Opioid Opioid Analgesics and Analgesics and

AntagonistsAntagonists

Heider Sh. QassamHeider Sh. QassamMSC.PH. & THMSC.PH. & TH..

OpioidsOpioids are natural or synthetic compounds that produce are natural or synthetic compounds that produce morphine-like effectsmorphine-like effects..

All drugs in this category act by binding to specific opioidAll drugs in this category act by binding to specific opioidreceptors in the central nervous system (CNS) to producereceptors in the central nervous system (CNS) to produceeffects that mimic the action of endogenous peptide effects that mimic the action of endogenous peptide neurotransmitters, the opiopeptins (for exampleneurotransmitters, the opiopeptins (for example , ,the endorphins, and the enkephalinsthe endorphins, and the enkephalins.).)

Opiod receptorsOpiod receptors

Distribution of receptorsDistribution of receptors

. ...BrainstemBrainstem::

. ...Medial thalamusMedial thalamus:: . ...Spinal cordSpinal cord::

..HypothalamusHypothalamus::

..Limbic systemLimbic system::

..PeripheryPeriphery::..Immune cellsImmune cells::

STRONG AGONISTSSTRONG AGONISTS

A. Morphine

Mechanism of action: Opioids exert their major effects by interact -ing with opioid receptors in the CNS and the gastrointestinal tract .Opioids cause hyperpolarization of nerve cells, inhibition of nerve firing, and presynaptic inhibition of transmitter release .

. .ActionsActions:: ..AnalgesiaAnalgesia::

..EuphoriaEuphoria::

..RespirationRespiration::

..Depression of cough reflexDepression of cough reflex

..MiosisMiosis

..EmesisEmesis

..Gastrointestinal tractGastrointestinal tract::

..CardiovascularCardiovascular:: . .

..Histamine releaseHistamine release::..Hormonal actionsHormonal actions::

Therapeutic usesTherapeutic uses

Analgesia .

SEDATION.

Treatment of diarrhea.

Relief of cough.

PharmacokineticsPharmacokinetics

Administration:Administration: Absorption of morphine from the gastrointesti Absorption of morphine from the gastrointesti - -nal tract is slow and erratic, and the drug is usually not givennal tract is slow and erratic, and the drug is usually not given orally. Codeine, by contrast, is well absorbed when given byorally. Codeine, by contrast, is well absorbed when given by mouth. Significant first pass metabolism of morphine occurs inmouth. Significant first pass metabolism of morphine occurs in the liverthe liverDistribution:Distribution: Morphine rapidly enters all body tissues, includ Morphine rapidly enters all body tissues, includ - -

ing the fetuses of pregnant women, and should not be used foring the fetuses of pregnant women, and should not be used for analgesia during laboranalgesia during labor . .

Fate:Fate: Morphine is metabolized in the liver to glucuronides Morphine is metabolized in the liver to glucuronides . .Morphine-6-glucuronide is a very potent analgesic, whereasMorphine-6-glucuronide is a very potent analgesic, whereas the conjugate at the 3-position is inactive. The conjugates arethe conjugate at the 3-position is inactive. The conjugates are excreted primarily in the urine, with small quantities appearingexcreted primarily in the urine, with small quantities appearing in the bilein the bile . .

Adverse effectsAdverse effects

Repeated use produces tolerance to respiratory depressent Repeated use produces tolerance to respiratory depressent , analgesic, euphoric, and sedative effects of morphine . , analgesic, euphoric, and sedative effects of morphine . However, tolerance usually does not develop to the pupil-However, tolerance usually does not develop to the pupil-constricting and constipating effects of theconstricting and constipating effects of the drugdrug . .

Tolerance and physical Tolerance and physical dependencedependence

Drug interactionsDrug interactions

The depressant actions of morphine are enhancedThe depressant actions of morphine are enhanced

by by phenothiazines, monoamine oxidase inhibitorsphenothiazines, monoamine oxidase inhibitors

, ,and and tricyclic antidepressantstricyclic antidepressants and and

Low doses ofLow doses of amphetamine amphetamine strangely enhance strangely enhance

analgesia. analgesia. HydroxyzineHydroxyzine also enhances analgesia also enhances analgesia..

MeperidineMeperidine MeperidineMeperidine is a synthetic opioid with a structure is a synthetic opioid with a structure unrelated to morphine. It is used for acute painunrelated to morphine. It is used for acute pain . .

Mechanism of action:Mechanism of action: Meperidine binds to opioid receptors, par Meperidine binds to opioid receptors, par - -ticularly k receptorsticularly k receptors . .

