Reading Assignment

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Reading Assignment

• Goodman Gilman, Chap. 10, pp. 237-254, 257-263.
• Goodman Gilman, Chap. 17, pp. 429-459.
• Goodman Gilman, pp. 620-622 (Cocaine)

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Selective Serotonin Reuptake Inhibitors (SSRIs)

• Selective serotonin reuptake inhibitors (SSRIs)
  are a class of antidepressants used in the
  treatment of depression, anxiety disorders and
  some personality disorders.
• SSRIs increase the extracellular level of the
  neurotransmitter serotonin by inhibiting its
  reuptake into the presynaptic cell, increasing
  the level of serotonin available to bind to the
  postsynaptic receptor.
• They have varying degrees of selectivity for the
  other monoamine transporters, having little
  binding affinity for the noradrenaline and
  dopamine transporters.
• Studies have also found that SSRIs, as a side
  effect of their action, may cause in many people
  either a delay of sexual climax or anorgasmia, so
  they can be used to develop drugs specifically
  targeted to treat premature ejaculation.

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Selective Serotonin Reuptake Inhibitors (SSRIs)

• The main indication for SSRIs is clinical
  depression. Apart from this, SSRIs are frequently
  prescribed for anxiety disorders like social
  anxiety, panic disorders, obsessive-compulsive
  disorder (OCD) and eating disorders. Though not
  specifically indicated by the manufacturers, they
  are also sometimes prescribed to treat irritable
  bowel syndrome (IBS).
• SSRIs are contraindicated with concomitant use of
  MAOIs (monoamine oxidase inhibitors). This can
  lead to increased serotonin levels which could
  cause a serotonin syndrome.

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SSRIs

• SSRIs are described as 'selective' because they
  affect only the reuptake pumps responsible for
  serotonin, as opposed to earlier antidepressants,
  which affect other monoamine neurotransmitters as
  well. Because of this, SSRIs lack some of the
  side effects of the more general drugs.
• There appears to be no significant difference in
  effectiveness between SSRIs and tricyclic
  antidepressants, which were the most commonly
  used class of antidepressants before the
  development of SSRIs.2 However, SSRIs have the
  important advantage that their toxic dose is
  high, and, therefore, they are much more
  difficult to use as a means to commit suicide.
  Further, they were initially claimed to have
  fewer and milder side effects.

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Other drugs that interfere with serotonin
reuptake MDMA (Ecstasy)

• The primary effects of MDMA include feelings of
  openness, euphoria, empathy, love, and heightened
  self-awareness. Some users also report a tactile
  effect that many users refer to as the
  "touchies". This is a very pleasureable sensation
  when touching other objects.

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How does MDMA work?

• Serotonin is a neurotransmitter believed to play
  a role in the regulation of mood and pleasure.
  MDMA causes serotonin vesicles in the neurons to
  release quantities of serotonin into the
  synapses. Although popular press accounts focus
  on the role of serotonin release, the mechanism
  by which MDMA causes its unusual psychoactivity
  is largely unknown. In vitro and nonhuman animal
  studies have established that MDMA also induces
  dopamine, norepinephrine, and acetylcholine
  release, and can act directly on a number of
  receptors, including a2-adrenergic (adrenaline)
  and 5HT2A(serotonin) receptors.

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Acute toxicity of MDMA

• Apart from the dangers from impurities, the
  primary acute risks of taking MDMA resemble those
  of other stimulant amphetamines. The majority of
  fatalities and cases requiring emergency care
  involve hyperthermic syndromes. MDMA appears to
  decrease heat loss in the body by causing
  constriction of blood vessels near the skin. In
  addition, it may sometimes increase heat
  production by muscles and the brain. These
  effects may be amplified in people who become
  dehydrated and are therefore unable to cool by
  sweating. On top of this, MDMA can mask the
  body's normal thirst and exhaustion responses,
  particularly if a user is dancing or is otherwise
  physically active for long periods of time
  without hydration. Because of these effects, MDMA
  can temporarily reduce the body's ability to
  regulate its core temperature so that
  high-temperature surroundings (e.g. clubs)
  combined with physical exertion may lead to
  hyperpyrexia if precautions are not taken to
  remain cool. Sustained hyperpyrexia may lead to
  rhabdomyolysis (skeletal muscle breakdown), which
  in turn can cause renal failure and death.

