Exam 1 Flashcards
(150 cards)
1
Q
What are some basic metrics regarding the BBB?
A
- 100 billion capillaries.
- Spans 400 miles
- Trans-endothelial resistance of 1.5-3 ohms. (1000x higher than other tissues)
- Highly resistant membrane. More resistant than any other tissue type.
2
Q
What are the cell types within the central nervous system?
A
Endothelial cells- makes the walls of the blood vessel. Very contractile
Pericytes
Astrocytes
Oligodendrocytes
Neurons
Microglia
3
Q
What are the basic drug characteristics that typically allow passage through BBB?
A
- Molecular weight less than 400 Da
- Less than 3 H bond donors
- Less than 7 H bond acceptors
- Total N and O less than 10
4
Q
Describe the graph.
A
Morphine has very little ability to get into the brain (less than 0.05%), but we still feel the effects of morphine due to it being a very potent drug. Domoic acid penetrates the brain at even smaller rates (0.002%), but it is even more potent and that small amount will kill the person.
5
Q
What are the 4 different receptor types?
A
- Ion channel
- Enzymes
- GPCRs
- Hormones
6
Q
What is pharmacokinetics (PK)?
A
PK is how a drug is absorbed, distributed, metabolized, and excreted from the body. What the body does to the drug.
7
Q
What is pharmacodynamics (PD)?
A
PD is what the drug does to the body. Relates to the drug and the receptor.
Relates to concentration of free drug [D], receptors [R], and drug-bond receptors [DR].
8
Q
What is Kd?
A
Kd is the equilibrium dissociation constant. The smaller the Kd, the more tightly bound the drug is to the receptor meaning it has a higher affinity for the receptor. A higher Kd means the drug is bound looser and has less affinity for that receptor.
9
Q
On average, how many drug targeting the CNS are FDA approved per year?
A
1 per year with 4 in 2023.
10
Q
What are the 5 conventional drug targets?
A
- Carriers/transporters
- Ion channels
- GPCRs
- Enzymes
- Receptors
11
Q
How many drug targets are there within the human body?
A
As of now, 3013.
12
Q
What are the two ways in which to test for drug selectivity?
A
- Electrophysiology- must use live tissue. Only advantage of having greater resolution to look at the properties of a single ion channel (open probability, conductance, channel density, etc). Much greater functional resolution with this technique.
- Imaging- can use live and dead tissue to ask questions regarding what type of neuron you see. (what ions they flow? what receptor channels are expressed? etc)
13
Q
What is the percentage of calories from alcohol itself is spent on the metabolism of alcohol?
A
20%
14
Q
EtOH is ____________ potent than most drugs like morphine, fentanyl, or carfentanil.
A
LESS
15
Q
What are the pharmacokinetics of ethanol?
A
- One drink =14grams
- 100% absorbed from gut
- 66% bioavailable in blood after first-pass metabolism
- Peak blood ethanol levels 30 minutes.
- Zero-order kinetics at 8 grams per hour.
16
Q
What is zero order kinetics?
A
Zero order metabolism is when there is a constant amount of a drug is eliminated per unit of time.
17
Q
Explain metabolism of ethanol in the liver.
A
Ethanol is converted to acetaldehyde via alcohol dehydrogenase (ADH). Then acetaldehyde is converted to acetic acid via aldehyde dehydrogenase (ALDH).
18
Q
There are ______ billion neurons in the adult human brain.
A
86
19
Q
There are ________ trillion synapses in the cerebral cortex. (each synapse is a data processor with a pre and post synaptic side)
A
125
20
Q
What are the pharmacodynamics of ethanol?
A
Ethanol binds to GABA receptors and increase GABA’s affinity for that receptor so therefore it enhances the effects of the inhibitory NT GABA.
21
Q
How can the suppression of glutamate signaling due to ethanol result in increased activity?
A
Disinhibition. Excitatory goes off at certain frequency. GABAergic modulation to keep it clean and steady. Increase GABA activity causes some part of excitatory circuit that feed an inhibitory neurons that feeds back to excitatory and shuts off the inhibitory signaling. This stops GABAergic activity and allows for free flow of glutamate.
