding properties
• Pathways – Mesocorticolimbic Dopamine system
Opiates increase DA release in the Nucleus Accumbens.
![Page 35: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/35.jpg)
Mood alterations &
Rewarding properties
![Page 36: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/36.jpg)
CNS depression – Respiration
• Respiratory depression: primary cause of morbidity secondary to opioid therapy.
• All phases of respiratory activity – rate, minute volume, tidal exchange; aperiodic & irregular breathing
1. Direct depression of rhythm generation in ventrolateral medulla
2. Desensitization of brainstem chemoreceptors which normally respond to rising PCO 2
3. Also desensitize the carotid & aortic chemosensors which usually respond to hypoxia.
![Page 37: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/37.jpg)
Effect on Cough
• Direct inhibitory effect on the cough centre of medulla
• Without loss protective glottic function• There is no relation between the suppression
of cough & respiratory depression.• Centrally acting antitussives –
dextromethorphan, codeine, pholcodeine
![Page 38: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/38.jpg)
Effect on Nausea & Emesis
• Direct stimulation of CTZ• A vestibular component is also involved• Apomorphine – a congener of morphine is
highly emetic but has no action on opioid receptors
• 5HT3 receptor antagonists are used for opioid induced nausea & vomiting
![Page 39: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/39.jpg)
Seizure & Convulsions
Some opioids at a slightly higher doses can produce epileptogenic activity
• Meperidine• Frank seizures & myoclonus • Several mechanisms– Inhibition of inhibitory interneurons– Direct stimulatory effects– Actions mediated by non-opioid receptors by their
metabolites
![Page 40: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/40.jpg)
Other effects
• Temperature regulation: Slight fall in body temperature– In withdrawal, there will be rise
• Miosis: Parasympathetic pathways by inhibition of GABAergic transmission– very last action to develop tolerance
• Motor tone: high doses increase the muscle tone chest wall rigidity, increased propensity to myoclonus
![Page 41: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/41.jpg)
Peripheral effects
![Page 42: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/42.jpg)
Neuroendocrine Effects
• Broadly Opioids block the release of many hormones of the HPA axis.
A. Adrenal & sex steroid hormones: general decrease in the release of testosterone, DHEA, cortisol and also the gonadotrophins from the pituitary– Direct effect on pituicytes & also a indirect effect
on hypothalamic neurons decreased releasing hormones
![Page 43: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/43.jpg)
Neuroendocrine Effects
• endocrinopathies, Hypogonadotrophic hypogonadism, decreased libido, menstrual irregularities, effect on secondary sexual characteristics!
B. Prolactin: increased secretion due to loss of inhibitory control of dopamine
C. Oxytocin & Vasopressin: KOR agonists inhibit the release of both the hormones
![Page 44: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/44.jpg)
Cardiovascular Effects
• Peripheral vasodilatation, reduced peripheral resistance and inhibition of baroreceptor reflexes – orthostatic hypotension– histamine release– Blunting of reflex vasoconstriction in response to PCO2
• Coronary Artery Disease:– Decreasing preload, inotropy and chronotropy– Decrease in O2 consumption, left ventricular end-
diastolic volume & cardiac work
![Page 45: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/45.jpg)
Cardiovascular Effects – (contd.)
• This protective effect is partly mediated by increase in the centrally mediated vagal outflow.
• Can aggravate hypovolemic shock• Respiratory depression CO2 retention
cerebral vasodilatation increase in ICT• Can be arrhythmogenic
![Page 46: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/46.jpg)
Effect on GI Tract
• Opioid receptors – dense distribution in the enteric plexuses
• Stomach: – delays gastric emptying– also decreases the secretion of HCl
• Intestine:– diminishes propulsive activity in both SI & LI– Intestinal secretions are reduced by inhibitpry
effects on secretomotor neurons
![Page 47: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/47.jpg)
Effect on other smooth muscle
Ureter & Urinary Bladder• Inhibition of urinary voiding reflex• Increase in the tone of external sphincter increase in
the volume of the bladder Uterus• Restores the tone of hyperactive bladder secondary to
oxytocicsBiliary Tract• Sphincter of Oddi contracts – hence some pts with biliary
colic will experience more pain when morphine is given
![Page 48: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/48.jpg)
Effect on Immune system
• Opioid receptors are present on different cells of the immune system like neutrophils, natural killer cells – direct modulation of their function
• Suppression of HPA axis• In toto, the appear to suppress the immune
function, but in the presence of pain syndromes they appear to improve immunity!!