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Long term effects of MDMA

• Long-term effects are still unknown and heavily
  debated among scientists. There are several
  reports of Hallucinogen Persisting Perception
  Disorder being induced by MDMA. In some cases,
  the disorder appears to be permanent. The
  disorder seems to occur in only a small fraction
  of a percentage of users, and its mechanism of
  causation is unknown.
• Some experiments indicate that use at very high
  doses may lead to the Synaptic Terminals of
  serotonin neurons being damaged. The precise
  mechanism of this action is unknown, but recent
  evidence (Jones 2004 Miller 1997 Monks et al.
  2004) suggests that the metabolic breakdown of
  MDMA includes the formation of reactive oxygen
  species (ROS), chemicals known to cause oxidative
  cell damage when taken up into the releasing
  synapse.

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Other drugs active at the synapse pseudoephedrine
Pseudoephedrine is a sympathomimetic amine
commonly used as a decongestant. Consumers often
refered to it by a product which contains
pseudoephedrine, such as Sudafed, the trademark
for a common brand of pseudoephedrine
hydrochloride
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Pseudoephedrine

• Since pseudoephedrine does not have the requisite
  catecholic OH groups, it does not exhibit agonist
  activity per se.
• However, it does get mistaken for
  noradrenaline, and is taken up into the
  presynaptic storage vesicles.

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• When pseudoephedrine is taken up, it displaces
  the natural messenger, norepinephrine, which gets
  released into the synapse.
• This activates the receptors lining the walls of
  the blood vessels, causing them to contract.
• The constricted blood vessels allow less fluid to
  leave, which results in less inflammation as well
  as decreased mucous production.
• Vasoconstriction in the nasal mucosa shrinks
  swollen nasal mucous membranes, reduces tissue
  hyperaemia, oedema, and nasal congestion. Other
  beneficial effects may include increasing the
  drainage of sinus secretions, and opening of
  obstructed Eustachian tubes.

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From Decongestants to Speed?

• The structural similarity between pseudoephedrine
  and methamphetamine has led to home brewing of
  speed.
• Thus, the purchases of pseudoephedrine are now
  more closely monitored.

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Stimulants

• Amphetamine is a stimulant that is now primarily
  used to treat narcolepsy and attention-deficit
  hyperactivity disorder. It is also used
  recreationally as a club drug and as a
  performance enhancer.
• Because of the widespread use of amphetamines as
  a treatment for narcolepsy and ADD/ADHD,
  prescription amphetamines are subject to
  diversion and are one of the most frequently-
  abused drugs in high schools and colleges.

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Historical

• Amphetamine was synthesized in 1887 by Lazar
  Edeleanu at the University of Berlin. It was one
  of a series of compounds related to the plant
  derivative Ephedrine, which had been purified two
  years previously by Nagayoshi Nagai. No medical
  use was found for Amphetamine until the 1900s,
  when it was introduced in most of the world in
  the form of the pharmaceutical Benzedrine. This
  drug was used by the militaries of several
  nations, especially the air forces, to fight
  fatigue and increase alertness among servicemen.
  After decades of reports of abuse, the FDA banned
  Benzedrine inhalers, and limited amphetamines to
  prescription use in 1959, but illegal use became
  common.

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Historical

• The related compound methamphetamine was first
  synthesized from ephedrine in Japan in 1893 by
  chemist Nagayoshi Nagai. In 1919, crystallized
  methamphetamine was synthesized by Akira Ogata
  via reduction of ephedrine using red phosphorus
  and iodine. The German military was notorious for
  their use of methamphetamine in World War Two.

