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PHAR 300 > Drugs acting on neurons > Flashcards

Drugs acting on neurons Flashcards

1
Q

where do Dopaminergic inputs start and where do they end?

A
  • start at VTA
  • go to nucleus accumbens and frontal cortex
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2
Q

what was nicotine used for historically?

A

as a botanical insecticide (natural insecticide in tobacco)

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3
Q

what is the number 1 avoidable killer in the world?

A

smoking

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4
Q

how long does it take for nicotine to reach the brain? how is that possible?

A
  • 7 seconds
  • high lung surface area and when gets into blood, goes right back to heart, which pumps it everywhere in the body
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5
Q

what are types of toxins that can be found in cigarettes?

A

carcinogens and ciliotoxins

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6
Q

what are ciliotoxins?

A

chemicals that impair the ability of the lung to get rid of all particles and pollutants that are inhaled – affects the mucociliary system in lungs

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7
Q

what can smoking cause?

A
  • lung and bladder cancer
  • coronary heart disease
  • strokes
  • peripheral vascular disease (impaired blood flow to legs making i harder for people to walk)
  • chronic lung disease
  • increase rate of influenza, diabetes, pneumonia, tuberculosis
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8
Q

what is the effect of smoking on blood vessels?

A

constricts blood flow to all the fine vessels in the periphery (effect on appearance – wrinkles, cataracts)

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9
Q

what is mainstream smoke vs sidestream smoke?

A
  • main: what person exhales
  • side: what comes off the burning end
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10
Q

explain the absorption of nicotine.

A
  • lipid-soluble
  • weak base: so ionized/more soluble at high pH, but cigarette companies will add chemicals to make it more alkaline so that it can be more readily absorbed, so will reach brain faster (more addictive)
  • bypasses first-pass
  • can easily diffuse into capillaries
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11
Q

are lower-nicotine cigarettes safer?

A

no since people will simply adjust the dose by smoking more/holding the smoke (smoker controls the bioavailability)

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12
Q

explain the distribution of nicotine.

A
  • goes everywhere (including fetus and breastmilk)
  • reaches Chemoreceptor trigger zone (CTZ), which is connected to vomiting center
  • will induce vomiting the first couple times, but will develop tolerance for that
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13
Q

explain the metabolism of nicotine.

A
  • mostly in liver by CYP2A6
  • that enzyme converts it to less active metabolite cotinine
  • half-life of 2 hours
  • takes about 4 cigarettes to get to steady state (about 4 half-lives)
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14
Q

what is the effect of having underactive CYP2A6 enzyme (it is a genetic variation)?

A
  • need to smoke fewer cigarettes, so less at risk of exposure to all the other chemicals in cigarettes
  • also responsible to convert some procarcinogens into carcinogens so more protected from those
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15
Q

explain the excretion of nicotine.

A
  • nicotine, cotinine, and carcinogens excreted in kidney, so makes urine carcinogenic (why risk of bladder disease)
  • alkaline urine: will decrease excretion since will be in unionized form so will tend to be reabsorbed in tubules
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16
Q

which receptor does nicotine act on? what type of receptor is it?

A

nicotinic cholinergic receptor, which is a ligand-gated ion channel selective to sodium and calcium

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17
Q

is nicotine an agonist or antagonist?

A

both

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18
Q

where are nicotinic receptors found?

A
  • found on postsynaptic side (but also act on presynaptic side to modulate amount of neurotransmitter release)
  • in ganglia of sympathetic and parasympathetic nervous systems in addition to brain
  • also found at innervation of skeletal muscle and in adrenal gland
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19
Q

what is the most common nicotinic receptor in the brain?

A

alpha-4, beta-2

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20
Q

what happens when nicotine binds to the receptor?

A

first stimulates then blocks the receptor

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21
Q

how many molecules does it take to activate the nicotinic receptor? which molecules can activate it?

A

2 molecules
- can be nicotine or/and acetylcholine

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22
Q

what is the difference between acetylcholine and nicotine binding to the nicotinic receptor?

A
  • acetylcholine: binds, and activation causes sodium to flow in, then the channel becomes desensitized and the agonist cannot bind but eventually goes back to standby state
  • nicotine: the desensitization phase is much longer so stimulates synthesis of more receptors and recruitment to the membrane (contributes to tolerance)
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23
Q

what is the effect of nicotine in the periphery?

