Pain ,opiate analgesics and antagonists - PowerPoint PPT Presentation


Title: Pain ,opiate analgesics and antagonists


1
Pain ,opiate analgesics and antagonists
  • Dr. Israa

2
Mechanism of pain and nociception
  • Polymodal nociceptors are the main type of
    peripheral sensory neuron that responds to
    noxious stimuli the majority are non-myelinated
    C fibers whose endings respond to thermal,
    mechanical and chemical stimuli.
  • Chemical stimuli causing pain includes
    bradykinin, protons, ATP and vanilloids (e.g.
    Capsaicin)

3
  • Stimuli to these receptors (agonist) open cation
    channel s and causing membrane depolarization
    and AP initiation .
  • Theses receptors are sensitized by prostaglandins
    which explain the analgesic effect of NSAIDs.
  • Nociceptive fibers terminate in the superficial
    fibers of the dorsal horn, forming synaptic
    connection with transmission neurons running to
    the thalamus

4
  • Transmission in the dorsal horn is subjective to
    various modulatory influence, constituting the
    gate control mechanism
  • Descending pathways from the midbrain and brain
    stem exert strong inhibitory effect on dorsal
    horn transmission.
  • The descending inhibition is mediated mainly by
    enkephalin, 5-HT from NRM(neuclus raphi magnus)
    and noradrenaline which is released from the
    locus coeruleus .

5
  • Opioids analgesics causes analgesia partly by
    inhibiting transmission in the dorsal horn,
    partly by activating the descending pathways,
    partly by inhibiting excitation of the sensory
    nerve terminals in the periphery
  • C-fiber activity facilitates transmission through
    the dorsal horn through substance P receptors
    and NMDA receptors.

6
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7
(No Transcript)
8
OPIOID ANALGESICS (NARCOTIC ANALGESICS)
  • Analgesia Relief of pain without loss of
    consciousness.
  • Opium Natural extract from Poppy plant used for
    social and medicinal purpose for thousands of
    years to produce euphoria, analgesia, sleep and
    to prevent diarrhea
  • Opioid drugs natural synthetic morphine-like
    drugs.

9
Opioids analgesics and antagonists
  • Strong agonists includes
  • Alfentanil
  • Fentanyl
  • Heroin
  • Mepridine
  • Methadone
  • Morphine
  • Oxycodone
  • Remifentanil
  • Sufentanil.
  • Moderate agonists includes
  • Codeine
  • Propoxyphene.

10
  • Mixed Agonists and Antagonists
  • Pentazocine
  • Nalbuphine
  • Butorphanol
  • Buprenorphine
  • Opioid Antagonists
  • Naloxone
  • Naltrexone
  • Nalmephine

11
Opioid receptors
  • The opioid agonists act at specific receptor
    sites to produce their pharmacological effects.
  • Opioid Receptors are
  • µ (µ1, µ 2)
  • ? (?1, ?2, ?3)
  • d (d1, d2)
  • They are for endogenous opioid-like
    substances(which also stimulate opioid
    receptors)
  • Metenkephalin Tyr-Gly-Gly-Phe-Met
  • Leuenkephalin Tyr-Gly-Gly-Phe-Leu
  • Beta Endorphin a 31 amino acid peptide with
    Metenkephalin at N-terminal sequence
  • Dynorphin a 17 amino acid peptide with
    Leuenkephalin at N-terminal sequence

12
Endogenous Opioid Peptides (Opiopeptins)
Families Precursors Peptides
Enkephalins Proenkephalins (also known as proenkephalin A) Met-enkephalin Leu-enkephalin
Endorphins Pro-opiomelonocortin (POMC) MSH ACTH ß-Lipoprotein ß-Endorphin
Dynorphins Prodynorphin (also known as proenkephalin B) Dynorphin A Dynorphin B a-Neoendorphin ?-Neoendorphin
Non-opioid peptides
13
Opioid Receptors and their Prototypic Ligands
Receptor type Representative Ligands Representative Ligands
Receptor type Endogenous Exogenous
Mu (µ) (µ1, µ2) ?-endorphin Morphine
Delta (d) (d1, d2) Met-enkephalin Etorphine
Kappa (?) (?1, ?2, ?3) Dynorphin A Ethyl-keto-cycla-zocine
14
Action and selectivity of some opioids (and opioid antagonists) at various opioid receptors Action and selectivity of some opioids (and opioid antagonists) at various opioid receptors Action and selectivity of some opioids (and opioid antagonists) at various opioid receptors Action and selectivity of some opioids (and opioid antagonists) at various opioid receptors Action and selectivity of some opioids (and opioid antagonists) at various opioid receptors
Drug Receptor type Receptor type Receptor type Receptor type
Drug Mu - µ Mu - µ Kappa - ? Delta - d
Agonists Agonists Agonists Agonists Agonists
Morphine
Codeine
Methadone
Meperidine
Fentanyl
Sufentanyl
Partial and Mixed Agonists Partial and Mixed Agonists Partial and Mixed Agonists Partial and Mixed Agonists Partial and Mixed Agonists
Buprenorphine PA PA Antagonist (-)
Pentazocine PA PA
Antagonists Antagonists Antagonists Antagonists Antagonists
Nalaxone and Naltrexone Nalaxone and Naltrexone Antagonist (---) Antagonist (--) Antagonist (-)
Endogenous Peptides Endogenous Peptides Endogenous Peptides Endogenous Peptides Endogenous Peptides
Met-enkephalin
Beta-endorphin
Dynorphin A
15
  • Three genes have been identified which code for
    opioid peptides
  • Beta endorphin and ACTH
  • Enkephalins
  • Dynorphins
  • These neuropeptides are released by stress and
    appear to modulate the release of other
    neurotransmitters.