![Page 49: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/49.jpg)
Clinical Pharmacology
![Page 50: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/50.jpg)
Classification
• Receptor AffinityA. Opioid Agonists: Morphine, Codeine,
Meperidine, Fentanyl, Methadone, TramadolB. Opioid Agonist/Antagonist & Partial Agonist:
Pentazocine, Nalbuphine, Butorphanol, Buprenorphine
C. Opioid Antagoinists: Nalorphine, Naloxone, Naltrexone, Naltrindole, Nalmefene,
![Page 51: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/51.jpg)
Pethidine (Meperidine)
• Potent MOR agonist• Used in post op pain, chronic pain of severe
degree & post anesthetic shivering• Its metabolite normeperidine is epileptogenic• It can block neuronal uptake of 5HT3 – can
cause serotonin syndrome if used with MAO inhibitors & SSRIs
• Concurrent use of Antihistaminics & TCAs can cause additive CNS depression
![Page 52: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/52.jpg)
Levorphanol
• Morphinian series• Agonist at MOR, DOR & KOR• T1/2 – 12 hours• Action & uses similar to morphine.
![Page 53: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/53.jpg)
Loperamide & Diphenoxylate
• Piperidine derivatives• Approved for treatment of diarrhoeas• It slows GI motility • Also may act by decreasing secretions• Loperamide has very less central effects
because of the activity of P-glycoprotein• Diphenoxylate is available in FDC with
atropine
![Page 54: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/54.jpg)
Fentanyl & Its Congeners
• Fentanyl, Alfentanil, Sufentanil & remifentanil• They are used as anesthetic adjuvants and
inducing agents• Short ‘time to peak’ analgesic effect• Rapid termination of effect if used in bolus • MAC-sparing effect on gaseous anesthetics• Can cause muscle rigidity• But very minimal effect on myocardial
parameters
![Page 55: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/55.jpg)
Fentanyl & Its Congeners
• Uses:– Inducing agents especially in cardiovascular
operations – high dose fentanyl & sufentanil– Short procedures – remifentanil– Chronic analgesia – epidural– Cancer pain – transdermal patches
![Page 56: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/56.jpg)
Methadone
• Long acting MOR agonist• Racemic mixture – L isomer is more potent• Similar to morphine but enhanced duration• Can cause prolongation of QT interval –series
cardiac arrhythmias
Propoxyphene: Similar to methadone
![Page 57: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/57.jpg)
Tramadol
• Synthetic codeine analogue• Weak MOR agonist• Used in the treatment of mild to moderate
pain• Epileptogenic
Tapentadol
![Page 58: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/58.jpg)
Pentazocine
• KOR agonist and a weak antagonist/partial agonist at MOR receptors
• Effects similar to morphine – analgesia, sedation, respiratory depression.
• At high doses – dysphoric & psychotomimetic effects
• Tachycardia & increase in BP• Can precipitate withdrawal in morphine
dependant patients
![Page 59: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/59.jpg)
Nalbuphine
• KOR agonist with competitive antagonistic activity at MOR
• Analgesia is similar• Respiratory depression
exhibits ceiling effect – so relatively safe drug
Butorphanol
• Morphinian compound• Similar to Nalbuphine
![Page 60: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/60.jpg)
Buprenorphine
• Highly lipophilic partial agonist at MOR• 20-50 times more affinity to MOR than
morphine• Used in analgesia & management of Opioid
dependence
![Page 61: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/61.jpg)
Opioid Antagonists
• Nalorphine, • Naloxone, • Naltrexone, • Naltrindole, • Nalmefene
They have very little effect if given alone. They produce their effects only when given with agonists or in some cases the endogenous opioid system is activated
![Page 62: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/62.jpg)
Opioid Antagonists
Effect in the absence of Agonists• Mild hyperalgesia• Reverse the hypotension associated with
different forms of shock to some extent• Mild dysphoria• Neuroendocrine effects
![Page 63: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/63.jpg)
Opioid Antagonists
Effect in the presence of Agonists• Effect on Acute opioid actions:– Increase in respiratory rate & depth– Reversal of dysphoric & psychotomimetic effects– Overshoot phenomenon– Rebound release of catecholamines tachycardia,
hypertension, ventricular arrhythmias
![Page 64: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/64.jpg)
Opioid Antagonists
Effect in the presence of Agonists• Effect on Opioid dependant patients:– Moderate to severe withdrawal – Depends on the dose of the antagonist and also
on the degree and duration of dependence– Methylnaltrexone & Alvimopan can reverse the GI
effects of opioid dependence without pptting central withdrawal syndrome.
