OPIOID ANALGESICS Dr.Abdul latif Mahesar Department of Pharmacology King Saud University
Pharmacology of opioid analgesics
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Transcript of Pharmacology of opioid analgesics
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Pharmacology of
Opioid AnalgesicsDr.Rathnakar U.P.
MD.DIH.PGDHM
MBBS. 5th Sem
2nd July 2013
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Pain
Unpleasant sensory and emotional experience
associated with actual or potential tissue damage
Subjective experience
Difficult to quantify
Warning signal
Can be pointless and contribute to discomfort
Demands instant relief-highly impresses layman
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Pain-Types
Superficial-cutaneous
Somatic
Deep non-visceral[muscles, joints]
Deep visceral
Referred
Psychogenic or functional pain
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Pain-characteristics
Superficial
Well defined
Skin-[pricking]
Inflammation
Neuralgia
Migraine-ishemia
TAO
Non visceral
Dull
BP, pulse-
normal
Visceral
Diffuse
Autonomicresponse
Renal colic, MI,
peptic ulcer
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Pain-characteristics
Referred
Deep pain can be
referred
To the cutaneous
area supplied by
the same segment
Heart- L.arm
Diaphragm-
shoulder
Psychogenic
Vague
No anatomicalpattern
Does not
disturb sleep
Followsexhaustion
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Pain pathways
Pain
receptors
Afferent-
fibres
SG-dorsal horn
Gate control
Spinothalamic tract
Thalamus & postcentral
gyrus & limbic system
Inhibitory pathways
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[Depress CNS]
[Do not depress CNS]
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Opioids
Opiates
[Products from opium
poppy]
Opioids
[Natural, synthetic &
semisynthetic drugs
with morphine like
action]
Opium -dried latex obtained from opiumpoppies Opium contains up to 12%morphine, - which is most frequentlyprocessed chemically to produce heroin.
The latex includes-
-Codeine-non-narcotic alkaloids, such aspapaverine, thebaine and noscapine .
The latex is obtained bylacerating the immaturefruits -the latex leaks out
and dries to a sticky brownresidue. This is scraped offthe fruit.
Papaver somniferum
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Opioids act on
endogenous opioidreceptors
Why should there be receptors in our
body for a substance found inPapaver somniferum???
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Endogenous opioids
[Peptides in CNS with opioid like action]
Beta-Endorphin
Enkephalin
Dynorphins Nociceptin/orphanin Endomorphins
Role: Endogenous analgesics, neurotransmittors, behavior modulators
OpioidReceptors
Mu, kappa, delta
Opioids
[Natural, synth, semisynth][Endogenous]
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Opioids-Classification[Agonists & Mixed action opioids & antagonists]
Natural
Morphine Codeine
Semisynthetic
Heroin Pholcodeine
Synthetic
Pethidine Fentanyl
Methadone
Tramadol
Classification-Chemical structure??????
Agonists
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Opioids- Receptors
Mu
.
Kappa
Others
Nociceptin/Orphanin
FQ
Delta
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MECHANISM OF ACTION
Ascending pathways
Block
Open
13
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MECHANISM OF ACTION
Descending pathways
Promote Inhibition of pain impulses
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Opioid-MOA
Inhibit
Inhibit pain impulse transmission
Inhibit pain perception
Modifies emotional component
3
5
5. Promotes descending inhibition
4
5
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Inhibition of pain
[Gate control]
Pain
Touch
Why when we bang our head, it feels better when we rub it.