16
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17
Mechanism of Action of opioids
  • Morphine binds opioid receptors and thus impairs
    the normal sensory pathways through
  • Blockade of calcium channels which leads to
    decreased release of substance P and glutamate
    from the 1st neuron of the sensory pathway (in
    substantia gelatinosa in spinal cord).
  • Decreased c-AMP which leads to opening of
    K-channels and hyperpolarization of the 2nd
    neuron of the sensory pathway.

18
(No Transcript)
19
Mechanism of Action of Opioids
20
  • A. Effects due to µ-receptor stimulation
  • Supraspinal, spinal peripheral analgesia
  • Euphoria
  • Respiratory depression
  • Miosis
  • Decreased GIT motility,
  • Sedation
  • Physical dependence.
  • .
  • B. Effects due to ?-receptor stimulation
  • Spinal and peripheral analgesia,
  • Dysphoria
  • Sedation
  • Respiratory depression (less)
  • Miosis (less)
  • Decrease GIT motility
  • Physical dependence

21
  • C. Effects due to d-receptor stimulation
  • Spinal analgesia
  • Respiratory depression
  • Decrease GIT motility .
  • They are not true opioid receptors only some
    opioids react with them .

22
I. Morphine
  • Effective orally, but is much less effective than
    when given parenterally due to first-pass
    metabolism in the liver.
  • Metabolism involves glucuronide formation, the
    product of which is excreted in the urine.

23
  • A. Effects of morphine
  • 1. Central Nervous System Effects
  • Morphine has mixed depressant and stimulatory
    actions on the CNS.
  • - Depressant effects predominate in man.
  • - Excitatory effects predominate in cats
    and
  • horses.

24
  • a) Analgesia
  • Drowsiness is common
  • Continuous dull pain relieved more effectively
    than sharp intermittent pain
  • Most patients indicate that they can still feel
    the pain, but that it no longer bothers them
  • Morphine is an agonist at µ and ? opioid
    receptors.

25
  • b) Euphoria and sedation
  • It is mainly due to activation of µ-receptor
  • c) Emesis
  • Morphine directly stimulates the chemoreceptor
    trigger zone, usually transient and disappear
    with repeated administration .
  • d) Antianxiety
  • e) Miosis (pinpoint pupil).
  • It is due to stimulation of the Edenger- Westphal
    nucleus of the oculomotor nerve .

26
  • f) Cough reflex is inhibited
  • This action ,surprisingly, does not correlate
    closely with analgesic and respiratory depressant
    effect of opiates, and its mechanism of action at
    receptor level is unclear
  • Chemical modification (Codiene and Pholcodiene )
    the antitussive effect can occur at sub-
    analgesic dose.

27
  • g) Respiration depression
  • Due to a direct effect on the brain stem
    respiratory center.
  • Death from narcotic overdose is nearly always due
    to respiratory arrest.
  • It occur at therapeutic doses but not accompanied
    with cardiac center depression in contrast to
    other CNS depressant like general anesthetic
    agents.

28
  • h) Other effects
  • Morphine is a basic drug causes the release of
    histamine causes the body to feel warm and the
    face, nose to itch ,bronchoconstriction and
    hypotension .
  • It also abolishes hunger
  • It dilate the cerebral vessels and increase
    intracranial pressure

29
  • 2. Cardiovascular Effects
  • Postural orthostatic hypotension due primarily to
    decreased V.M.C. activity leading to peripheral
    vasodilation, which may be also due in part to
    histamine release.
  • In congestive heart failure, morphine decreases
    the left ventricular workload and myocardial
    oxygen demand.

