Morphine

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Morphine
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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)

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• 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.

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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.

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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.

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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

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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

• 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).

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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.

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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)

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Heroin
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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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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).

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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.
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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.
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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.
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Oxycodone
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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.'

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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.

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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.

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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.

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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
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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.

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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. ?
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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
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.
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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.