Opioids Pharmacology

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    Analgesics in DentistryOpioids

    PharmacologyHiwa K. Saaed PhD

    Pharmacology & ToxicologyCollege of Pharmacy

    University of Sulaimani 11

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    Analgesic

    Analgesic an agent that selectivelyrelieves pain by acting in the CNS oron peripheral pain mechanisms, withoutsignificantly altering the consciousness

    Pain is:

    acute or chronic

    Consequence of complex neurochemicalprocesses

    Subjective: perceptive and descriptive

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    Analgesic

    Alleviation of pain depend on its type

    Headache, arthritic pain Rx NSAIDs

    Neurogenic pain Rx TCA Amitriptyline or

    SSRI Fluoxetine

    Severe or chronic malignant pain Rx Opiodsare DOC

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    History / Definitions

    Ancient Egypt papyrus records reported theuse of opium for pain Relief

    Opium mixture of alkaloids from the poppyseed

    Opiates naturally occurring alkaloids suchas morphine or codeine obtained from the

    juice of the opium poppy

    Opioid broad term to describe all naturalor synthetic compounds that work at theopioid receptors and produce morphine-likeeffects 44

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    Endogenous Opioid peptidesneurotransmitters

    endorphin, enkephalins & dynorphins

    Opiods act by binding to specific opioidreceptors in the CNS to produce the actionof endogenous peptide neurotransmitters

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    Opioid Classifications

    Chemistry Natural Semisynthetic Synthetic

    OPIOIDRECEPTOR

    Mu( ) Kappa( ) Delta ( )

    INTRINSICACTIVITY

    Agonists Antagonists Mixed Agonistsand Antagonists

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    Opioid Classifications

    Opioids can further be classified by their actions:

    agonist,

    or partial/weak agonist,

    or antagonist Mixed agonist/antagonist

    An agonist has both affinity and efficacy

    An antagonist has affinity but no efficacy

    A partial or weak agonist has affinity, butonly partial efficacy

    Compounds can have differing degrees of affinity

    and efficacy at these various receptors 77

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    Opioid receptorsMu( ), Kappa( ), Delta ( )

    Opioids interact with:

    receptors on the membranes of certain

    cells in the CNS,

    on nerve terminals in the periphery

    on cells of the gastrointestinal tract and

    the anatomic regions urinary bladder.

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    Opioid receptors

    Analgesic properties are mediated:

    mainly via receptors and receptors of the dorsal horn of the

    spinal cord.

    Enkephalins interact more selectivelywith the receptors in the periphery.

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    Endogenous opioid receptors

    MuAnalgesia (supraspinal)MiosisRespiratory depressionEuphoriaPhysical dependenceDecrease GIT motility

    KappaSpinal analgesiaSedationmiosis

    Deltaanalgesia (spinal &supraspinal)release ofgrowth hormoneAffective behaviorPresent in limbic system

    Sigma#DysphoraHallucination (both visual &auditory)Respiratory and vasomotorstimulationmydriasis#less specific bind with nonopioid agent e.g hallucinogen

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    Mechanism ofAction

    All are G-protein coupledreceptors and inhibitadenylate cyclase.

    They are also involved inpostsynaptichyperpolarization:

    (increasing K+ efflux)

    or reducing presynaptic Ca++ influx;

    thus inhibits neuronalactivity.

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    Receptor distribution

    High densities of opioid receptors on peripheralnerve fibers, immune cells and five general areasof the CNS:

    1. Brainstem: respiration, cough, nausea &vomiting, BP, papillary diameter and stomachsecretion.

    2. Medial thalamus: mediating poorly localized

    deep pain3. Spinal cord: in the substantia gelatinosa areinvolved in the receipt & integration on sensoryinput leading to the attenuation of painful

    afferent stimuli. 12

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    Receptor distribution

    4. Hypothalamus: neuroendocrine secretion.

    5. Limbic system: the greatest concentrationin the amygdale, a major role in emotional

    behavior & response and little analgesiceffect.