30
  • 3. Endocrine Effects
  • Increases prolactin secretion
  • Increases vasopressin (ADH) secretion (oliguria).
  • Decreases pituitary gonadotropin (LH FSH)
    secretion.
  • Decreases stress induced ACTH secretion.

31
  • 4. Gastrointestinal Effects
  • It decrease the motility and increase the tone of
    the intestinal circular muscle and the tone of
    the anal sphincter , it also causes contraction
    of the gallbladder and constriction of the
    biliary sphincter
  • Constipation (tolerance does not develop to this
    effect).
  • Diphenoxylate and Loperamide can be used in the
    treatment of diarrhea.
  • They decrease GIT motility and peristalsis

32
  • 5. Genitourinary Effects
  • Morphine prolong the second stage of labor by
    decreasing the strength, duration and frequency
    of uterine contraction
  • Inhibit urinary bladder voiding reflex (sometimes
    catheterization may be required in some cases )

33
  • B. Adverse Reactions
  • Generally direct extensions of their
    pharmacological actions.
  • Respiratory depression, apnea
  • Nausea and vomiting
  • Dizziness, orthostatic hypotension, edema
  • Mental clouding, drowsiness
  • Constipation, ileus
  • Biliary spasm (colic)
  • Dry mouth
  • Urine retention, urinary hesitancy
  • Hypersensitivity reactions (contact dermatitis,
    urticaria)
  • Immunosuppression (recurrent infections)

34
  • C. Precautions
  • Respiratory depression, particularly in the
    newborn and patients with COPD
  • Orthostatic hypotension
  • Histamine release (asthma)
  • Drug interactions (with other CNS depressants)
  • Tolerance and cross tolerance to other opioids
  • Benign prostatic hyperplasia(may precipitate
    urine retention
  • Dependence (psychological physical)
  • Liver disease(accumulation of the drug)
  • Increase intracranial pressure and head injury
    (it enhances cerebral ischemia)

35
  • D. Therapeutic uses
  • - Analgesia myocardial infarction, terminal
    cancer, surgery, obstetrical procedures
  • - Dyspnea due to pulmonary edema
  • - Severe diarrhea.

36
II. Other Opioid (Narcotic) Analgesics
  • A. Heroin (diacetyl morphine)
  • µ- agonist
  • Heroin is more lipid soluble than morphine and
    about 2½ times more potent
  • It enters the CNS more readily
  • It is a schedule I drug and is not used
    clinically, but it is a drug of abuse.

37
  • B. Codeine
  • From opium or synthesized by methylation of
    morphine
  • Has a much better oral /parenteral absorption
    ratio than morphine.
  • Effective for mild to moderate pain, cough,
    diarrhea.
  • Metabolized in part to morphine by
    O-demethylation.
  • µ- receptor agonist.
  • Has a more potent histamine-releasing action than
    morphine.
  • Dependence liability of codeine is less than
    that of morphine, .
  • It is 1/12 as potent as morphine

38
  • C. Dextromethorphan
  • Excellent oral antitussive
  • No analgesic effect
  • No GI effects
  • No respiratory depression

39
  • D. Meperidine (Pethidine)
  • Produces analgesia, sedation, euphoria and
    respiratory depression.
  • Less potent than morphine, 80-100 mg meperidine
    equals 10 mg morphine.
  • Shorter duration of action than morphine (2-4
    hrs).
  • Meperidine has greater excitatory activity than
    does morphine and toxicity may lead to
    convulsions.
  • Meperidine appears to have weak atropine-like
    activity.
  • It does not constrict the pupils to the same
    extent as morphine.

40
  • Does not cause as much constipation as morphine
  • Purely synthetic µ- agonist
  • Not an effective antitussive agent.
  • less effect in uterine contraction commonly
    employed in obstetrics also causes less urine
    retention
  • Adverse reactions to Meperidine
  • Respiratory depression
  • Tremors
  • Delirium and possible convulsions
  • Dry mouth
  • Severe reaction if given with MAOI, consists of
    excitement, hyperthermia and convulsions it is
    due to accumulation of pethidine(norpethidine)
    metabolite but the details are still unclear.

