L9 CNS stimulants (cocaine, amphetamines, caffeine) Flashcards
What are 3 CNS stimulants (other than nicotine)
Cocaine, Amphetamine, Caffeine
TF: all CNS stimulates activate the rewards pathway and cause psychological and sometimes physiological dependence
True
How is powder cocaine referred to? and the solid form?
powder = cocaine hydrochloride
solid = crack (free base cocaine)
TF: cocaine has very rapid onset
True
and this promotes addiction if smoked
How does cocaine act as a local anesthetic
is interferes with voltage gated ion channels located in the axons which decreases axon conduction
Where are the 2 main places that cocaine acts on
1) the synapse at the nerve ending at reuptake pumps
2) ion channels along the axons (signal transmission)
In what way does cocaine affect the reuptake pumps at the presynaptic terminal
it blocks the reuptake of multiple neurotransmitters (dopamine, NE, serotonin) which increases the levels of these neurotransmitters in the synapses (CNS) and in the periphery (NE)
What major neurotransmitters does cocaine affect?
dopamine (reward pathways)
serotonin (many pathways)
NE (ANS - autonomic nervous system)
What is consequence of increasing neurotransmitter levels in the synapse?
leads to increase postsynaptic response
TF: cocaine is an appetite-suppresant
true
Why did people postulate the cocaine could help with opium and alcohol addicts?
People thought that the use of a CNS stimulant would counteract the effects of CNS depressants
What are the pharmacodynamic effects of cocaine
it blocks voltage gated Na+ (sodium) channels on axons which makes it an effective local anesthetic
Does cocaine increase or decrease glucose utilization by the brain
decrease
When cocaine is smoked or sniffed or injected, the effects are systemic or localized? Why?
systemic since Na+ channels are present on all excitable tissue
Why are the initial effects of cocaine use in the CNS excitatory?
there is decreased dopamine, NE, and serotonin reuptake resulting in convulsions
then inhibition occurs at higher doses which can lead to respiratory arrest
Why is cocaine a risk factor for cardiac arrest
the SA node can be blocked due to cocaine’s effects on Na+ channels in the heart and the Purkinje system (no depolarization due to blockage of action potential)
TF: other local anesthetics can also block neurotransmitter reuptake like cocaine
false, cocaine is unique in this function
what is the pharmacodynamic explanation has to why cocaine users experience a high
cocaine blocks the reuptake of neurotransmitters causing high levels of dopamine, NE, or 5HT in the synapse
How are cocaine derivatives which are used as local anesthetics today different from cocaine
cocaine derivatives only act on blocking the Na+ ion channels without interfering with neurotransmitter reuptake
what family of receptors is involved in amine neurotransmitter reuptake?
neurotransmitter/sodium symporter (NSS)
TF: excess dopamine is neurotoxic
true
why does cocaine cause hyperactivity
because it blocks the reuptake of NE at autonomic nerve endings (sympathetic nervous system, part of the ANS - autonomic nervous system)
TF: cocaine activates the reward pathway and the sympathetic fight-or-flight response simultaneously
true
dopamine (and serotonin) for reward pathway
NE for fight-or-flight in ANS, sympathetic system
How was the role of cocaine in the mesolimbic reward pathway identified
destruction of dopaminergic neurons (involved in the mesolimbic reward pathway) resulted in disinterest in cocaine
What kind of receptors does dopamine act on
GPCRs, mainly D2 dopaminergic receptors is involved in the mesolimbic reward pathway
How many kinds of dopaminergic receptors are there
at least 5 kinds
TF: inhibiting dopamine reuptake stimulates dopamine rectors only in specific areas of the brain
false, the whole brain is affected
the method of drug delivery affects what two things?
the rate of absorption
the peak concentration of the drug in blood
Why is snorting cocaine dangerous for blood flow?
snorting causes intense vasoconstriction -vasospasm- that could lead to tissue death in the nose due to impaired blood flow - physical injury to the nose to the point of ischemia (insufficient blood supply to organs)
TF: cocaine can cross the blood brain barrier
True
because it is small and lipid soluble
Why do people tend to binge use cocaine?