16
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Morphine-prototypePharmacological actions-CNS
CNS-Depressant effects
Analgesia
Sedation
Euphoria
Resp.depression
Depress cough center
Temp reg.center
Vasomotor center
CNS-stimulant effects
CTZ
E.W.Nucleus
Vagal center
Truncal rigidity
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Morphine-prototypeOther-Pharmacological actions
Endocrine-ADH
CVS-Vasodilation
GIT-constipation Biliary tract-spasm of
Oddi
UB-urgency and
difficulty
RS-bronchospasm ANS-Symp.stim-
hyperglycemia
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Morphine-prototype
ADEs
Sedation, lethargy, dysphoria
Vomiting
Allergy Apnoea
Poisoning
Tolerance & Dependence
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Morphine-prototype Pharmacologicalactions CNS - depressant
Analgesia
Very strong
Dull, deep visceral pain
Peripheral and central
Anxiety, fear, apprehension,
autonomic [emotional
components]
Pain is no longer unpleasant-ignores
No proportionate CNS
dep.[unlike GA]
No ceiling effect
Sedation
Different from hypnotics
No ataxia, motor in-
cordination or excitement Not anitconvulsant
[epileptogenic]
Mood
Euphoria [dysphoria-rare]
rush Kick =orgasm
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Morphine-prototype Pharmacologicalactions CNS - depressant
Respiration
Dose dependent dep.-Resp
center
Indifference to breathing In morphine poisoning hypoxic
drive maintains respiration
Dangerous to give 100%
continuous oxygen in poisoning Resp arrest - cause of death in
poisoning
Cough
Depressed
Temperature
Hypothermia
VMC
Fall of BP
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Morphine-prototypePharmacological actions-CNS
CNS-Depressant effects
Analgesia
Sedation
Euphoria
Resp.depression
Depress cough center
Temp reg.center
Vasomotor center
CNS-stimulant effects
CTZ-
E.W.Nucleus
Vagal center
Truncal rigidity
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Morphine-prototype Pharmacological actionsCNS-StimulantCTZ
Vomiting
E.W.Nucleus [
Miosis [No tolerance]
Not topical-central action
Some cats-mydriasis!
Vagal center
Bradycardia
Cortical areas, hippocapus
Truncal rigidity
Proconvulsant [No tolerance]
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Morphine-prototype Pharmacologicalactions Other actions
CVS-Vasodilation
1. Histamine release
2. VMC depressed
3. Direct on BV
Shifts bloodpulmonary-
systemic=acute LVF
Decreases cardiac load=MI
CO2=Cerebral vasodilation=
ICT= CI in head injuries
GIT-constipation [No tolerance]
1. Movement
2. Spasm of sphincters
3. Decreases secretions
4. Inattention to defecation reflex
Neuroendocrine
ADH -reduce urine
FSH, LH, ACTH-Impotence,
libido, infertility
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Morphine-prototype Pharmacologicalactions On Other Smooth muscles
Biliary
1. Spasm of ODDI
U.Bladder Tone-detrusor and sphincter-
urgency & difficulty
Uterus
1. May prolong labour
Bronchi
Spasm-histamine
ANS
Mild Symp.stimulation-
hyperglycemia
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Receptor ORL1Analgesia
Supraspinal +++ -? - Antiopioid
Spinal ++ ++ + ++
Peripheral ++ - ++ -
Respiratory depression +++ ++ - -
Pupil constriction ++ - + -
Reduced GI motility ++ ++ + -
Euphoria +++ - - -
Dysphoria & hallucinations - - +++ -
Sedation ++ - ++ -Physical dependence +++ - - -
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Morphine
PK
Oral- BA to 1/6 of parenteral
Rectal, s.c, i.m, i.v.
Spinal-less resp.dep. Route is chosen depending upon the
condition
Crosses placenta Metabolized in liver[first pass]
Duration of action-4-6 hours
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Morphine ADEs
Th.doses[side effects]
Resp.dep
Idiosyncratic
Hypotension
Bronchospasm
Allergic
Constipation
Toxic doses
Acute morphine poisoning
Prolonged use
Tolerance
Physical dependenceHistamine
Morphine
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Morphine
Adverse effectsTolerance and dependence
Tolerance
Repeated use
PK and PD
For all actions except-Miosis, Constipation,
proconvulsant
Constipated & pin point pupils
Cross tolerance with opioids and other CNSdepressants
Cross tolerance incomplete- opioid rotation
Addicts tolerate grams
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Tolerance
Morphine
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Morphine
Adverse effectsTolerance and dependence
Dependence Psychological & physical-state of addiction
Dependence leads to abuse [more among medical personnel]
Withdrawal: Drug seeking behaviour, lacrimation, sweating, yawning,
anxiety, fear, mydriasis, insomnia, tremors, diarrhoea, colic,
dehydration, rise in BP, wt.loss, convulsions, CV collapse.
Treatment of dependence Acute [Detoxification]- Clonidine orLofexidine [reduce NA effects]
Chronic-[substitution] therapy with methadone
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Morphine
Adverse effects
Side effects[Th.doses]: Sedation, mental
clouding, dysphoria, vomiting,
constipation, resp.depression, blurred
vision, urinary retention, fall of BP
idiosyncrasy and allergy; Urticaria, itching,
swelling of lips
A local reaction at injection site,generalized itching may occur due to
histamine release.