22
Q
What other drugs enhance GABA?
A
EtOH, Benzodiazepines, and barbiturates
23
Q
What is happening in the brain when someone blacks out from alcohol?
A
Ethanol is an antagonist of the NMDA glutamate receptor which is partially responsible for making memories.
24
Q
Why does drinking alcohol make you dehydrated?
A
The metabolism of alcohol leads to dehydration due to it inhibiting the release of vasopressin/ADH. This means we conserve less fluids and become thirsty.
25
What are scientifically backed ways to help a hangover?
Original Alka Seltzer, coffee, water, gatorade, and sleep.
26
What is asian flush?
This is where a certain group of people lack the aldehyde dehydrogenase enzyme. This means that acetaldehyde cannot be converted to acetic acid. Acetaldehyde is toxic and causes redness.
27
How does alcohol effect the reward pathway in the brain?
Dopamine release in the brain goes to outer shell of nucleus accumbens and olfactory tubercles after ethanol intake to make people feel good.
28
Tolerance related to alcohol mostly effects what part of the body?
The liver- specifically up regulation of liver enzymes
29
Dependence related to alcohol mostly effects what part of the body?
The brain. Withdrawal effects include sleep disturbances, autonomic sympathetic signs, and cravings.
30
What causes fatty liver disease?
The metabolism of alcohol requires lots of NAD+. This means when the liver is focused on the breakdown of alcohol, other pathways that use NAD+ are not active. This change in metabolism promotes fat storage in the liver. This leads to scarring and cirrhosis.
31
What is Wernicke-Korsakov Syndrome?
This is a syndrome that effects Broca's and Wernicke's areas in the brain. It is due to a long-term alcohol exposure mixed with thiamine deficiency. Symptoms of this include opthalmoplegia, ataxia, confusion, confabulation, and peripheal neuropathy.
32
What is the MOA of the drug Naltrexone?
This drug blocks the opioid receptors which, for a small subset of those with alcohol use disorder, does a good job in blocking the euphoria and therefore reduces the desire to drink
33
What is the MOA of disulfiram?
This drug blocks the actions of aldehyde dehydrogenase therefore leaving acetaldehyde in that form and not converting it to acetic acid. Leads to unpleasant and nauseous sensations when alcohol is consumed.
34
What is Acamprosate?
This is a drug that is likely a direct agonist of the GABA A receptor or an NMDA receptor antagonist.
35
What is the most common cause of preventable mental retardation?
Ethanol consumption while pregnant.
36
Who discovered the blood brain barrier? Describe the experiment used.
Paul Ehrlich discovered the BBB when he was looking at oxygen consumption in the body. He saw if you injected blue dye into the peripheral, it stays there and does not enter brain or spinal cord.
37
What is the average size of the capillaries composing the BBB?
Range from 3 to 7 microns. This is big enough diameter to fit one red blood cell at a time. The size also allows for a slow flow of blood for proper exchange.
38
If you were to spread out the BBB, what would the square footage be?
Square footage of BBB is between 200-300 feet. This is the third largest behind the lungs and GIT.
39
What makes up the neurovascular unit/BBB?
Includes the endothelial cells composing the blood vessels. Include pericytes which aid in blood flow. Astrocytes and neurons are also apart of this.
40
How are the blood vessels composing the BBB different from blood vessels in the periphery?
The tight junctions between endothelial cells is the physical barrier in the BBB. There is much less exchange and more regulation in the blood vessels of the BBB. Periphery blood vessels exchanges things much more and is less regulated.
41
What are the 3 main functions of the BBB?
1. act as physical barrier
2. act as biochemical barrier
3. act as immunological barrier
42
How does the BBB act as a physical barrier?
The physical barrier is due to the tight junctions between endothelial cells.
43
How does the BBB act as a biochemical barrier?
There are transporters that act like gate keeps and scan blood to allow things to enter or not enter. Red is the gatekeepers while blue and yellow are enzymes that could metabolize the drug before it could even get to the brain. The main big efflux transporter is the P-glycoprotein.