41
  • E. Fentanyl
  • µ- agonist, related chemically to meperidine.
  • Approximately 80 times more potent than morphine,
    main use in anesthesia .
  • Duration of action very short (t1/2 20 min).
  • Can be given IM, IV, transdemally or via patient
    controlled infusion system may be given
    intrathecally
  • Often used during cardiac surgery because of its
    negligible effect on the myocardial
    contractility

42
  • F. Sufentanil
  • A synthetic opioid related to fentanyl.
  • About 7 times more potent than fentanyl.
  • Has a slightly more rapid onset of action than
    fentanyl.

43
  • G. Methadone
  • Pharmacology and analgesic potency similar to
    morphine µ- receptor agonist.
  • Very effective following oral administration.
  • Longer duration of action than morphine due to
    plasma protein binding (t1/2 approximately 25
    hrs).
  • Used in methadone maintenance programs for
    treatment of opioid addicts and for opiate
    withdrawal syndrome(it reduces the physical
    abstinence syndrome)make it possible to wean the
    addict from opioids.

44
  • H. Propoxyphene
  • A methadone analog.
  • Used orally to relieve mild to moderate pain, it
    is weak analgesic often combined with
    Paracetamol .
  • Has a low addiction potential
  • The most common adverse effects are dizziness,
    drowsiness, and nausea and vomiting.
  • CNS depression is additive with other CNS
    depressants (alcohol and sedatives).
  • can cause cardio- toxicity and pulmonary edema
    which can not reversed by naloxone

45
III. Mixed Narcotic Agonists/Antagonists
  • These drugs produce analgesia, but have a lower
    potential for abuse and do not produce as much
    respiratory depression.

46
  • A. Pentazocine
  • ?- agonist (analgesia) and µ-antagonist (less
    respiratory depression).
  • Orally, it has about the same analgesic potency
    as codeine.
  • Adverse reactions to Pentazocine Nausea,
    vomiting, dizziness, dysphoria, nightmares and
    visual hallucinations.
  • Rarely used nowadays

47
  • B. Nalbuphine
  • Resembles pentazocine pharmacologically.
  • Like morphine, nalbuphine reduces myocardial
    oxygen demand. May be of value following acute
    myocardial infarction due to both its analgesic
    properties and reduced myocardial oxygen demand.
  • Most frequent side effect is sedation.
  • Less propensity to produce psychotomimetic side
    effects

48
  • C. Butorphanol
  • Resembles pentazocine pharmacologically.
  • 3.5 to 7 times more potent than morphine.
  • Not available for oral administration
  • They exhibit ceiling of respiratory depression
    effect

49
  • D. Buprenorphine
  • A partial agonist at µ-receptor.
  • 200 times more potent than morphine.
  • Low potential abuse, but can precipitate
    withdrawal in addicts
  • In naive persons it acts like morphine
  • Major use is office-based detoxification of
    opioids
  • Causes less sedation, respiratory depression and
    hypotension even in high doses.

50
IV. Opiate Antagonists
  • Opiate antagonists have no agonist properties.
    They are utilized to reverse opiate induced
    respiratory depression and to prevent drug abuse.
  • A. Naloxone (Narcan)
  • Pure opiate antagonist at all opioid receptors
  • Given parenterally -Short duration of action
    (1-4 h)
  • Can precipitate withdrawal in addicts.

51
  • B. Naltrexone
  • Oral pure opioid antagonist
  • Long duration of action
  • Contraindicated in liver disease
  • Used in late stages of opioid addiction treatment
    ( also in treatment of alcoholism).
  • C. Nalmephine
  • Long-acting parenteral opioid antagonist.

52
Antitussives

  • Chemical mechanical Afferents
    EFFerents
  • Stimuli


  • Respiratory muscles
  • Sensory receptors in upper respiratory tract

Cough Center medulla
53
Antitussives
  • Antitussives against cough
  • Coughing is a protective reflex
  • Antitussives depress cough center, therefore
    depress the cough reflex.
  • Antitussives should not be used in productive
    cough.

54
  • Antitussives include
  • 1. Opioids
  • Codeine, dextromethorphan, hydrocodone,
    hydromorphone.
  • They are opioid agonists against dry cough.
  • They are of low abuse potential.
  • Side effects include drowsiness and
    constipatiopn.

