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Morphine

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Morphine is a highly potent opiate analgesic drug and is the principal active ... or dihydrocodeinone (marketed as Vicodin, Anexsia, Dicodid, Hycodan, Hycomine, ... – PowerPoint PPT presentation

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Title: Morphine


1
Morphine
2
Brand Names
  • AstramorphTM PF DuramorphTM InfumorphTM
    KadianTM MS ContinTM MSIRTM Oramorph SRTM
    RMSTM RoxanolTM Roxanol RescudoseTM RoxanolTM
  • EpimorphTM (Canada) Morphine-HPTM (Canada)
    MST-ContinusTM (Mexico) MS-IRTM (Canada)
    StatexTM (Canada)

3
  • Morphine is a highly potent opiate analgesic drug
    and is the principal active agent in opium and
    the prototypical opiate.
  • Like other opioids, e.g. Diamorphine (heroin),
    morphine acts directly on the central nervous
    system (CNS) to relieve pain, and at synapses of
    the nucleus accumbens in particular.
  • Morphine is highly addictive when compared to
    other substances, and tolerance and physical and
    psychological dependences develop very rapidly.

4
Administration of Morphine
  • Parenterally as subcutaneous, intravenous, or
    epidural injections. When injected, particularly
    intravenously, morphine produces an intense
    contraction sensation in the muscles due to
    histamine release and also produces a very
    intense 'rush' which is mediated by several
    different receptors in the CNS. The military
    sometimes issues morphine loaded in an
    autoinjector.

5
Administration
  • Orally, it comes as an elixir, concentrated
    solution, powder (for compounding) or in tablet
    form. Morphine is rarely supplied in suppository
    form. Due to its poor oral bioavailability, oral
    morphine is only one-sixth to one-third of the
    potency of parenteral morphine. Morphine is
    available in extended release capsules for
    chronic administration, as well as
    immediate-release formulations.

6
Side Effects
  • Morphine has many side effects. The most
    dangerous is respiratory depression. With higher
    doses or in frail patients, the respiratory rate
    decreases, the patient becomes increasingly
    sedated, and the pupils very small.
  • Common side effects are nausea and vomiting due
    to a central action of morphine stimulating one
    of the centres in the brain concerned with
    vomiting called the chemotactic trigger zone.

7
Side Effects
  • Other central nervous system side effects of
    morphine are cough suppression, sedation, and
    dependence leading to addiction.
  • Morphine also has an effect on the muscle of the
    bowel and urinary tract, causing the sphincter to
    contract and reduce the peristalsis (the wavelike
    movements of the bowel muscle that propel its
    contents forwards). This results in a delayed
    emptying of the stomach, constipa tion, and may
    also lead to urinary retention.

8
Side Effects
  • Morphine can also cause histamine release, which
    causes itching of the skin and nose and a mild
    flushing of the skin.

9
How do opioid analgesics work?
There are three known types of receptors for
opioid analgesics ?, ?, and ?.
  • http//www.thirteen.org/closetohome/animation/opi-
    anim2-main.html
  • http//thebrain.mcgill.ca/flash/i/i_03/i_03_m/i_03
    _m_par/i_03_m_par_heroine.htmldrogues

10
The ? receptor seems to be the major opioid target
  • Activation of the µ receptor by an agonist such
    as morphine causes analgesia, sedation, reduced
    blood pressure, itching, nausea, euphoria,
    decreased respiration, miosis (constricted
    pupils) and decreased bowel motility often
    leading to constipation.
  • Some of these effects, such as sedation, euphoria
    and decreased respiration, tend to disappear with
    continued use as tolerance develops. Analgesia,
    miosis and reduced bowel motility tend to
    persist little tolerance develops to these
    effects.

11
The ? receptor
  • Tolerance develops to different effects at
    different rates largely because these effects are
    caused by activation of different µ-receptor
    subtypes.
  • Stimulation of µ1-receptors blocks pain while
    stimulation of µ2-receptor causes respiratory
    depression and constipation.

12
Overview Opioid Receptors
  • Opioid receptors are a group of G-protein coupled
    receptors with opioids as ligands. The endogenous
    opioids are dynorphins, enkephalins and
    endorphins. The opioid receptors are 40
    identical to somatostatin receptors (SSTRs).

13
Overview Opioid Receptors
  • d-Opioid receptor activation produces analgesia.
    Some research suggests that they may also be
    related to seizures. The endogenous ligands for
    the d receptor are the enkephalins. Until quite
    recently, there were few pharmacological tools
    for the study of d receptors. As a consequence,
    our understanding of their function is much more
    limited than those of the other opioid
    receptors.Recent work indicates that exogenous
    ligands which activate the delta receptors mimic
    the phenomenon known as 'ischemic
    preconditioning'. Experimentally, if short
    periods of transient ischemia (restriction in the
    blood supply) are induced the downstream tissues
    are robustly protected if permanent interruption
    of the blood supply is then effected.Opiates and
    opioids with delta activity mimic this effect. In
    the rat model introduction of delta active
    ligands results in significant cardioprotection.