A
  • blocks/stimulates the autonomic nervous system (can contribute to side effects)
  • stimulates receptors then blocks then from acetylcholine due to high affinity
  • leads to release of norepinephrine and adrenaline/epinephrine which contributes to increased HR, vasoconstriction, increase BP, and vessel damages caused by other toxic compounds
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24
Q

what is another psychoactive compound in cigarettes? what does it do?

A
  • monoamine oxidase inhibitor
  • blocks monoamine oxidase, which usually breaks down norepinephrine and dopamine in the presynaptic terminal
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25
Q

what is methanol?

A

used to be added to cigarettes
- gives minty flavour
- is a bioactive drug that modulates cholinergic receptors, making nicotine more addictive

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26
Q

what is the mechanism that leads to nicotine addiction?

A
  • nicotine can stimulates nicotinic receptors at GABA neurons to then inhibit the dopaminergic pathway
  • but, these desensitize very quickly (and for a long time), so leads to less GABA neurotransmitter inhibiting dopaminergic neurons
  • nicotine also stimulates release of glutamate that stimulate dopaminergic neurons to release even more dopamine
  • so, increase excitation and decrease inhibition
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27
Q

what are ways to treat nicotine addiction?

A
  • replacement therapy: substitute to get only nicotine without all the other chemicals in cigarettes (does get “high”)
  • bupropion: blocks nicotinic receptors on dopaminergic neurons in the VTA
  • varenicline: partial agonist at the a4b2 nicotinic receptor in the VTA
  • block CYO2A6 with methoxsalen (can help decrease blood levels of all the other toxic compounds)
  • topiramate: blocks the ability of nicotine to give high (decreased DA function(
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28
Q

what are the general effects of ethanol?

A
  • general CNS depressant
  • relief from anxiety
  • disinhibition (brief excitation)
  • sedation
  • hypnosis
  • general anesthesia
  • coma
  • death
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29
Q

what are the 5 concepts of CNS depressants?

A
  1. have additive effects when combines
  2. can’t reverse effect with stimulant
  3. general depressant aren’t that general
  4. chronic use leads to rebound excitation when stopping
  5. all CNS depressants result in some degree of tolerance (frequent cross-tolerance)
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30
Q

what are 2 types of amnesia tat can be seen with alcohol consumption?

A
  • partial: fragmentary loss of memory (universal and dose-related)
  • total (blackout): total loss of memory, susceptibility varies with person (don’t need to be comatose to blackout)
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31
Q

which parts of the brain does ethanol act on? what effect does this have?

A
  • cortex: affects judgment
  • hippocampus: affects memory
  • cerebellum: coordination
  • other: vision, movement, sensation, reward pathway
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32
Q

on which receptors does ethanol act on?

A
  • sodium, potassium, and calcium channels
  • 5HT and ACh receptors
  • inhibitory: GABA, glycine
  • excitation: glutamate
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33
Q

what are GABAa receptors? where are they located/where do they act? what is the effect of ethanol on them?

A
  • inhibitory receptor and chloride ion channel
  • there are synaptic and extra-synaptic receptors that are both inducible by ethanol
  • ethanol increases inhibition of inhibitory pathways
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34
Q

how does ethanol affect glycine release? what is the effect of this?

A
  • causes release of glycine
  • acts pre-synaptically to release glycine which acts on post-synaptic glycine receptors to cause inhibition
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35
Q

what is the effect of ethanol of NMDA receptors? what is the effect?

A
  • blocks NMDA receptors (they excite cells via glutamate release)
  • chronic use leads to increase NMDA receptors – causes increase excitation when no ethanol
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36
Q

what is the effect of ethanol of serotonin, acetylcholine, and opiate receptors?

A
  • decreases serotonin and acetylcholine release
  • endorphins released by ethanol act on opiate receptors (linked to dependance)
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37
Q

explain the absorption of ethanol. (how easily it is absorbed, when is peak, site of absorption)

A
  • is small, lipid-soluble so absorbed easily
  • in brain after 5 mins
  • peak at 30-90 mins (high on empty stomach)
  • 20% absorbed in stomach (especially on empty stomach)
  • rate increases with presence of carbonation
  • some is broken down in stomach by alcohol dehydrogenase
  • side effect: gastritis
  • most absorption in small intestine
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38
Q

explain the distribution of ethanol.

A
  • goes everywhere
  • distributed in total body water
  • so, AVD is equal to Total body water (which is why females need less alcohol for same effect – have less body water)
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39
Q

can ethanol cross the BBB? what does this cause?