55
  • 2. Non-opioids
  • E.g. butamirate citrate which depress the cough
    center.
  • 3. Peripherally acting antitussives
  • These prevent irritation of sensory receptors in
    the upper respiratory tract.
  • 4. Local anesthetics
  • also depress the cough center. They include
  • demulcents liquorice, honey
  • local anesthetics benzonatate

56
  • THANK YOU
  • REFRENCES
  • RANG AND DALE
  • LIPPINCOTTOS
  • LANGE
  • TABLES FROM DR.KUKAB SLIDES
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Pain ,opiate analgesics and antagonists

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Title: Pain ,opiate analgesics and antagonists


1
Pain ,opiate analgesics and antagonists
  • Dr. Israa

2
Mechanism of pain and nociception
  • Polymodal nociceptors are the main type of
    peripheral sensory neuron that responds to
    noxious stimuli the majority are non-myelinated
    C fibers whose endings respond to thermal,
    mechanical and chemical stimuli.
  • Chemical stimuli causing pain includes
    bradykinin, protons, ATP and vanilloids (e.g.
    Capsaicin)

3
  • Stimuli to these receptors (agonist) open cation
    channel s and causing membrane depolarization
    and AP initiation .
  • Theses receptors are sensitized by prostaglandins
    which explain the analgesic effect of NSAIDs.
  • Nociceptive fibers terminate in the superficial
    fibers of the dorsal horn, forming synaptic
    connection with transmission neurons running to
    the thalamus

4
  • Transmission in the dorsal horn is subjective to
    various modulatory influence, constituting the
    gate control mechanism
  • Descending pathways from the midbrain and brain
    stem exert strong inhibitory effect on dorsal
    horn transmission.
  • The descending inhibition is mediated mainly by
    enkephalin, 5-HT from NRM(neuclus raphi magnus)
    and noradrenaline which is released from the
    locus coeruleus .

5
  • Opioids analgesics causes analgesia partly by
    inhibiting transmission in the dorsal horn,
    partly by activating the descending pathways,
    partly by inhibiting excitation of the sensory
    nerve terminals in the periphery
  • C-fiber activity facilitates transmission through
    the dorsal horn through substance P receptors
    and NMDA receptors.

6
(No Transcript)
7
(No Transcript)
8
OPIOID ANALGESICS (NARCOTIC ANALGESICS)
  • Analgesia Relief of pain without loss of
    consciousness.
  • Opium Natural extract from Poppy plant used for
    social and medicinal purpose for thousands of
    years to produce euphoria, analgesia, sleep and
    to prevent diarrhea
  • Opioid drugs natural synthetic morphine-like
    drugs.

9
Opioids analgesics and antagonists
  • Strong agonists includes
  • Alfentanil
  • Fentanyl
  • Heroin
  • Mepridine
  • Methadone
  • Morphine
  • Oxycodone
  • Remifentanil
  • Sufentanil.
  • Moderate agonists includes
  • Codeine
  • Propoxyphene.

10
  • Mixed Agonists and Antagonists
  • Pentazocine
  • Nalbuphine
  • Butorphanol
  • Buprenorphine
  • Opioid Antagonists
  • Naloxone
  • Naltrexone
  • Nalmephine

11
Opioid receptors
  • The opioid agonists act at specific receptor
    sites to produce their pharmacological effects.
  • Opioid Receptors are
  • µ (µ1, µ 2)
  • ? (?1, ?2, ?3)
  • d (d1, d2)
  • They are for endogenous opioid-like
    substances(which also stimulate opioid
    receptors)
  • Metenkephalin Tyr-Gly-Gly-Phe-Met
  • Leuenkephalin Tyr-Gly-Gly-Phe-Leu
  • Beta Endorphin a 31 amino acid peptide with
    Metenkephalin at N-terminal sequence
  • Dynorphin a 17 amino acid peptide with
    Leuenkephalin at N-terminal sequence

12
Endogenous Opioid Peptides (Opiopeptins)
Families Precursors Peptides
Enkephalins Proenkephalins (also known as proenkephalin A) Met-enkephalin Leu-enkephalin
Endorphins Pro-opiomelonocortin (POMC) MSH ACTH ß-Lipoprotein ß-Endorphin
Dynorphins Prodynorphin (also known as proenkephalin B) Dynorphin A Dynorphin B a-Neoendorphin ?-Neoendorphin
Non-opioid peptides
13
Opioid Receptors and their Prototypic Ligands
Receptor type Representative Ligands Representative Ligands
Receptor type Endogenous Exogenous
Mu (µ) (µ1, µ2) ?-endorphin Morphine
Delta (d) (d1, d2) Met-enkephalin Etorphine
Kappa (?) (?1, ?2, ?3) Dynorphin A Ethyl-keto-cycla-zocine
14
Action and selectivity of some opioids (and opioid antagonists) at various opioid receptors Action and selectivity of some opioids (and opioid antagonists) at various opioid receptors Action and selectivity of some opioids (and opioid antagonists) at various opioid receptors Action and selectivity of some opioids (and opioid antagonists) at various opioid receptors Action and selectivity of some opioids (and opioid antagonists) at various opioid receptors
Drug Receptor type Receptor type Receptor type Receptor type
Drug Mu - µ Mu - µ Kappa - ? Delta - d
Agonists Agonists Agonists Agonists Agonists
Morphine
Codeine
Methadone
Meperidine
Fentanyl
Sufentanyl
Partial and Mixed Agonists Partial and Mixed Agonists Partial and Mixed Agonists Partial and Mixed Agonists Partial and Mixed Agonists
Buprenorphine PA PA Antagonist (-)
Pentazocine PA PA
Antagonists Antagonists Antagonists Antagonists Antagonists
Nalaxone and Naltrexone Nalaxone and Naltrexone Antagonist (---) Antagonist (--) Antagonist (-)
Endogenous Peptides Endogenous Peptides Endogenous Peptides Endogenous Peptides Endogenous Peptides
Met-enkephalin
Beta-endorphin
Dynorphin A
15
  • Three genes have been identified which code for
    opioid peptides
  • Beta endorphin and ACTH
  • Enkephalins
  • Dynorphins
  • These neuropeptides are released by stress and
    appear to modulate the release of other
    neurotransmitters.