14
Overview Opioid Receptors
  • ?-Opioid receptors are also involved with
    analgesia, but activation also produces marked
    nausea and dysphoria (sadness, irritability,
    anxiety)

15
Heroin
16
Codeine
17
Uses of Codeine
  • Approved indications for codeine include
  • ?Cough, though its efficacy in low dose over the
    counter formulations has been disputed.
  • Diarrhea
  • Moderate to severe pain?Irritable bowel syndrome
  • Codeine is sometimes marketed in combination
    preparations with paracetamol (acetaminophen) as
    co-codamol (best known in North America as
    Tylenol 3), with aspirin as co-codaprin or with
    ibuprofen. These combinations provide greater
    pain relief than either agent (drug synergy see
    synergy).

18
Codeine
  • Codeine is considered a prodrug, since it is
    metabolised in vivo to the principal active
    analgesic agent morphine. It is, however, less
    potent than morphine since only about 10 of the
    codeine is converted. It also has a
    correspondingly lower dependence-liability than
    morphine.
  • The conversion of codeine to morphine occurs in
    the liver and is catalysed by the cytochrome P450
    enzyme CYP2D6. Approximately 6?10 of the
    Caucasian population have poorly functional
    CYP2D6 and codeine is virtually ineffective for
    analgesia in these patients (Rossi, 2004).

19
Hydrogenation of morphines CC produced
dihydromorphine
Dihydromorphine is slightly stronger than
morphine as an analgesic with a nearly identical
side-effect profile, and is a somewhat more
active euphoriant -- therefore making it
theoretically a bit superior in alleviating
suffering -- and perhaps in a way subjectively
closer to that of morphine than hydromorphone,
other morphine derivatives, the codeine-based
series, or the synthetics. Like metopon,
dihydromorphine may be less addictive overall and
have better bioavailability after oral
administration than morphine. The onset of action
is more rapid than morphine and it also tends to
have a longer duration of action, generally 4-7
hours.
20
However, this led to a cmpd with improved activity
Hydromorphone is a drug developed in Germany in
the 1920s and introduced to the mass market
beginning in 1926. It is used to relieve moderate
to severe pain and severe, painful dry coughing.
Hydromorphone is known by the trade names Hydal,
Sophidone, Hydrostat, and most famously,
"Dilaudid?", though an extended-release version
called Palladone? SR was available for a short
time in the United States before being
voluntarily withdrawn from the market after an
FDA advisory released in July 2005 warned of a
high overdose potential when taken with alcohol
it is still available in the United Kingdom as of
March 2007. Another extended-release version
called Hydromorph Contin?, manufactured as
controlled release capsules, continues to be
produced and distributed in Canada by Purdue
Pharma Inc. in Pickering, Ontario.
21
Hydromorphone
  • Hydromorphone is becoming more popular in the
    treatment of chronic pain in many countries, and
    it is used as a substitute for heroin and
    morphine where these two drugs are not marketed
    on account of hydromorphone's superior solubility
    and speed of onset and less troublesome side
    effect and dependence liability profile as
    compared to morphine and heroin. Many chronic
    pain patients find that hydromorphone has a
    spectrum of actions which suit them just as well
    as morphine, and better than synthetics like
    methadone or levorphanol in alleviating
    suffering, as contrasted with simple pain of
    equal objective intensity.

22
Similar synthetic manipulations make hydrocodone
more potent than codeine
Hydrocodone or dihydrocodeinone (marketed as
Vicodin, Anexsia, Dicodid, Hycodan, Hycomine,
Lorcet, Lortab (or Loritab), Norco, Novahistex,
Hydroco, Tussionex, Vicoprofen, Xodol) is a
semi-synthetic opioid derived from two of the
naturally occurring opiates, codeine and
thebaine. Hydrocodone is an orally active
narcotic analgesic and antitussive. Sales and
production of this drug have increased
significantly in recent years, as have diversion
and illicit use. Hydrocodone is commonly
available in tablet, capsule and syrup form.
23
Oxycodone
24
Oxycodone
  • Oxycodone is a potent and potentially addictive
    opioid analgesic medication synthesized from
    thebaine. Its name is derived from codeine - the
    chemical structures are very similar, differing
    only in that the hydrogen on the codeine is
    oxidised to a hydroxyl group, hence 'oxy' and the
    hydroxyl group from the codeine becomes a ketone
    group, hence 'oxycodone.'