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How does amphetamine work?

• Amphetamines release stores of norepinephrine and
  dopamine from nerve endings by converting the
  respective molecular transporters into open
  channels.
• Like methylphenidate (Ritalin), amphetamines
  prevent the monoamine transporters for dopamine
  and norepinephrine from recycling them (called
  reuptake inhibition), which leads to increased
  amounts of dopamine and norepinephrine in
  synaptic clefts.

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How does amphetamine work?

• http//thebrain.mcgill.ca/flash/i/i_03/i_03_m/i_03
  _m_par/i_03_m_par_amphetamine.html
• http//www.wadsworth.com/psychology_d/templates/st
  udent_resources/media_works/consciousness.htmlmw8

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Amphetamine Tolerance

• Tolerance is developed rapidly in amphetamine
  abuse, therefore increasing the amount of the
  drug that is needed to satisfy the addiction
• Short term tolerance can be caused by depleted
  levels of neurotransmitters within the vesicles
  available for release into the synaptic cleft
  following subsequent reuse (tachyphylaxis). Short
  term tolerance typically lasts 2-3 days, until
  neurotransmitter levels are fully replenished.
  Prolonged overstimulation of dopamine receptors
  caused by methamphetamine may eventually cause
  the receptors to downregulate in order to
  compensate for increased levels of dopamine
  within the synaptic cleft.20 To compensate,
  larger quantities of the drug are needed in order
  to achieve the same level of effects.

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Another drug that interferes with dopamine
reuptake cocaine
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Cocaine

• Cocaine (or crack in its impure freebase form) is
  a crystalline tropane alkaloid that is obtained
  from the leaves of the coca plant. It is a
  stimulant of the central nervous system and an
  appetite suppressant, giving rise to what has
  been described as a euphoric sense of happiness
  and increased energy, and post production. It is
  most often used recreationally for this effect.
  Nonetheless, cocaine is formally used in medicine
  as a topical anesthetic, specifically in eye,
  throat, and nose surgery.

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Cocaine Historical

• The stimulating qualities of the coca leaf were
  known to the ancient peoples of Peru and other
  pre-Columbian Andean societies.
• There is a long list of prominent intellectuals,
  artists, and musicians who have used the drug ?
  ranging from Sir Arthur Conan Doyle and Sigmund
  Freud to U.S. president Ulysses S. Grant. Cocaine
  could be found in trace amounts in the Coca-Cola
  beverage for several decades after the beverage's
  release, though that is no longer the case.

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Cocaine Historical

• One famous fan of cocaine use was Sigmund Freud.
  In 1884 Freud was in search of fame as a
  struggling doctor and wanted a cure for nervous
  exhaustion and morphine addiction. He found that
  cocaine relieved his own chronic depression and
  wrote a series of papers on cocaine, praising its
  results as a "magical drug," superior to
  morphine. Years later he backed off from his
  former praises. Freud was also a catalyst for a
  great medical development in 1884 he asked Dr.
  Karl Koller of Vienna to work with coca leaves.
  Koller was an ophthalmologist, and he was looking
  for something to use during eye operations. Freud
  recommended cocaine as a local anesthetic,
  because it could numb the tongue. Koller soon
  discovered that cocaine hydrochloride was a
  successful eye anesthetic and also fine for
  surgery of the ear, nose, and throat. In 1885
  Wilhelm Filehne showed that atropine has a
  chemical structure close to that of cocaine, and
  atropine became the anesthesia of choice.
  Nonetheless, interest in cocaine had opened
  research on this class of medical chemicals.