44
Explain the P-glycoprotein.
This is an efflux transporter only located in the blood vessels of the BBB. It is not specific to anything and is supposed to keep out lots of things. This is the most potent transporter protein in the BBB.
45
How does the BBB act as an immunological barrier?
Leukocytes can get captured and roll and then crawl past the BBB on a needed basis. They either go through the tight junctions of straight through an endothelial cell. Leukocytes are huge so the scientific community is not exactly sure how this happens.
46
Explain the following graph.
Y axis is BBB permeability.
X axis is Octanol water partition coefficient. Water is hydrophilic and lipophobic while octanol is lipophilic and hydrophobic. As you go up the line, the substances get more lipophilic and therefore should have an easy time bypassing the BBB.
47
Looking at the same graph, explain why the standard curve is not always applicable.
It appears that some water soluble substances do pass through the BBB like lactate. All the substances in red are things the brain needs which gives reason to believe they may have their own transporters on the BBB.
48
Explain the process of glucose crossing the BBB.
Glucose binds to GLUT-1 transporter in BBB. This causes a conformation change to GLUT-1 which allows glucose to pass into endothelial cell. Within the endothelial cell, the glucose is phosphorylated and then crosses other over other side and enters the brain. Phosphorylated glucose cannot diffuse out of cell so the concentration of phosphorylated glucose is higher in brain than BBB which creates a concentration gradient that drives glucose into the brain.
49
What are the different physiological pathways that allow for passage through BBB and into the CNS?
1. Paracellular diffusion- between tight junctions. small hydrophilic only.
2. Transcellular diffusion
3. Carrier mediated transport- GLUT-1, LAT-1 (large AA transporter), CAT-1, MCT-1, choline transporter, etc
4. Receptor mediated transcytosis- insulin, leptin, transferring, lipoprotein receptors.
5. Adsorptive transcytosis
50
What is one way to optimize drug properties?
Drugs that are small, lipophilic, and unipolar are more likely to pass BBB. A drug that is a pro-drug that becomes more lipophilic once it bypasses the BBB works well too. An example of this is L-DOPA to treat parkinson's.
51
Explain the failure of liposomes and nanoparticles regarding getting drugs past the BBB.
Drug was within the liposome. It did not work quickly and attached to the BBB but did not cross it. Then came nanoparticles which just got stuck in the liver. These things are now used in the cosmetics business.
52
Explain the Trojan Horse technology regarding bypassing the BBB.
Drugs can be attached to peptidomimetic monoclonal antibodies or endogenous ligands that use receptors to get into the brain. It kind of worked but research was never able to get the needed concentration of the drug into the brain in order to see results.
53
What is the process of osmotic disruption regarding the BBB?
Dr. Edward Neuwelt came up with idea. This is where a 25% injection of mannitol is given into the intracarotid artery. This causes transient shrinkage of the endothelial cells which separates the tight junctions so things can pass through the BBB. Cons of this process include possible leakage of harmful things into brain, seizures, super invasive, tissue swelling, and possible infection. Right now it is only used for terminally ill patients as a last resort.
54
Explain the process of using ultrasound and microbubbles to bypass the BBB.
Microbubbles and the drug are injected into the BBB. The ultrasound is then used to vibrate the bubbles and forces apart of the endothelial cells so the drug can bypass the BBB. Cons include ultrasounding the entire brain and not getting a high enough concentration of the drug into the brain.
55
Explain the process of focused ultrasound in regards to bypassing the BBB.
Injection of microbubbles and drug to a certain brain region. Ultrasound is then focused on that specific area. This is still experimental.
56
Do BBB drug efflux inhibitors work?
They work great in animal studies but not at all in humans studies. Humans needed such a high dose of the efflex inhibitor it would have induced severe side effects. There is no FDA approved drug in this class.
57
Describe intranasal delivery of drugs.
Nasal sprays cross the nasal epithelial barrier into the submucosal space. Then the drug diffuses across the arachnoid membrane and entering the CSF in the olfactory region. This route works well for pain, migraines, epilepsy, and anxiety.