25
Oxycodone Brand Names
  • It is effective orally and is marketed in
    combination with aspirin (Percodan, Endodan,
    Roxiprin) or paracetamol/acetaminophen (Percocet,
    Endocet, Roxicet, Tylox) for the relief of pain.
    More recently, ibuprofen has been added to
    oxycodone (Combunox).
  • It is also sold in a sustained-release form by
    Purdue Pharma under the trade name OxyContin as
    well as generic equivalents, and instant-release
    forms Endone, OxyIR, OxyNorm, Percolone, OxyFAST,
    and Roxicodone.

26
Oxycodone Uses
  • Percocet tablets (Oxycodone with acetaminophen)
    are routinely prescribed for post-operative pain
    control. Oxycodone is also used in treatment of
    moderate to severe chronic pain. When used at
    recommended doses for any period of time it
    provides effective pain control with manageable
    side effects. Both immediate release oxycodone
    (OxyNorm in the UK) and sustained-release
    oxycodone (OxyContin in the UK) are prescribed
    for pain due to cancer more than for any other
    condition.

27
Oxycodone Recreational Use
  • The introduction of OxyContin in 1995 resulted in
    increasing patterns of abuse. Unlike Percocet,
    whose potential for abuse is limited by the
    presence of paracetamol, OxyContin contains only
    oxycodone and inert filler. Abusers simply crush
    the tablets, then either ingest the resulting
    powder orally, intranasally, via intravenous,
    intramuscular or subcutaneous injection (by
    dissolving the powder), or rectally to achieve
    rapid absorption into the bloodstream.

28
Oxycodone Recreational Use
  • Injection of OxyContin is particularly dangerous
    since it contains binders which enable the time
    release of the drug. Often mistaken as the time
    release, the outside coating of the pill is
    merely used as a color code for different dosage
    amounts. The vast majority of OxyContin-related
    deaths are attributed to ingesting substantial
    quantities of oxycodone in combination with
    another depressant of the central nervous system
    such as alcohol or benzodiazepines.

29
Oxymorphone
30
Oxymorphone
  • Oxymorphone (Opana, Numorphan) or
    14-Hydroxydihydromorphinone is a powerful
    semi-synthetic opioid analgesic that is derived
    from thebaine, and is approximately 6-8 times
    more potent than morphine. Clinically, it is
    administered as its hydrochloride salt via
    injection, or suppository typically in dosages
    of 1 mg (injected) to 5 mg (suppository). Endo
    Pharmaceuticals markets oxymorphone in the United
    States as Opana and Opana ER. Opana is available
    as 5 mg and 10 mg tablets Opana ER, an
    extended-release form of oxymorphone, is
    available as tablets in strengths of 5 mg, 10 mg,
    and 20 mg. As with other opioids, oxymorphone can
    cause physical dependency, and may be abused.

31
Thebaine
Thebaine (paramorphine) is an opiate alkaloid. A
minor constituent of opium, thebaine is
chemically similar to both morphine and codeine,
but produces stimulatory, with strychnine-like
convulsions, rather than depressant effects.
Thebaine is not used therapeutically, but is
converted industrially into a variety of
compounds including oxycodone, oxymorphone,
nalbuphine, naloxone, naltrexone, buprenorphine
and etorphine. It is controlled in Schedule II of
the Controlled Substances Act as well as under
international law. Thebaine is listed as a Class
A drug under the Misuse of Drugs Act 1971 in the
United Kingdom.
32
Changing substitutents on nitrogen can either
improve agonist activityor create antagonists!
Nalorphine , derivative of morphine that acts to
reverse the effects of morphine and other
narcotics . It counteracts narcotic-induced
nervous system and respiratory system depression
but is not effective against depression induced
by other sedatives such as barbiturates .
Nalorphine and other narcotic antagonists are
useful in reversing the effects of narcotic
overdoses. Because nalorphine causes withdrawal
symptoms in addicts, it is administered to
apparent ex-addicts to determine if they have
returned to drug use. Nalorphine is marketed
under the trade name Nalline. ?
33
Still more potent antagonists can be made by
incorporating the same structural changes used to
make morphine a more potent analgesic
Naloxone is a drug used to counter the effects of
opioid overdose, for example heroin or morphine
overdose. Naloxone is specifically used to
counteract life-threatening depression of the
central nervous system and respiratory system. It
is marketed under various trademarks including
Narcan, Nalone, and Narcanti, and has sometimes
been mistakenly called "naltrexate." It is not to
be confused with Naltrexone, another opioid
receptor antagonist with qualitatively different
effects.
34
Naltrexone
  • Naltrexone is an opioid receptor antagonist used
    primarily in the management of alcohol dependence
    and opioid dependence. It is marketed in generic
    form as its hydrochloride salt, naltrexone
    hydrochloride, and was formerly marketed using
    the trade name Revia. In some countries, an
    extended-release formulation is marketed under
    the trade name Vivitrol. It should not be
    confused with naloxone, which is used in
    emergency cases of overdose rather than for
    longer term dependence control.
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