cocaine levels quickly rise in the brain, followed by a decrease due to it being redistributed to the rest of the body. In other words, the effects wear off quite quickly causing people to binge use cocaine
Which enzyme metabolizes cocaine
Human carboxylesterase 1 (hCE1)
Are cocaine metabolites biologically active?
yes, some but not all
TF: Consuming alcohol with cocaine does not change the pharmacokinetics of cocaine metabolism
False,
consuming alcohol with cocaine results in a different and toxic metabolite called cocaethylene
What makes cocaethylene a toxic metabolite?
it has a longer half-life (3-5x longer, 1-2 hours) resulting in a much lower LD (lethal dose)
it has similar but worse toxicity as cocaine - higher risks of cardiac arrest, chronic use can lead to severe liver damage and cerebral infarct (an area of the brain that has suffered from a lack of blood supply, resulting in tissue damage or cell death due to insufficient oxygen and nutrients)
TF: you can tell whether an individual has been exposed to cocaine by examining their hair
true, cocaine metabolites are deposited in hair
What are some cardiovascular toxicities that cocaine can cause
arrythmias
myocardial infract (heart attack) (largely due to Na+ channel blocking affecting the heart’s conduction system)
vasoconstriction
what is vasospam
it is when the diameter of your blood vessel becomes so small it can affect blood flow, it is particularly dangerous if it occurs in the coronary artery because the heart muscle can die and it can cause arrythmias. It can also occur in the brain and affect breathing and cardiovascular function
what is the difference between vasoconstriction and vasospasm
Vasospasm is a specific type of vasoconstriction, but it typically refers to an abnormal and sudden, often exaggerated, constriction of blood vessels. Vasospasms can be more intense and prolonged than regular vasoconstriction
what causes hypertension (particularly in cocaine users)
increase in NE that stimulates the sympathetic system of the ANS resulting in vasoconstriction
TF: chronic cocaine users then to get artherosclerosis
true
TF: strokes can occur even after acute use of cocaine
True
due to vasospasm in the nose
chronic use results in damage to vasculature in the brain
Why does cocaine abuse increase the likelihood of rupturing an aneurysm (bulging in the wall of a vessel)
it increases pressure in the vascular system in the brain, facilitating the rupture and thus causing a hemorrhagic stroke
What are some consequences of constant activation of the sympathetic system (ANS fight or flight)
hypertension
vasoconstriction and vasospasm
arrythmias
sudden death
** not seizures since that is controlled by CNS
what is agitated delirium and how much cocaine is needed to cause this
it is caused by a moderate dose meaning first time users can die from this - it is only in a subgroup of cocaine users
it is fatal
it results in respiratory arrest and hyperthermia (increase in body temperature incompatible with life) +delirium and agitation
it is unclear what causes it but some suggest its due to D2 variant receptors being linked to temperature control
What is crack lung and what causes it
it is acute pulmonary injury due to altered blood flow which causes pulmonary embolism and tissue death
people can recover from this
TF: cocaine can stimulate aggressive tendencies which can also cause death i.e. cocaine can indirectly cause death
true
how are “crack babies” characterized
fetal hypoxia due to vasocontraction (less blood flow to placenta), premature labor, limb abnormalities, impaired brain development
TF: the accumulated dopamine in the synaptic cleft isn’t broken down and remains there until reuptake is possible
false,
dopamine is broken down by enzymes eventually
TF: the newly synthesized dopamine receptors are also more sensitized
true
Why would the body create more dopamine receptors if they are already being activated at a higher extent?
Lack of dopamine in presynaptic terminals due to blocked reuptake signals the body to make new receptors
how do glutamate receptors change with addiction?
there are fewer receptors (think of the rebound excitation effect) and new types of glutamate receptors (combination of different subunits)
TF: the effects of substance abuse in ex-alcoholics last longer than ex-cocaine users
false
residual effects from cocaine use are longer lasting than those from alcohol use
TF: chronic cocaine use results in increased cell density in the brain
false, cell density decreases
why do cocaine users commonly use alcohol and heroin/fentanyl with cocaine
because cocaine makes people irritable, alcohol and heroin are used in hopes to counter this irritability
Explain why cocaine users experience dysphoria (despair) when going through withdrawals
This is because during withdrawal, D2 receptors which were overstimulated during cocaine use have been downregulated, transporters have been upregulated resulting in dopamine deficiency
which neurotransmitters do amphetamines act on and in what way?