    6. Periphery: they inhibit Ca+2 dependentrelease of excitatory, pro-inflammatorysubstances (substance P)

    7. Immune cells: undetermined.

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    Opioids

    Strong

    Alfentanil

    Fentanyl

    Heroin

    Meperidine

    Methadone

    Morphine

    Oxycodone

    Remifentanil

    Sufentanil 14

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    Opioid Agonists

    The strongest naturally occurring analgesic drugsare found in opium from the poppy flower,

    morphine and less potent codeine.

    These drugs show a high affinity for the receptor and less affinity for the and receptors.

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    Morphine

    Exert its effects through interaction with central &peripheral opioid receptors, binding results inhyperpolarization, inhibition of nerve firing andpresynaptic inhibition of transmitter release

    Acts at the receptors in lamina I & II of thesubstantia gelatinosa of the cord and decreases therelease of substance P,

    it also inhibits the release of excitatory transmitters

    from nociceptive nerve terminals centrally and inthe cord

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    Morphine Pharmacological

    Actions-Analgesia: Opioids cause pain relief by both

    raising the pain threshold at the spinal cord level

    altering the central perception of pain; awarenessof pain remains but it loses its unpleasant

    character

    Euphoria:

    Opioids produce a sense of contentment and wellbeing, this may be related to stimulation of theventral tegmental tract

    Respiration:

    Opioids cause respiratory depression by decreasing

    the sensitivity of central respiratory neurons to17

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    MorphinePharmacological Actions-

    Suppression of cough reflex:

    Antitussive properties do not correlate

    with analgesic or respiratory depressioneffects; this appears mediated via adifferent receptor complex

    Miosis:

    Results from stimulation of and

    receptors located in the Edinger 18

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    MorphinePharmacological

    Actions-Emesis:Opioids directly stimulate the

    chemoreceptor trigger zone in the areapostrema that causes vomiting

    GI tract:

    Opioids relieve diarrhea by decreasinggut motility and increasing the tone ofintestinal smooth muscle

    Constipation is also resistant totolerance 19

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    MorphinePharmacological

    Actions-Histamine release:

    Morphine causes mast celldegranulation, the release of histamine

    causing urticaria, itching, diaphoresisand vasodilation

    In asthmatics it may precipitate

    bronchospasmHormonal Actions:o

    inhibits the release of GnRH, CRH

    and deceases the release of LH, FSH &20

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    MorphineTherapeutic

    Uses Analgesia:

    Few drugs are as effective as morphine for

    the relief of pain Treatment of Diarrhea

    Anti tussive:

    codeine and dextromethorphanarecongeners with greater antitussive effects

    Acute Pulmonary Edema:

    IV morphine dramatically relieves the21

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    MorphinePharmacokinetics

    Administration: Morphine is poorly absorbed orally; codeine

    is a much more effective oral analgesic

    Both undergo extensive first passmetabolism in the liver. Inhalation is aneffective route but has found favor onlywith non medicinal administration

    Implantable morphine pumps are also nowuse for chronic pain

    Distribution:

    Morphine readily enters all body tissues22

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    MorphinePharmacokinetics

    Metabolism:

    Conjugated in the liver,

    morphine6 glucuronide is a much morepotent analgesic;

    however morphine 3 glucuronide is less analgesic

    Both are excreted in the urine

    with small amounts excreted in the bile

    Hepatic & renal dysfunction both prolongthe normal 4 6 hour duration of action 23

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    MorphinePharmacokinetics

    Note: A patient's age can influence theresponse to morphine.

    Elderly patients are more sensitive tothe analgesic effects of the drug,possibly due to decreased metabolismor other factors, such as decreased lean

    body mass, renal function, etc. Theyshould be treated with lower doses.