58
Why is it not possible to solely inject a drug into the brain?
It was tried. The issue is that the drug stays exactly where it is placed. This is due to the tightness of the brain cells not allowing the medication to move.
58
What is convection enhanced delivery (CED)?
This is when little needles inject drugs into the brain. The same issue of no drug distribution occurs with this method too.
59
What are Gliadel wafers?
These are pellets of material soaked in a drug that is implanted into an open cavity from which a tumor was removed.
60
What are the 3 most common techniques to bypass the BBB?
1. Intracerebroventricular injection using the OMMaya reservoir.
2. Convection enhanced delivery (CED) using intracerebral catheters.
3. Wafers placed in cavity after tumor resection.
61
Antipsychotics target ___________ signalling.
Dopamine
62
Antipsychotics treat __________________.
Schizophrenia
63
What is schizophrenia?
It is a mental illness is which the patient exhibits a dissociation with reality.
64
What are some positive, negative, and cognitive symptoms of schizophrenia?
Positive- hallucinations, delusions, feelings of persecution, agitation, combativeness, hyperactivity
Negative- withdrawal, scarcity of speech/movement, blunt effect, lack of motivation
Cognitive- attention deficits, impaired working memory, organizational problems.
65
What is the dopamine hypothesis of schizophrenia?
1. Pharmacological efficacy of an antipsychotic typically corresponds to the drug's affinity for dopamine receptors
2. Drugs that increase dopamine can cause psychotic symptoms.
3.Unmedicated subjects diagnosed with schizophrenia typically exhibit greater dopamine receptor density and dopamine levels.
However, dopamine does not explain it all. Some antipsychotics act on serotonin receptors. Other times dopamine deficits contribute to negative and cognitive symptoms.
66
What are the 4 dopaminergic pathways in the brain?
1. Mesolimbic/mesocortical tract
2. Nigrostriatal tract
3. Tuberoinfundibular tract
4. Medullary-periventricular tract
67
What is the mesolimbic/mesocortical dopamine tract?
Mesolimbic goes from ventral tegmental area to nucleus accumbens. This is the reward circuit.
Mesocortical goes from ventral tegmental area to prefrontal cortex. This is where organizational and planning behavior happens.
68
What is the nigrostriatal dopamine tract?
This starts in the substantia nigra and goes to the striatal nuclei. Works in fine tuning movement.
69
What is the tuberoinfundibular dopamine tract?
This starts in the arcuate and periventricular neurons and extends to the pituitary portal system. Functions in the regulation of release of hormones and pro-hormones.
70
What is the medullary-periventricular dopamine tract?
This starts at the motor nucleus of the vagus nerve, the area postrema, and other brainstem nuceli. The end projections are unclear. Functions in antiemetic effects and changes in eating behavior associated with antipsychotics.
71
Explain the two types of dopamine receptors.
D1 "like"- includes D1 and D5 receptors. G proteins coupled to stimulatory G protein. Stimulation of cAMP and PKA-dependent pathways.
D2"like"- includes D2, D3, and D4. G proteins coupled to inhibitory G proteins. Inhibition of cAMP and PKA-dependent pathways.
72
What are the 4 types of typical antipsychotics and their prototype drug?
Phenothiazine (aliphatic)- Chloropromazine
Phenothiazine (piperazine)- Fluphenazine
Thioxanthene- Thiothixene
Butyrophenone- Haloperidol
PTB!
73
What are the 6 Atypical antipsychotic drugs with their prototype?
Dibenzodiazepine- Clozapine
Benzisoxazole- Risperidone
Thienobenzodiazepine- Olanzapine
Dibenzothiazepine- Quetiapine
Dihydroindolone- Ziprasidone
Dihydrocarbostyril- Aripiprazole
74
What are the overall pharmacological effects of antipsychotics?
Amelioration of thought and mood disorders associated with schizophrenia.
Sedation
prevention of vomiting and nausea
75
When are long-acting depot injectables of antipsychotics used?