amphetamines increase the release of dopamine and NE as well as block their reuptake
what is the function of the noradrenaline pathway in the brain
involved in keeping you awake and alert
TF: you gain resistance to the effects of amphetamines on motor activities after chronic use
false, you never get resistance to the effects of amphetamines on motor activity, though there is an increase in tolerance
what are some derivatives of amphetamines
methamphetamine (meth) - “ice” refers to the smokable form
MDMA (ecstasy)
How do amphetamines act on MOA (monoamine oxidase)
amphetamine derivatives block MAO, thus blocking the breakdown of dopamine and noradrenaline
how does amphetamine act on the dopamine transporter at the synaptic terminal?
i causes reverse translocation of dopamine - the transporter pushes out dopamine into the synaptic cleft instead to recycling the dopamine back into the neuron
through which mechanisms does meth lead to apoptosis
oxidative stress, excitotoxicity and neuroinflammation
why does chronic use of meth result in neuronal loss?
the dopaminergic neurons are damaged due to increased calcium in the cell (which is cytotoxic)
How is meth abuse related to Parkinson’s disease?
meth can destroy dopaminergic neurons, which is a predisposition to PD
Are there more or less dopamine receptors in the brain of a meth user? Why?
Less, because meth and amphetamines upregulate dopamine levels in the synaptic cleft and to adapt to these elevated dopamine levels, neurons express less receptors
TF: cognitive function recovers in meth users
false
although dopamine transporters can recover, there is permanent loss of function due to neuronal loss
ecstasy (MDMA) acts on what kinds of neurons? are they different from the neurons meth acts on?
serotonergic, dopaminergic, and noradrenergic neurons
(same as meth)
TF: ecstasy has hallucinogenic effects
true
ecstasy blocks or activates serotonin transporter 5-HT transporter? how does this affect the level of serotonin in the synaptic cleft
it blocks 5-HT transporters, thus increasing the level of serotonin in the synaptic cleft
TF: serotonin only affects the reward pathways
false, serotonin is important in many regions of the brain thus many pathways
what unpleasant symptoms can MDMA (ecstasy) cause? what are the short-term and long term effects?
bruxism (jaw-clenching), hyperthermia, clouded thinking, arrythmia, renal failure
short term: irritability, depression, heightened perceptions, stimulation, reduced appetite, elevated moods
long term: neurotoxicity, change in brain chemistry (less serotonin and metabolites), change in brain structure & transporters in the cerebral cortex
TF: An individual that abuses meth can recover back to normal within 5 years
false,
neurons and transporters are still damaged after 7 years, research shows
what is herbal ecstasy? is it safer than normal ecstasy
it is a plant derived amphetamine that is safer than MDMA but still not safe
When using ecstasy, what happens to serotonin and serotonin transporters/terminal
serotonin and its metabolites are reduced, serotonin transporters are reduced and serotonin terminals degenerate
which family is caffeine part of
xanthine
explain the pharmacokinetics of caffeine
rapid absorption & distribution to all tissues and through the BBB
rapidly metabolized by liver
why is the half-life of caffeine lesser in smokers?
drug metabolizing enzymes are induced in smokers (metabolizes faster in smokers)
How does the half-life of caffeine change with age
newborns have long caffeine half-lives since they do not possess the right enzyme for caffeine metabolism
TF: caffeine is a competitive agonist of adenosine receptors
False, it is a competitive antagonist of adenosine receptors
what kind of receptors are adenosine receptors? what is the effect of adenosine on neurotransmitters such as glutamate, ACh, DA, NA, GABA?
GPCRs, it is a neuromodulator that inhibits the release of various neurotransmitters
Adenosine lowers/enhances activity in cholinergic stimulatory networks
lowers
knowing that adenosine acts on cholinergic networks, how does caffeine act as a CNS?
it blocks adenosine receptors (competitive antagonist) resulting in lowered inhibition of neurotransmitter release (more excitation)
which organs does caffeine affect
brain, heart, cerebral vessels, GIT (increase gastric acid), kidneys (diuresis)
TF: tolerance to caffeine is slow
false, it is rapid
tolerance = more adenosine receptors are synthesized
TF: individual prone to panic attacks can drink coffe
false