    Neonates should not receive morphine

    because of their low conjugating 24

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    MorphineAdverse Effects

    Severe respiratory depression ( , and receptors)

    Constipation (variable, and receptors)

    Nausea and vomiting

    Pupillary constriction ( / receptors)

    Caution must be exercised whenopiates are used in those with liver or

    renal failure 25

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    MorphineAdverse Effects

    In BPH, morphine cause acute urinaryretension

    Patients with adrenal insufficiency ormyxedema may experience extendedand increased effects from the opioids.Morphine should be used with

    cautiously in patients with bronchialasthma or liver failure.

    Note: Many of the effects above can be

    inhibited by opioid receptor antagonists26

    orp ne

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    orp neTolerance &

    Physical

    Dependence Repeated use produces tolerance to the

    effects of respiratory depression,analgesia, euphoria and sedation

    Tolerance does not develop to miosisand constipation

    Physical & psychological dependencereadily occurs

    Withdrawal induces a syndromeassociated with autonomic, motor ands cholo ical res onses that are 27

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    Opioid withdrawal syndrome

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    comparison of the maximum Efficacy versusAddiction / Abuse Potential of Various

    Opioids

    Detoxification of heroin-or morphine-dependentindividuals is usually

    accomplished throughthe oral administrationof

    methadone,

    buprenorphine, or

    clonidine.

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    Drug interactions:

    The depressant actions of morphine areenhanced by phenothiazines, MAOIs,and TCAs.

    Low doses of amphetamine inexplicablyenhance analgesia, as doeshydroxyzine.

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    Meperidine Pethidine ( ,)

    A synthetic opioid structurally unrelatedto morphine

    Mechanism:

    It binds to receptors with some bindingat receptors

    Actions:

    Causes respiratory depression similar tomorphine, but less urine retention

    no significant CV effect when given orally.

    IV administration produces a decrease in31

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    Meperidine

    Therapeutic uses:

    Severe acute pain

    Lacks antitussive activity No anti diarrhea;

    Obstetrics; Produces less smooth musclecontraction/ spasm than morphine

    Pharmacokinetics:

    Well absorbed form the GI tract; it is mostoften given IM

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    Meperidine-Adverseeffects:

    With large repeated doses normeperidine(demethylated meperidine) accumulatescausing

    anxiety, muscle tremors and convulsions

    Causes papillary dilation (vs. miosis withmorphine) in large doses

    Hyperactive reflexes

    Severe hypotension when admin.postop.

    +neurole tics: enhanced de ression33

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    Methadone ( )

    This is a synthetic orally effective opioidthat

    is equipotent to morphine

    but induces less euphoria

    has a longer duration of action

    Mechanism of action: Binds to the receptor.

    Actions:

    An equipotent analgesic to morphine 34

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    Methadone

    Therapeutic uses:

    Used for controlled withdrawal from heroin& morphine

    Self addictive but the withdrawal syndromeis somewhat milder but more protractedthan with other opioids

    Pharmacokinetics:

    Readily absorbed orally, t1/2 24hrs

    Highly protein bound so remains in tissuesfor a prolonged period.

    Transformed in the liver and excreted b35

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    Fentanyl

    Chemically related to meperidine butmiosis

    has 100 times the analgesic potency of

    morphine; used in anesthesia and asanalgesia postop & during labor

    Highly lipophilic: elimination half life is

    longer than morphines as redistributionoccurs

    Rapid onset of action and a short

    duration (15 30 minutes) 36

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    Fentanyl

    Like morphine fentanyl causes miosis(vs. mydriasis)

    Particular risk of the transmucosal ortransdermal routes is respiratorydepression; these delivery routes createa reservoir of drug in the skin or

    mucosa. Hence, the onset is delayed 12hours, and the offset is prolonged

    Fentanyl is often used during cardiac

    surgery because of its negligible effects37

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    Fentanyl derivative

    Adverse effects of fentanyl are similar tothose of other -receptor agonists.