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Morphine
Adverse effects
Apnoea of new born-
When morphine is given to the mother
during labour.
Naloxone 10 g/kg injected into
umbilical cord is the treatment of choice
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Morphine
Adverse effects
Acute morphine poisoning
Accidental, suicidal, overdose in abusers
Toxicity-50mg. Lethal-250mg Respiratory support
Gastric lavage- KMno4even when injected
[highly basic drug] Antidote-Naloxone 0.4 to 0.8 mg i.v. every
2mts-till resp.normal
Repeated every 1-4 hours[short duration
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Morphine
Precautions
Infants, elderly, with
resp.insufficiency[emphysema]
Bronchia asthma- histamine release
Hypotensive states
Urinary retension-elderly
Hypothyroidism, liver or renal failure-moresensitive
Unstable personalities-likely to be addicted
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Morphine
Precautions
Head injury-Contraindicated
1. Retained CO2- raises ICT2. Therapeutic doses-resp.depression
3. Vomiting, miosis, mental clouding by
morphine interferes with head injuryassesment [Glasgow scale???]
Drug interactions
Tripathi VIIth ed. Page 474
Morphine Respiratorydepression
CO2retention
Celebral
vasodilatation
Intracranialtension
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Morphine-CIs
Head Injury Bronchial asthma
Undiagnosed abdominal pain
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Morphine
Dose
Oral-10-50mg
S.c or I,m-10-15mg
i.v.-2-3 mg Epidural,
Preparations:Tablets, slow release tablets,
ampoules[10mg/ml]
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Morphine
Uses
To relieve severe visceral pain
MI, Burns, Post op.pain, fracture of long bones
Acute LVF
Relieves pulm.congestion
Preanesthetic
Analgesic & antianxiety[not in surgical anesthesia]
Frightening situations
RTA without head injury Not to be used as antitussive & antidiarrhoeal though effective
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Opioids-Classification
Natural
Morphine
Codeine
Semisynthetic
Heroin
Pholcodeine
Synthetic
Pethidine
Fentanyl
Methadone
Tramadol
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Opioids
Pethidine[meperidine]
1. 1/10th analgesic potency of morphine
2. Rapid onset-short duration
3. Not anti-tussive
4. Action on smooth muscles [, ]
5. Resp dep=morphine
6. Abuse=morphine
7. Tachycardia [anticholinergic]
8. Less histamine release[safe in asthmatics]
9. LA action
10.Orally better absorbed
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Opioids
Pethidine [Metabolism]
Pethidine
Meperidinic acid[Major metabolite]
Norpethidine[Minor metabolite]
Hydrolysis
DemethylationExcitatory
symptoms in
over dosage
MAO
inhibitors
interfere
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Opioids
Pethidine [ADEs]
Similar to morphine
Atropinic like[dry mouth, blurred vision]
Tolerance and physical dependence slow
Interaction with
MAO inhibitors[block hydrolysis]
And SSRIs [Pethidine blocks uptake of 5HT]
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Opioids
Pethidine [Uses]
Analgesic [Substitute to morphine]
Preanesthetic
Shivering during anesthesia & i.v. infusion [2action ADEs-CNS stimulation-norpethidine [accumulates]
Preferred during labour [not absolute]-does not delay labour
Dose: 50-100mg-i.m. , s.c.
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How pethidine differs from
morphine?
1. Less potent[1/10]
2. Rapid onset/ short duration
3. Less histamine
4. Anticholinergic-tachycardia5. Less sedation
6. Less antitussive
7. Less constipation
8. Less retention of urine9. Does not delay labour, less resp dep. In neonates
10. LA action
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Diphenoxylate & loperamide
Pethidine congeners
Not analgesics
Antimotility action on GIT
Symptomatic treatment of diarrhea
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Opioids
Codeine
Less potent analgesic
[CodeineMorphine]
Selective antitussive-own action [Linctus
codeine]
Orally effective
Abuse liability is low.