Actions:Actions: Meperidine causes a depression of respiration similar to Meperidine causes a depression of respiration similar to that of morphine, but there is no significant cardiovascular actionthat of morphine, but there is no significant cardiovascular action when the drug is given orally. On intravenous (IV) administrationwhen the drug is given orally. On intravenous (IV) administration , ,meperidine produces a decrease in peripheral resistance and anmeperidine produces a decrease in peripheral resistance and an increase in peripheral blood flow, and may cause an increase inincrease in peripheral blood flow, and may cause an increase in cardiac ratecardiac rate . .

Therapeutic uses:Therapeutic uses: Meperidine provides analgesia for any type of Meperidine provides analgesia for any type of severe pain. Unlike morphine, meperidine is not clinically useful insevere pain. Unlike morphine, meperidine is not clinically useful in the treatment of diarrhea or cough. Meperidine produces less ofthe treatment of diarrhea or cough. Meperidine produces less of an increase in urinary retention than does morphinean increase in urinary retention than does morphine . .

Pharmacokinetics:Pharmacokinetics: Unlike morphine, meperidine is well absorbed Unlike morphine, meperidine is well absorbed from the gastrointestinal tract and is useful when an orally-adminfrom the gastrointestinal tract and is useful when an orally-admin - -

istered, potent analgesic is needed. However, meperidine is mostistered, potent analgesic is needed. However, meperidine is most often administered intramuscularly. The drug has a duration ofoften administered intramuscularly. The drug has a duration of action of 2 to 4 hours, which is shorter than that of morphineaction of 2 to 4 hours, which is shorter than that of morphine..

Adverse effects:Adverse effects: Large doses of meperidine cause Large doses of meperidine cause tremors, muscle twitches, and rarely,convulsions. tremors, muscle twitches, and rarely,convulsions. The drug differs from opioids in that in large The drug differs from opioids in that in large doses it dilates the pupil and causes hyperactive doses it dilates the pupil and causes hyperactive reflexesreflexes . .

MethadoneMethadone MethadoneMethadone is a synthetic, orally effective opioid that is a synthetic, orally effective opioid that is approximately equal in potency to morphine, but induces less euphoria and is approximately equal in potency to morphine, but induces less euphoria and

has a longer duration of actionhas a longer duration of action.. . .

Mechanism of actionMechanism of action: Methadone has its greatest action on m receptors: Methadone has its greatest action on m receptors . .

Actions:Actions: The analgesic activity of methadone is equivalent to that The analgesic activity of methadone is equivalent to that of morphine. Methadone exhibits strong analgesic action whenof morphine. Methadone exhibits strong analgesic action when administered orallyadministered orally..

Therapeutic usesTherapeutic uses: Methadone is used in the controlled withdrawal: Methadone is used in the controlled withdrawal of addicts from heroin and morphineof addicts from heroin and morphine . .

Pharmacokinetics:Pharmacokinetics: Readily absorbed following oral administration Readily absorbed following oral administration , ,methadone has a longer duration of action than does morphine.. The drug is methadone has a longer duration of action than does morphine.. The drug is biotransformed in the liver and excreted in the urine, mainly as inactive biotransformed in the liver and excreted in the urine, mainly as inactive metabolitemetabolite..

Adverse effects:Adverse effects: Methadone can produce dependence like that of Methadone can produce dependence like that of morphine. The withdrawal syndrome is much milder but is moremorphine. The withdrawal syndrome is much milder but is more protracted (days to weeks) than with opiatesprotracted (days to weeks) than with opiates . .

FentanylFentanyl

FentanylFentanyl which is chemically related to which is chemically related to meperidine, has 80 times the analgesic meperidine, has 80 times the analgesic potency of morphine, and is used in potency of morphine, and is used in anesthesia. It has a rapid onset and short anesthesia. It has a rapid onset and short duration of action (15 to 30 minutes). duration of action (15 to 30 minutes). Sufentanil a related drug, is even more Sufentanil a related drug, is even more potent than fentanylpotent than fentanyl . .

HeroinHeroin

HeroinHeroin does not occur naturally but is produced does not occur naturally but is produced by acetylation of morphine, which leads to a by acetylation of morphine, which leads to a three-fold increase in its potency. Its greater lipid three-fold increase in its potency. Its greater lipid solubility allows it to cross the blood-brain barrier solubility allows it to cross the blood-brain barrier more rapidly than morphine, causing a more more rapidly than morphine, causing a more exaggerated euphoria when the drug is taken by exaggerated euphoria when the drug is taken by injection.. It has no accepted medical use in the injection.. It has no accepted medical use in the United StatesUnited States..