    Because of life-threatening

    hypoventilation, the fentanyl patch iscontraindicated in the management ofacute and postoperative pain or painthat can be ameliorated with otheranalgesics.

    Sufentanil, Alfentanil & Remifentanil arerelated to fentanyl they differ in their

    potency and metabolic disposition. 38

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    Heroin

    Heroin is produced by the diacetylationof morphine which results in a three foldincrease in its potency

    Acetylation allows it to cross the BBBmuch more rapidly yielding a morepronounced euphoria

    May be used IV or smoked, both allowfor rapid distribution,

    heroin is metabolized to morphine

    No medical indication for its use in the39

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    oxycodone

    is a semisynthetic derivative ofmorphine.

    It is orally active and is sometimes

    formulated with aspirin oracetaminophen.

    It is used to treat moderate to severe

    pain and has many properties in commonwith morphine.

    Oxycodone is metabolized to productswith lower analgesic activity.

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    Moderate/Weak Agonists

    CodeineConverted to morphine thus:

    Much less analgesic than morphine

    Less euphoria and has much lowerabuse potential and rarely producesphysical dependence

    An effective oral analgesic

    Does possess significant anti tussiveeffects at sub analgesic doses

    Often formulated with either 41

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    Moderate/Weak AgonistsPropoxyphene

    Derivative of methadone,

    dextro isomer is analgesic, levo isomer is antitussive

    Used for mild to moderate pain; its opioid dose

    equipotency is about half of codeine (require twicedose)

    Often formulated with another over the counter analgesic; combination has greater effect than either

    drug aloneToxic doses may produce cardio and pulmonary

    toxicity particularly when taken in combination withalcohol and/or sedatives in addition to CNSdepression

    O ioid anta onists can reverse the ulmonar and42

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    Mixed Agonists Antagonists& Partial Agonists

    Pentazocine

    Buprenorphine

    Butorphanol

    Nalbuphine

    Drugs that stimulate one receptor but

    block another

    Effects of these drugs depend on previousexposure to opioids

    Nave patients drugs act as agonists;43

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    Pentazocine

    Pentazocine acts as an agonist on kreceptors and is a weak antagonist at and delta receptors.

    Pentazocine promotes analgesia byactivating receptors in the spinal cord,and it is used to relieve moderate pain.

    It may be administered either orally orparenterally.

    Pentazocine produces less euphoria

    compared to morphine. 44

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    Pentazocine

    In angina, pentazocine increases themean aortic pressure and pulmonaryarterial pressure and, thus, increasesthe work of the heart.

    The drug decreases renal plasma flow.

    Despite its antagonist action,pentazocine does not antagonize therespiratory depression of morphine,

    but it can precipitate a withdrawalsyndrome in a morphine abuser.

    Tolerance and dependence develop on45

    Mixed Agonists

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    Mixed AgonistsAntagonists & Partial

    AgonistsBuprenorphine

    A partial agonist at receptors

    producing morphine like effects innave users but precipitating withdrawalin morphine dependents

    Metabolized in the liver and excreted inthe urine and bile

    May be taken sublingually or parenteraland possess a long duration of action

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    Buprenorphine

    Main use is in opioid detoxification asits withdrawal syndrome appears less

    severe and of shorter duration thanmethadone

    Available outside of the specialized

    clinic allowed to dispense methadonefor opiate withdrawal

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    Antagonists

    Bind with high affinity to the , & receptors but fail to activate thereceptor

    In normal individuals, these agentsproduce no effect but in those withopiates present, they induce an acute

    withdrawal syndromeNaloxone

    Reverses the coma and respiratory

    depression associated with opioid 48

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    Antagonists

    Naltrexone (hepatotoxic)

    Similar actions as naloxone but an oralagent with a much longer duration ofaction

    Single dose able to antagonize theeffects of heroin for up to 48 hours

    Nalmefene

    is a parenteral opioid antagonist withactions similar to that of naloxone and

    naltrexone. 49

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