PHAR 300 Lecture Notes - Serotonin Transporter, Free Base, Local Anesthetic
7 Jun 2018
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Cocaine and amphetamines, CNS stimulants
-some drugs can do many things : stimulants, depressants, hallucinogens
-stimulants
-cocaine is strong, rapid and is injected IV or crack
-amphetamine is strong, less rapid unless IV
-caffeine is weak and slow
-nicotine is weak, rapid when smoked
-chronic use of these drugs leads to addiction
-interactions with other drugs can be dangerous and toxicity is linked to their use
-deaths from acute poisoning -> stimulants are fairly high on the list
-widely used in Canada
Cocaine
-2 forms in use : hydrochloride or free base (powder and pellets)
-pharmacokinetic differences between the 2 forms
-hydrochloride not smokable, but free base can be smokable and forms a cracky sound when
it burns
-acts in 2 places
-synapse itself (at the mechanism that transports the transmitter back into the pre-synaptic
terminal after it is being released in the synapse) -> if we block the reuptake, the quantity
of neurotransmitter will be higher for longer in the synapse
-transporters in the terminals of the
aminergic synapses (domaine,
noradernaline, serotonin = amines involved
in the reuptake of the transmitter in the pre-
synaptic terminal)
-cocaine has an effect on the 3 of them
-impairs the ability of the pre-synaptic
terminal to take up the transmitters => we
increase their effects
-dopamine and serotonin mainly in CNS ;
noradrenaline is everywhere (CNS,
ANS…) => effects on the CNS and in the
periphery (ANS)
-very powerful drug
-neurotransmitter sodium symporter
family -> cocaine can block the reuptake of
all 3 of the neurotransmitters
-use cocaine as tools to see how the transporters work
-blocks the voltage gated sodium channels
-cocaine, by blocking these channels, interferes with axonal conduction => impulse
not transmitted from one neuron to the next
-will act on all the neuronal appendages
-thus works as a local anaesthetic (not used anymore -> derivatives of cocaine well
developed to just block the sodium channels, much more selective and less side effects)
-blocks all the sensations (touch, pressure, temperature…)
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-these channels are necessary for the function of all excitable tissues (brain, spinal
cord, autonomic nervous system, sensory nervous system ; heart muscle is full of
sodium channels) => cocaine will have an effect at many sites in our body, acts on all
excitable tissues everywhere
-history of cocaine : known in south America -> used by the natives to suppress appetite by
chewing the leaves of the plant -> very small dose in the body, absorption rate is slow => not
very pronounced effects apart from the appetite suppression
-contents of the leaves were purified
-1884 : discovered to be a local anaesthetic if put on wound in the periphery => sold as a
cure for toothache… -> marketed for about everything (e.g. cure for opium addiction and
alcohol) ; coca wine ; originally in Coca Cola (sold as a way to ease a tired brain) -> tonic to
make people think more clearly…but it killed many children so cocaine was banned in Coca
Cola
-purify/concentrate cocaine from the plant leaves -> mixed with gazoline, acid…
-pharmacodynamics
-CNS : excitatory effect (convulsions) then inhibitory (respiratory arrest) -> rapid
administration may produce immediate inhibition and death => high doses are very
dangerous
-heart : block SA node or conduction -> the person can rapidly go into cardiac arrest (we
never know the exact concentration of cocaine in one dose sold in the street)
-dopamine found in the reward pathway ; powerful effect on the sympathetic nervous system =>
central and peripheral effects
-triggers fight or flight reaction -> comes into play when extremely high alert
-if we destroy the dopamine neurons in nucleus accumbens => animal stops taking cocaine
(no more reward is associated with the drug)
-experiment : rat with cocaine and rat with no -> first rat runs all over the place compared to the
control rat
-dopaminergic receptors in the brain -> more than one type
-2 major categories : D1 and D2 (or like D1 and like D2)
-distribution of these receptors is different depending on which receptor we are looking at
(cortex…) => distributed unequally => complex effects of the drug
-several in tegmental area involved in addictive properties of cocaine
Pharmacokinetics
-absorption : powder or crack
-smoke it : absorbed from the lungs, fast,
cheap, easier to get kids to try => greatest
profit for drug dealers
-route affects amount absorbed : smoking
is equivalent to IV injection, hits the brain
very quickly
-intranasal (powder) doesn’t increase
rapidly in the blood -> peak not as high but
duration is longer (intense vasoconstriction
can be very severe -> cuts off blood flow,
intense vasoconstriction => we get death
from lack of oxygen supply to the tissue) ; powder is sniffed, absorbed rapidly from the nose
-> high blood flow in the nose
-oral : chew and swallow it : absorption is very slow, peak never as high -> most of it is
metabolised in first pass, by the liver => no rapid sensation of the affect of the drug (75%
first pass), little euphoria
2
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Some drugs can do many things : stimulants, depressants, hallucinogens. Cocaine is strong, rapid and is injected iv or crack. Amphetamine is strong, less rapid unless iv. Chronic use of these drugs leads to addiction. Interactions with other drugs can be dangerous and toxicity is linked to their use. Deaths from acute poisoning -> stimulants are fairly high on the list. 2 forms in use : hydrochloride or free base (powder and pellets) Hydrochloride not smokable, but free base can be smokable and forms a cracky sound when it burns. Transporters in the terminals of the aminergic synapses (domaine, noradernaline, serotonin = amines involved in the reuptake of the transmitter in the pre- synaptic terminal) Cocaine has an effect on the 3 of them. Impairs the ability of the pre-synaptic terminal to take up the transmitters => we increase their effects. Dopamine and serotonin mainly in cns ; noradrenaline is everywhere (cns,