MODERATE AGONISTSMODERATE AGONISTS

PropoxyphenePropoxyphene is a derivative of methadone. Theis a derivative of methadone. The

dextro isomer is used as an analgesic to relieve mild to dextro isomer is used as an analgesic to relieve mild to moderate pain. The levo isomer is not analgesic but has moderate pain. The levo isomer is not analgesic but has antitussive action. Propoxyphene is a weaker analgesic antitussive action. Propoxyphene is a weaker analgesic than codeine.. It is well absorbed orally, , and it is than codeine.. It is well absorbed orally, , and it is metabolized in the liver. Propoxyphene can produce metabolized in the liver. Propoxyphene can produce nausea, anorexia, and constipationnausea, anorexia, and constipation . .

CodeineCodeine CodeineCodeine is a much less potent analgesic thanis a much less potent analgesic than

morphine, but it has a higher oral efficacy. Codeine morphine, but it has a higher oral efficacy. Codeine shows good antitussive activity at doses that do shows good antitussive activity at doses that do not cause analgesia. Codeine produces less not cause analgesia. Codeine produces less euphoria than morphine. Codeine is often used in euphoria than morphine. Codeine is often used in combination with aspirin or acetaminophencombination with aspirin or acetaminophen..

. .

MIXED AGONIST-ANTAGONISTSMIXED AGONIST-ANTAGONISTS

Drugs that stimulate one receptor but block another Drugs that stimulate one receptor but block another are termed mixed agonist-antagonists. The are termed mixed agonist-antagonists. The effects of these drugs depend on previous effects of these drugs depend on previous exposure to opioidexposure to opioid..

PentazocinePentazocineacts as an agonist on K receptors and is a weak antagonist at acts as an agonist on K receptors and is a weak antagonist at m receptorsm receptors . .

Pentazocine promotes analgesia by activating receptors in thePentazocine promotes analgesia by activating receptors in the

spinal cord, and is used to relieve moderate pain. It may be spinal cord, and is used to relieve moderate pain. It may be administered either orally or parenterally. Pentazocine administered either orally or parenterally. Pentazocine produces less euphoria than does morphineproduces less euphoria than does morphine..

Pentazocine should not be used with agonists such as Pentazocine should not be used with agonists such as morphine,since the antagonist action of pentazocine may morphine,since the antagonist action of pentazocine may block the analgesic effects of morphine. Tolerance and block the analgesic effects of morphine. Tolerance and dependence develop on repeated usedependence develop on repeated use . .

BuprenorphineBuprenorphine

Although buprenorphine is classified as a partial Although buprenorphine is classified as a partial agonist acting at the m receptor,. Buprenorphine agonist acting at the m receptor,. Buprenorphine is administered parenterally and has a long is administered parenterally and has a long duration of action because of its tight binding to duration of action because of its tight binding to the receptor. It is metabolized by the liver and the receptor. It is metabolized by the liver and excreted in the bile and urine. Adverse effectsexcreted in the bile and urine. Adverse effects include respiratory depression, decrease (or, rarely, include respiratory depression, decrease (or, rarely, increase) in blood pressure, nausea and dizzinessincrease) in blood pressure, nausea and dizziness . .

ANTAGONISTSANTAGONISTS

naloxone is used to reverse coma & respiretary depression of opiod overdose . Within 30 seconds of intravenous injection of naloxone, the respiratory depression and coma characteristic of high doses of heroin are reversed, causing the patient to be revived and alert .

NaltrexoneNaltrexone

Naltrexone has actions similar to those of Naltrexone has actions similar to those of naloxonenaloxone . .

This drug has a longer duration of action This drug has a longer duration of action than naloxone, and a single oral dose of than naloxone, and a single oral dose of naltrexone blocks the effect of injected naltrexone blocks the effect of injected heroin for up to 48 hours. Naltrexone is heroin for up to 48 hours. Naltrexone is used in opiate-dependence maintenance used in opiate-dependence maintenance programs and may also be beneficial in programs and may also be beneficial in treating chronic alcoholismtreating chronic alcoholism . .

MISCELLANEOUSMISCELLANEOUS

Tramadol Tramadol is a centrally acting analgesic whose is a centrally acting analgesic whose mechanism of action is based on blockade of mechanism of action is based on blockade of serotonin reuptake. it is believed to be only a serotonin reuptake. it is believed to be only a weak m-receptor agonist. It is surprising that no weak m-receptor agonist. It is surprising that no clinically significant effects on respiration or the clinically significant effects on respiration or the cardiovascular system have thus far been cardiovascular system have thus far been reported. tramadol may serve as an adjunct with reported. tramadol may serve as an adjunct with pure opioid agonists in the treatment of chronic pure opioid agonists in the treatment of chronic neuropathic painneuropathic pain..

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