![Page 65: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/65.jpg)
Opioid Antagonists - Uses
• Acute toxicity /overdosage• Management of constipation• Management of abuse syndromes• Trauma – shock, stroke, brain trauma
![Page 66: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/66.jpg)
Centrally acting antitussives
• Codeine, hydrocodone & oxycodone• Dextromethorphan:– Analog of codeine– Elevates the threshold of – Fewer subjective & GI side effects
• Pentoxyverine & Caramiphen
![Page 67: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/67.jpg)
Therapeutic Uses of OPIOIDS
Analgesia• Most potent pain-relieving drugs available• Adequate pain relief• Many guidelines are available – WHO,
American pain Society, Federation of State medical board
![Page 68: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/68.jpg)
![Page 69: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/69.jpg)
![Page 70: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/70.jpg)
Therapeutic Uses – Routes of administration
1. Patient controlled analgesia2. Spinal Delivery3. Local drug action4. Rectal administration5. Inhalation6. Oral transmucosal administration7. Transnasal Administration8. Transdermal & Iontophoretic Administration
![Page 71: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/71.jpg)
Therapeutic Uses – Other uses
• Dyspnoea- Acute LVF & Acute Pulmonary edema– Pink puffers
• Cough• Diarrhoea• Shivering• Anaesthetic adjuvants
![Page 72: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/72.jpg)
Contraindications & Cautions
• Use of pure agonists with weak partial agonists
• Use in patients with head injuries• Use in pregnancy• Use in impaired pulmonary reserve• Use in patients with impaired hepatic &/or
renal function• Use in patients with endocrine disease
![Page 73: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/73.jpg)
Toxicity, Tolerence & Dependence
![Page 74: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/74.jpg)
Tolerance
• When large doses are given at short intervals• Analgesia, sedation & respiratory depression
are the commonest effects to develop tolerance• Respiratory depression 60mg & 200mg• Tolerance does not develop to miotic,
convulsant & constipatory effects• Cross tolerance – partial & incomplete opioid
rotation
![Page 75: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/75.jpg)
PhysicalDependence
• Dependence refers to a state of adaptation manifested by receptor/drug class-specific withdrawal syndrome produced by cessation of drug exposure.
• Signs & symptoms – rhinorrhoea, yawning, chills, piloerection, hyperventilation, hyperthermia, diarrhoea, hostility & anxiety
• Antagonist precipitated withdrawal
![Page 76: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/76.jpg)
Psyschological Dependence
• Reason for opioid abuse:– Euphoria, indifference to stimuli, sedation, abdominal
experiences similar to intense orgasm– Reinforced by physical dependance
• Therapy:– Methadone– Clonidine– Transcutaneous electrical stimulation– Buprenorphine– Naltrexone
![Page 77: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/77.jpg)
Toxicity & Overdosage
• Clinical overdosage, accidental overdosage or suicidal
• Signs & symptoms: – Triad of coma, pinpont pupils & depressed
respiration– Anuria, frank convulsions in children– Noncardiogenic pulmonary edema
![Page 78: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/78.jpg)
Treatment of Opioid toxicity & Overdosage
• Ventilatory support• DOC – IV Naloxone 0.01mg/kg• Treatment should be such that reversal should
occur without precipitation of withdrawal• If the poisoning is due to methadone the pts
may slip back into coma as antagonist have short half lives
![Page 79: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/79.jpg)
Screening Methods
![Page 80: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/80.jpg)
Acute pain• MODELS USING THERMAL STIMULUS1. Hot plate method2. Tail –Flick method• MODELS USING ELECTRICAL STIMULUS1. Tooth pulp test2. Monkey shock titration test• MODELS USING CHEMICAL STIMULUS1. Formalin test2. Writhing test3. Rat sigmoid colon model4. Inflammatory uterine pain model
![Page 81: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/81.jpg)
• MODELS USING MECHANICAL STIMULUS1. Haffner’s tail clip method2. Randall Selitto test_______________________________________ Chronic pain3. Neuropathic pain models4. Vincristine-induced Neuropathy model5. Diabetic neuropathy model6. Persistent postthoracotomy pain model7. Rat model of incisional pain
![Page 82: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/82.jpg)
Cancer pain• Rat model of bone cancer pain
_____________________________________
In Vitro Methods1. 3H-Naloxone binding assay2. µ Opiate receptor binding assay3. Assay to study cannabinoids activity
![Page 83: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/83.jpg)
References
1. Essentials of Medical Pharmacological, K D. Tripathi, 6th ed2. Pharmacology and Pharmacotherapeutics, R S. Satoskar, S
D. Bhandarkar, Nirmala N. Rege, 21st ed.3. Goodman & Gilman’s The Pharmacological Basis of
Therapeutics, 12th ed4. Rang & Dale’s Pharmacology 6th ed,5. Basic & Clinical Pharmacology, Katzung’s, 11th ed.6. Principles of Pharmacology: The Pathophysiologic Basis of
Drug Therapy, Golan, LippinCott’s7. Harrison’s Principles of Internal Medicine, 17th ed.
![Page 84: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/84.jpg)
References
8. Anatomy of a scientific Discovery, Jeff Goldberg, Bantam Books.
![Page 85: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/85.jpg)
Thank you!
“Religion is the opium of the masses.” – Karl Marx
![Page 86: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/86.jpg)
Mechanisms of tolerance
• Receptor disposition• Adaptation of intracellular signalling
mechanisms in the opioid receptor bearing neurons
• System level counteradaptation• Fractional occupancy requirements
![Page 87: Opioid pharmacology - A comprehensive subject seminar on Opioids](https://reader037.vdocuments.net/reader037/viewer/2022103113/554b55e3b4c905793d8b4ab2/html5/thumbnails/87.jpg)
Structure Activity Relationship
• Message – Address concept• Message: a protonated nitrogen, a phenolic
ring, a hydrophobic domain.