A
  • yes
  • means that passes through chemoreceptor trigger zone, so causes nausea and vomiting
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40
Q

explain the metabolism of ethanol.

A
  • first-order at low doses, but turns into zero-order with more (get rid ~1/2 drink per hour)
  • mostly in liver
  • step 1: ethanol to acetaldehyde by alcohol dehydrogenase in liver and gastric mucosa – 6 polymorphisms of alcohol dehydrogenase (lots of variation)
  • step 2: acetaldehyde to acetate to water and CO2 by acetaldehyde dehydrogenase – less active form in 50% Asians so accumulate acetaldehyde (cause headache, nausea, sweating…)
  • other: CYP450s can also metabolize it, direct elimination (through breath, sweat, urine), CYP2E1 (less than 10%)
41
Q

what is the effect of ethanol on the kidneys?

A
  • blocks water reabsorption (inhibits ADH)
  • increases excretion via urine
42
Q

what is the therapeutic window for ethanol?

A

4 (very low – not safe)

43
Q

what are the chronic toxicity effects of ethanol?

A
  • cirrhosis (damaged liver)
  • liver impairment damages blood flow (hepatic encephalopathy)
  • muscle weakness
  • Cardio: arrythmia, hypertension, stroke, cardiomyopathy
  • brain: hallucination, confusion
  • nervous: neurodegeneration (potentiated by vitamin b deficiency)
  • associated with dementia, cerebellar ataxia, depression, psychiatric illnesses
  • brain damage
  • sexual function
  • acute pancreatitis
  • esophageal cancer
44
Q

what is the effect of chronic tolerance of ethanol? what are the withdrawal effects?

A
  • enhances inhibition and decreases excitation, so result is increased glutamate receptors
  • withdrawal: too much stimulation from excess excitatory system – anxiety, insomnia, tremor, palpitations, nausea, anorexia, seizures, hallucinations
45
Q

what is the powder form of cocaine? what is the form that is smoked (solid)?

A
  • cocaine hydrochloride
  • crack
46
Q

what are the two places where cocaine acts?

A
  • synapse at reuptake pumps for many transmitters in brain and sympathetic nervous system (dopamine, noradrenaline, serotonin) – blocks reuptake so leads to more in them at synapses
  • ions channels along the axons (blocks voltage-gated sodium channels)
47
Q

what makes cocaine a good local anesthetic?

A

it blocks sodium channels, which prevents axonal conduction and blocks action potentials

48
Q

what is the effect of cocaine?

A
  • initial is CNS excitation (resulting in convulsions) then inhibition occurs and at high enough doses, it can lead to respiratory arrest
49
Q

why is cardiac arrest a risk of cocaine?

A

SA node can be blocked due to its affect on sodium channels

50
Q

what provides the “high” of cocaine?

A

the fact that it blocks neurotransmitter reuptake, so there is more dopamine in the synapse available for reward pathway

51
Q

what is the effect of the blocking of noradrenaline reuptake by cocaine?

A
  • causes hyperactivity
  • activates the fight-or-flight response
52
Q

what is the recepetor type of dopamine receptors?

A

GPCR

53
Q

what is the major receptor important in the mesolimbic dopaminergic pathway?

A

D2 receptor

54
Q

explain the absorption of cocaine.

A
  • doesn’t go through first-pass
  • reaches brain and heart very quickly
  • orally: mild effect since high first-pass (75%)
  • snorting: intense vasoconstriction: could lead to tissue death in nose
  • smoking: fast onset
55
Q

explain the distribution of cocaine.

A
  • can cross BBB because is small and lipid-soluble
  • is redistributed quickly (~half-hour) after goes to brain so effect wears off quickly
56
Q

explain the metabolism of cocaine.

A
  • liver
  • metabolized by human carboxylesterase 1 (hCE1) which creates biologically active metabolites
  • T1/2: 1-2 hours
57
Q

what happens when you take ethanol and cocaine at the same time?

A
  • cocaine is metabolized differently and makes cocaethylene, which has a longer half-life than cocaine
  • its lethal dose is also much lower
  • high risk of cardiac arrest
58
Q

explain the excretion of cocaine.

A
  • metabolites in urine for days
  • some metabolites deposited in hair and stay there
59
Q

what is agitated delirium? what is hypothesized to be the cause?

