Reading Assignment
• Goodman & Gilman, Chap. 10, pp. 237254, 257-263.
• Goodman & Gilman, Chap. 17, pp. 429459.
• Goodman & Gilman, pp. 620-622
(Cocaine)
Selective Serotonin Reuptake Inhibitors (SSRI’s)
•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.
Selective Serotonin Reuptake
Inhibitors (SSRI’s)
• 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.
SSRI’s
• 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, SSRI’s 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.
Neurotransmitters
OH groups necessary for agonist activity
OH
HO
NH2
HO
NH2
N
H
HO
Serotonin
5-Hydroxytryptamine
(5-HT)
Norepinephrine
(Noradrenaline)
Commercial SSRI's
OCH3
F
Me
CF3
Me
N
O
Me
O
N
H
O
C
F3C
N
Citalopram
(CelexaTM)
Fluvoxamine
(LuvoxTM)
Fluoxetine
(ProzacTM)
H
N
O
NH2
N
Me
H
N
O
Me
N
O
Cl
O
Cl
Paroxetine
(PaxilTM)
F
Sertraline
(ZoloftTM)
Dapoxetine
Other drugs that interfere with
serotonin reuptake: MDMA (Ecstasy)
OH
HO
NH2
HO
NH2
O
O
H
N
CH3
CH3
HO
HO
Norepinephrine
(Noradrenaline)
Dopamine
Methylenedioxymethamphetamine
(MDMA)
NH2
HO
N
H
Serotonin
5-Hydroxytryptamine
(5-HT)
•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.
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.
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.
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.
Other drugs active at the synapse:
pseudoephedrine
OH
HO
OH
NH2
NHCH3
CH3
HO
Norepinephrine
(Noradrenaline)
Pseudoephedrine
(nasal decongestant)
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
Pseudoephedrine
OH
HO
OH
NH2
NHCH3
CH3
HO
Norepinephrine
(Noradrenaline)
Pseudoephedrine
(nasal decongestant)
• 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.
OH
HO
OH
NH2
NHCH3
CH3
HO
Norepinephrine
(Noradrenaline)
Pseudoephedrine
(nasal decongestant)
• 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.
From Decongestants to ‘Speed’?
OH
HO
OH
NH2
NHCH3
CH3
HO
Norepinephrine
(Noradrenaline)
Pseudoephedrine
(nasal decongestant)
NH2
CH3
Amphetamine
NHCH3
CH3
Methamphetamine
• The structural similarity between
pseudoephedrine and methamphetamine
has led to ‘home brewing’ of ‘speed’.
• Thus, the purchases of pseudoephedrine are
now more closely monitored.
Stimulants
Me
O
O
OH
HO
NH2
NH2
CH3
H
N
NHCH3
CH3
HO
Norepinephrine
(Noradrenaline)
Amphetamine
Methamphetamine
Methylphenidate
(RitalinTM)
• 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.
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.
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.
How does amphetamine work?
OH
OH
NHCH3
CH3
Pseudoephedrine
(nasal decongestant)
HO
NH2
NH2
HO
NH2
CH3
HO
HO
Norepinephrine
(Noradrenaline)
Amphetamine
Dopamine
• 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.
How does amphetamine work?
• http://thebrain.mcgill.ca/flash/i/i_03/i_03
_m/i_03_m_par/i_03_m_par_amphetam
ine.html
• http://www.wadsworth.com/psychology_
d/templates/student_resources/media_
works/consciousness.html#mw8
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.
Another drug that interferes with
dopamine reuptake: cocaine
CH3
CH3
N
N
O
CH3
O
HO
NH2
O
O
HO
O
Dopamine
Cocaine
Atropine
O
OH
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.
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 ﾑ
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.
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.
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.
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ﾐ).
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-H+Clﾐ + 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!
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 ﾒ
rockﾓ 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 ﾒcrackﾓ).
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.
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.
How does cocaine work?
• http://www.wadsworth.com/psychology_
d/templates/student_resources/media_
works/consciousness.html#mw8