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Fentanyl[Sufentanyl, Alfentanyl, Remfentanyl]
Pethidine congener
100 times potent than morphine
Highly lipid soluble
i.v-in anesthesia[TIVA]
Transdermal patch-cancer analgesia
Anesthetic adjunct Epidural & spinal routes
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Methadone
Synthetic
Similar to morphine
Orally effective, longer acting
Accumulates
Less euphoria, no kick
Withdrawal symptoms are mild Used as substitute in morphine
dependence [1mg=4mg of morphine, 2mg
of heroin, 20mg of pethidine]
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Tramadol
Weak agonist at receptors
Inhibitor of reuptake of noradrenaline / 5-HT
Naloxone blocks resp.dep, not analgesia
Orally effective, metabolite is also analgesic
Better side effect profile than most opioids
Preferred in mild to moderate pain-not effective in severe pain
Caution in epileptics
Do not use along with MAOI
Tapentadol
U
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Uses
Morphine and congeners
Severe pain [any pain with care]
Preanaesthetic
Balanced anaesthesia
Relief of anxiety/apprehension
Acute LVF
Cough [Codeine-not morphine!] Diarrhoea [loperamide, diphenoxylate]
U
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Uses
Morphine and congeners
Severe pain
Mild pain-morphine or Pethidine not used
Abuse potential should be considered
Severe pain opioids should not be
withheld
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O i id t
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Opioid receptors
1. - Most of the analgesic effects of opioids, and for some majorunwanted effects (e.g. respiratory depression, euphoria, sedation and
dependence). Most of the analgesic opioids are -receptor agonists.
2. - Receptor activation results in analgesia but also can beproconvulsant.
3. - Analgesia at the spinal level -sedation, dysphoria andhallucinations. Some analgesics are mixed agonists/ antagonists.
4. ORL15.
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Opioids[Functional classification]
Agonists [,, k] [natural, semi synth.,synth]
Strong [Morphine] Mild [Codeine]
Mixed[agonist & antagonist]
Nalorphine, pentazocine, butorphanol,
Buprenorphine [Partial agonist]
Antagonists [,, k]
[Naloxone, Naltrexone, Nalmiphene]
Mi d[ g i t & t g i t]
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Mixed[agonist & antagonist]
Pentazocine
[antagonist]k [agonist]
Analgesia at spinal level
Withdrawal symptoms in morphine addicts
Dysphoria
Weak analgesic & less ADEs
Raise in BP & tachycardia- CI in ischemia Tolerance & dependence+
Mi ed[agonist & antagonist]
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Mixed[agonist & antagonist]
Butorphanol
[antagonist]k [agonist]
Similar to pentazocine
Three times more potent -morphine
Moderate painful conditions
Can be given by nasal route
Levorphanol
Mixed[agonist & antagonist]
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Mixed[agonist & antagonist]
Buprenorphine
[Partial]k [antagonist]
More potent than morphine, lower analgesic
Effective sublingually
Orally absorbed-First pass-not effective
Actions not completely reversed by
Naloxone [tight binding to receptors] CI-in labour
Pure antagonist
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Pure antagonist
Naloxone
Blocks all opioid receptors[more effectively ]
In the absence of opioids-
Increases pituitary hormonal levels
In the presence of opioids-
Injected i.v. All actions of morphine are reversed
Also antagonizes the actions of mixed action opioids
[Buprenorphine less]
Precipitates withdrawal effects in morphine addicts Blocks actions of endogenous opioids [no hyperalgesia!]
Blocks effects of acupuncture, placebo [?endogenous opioids
are involved]
Pure antagonist
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Pure antagonist
Naloxone-uses
Drug of choice for morphine poisoning-i.v. dose???
To reverse neonatal asphyxia-morphine induced
Overdose of mixed action opioids[except
buprenorphine] Adjunct in intraspinal anesthesia[low dose has no
effect on analgesia]-respiratory depression
Diagnosis of opium addicts Partly reverses alcohol intoxication
To raise BP in shock-increases cortisol levels
Other pure antagonists
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Other pure antagonists
Naltrxeone:
More potent than naloxone-long acting
Orally effective
To block the effects of opioids in addicts in deaddicted
To reduce alcohol craving
Hepatotoxic
Nalmefene-orally effective. No hepatotoxicitry
Alvimopan, Methyl naltrexone:
Does not cross BBB-no withdrawal symptoms in addicts
Used to reverse peripheral actions of morphine[eg.
constipation in cancer pts. on opioids]
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Differences
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NSAIDs OPIOIDS
Source Synthetic Natural alkaoids/semisynthetic/ syntheticderivatives
MOA Inhibition of PGsynthesisActs on opioid receptors(, , , , )
CNS Does not depress CNS Depress CNS
Effect on painRaises pain threshold +Also alters painperceptionOther actions Most are
antiinflammatory andantipyretic
No such action
ADEs GIT and othersNo dependence &tolerance
Dependence & tolerancemost important
Availability Many are OTC drugs Very strictly controlled