A
  • it is a particular sensitivity to cocaine in a subgroup of users
  • fatal disorder that results in hypertension, delirium/agitation, respiratory arrest, hyperthermia, and death
  • thought to be due to variant in D@ receptor linked to temperature control in body
60
Q

what is crack lung?

A
  • acute pulmonary injury
  • alteration in blood flow, pulmonary embolism, destruction of sections of the lung
61
Q

why can chronic use of cocaine lease to neuronal injury?

A

since excess dopamine is neurotoxic

62
Q

what are the changes seen with chronic use of cocaine?

A
  • less dopamine in presynaptic terminal, so body synthesizes more and postsynaptic membrane and the receptors are more sensitized to dopamine
  • changes in glutamate receptors and are less receptors on postsynaptic membranes to deal with excess neurotransmitters in the cleft
63
Q

what are ways to help with cocaine withdrawal?

A
  • group therapy
  • medical assistance
  • a drug exists that blocks the dopamine transporter so decreases affect of cocaine
64
Q

what is the effect of amphetamines?

A

increases release of dopamine and noradrenaline as well as blocking their reuptake

65
Q

where do amphetamines act?

A
  • on noradrenergic pathways in brain
  • act pre- and post-synaptically
66
Q

what is role of noradrenergic pathway?

A

involved in keeping you awake and alert

67
Q

what are some amphetamine derivatives? what other effect do they have?

A
  • methamphetamine
  • MDMA (ecstasy)
  • block monoaminase oxidase so block breakdown of dopamine and noradrenaline
  • meth can lead to apoptosis
68
Q

what is the affect of chronic use of meth?

A
  • leads to decreased dopaminergic receptors, which is concern since causes predisposition to parkinson’s
  • dopamine transporters recoverin users, but seems to be a loss of cognitive function
69
Q

what is the effect of ecstacy (MDMA)?

A
  • acts on serotonergic neurons as well as dopaminergic and noradrenergic
  • blocks serotonin transporter which increases level in synaptic cleft
  • elevated mood
  • jaw-clenching, hyperthermia, clouded thinking…
70
Q

what are some short-term and long-term affects of ecstasy?

A
  • short: irritable, depressed, heightened perceptions, stimulations, reduced appetite, and elevated mood
  • long: neurotoxicity
71
Q

what are the brain changes caused by ecstasy?

A
  • chemistry: serotonin reduced, metabolites reduced
  • structure: reduced serotonin transporters, serotonin terminals degenerate (memory can be impaired)
72
Q

explain the pharmacokinetics of caffeine.

A
  • rapid absorption (peak in blood is 0.5-2 hours)
  • can cross BBB
  • rapidly metabolized in liver
  • half-life: 4-5 hours (less in smokers)
  • excreted in kidneys
  • t1/2 changes with age
73
Q

explain the pharmacodynamics of caffeine.

A
  • competitive antagonist at adenosine receptors (are GPCRs with inhibitory effects)
  • adenosine is a neuromodulator which inhibits release of glutamate, ACh, DA, NA, and GABA
  • so caffeine decreases inhibition (blocking signal in forebrain decreases signals to induce sleep)
  • increased HR and diuresis
74
Q

explain the pharmacodynamic tolerance of caffeine.

A
  • tolerance is rapid
  • more adenosine receptors are synthesized in response
  • mild withdrawal
75
Q

what are the 2 major compounds in marijuana?

A
  • THC and CBD
76
Q

what is the therapeutic use for cannabis?

A

chronic pain in adults and chemotherapy-induced nausea/vomiting

77
Q

where do cannabinoids act?

A

on CB1 and CB2

78
Q

where are CB1 and CB2 located and what are their effects?

A
  • CB1: mostly in brain but also found throughout body, responsible for psychiatric effect, acts on CNS (hypothalamus - appetite, basal ganglia/cerebellum - movement, cerebral cortex - higher cognitive function, hippocampus - learning/memory/stress, medulla - nausea/vomiting/chemoreceptor trigger zone, spinal cord - peripheral sensation)
  • CB2: high concentration in immune system, mainly postsynaptic side of synapses
79
Q

what are the types of compounds that act on cannabinoid receptors?

A
  • endocannabinoids: natural ligand, acts on CB1 receptor to inhibit transmitter release
  • phytocannabinoids: plant-derived (THC and CBD)
  • synthetic cannabinoids: mimics THC and other plant-derived compounds (e.g. nabilone)
80
Q

what type of signaling system occurs with cannabinoids? explain the mechanism.

