Morphine

1
Morphine
2
3D Structure of Morphine

• The T-shape of this molecule is difficult to
  visualize from the 2D representation
• http//www.3dchem.com/molecules.asp?ID186

3
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)

4

• 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.

5
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.

6
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.

7
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.

8
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, constipation, and may
  also lead to urinary retention.

9
Side Effects

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

10
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
• http//thebrain.mcgill.ca/flash/d/d_03/d_03_cr/d_0
  3_cr_que/d_03_cr_que.html

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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.

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The mu Receptor

• The main endogenous ligands for the mu receptor
  are the endorphins, peptides having 31 amino
  acids, with Tyr at the N-terminal end (note that
  the phenolic -OH group of tyrosine resembles that
  of morphine)

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Tyrosine and Morphine
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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.

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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.

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Overview Opioid Receptors

• Activation of the d-Opioid receptor produces some
  analgesia, although not as much as activation of
  the mu receptor
• The natural ligands for this receptor are the
  enkephalins, pentapeptides with the structures
  Tyr-Gly-Gly-Phe-Met or Tyr-Gly-Gly-Phe-Leu
• There is a recent interest in using delta
  agonists as antidepressants.

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Overview Opioid Receptors

• ?-Opioid receptors are also involved with
  analgesia, but activation also produces marked
  nausea and dysphoria (sadness, irritability,
  anxiety)
• The main endogenous ligands of the k receptor are
  the dynorphins, another class of endogenous
  peptide

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Heroin
19
Codeine
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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).

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Commercial Products Containing Codeine
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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.

23
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
24
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.
25

• Hydromorphone is known by the trade name,
  "Dilaudid.
• Another extended-release version called
  Hydromorph Contin, manufactured as controlled
  release capsules, continues to be produced.

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Hydromorphone

• Compared to morphine and heroin, hydromorphone
  has superior solubility and speed of onset and
  less troublesome side effect and dependence
  liability profile.
• 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.

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Similar synthetic manipulations make hydrocodone
more potent than codeine

• Hydrocodone (marketed as Vicodin, Lortab,
  Dicodin, others)
• Usually sold mixed with other milder analgesics,
  such as acetaminophen (Tylenol, paracetamol)
• Such combination products are more effective
  analgesics and also limit the potential for abuse.

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Oxycodone
29
Oxycodone Uses

• Percocet tablets (Oxycodone with acetaminophen)
  are routinely prescribed for post-operative pain
  control.
• 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.

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Oxycodone Recreational Use

• Unlike Percocet, whose potential for abuse is
  limited by the presence of acetaminophen
  (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.
  

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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.

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Oxymorphone
33
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.
34
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 .
35
Nalorphine

• 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. ?

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Still more potent antagonists can be made by
incorporating the same structural changes used to
make morphine a more potent analgesic
37

• 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.

38
Naltrexone
39
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.