16
(No Transcript)
17
Mechanism of Action of opioids
  • Morphine binds opioid receptors and thus impairs
    the normal sensory pathways through
  • Blockade of calcium channels which leads to
    decreased release of substance P and glutamate
    from the 1st neuron of the sensory pathway (in
    substantia gelatinosa in spinal cord).
  • Decreased c-AMP which leads to opening of
    K-channels and hyperpolarization of the 2nd
    neuron of the sensory pathway.

18
(No Transcript)
19
Mechanism of Action of Opioids
20
  • A. Effects due to µ-receptor stimulation
  • Supraspinal, spinal peripheral analgesia
  • Euphoria
  • Respiratory depression
  • Miosis
  • Decreased GIT motility,
  • Sedation
  • Physical dependence.
  • .
  • B. Effects due to ?-receptor stimulation
  • Spinal and peripheral analgesia,
  • Dysphoria
  • Sedation
  • Respiratory depression (less)
  • Miosis (less)
  • Decrease GIT motility
  • Physical dependence

21
  • C. Effects due to d-receptor stimulation
  • Spinal analgesia
  • Respiratory depression
  • Decrease GIT motility .
  • They are not true opioid receptors only some
    opioids react with them .

22
I. Morphine
  • Effective orally, but is much less effective than
    when given parenterally due to first-pass
    metabolism in the liver.
  • Metabolism involves glucuronide formation, the
    product of which is excreted in the urine.

23
  • A. Effects of morphine
  • 1. Central Nervous System Effects
  • Morphine has mixed depressant and stimulatory
    actions on the CNS.
  • - Depressant effects predominate in man.
  • - Excitatory effects predominate in cats
    and
  • horses.

24
  • a) Analgesia
  • Drowsiness is common
  • Continuous dull pain relieved more effectively
    than sharp intermittent pain
  • Most patients indicate that they can still feel
    the pain, but that it no longer bothers them
  • Morphine is an agonist at µ and ? opioid
    receptors.

25
  • b) Euphoria and sedation
  • It is mainly due to activation of µ-receptor
  • c) Emesis
  • Morphine directly stimulates the chemoreceptor
    trigger zone, usually transient and disappear
    with repeated administration .
  • d) Antianxiety
  • e) Miosis (pinpoint pupil).
  • It is due to stimulation of the Edenger- Westphal
    nucleus of the oculomotor nerve .

26
  • f) Cough reflex is inhibited
  • This action ,surprisingly, does not correlate
    closely with analgesic and respiratory depressant
    effect of opiates, and its mechanism of action at
    receptor level is unclear
  • Chemical modification (Codiene and Pholcodiene )
    the antitussive effect can occur at sub-
    analgesic dose.

27
  • g) Respiration depression
  • Due to a direct effect on the brain stem
    respiratory center.
  • Death from narcotic overdose is nearly always due
    to respiratory arrest.
  • It occur at therapeutic doses but not accompanied
    with cardiac center depression in contrast to
    other CNS depressant like general anesthetic
    agents.

28
  • h) Other effects
  • Morphine is a basic drug causes the release of
    histamine causes the body to feel warm and the
    face, nose to itch ,bronchoconstriction and
    hypotension .
  • It also abolishes hunger
  • It dilate the cerebral vessels and increase
    intracranial pressure

29
  • 2. Cardiovascular Effects
  • Postural orthostatic hypotension due primarily to
    decreased V.M.C. activity leading to peripheral
    vasodilation, which may be also due in part to
    histamine release.
  • In congestive heart failure, morphine decreases
    the left ventricular workload and myocardial
    oxygen demand.