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Forms of Cocaine

• Cocaine sulfate is produced by macerating coca
  leaves along with water that has been acidulated
  with sulfuric acid, or an aromatic-based solvent,
  like kerosene or benzene. This is often
  accomplished by putting the ingredients into a
  vat and stamping on it, in a manner similar to
  the traditional method for crushing grapes. After
  the maceration is completed, the water is
  evaporated to yield a pasty mass of impure
  cocaine sulfate.
• The sulfate salt itself is an intermediate step
  to producing cocaine hydrochloride. In South
  America, it is commonly sold Cocaine sulfate is
  produced by Maceration to consumers as such, and
  smoked along with tobacco, also known as pasta,
  basuco, basa, pitillo, paco or simply paste. It
  is also gaining popularity as a cheap drug (30 to
  70 U.S. cents per "hit" or dose) in many South
  American countries.

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Forms of Cocaine

• Freebase cocaine is produced by first dissolving
  cocaine hydrochloride in water. Once dissolved in
  water, cocaine hydrochloride (Coc HCl)
  dissociates into protonated cocaine ion (Coc-H)
  and chloride ion (Cl?). Any solids that remain in
  the solution are not cocaine (they are part of
  the cut) and are removed by filtering. A base,
  typically ammonia (NH3), is added to the
  solution. The following net chemical reaction
  takes place
• Coc-HCl? NH3 ? Coc NH4Cl
• As freebase cocaine (Coc) is insoluble in water,
  it precipitates and the solution becomes cloudy.
  To recover the freebase, a nonpolar solvent like
  diethyl ether is added to the solution Because
  freebase is highly soluble in ether, a vigorous
  shaking of the mixture results in the freebase
  being dissolved in the ether. As ether is
  insoluble in water, it can be siphoned off. The
  ether is then evaporated, leaving behind the
  cocaine base.
• This is a highly dangerous process, since ether
  is extremely flammable!

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Crack Cocaine (Wikipedia)

• Due to the dangers of using ether to produce pure
  freebase cocaine, cocaine producers began to omit
  the step of removing the freebase cocaine
  precipitate from the ammonia mixture. Typically,
  filtration processes are also omitted. The end
  result of this process is that the cut, in
  addition to the ammonium salt (NH4Cl), remains in
  the freebase cocaine after the mixture is
  evaporated. The ?rock? that is thus formed also
  contains a small amount of water. Sodium
  bicarbonate (baking soda) is also preferred in
  preparing the freebase, for when commonly
  "cooked" the ratio is 50/50 to 40/60 percent
  cocaine/bicarbonate. This acts as a filler which
  extends the overall profitability of illicit
  sales. Crack cocaine may be reprocessed in small
  quantities with water (users refer to the
  resultant product as "cookback"). This removes
  the residual bicarbonate, and any adulterants or
  cuts that have been used in the previous handling
  of the cocaine and leaves a relatively pure,
  anhydrous cocaine base.When the rock is heated,
  this water boils, making a crackling sound (hence
  the onomatopoeic ?crack?). Baking soda is now
  most often used as a base rather than ammonia for
  reasons of lowered stench and toxicity however,
  any weak base can be used to make crack cocaine.
  Strong bases, such as sodium hydroxide, tend to
  hydrolyze some of the cocaine into
  non-psychoactive ecgonine.

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How does cocaine work?

• The pharmacodynamics of cocaine are complex. One
  significant effect of cocaine on the central
  nervous system is the blockage of the dopamine
  transporter protein (DAT). Dopamine transmitter
  released during neural signaling is normally
  recycled via the transporter i.e., the
  transporter binds the transmitter and pumps it
  out of the synaptic cleft back into the
  pre-synaptic neuron, where it is taken up into
  storage vesicles. Cocaine binds tightly at the
  DAT forming a complex that blocks the
  transporter's function. The DAT can no longer
  perform its reuptake function, and thus dopamine
  accumulates in the extracellular space (synaptic
  cleft). This results in an enhanced and prolonged
  post-synaptic effect of dopaminergic signalling
  at dopamine receptors on the receiving neuron.

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How does cocaine work?

• http//www.wadsworth.com/psychology_d/templates/st
  udent_resources/media_works/consciousness.htmlmw8

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