A

retrograde signaling system
1. AEA or 2-AG are synthesized naturally and act at CB1 (THC and others also act on this receptor)
2. activation decreases calcium intake (blocks channel) and increases potassium intake (opens channel)
3. hyperpolarizes cell
4. decreased stimulation of postsynaptic neurotransmitter receptor

81
Q

explain the pharmacokinetics of cannabis.

A
  • absorption: lungs (THC rapidly absorbed and distributed), intestine (less absorption since first-pass), skin (are lipid soluble so can cross plasma membrane dermally)
  • distribution: distributed in extracellular water easily, and because lipid-soluble, can be stored in fat, rapidly cross BBB
  • metabolism: in liver
  • excretion: metabolites secreted in saliva and sweat, but largely in urine, some in feces and bile
  • site of action depends on what active ingredient is: THC induces CYP1A2 and CBD is CYP3A4 inhibitor
82
Q

what is the toxicity if cannabis?

A
  • carcinogens when smoking similar to cigarettes
  • main risks: cancers, heart attack, stroke
  • long-term unknown
83
Q

what is schizophrenia?

A
  • a chronic brain disorder causing delusions, hallucinations, disorganized thinking, etc…
  • elevated dopamine in brain
84
Q

how do we measure effectiveness of antipsychotics?

A

by how effective they are at blocking D2 receptors

85
Q

what are the 4 major categories of antidepressants?

A
  1. monoamine oxidase inhibitors
  2. tricyclic antidepressants
  3. selective serotonin reuptake inhibitors
  4. NA + 5-HT reuptake inhibitors
86
Q

how do MAOIs work as antidepressants?

A
  • increases excitatory NA and 5-HT (serotonin) at the synapses and post-synaptic receptors
87
Q

how do tricyclic antidepressants work?

A
  • interfere with reuptake of neurotransmitters by blocking 5-HT and noradrenaline reuptake
  • leads to increase in neurotransmitters 5-HT and NA
  • many side effects: block adrenergic receptors (acts on vascular system), histamine receptors (produces sedation) , and cholinergic receptors (acts on GI tract and vision)
88
Q

how do selective serotonin reuptake inhibitors work?

A
  • block 5-HT reuptake transporters but not others
  • leads to increase 5-HT
89
Q

what is seasonal affective disorder? what is the treatment?

A
  • seasonal depression during winter (less sun)
  • treatment: exposure to light source that emits same wavelength as the sun
90
Q

what are benzodiazepines used for?

A

mainly anxiety

91
Q

what are causes of anxiety?

A
  • stress-related (overreaction)
  • generalized anxiety disorder
  • panic attacks
  • phobias
  • secondary anxiety, caused by disease
  • drug-induced
92
Q

what are the major effects of benzodiazepines?

A
  • antianxiety
  • induce sleep
  • anticonvulsant
  • muscle relaxant
  • impair memory formation
  • abuse potential
  • antiepileptic
93
Q

are benzodiazepines safe?

A

yes, have TI of 1000

94
Q

explain the pharmacodynamics of benzodiazepines.

A
  • acts allosterically on GABAa receptors
  • increases activity of GABA neurotransmitters
  • different GABAa subtypes each account for the different affects of benzodiazepines
95
Q

what is difference between benzodiazepines and barbituates?

A
  • benzo: affects frequency of opening and has no direct action so is safer and more selective
  • bar: increase duration of channel opening and acts directly to increase chloride, so much more dangerous
96
Q

what are the effects of benzodiazepine antagonists and inverse agonists?

A
  • anta: can reverse effects of benzo (can be used to wake someone who is very heavily sedated)
  • inv: opposite effect of benzo (increases anxiety) – reduces effect of benzo
97
Q

explain the absorption, distribution, metabolism, and excretion of benzodiazepines.

A
  • absor: well absorbed, lipid-soluble, get in brain fast, peak in 1hr
  • dis: widely distributed, variable protein binding
  • met: by CYP3A and CYP2C19 into intermediates, multiple active metabolites with long half-lives
  • excretion: kidney
98
Q

what are side effects of benzodiazepines?

A
  • amnesia: cognitive impairment, chronic high blood pressure
  • sedation: cannot combine with other CNS depressants
  • muscle relations/ataxia: don’t drive
  • anxiolysis
  • anti-convulsive
  • tolerance may develop (differential tolerance)
  • dependance liability
  • withdrawal seizures
99
Q
A

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