30
  • 3. Endocrine Effects
  • Increases prolactin secretion
  • Increases vasopressin (ADH) secretion (oliguria).
  • Decreases pituitary gonadotropin (LH FSH)
    secretion.
  • Decreases stress induced ACTH secretion.

31
  • 4. Gastrointestinal Effects
  • It decrease the motility and increase the tone of
    the intestinal circular muscle and the tone of
    the anal sphincter , it also causes contraction
    of the gallbladder and constriction of the
    biliary sphincter
  • Constipation (tolerance does not develop to this
    effect).
  • Diphenoxylate and Loperamide can be used in the
    treatment of diarrhea.
  • They decrease GIT motility and peristalsis

32
  • 5. Genitourinary Effects
  • Morphine prolong the second stage of labor by
    decreasing the strength, duration and frequency
    of uterine contraction
  • Inhibit urinary bladder voiding reflex (sometimes
    catheterization may be required in some cases )

33
  • B. Adverse Reactions
  • Generally direct extensions of their
    pharmacological actions.
  • Respiratory depression, apnea
  • Nausea and vomiting
  • Dizziness, orthostatic hypotension, edema
  • Mental clouding, drowsiness
  • Constipation, ileus
  • Biliary spasm (colic)
  • Dry mouth
  • Urine retention, urinary hesitancy
  • Hypersensitivity reactions (contact dermatitis,
    urticaria)
  • Immunosuppression (recurrent infections)

34
  • C. Precautions
  • Respiratory depression, particularly in the
    newborn and patients with COPD
  • Orthostatic hypotension
  • Histamine release (asthma)
  • Drug interactions (with other CNS depressants)
  • Tolerance and cross tolerance to other opioids
  • Benign prostatic hyperplasia(may precipitate
    urine retention
  • Dependence (psychological physical)
  • Liver disease(accumulation of the drug)
  • Increase intracranial pressure and head injury
    (it enhances cerebral ischemia)

35
  • D. Therapeutic uses
  • - Analgesia myocardial infarction, terminal
    cancer, surgery, obstetrical procedures
  • - Dyspnea due to pulmonary edema
  • - Severe diarrhea.

36
II. Other Opioid (Narcotic) Analgesics
  • A. Heroin (diacetyl morphine)
  • µ- agonist
  • Heroin is more lipid soluble than morphine and
    about 2½ times more potent
  • It enters the CNS more readily
  • It is a schedule I drug and is not used
    clinically, but it is a drug of abuse.

37
  • B. Codeine
  • From opium or synthesized by methylation of
    morphine
  • Has a much better oral /parenteral absorption
    ratio than morphine.
  • Effective for mild to moderate pain, cough,
    diarrhea.
  • Metabolized in part to morphine by
    O-demethylation.
  • µ- receptor agonist.
  • Has a more potent histamine-releasing action than
    morphine.
  • Dependence liability of codeine is less than
    that of morphine, .
  • It is 1/12 as potent as morphine

38
  • C. Dextromethorphan
  • Excellent oral antitussive
  • No analgesic effect
  • No GI effects
  • No respiratory depression

39
  • D. Meperidine (Pethidine)
  • Produces analgesia, sedation, euphoria and
    respiratory depression.
  • Less potent than morphine, 80-100 mg meperidine
    equals 10 mg morphine.
  • Shorter duration of action than morphine (2-4
    hrs).
  • Meperidine has greater excitatory activity than
    does morphine and toxicity may lead to
    convulsions.
  • Meperidine appears to have weak atropine-like
    activity.
  • It does not constrict the pupils to the same
    extent as morphine.

40
  • Does not cause as much constipation as morphine
  • Purely synthetic µ- agonist
  • Not an effective antitussive agent.
  • less effect in uterine contraction commonly
    employed in obstetrics also causes less urine
    retention
  • Adverse reactions to Meperidine
  • Respiratory depression
  • Tremors
  • Delirium and possible convulsions
  • Dry mouth
  • Severe reaction if given with MAOI, consists of
    excitement, hyperthermia and convulsions it is
    due to accumulation of pethidine(norpethidine)
    metabolite but the details are still unclear.

41
  • E. Fentanyl
  • µ- agonist, related chemically to meperidine.
  • Approximately 80 times more potent than morphine,
    main use in anesthesia .
  • Duration of action very short (t1/2 20 min).
  • Can be given IM, IV, transdemally or via patient
    controlled infusion system may be given
    intrathecally
  • Often used during cardiac surgery because of its
    negligible effect on the myocardial
    contractility

42
  • F. Sufentanil
  • A synthetic opioid related to fentanyl.
  • About 7 times more potent than fentanyl.
  • Has a slightly more rapid onset of action than
    fentanyl.

43
  • G. Methadone
  • Pharmacology and analgesic potency similar to
    morphine µ- receptor agonist.
  • Very effective following oral administration.
  • Longer duration of action than morphine due to
    plasma protein binding (t1/2 approximately 25
    hrs).
  • Used in methadone maintenance programs for
    treatment of opioid addicts and for opiate
    withdrawal syndrome(it reduces the physical
    abstinence syndrome)make it possible to wean the
    addict from opioids.

44
  • H. Propoxyphene
  • A methadone analog.
  • Used orally to relieve mild to moderate pain, it
    is weak analgesic often combined with
    Paracetamol .
  • Has a low addiction potential
  • The most common adverse effects are dizziness,
    drowsiness, and nausea and vomiting.
  • CNS depression is additive with other CNS
    depressants (alcohol and sedatives).
  • can cause cardio- toxicity and pulmonary edema
    which can not reversed by naloxone

45
III. Mixed Narcotic Agonists/Antagonists
  • These drugs produce analgesia, but have a lower
    potential for abuse and do not produce as much
    respiratory depression.

46
  • A. Pentazocine
  • ?- agonist (analgesia) and µ-antagonist (less
    respiratory depression).
  • Orally, it has about the same analgesic potency
    as codeine.
  • Adverse reactions to Pentazocine Nausea,
    vomiting, dizziness, dysphoria, nightmares and
    visual hallucinations.
  • Rarely used nowadays

47
  • B. Nalbuphine
  • Resembles pentazocine pharmacologically.
  • Like morphine, nalbuphine reduces myocardial
    oxygen demand. May be of value following acute
    myocardial infarction due to both its analgesic
    properties and reduced myocardial oxygen demand.
  • Most frequent side effect is sedation.
  • Less propensity to produce psychotomimetic side
    effects

48
  • C. Butorphanol
  • Resembles pentazocine pharmacologically.
  • 3.5 to 7 times more potent than morphine.
  • Not available for oral administration
  • They exhibit ceiling of respiratory depression
    effect

49
  • D. Buprenorphine
  • A partial agonist at µ-receptor.
  • 200 times more potent than morphine.
  • Low potential abuse, but can precipitate
    withdrawal in addicts
  • In naive persons it acts like morphine
  • Major use is office-based detoxification of
    opioids
  • Causes less sedation, respiratory depression and
    hypotension even in high doses.

50
IV. Opiate Antagonists
  • Opiate antagonists have no agonist properties.
    They are utilized to reverse opiate induced
    respiratory depression and to prevent drug abuse.
  • A. Naloxone (Narcan)
  • Pure opiate antagonist at all opioid receptors
  • Given parenterally -Short duration of action
    (1-4 h)
  • Can precipitate withdrawal in addicts.

51
  • B. Naltrexone
  • Oral pure opioid antagonist
  • Long duration of action
  • Contraindicated in liver disease
  • Used in late stages of opioid addiction treatment
    ( also in treatment of alcoholism).
  • C. Nalmephine
  • Long-acting parenteral opioid antagonist.

52
Antitussives

  • Chemical mechanical Afferents
    EFFerents
  • Stimuli


  • Respiratory muscles
  • Sensory receptors in upper respiratory tract

Cough Center medulla
53
Antitussives
  • Antitussives against cough
  • Coughing is a protective reflex
  • Antitussives depress cough center, therefore
    depress the cough reflex.
  • Antitussives should not be used in productive
    cough.

54
  • Antitussives include
  • 1. Opioids
  • Codeine, dextromethorphan, hydrocodone,
    hydromorphone.
  • They are opioid agonists against dry cough.
  • They are of low abuse potential.
  • Side effects include drowsiness and
    constipatiopn.

55
  • 2. Non-opioids
  • E.g. butamirate citrate which depress the cough
    center.
  • 3. Peripherally acting antitussives
  • These prevent irritation of sensory receptors in
    the upper respiratory tract.
  • 4. Local anesthetics
  • also depress the cough center. They include
  • demulcents liquorice, honey
  • local anesthetics benzonatate

56
  • THANK YOU
  • REFRENCES
  • RANG AND DALE
  • LIPPINCOTTOS
  • LANGE
  • TABLES FROM DR.KUKAB SLIDES
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