These are not recommended to treat acute episodes. Reserved for patients with history of non-adherence to daily medication.
76
What are the basic pharmacokinetic principles of antipsychotic?
Drugs accumulate in lipid storage sites and are released slowly.
Steady state concentration reached in 4-7 days.
Half life of 12-24 hours.
Liver metabolism by cytochrome P450 enzymes.
77
What are the characteristics of the typical antipsychotic, phenothiazine (aliphatic and piperazine derivative)?
Phenothiazine prototype drugs include chloropramize (aliphatic) and fluphenazine (piperazine). This is the least potent antipsychotic. It causes the greatest amount of sedation and weight gain.
78
What are the characteristics of the typical antipsychotic, Butyrophenone?
Butyrophenone was approved after the phenothiazines. It is much more potent than the phenothiazines. Has less effect on weight gain and sedation. Much higher propensity for extrapyramidal effects. Haloperidol is most commonly used typical antipsychotic.
79
Typical antipsychotics are not effective at all in treating _________ side effects associated with schizophrenia.
Negative
80
What are the characteristics of the atypical antipsychotic drug, dibenzodiazepine, also known as Clozapine?
This was the first developed atypical antipsychotic drug approved in 1989. It showed efficacy in treating positive and negative symptoms regarding schizophrenia. Limited prescription of this drug due to life threatening side effect of agranulocytosis. Now only used in those who are at greatest risk for suicide.
81
Why were all the other atypical antipsychotics developed?
Other atypical antipsychotics liked olanzipine, quetiapine, risperidone, and more were developed due to the shortcomings of clozapine and the typical antipsychotics.
82
Typical antipsychotics have a higher affinity for _______ receptors and a lower affinity for ________ receptors.
D2
5HT
83
Atypical antipsychotics have higher affinity for ________ receptors and a lower affinity for _________ receptors.
5HT
D2
84
Between the typical and atypical antipsychotics, which creates greater extrapyramidal side effects and why?
Typical antipsychotics are more likely to cause extrapyramidal motor disturbances due to its higher affinity for the D2 dopamine receptor. The specific brain region this occurs in is that nigrostriatal tract.
85
What are the adverse effects associated with antipsychotics?
Tardive dyskinesia- facial ticks, tongue protrusion, lip twitches.
Extrapyramidal syndrome- parkinson like symptoms, tremors, acute dystonia. Can be treated with anti-muscarinic
Akathisia- restlessness, pacing, rocking. Can b treated with propranalol.
Neuroleptic malignant syndrome- triade of symptoms includes rigidity, fever, and cognitive changes. Most lethal.
Cardiac toxicity- QT prolongation seen with thioridazine and ziprasidone.
Weight gain, hypotension, high resting HR, dry mouth, constipation, confusion, sedation, blunt effect, antiemetic actions.
All adverse effects are associated with hypoactiviation of D2 receptors!
86
Propensity for alleviating __________ symptoms and causing extrapyramidal disturbances is proportional to the drug's affinity for the _____________ receptor.
Positive
D2 type dopamine
87
Simon is admitted to a psychiatric clinic and a toxicology screen comes back negative. A diagnosis of schizophrenia is made. The doctor prescribes drug Y to Simon. Within a couple of weeks, Simon is no longer experiencing hallucinations and delusions. After a few months, Simon begins to exhibit severe facial tics and involuntary movements with his mouth and tongue. No other adverse effects like weight gain are evident. What is drug Y?
Drug Y is a typical antipsychotic. Typical antipsychotics have a higher affinity for D2 receptor and therefore are notorious for those extrapyramidal side effects.
88
Back to Simon. The doctor changes from drug Y to drug Z. Drug Z continues to suppress Simon's psychotic symptoms and the occurrence of facial tics has stopped. After a couple month, Simon has gained 30 pounds. What is drug Z?
Drug Z is an atypical antipsychotic. More likely to see weight gain with atypical antipsychotics but it is not a hard fast rule.
89
What is the most common mental health problem within the US?
Anxiety disorders
90
What are the 4 most common benzodiazepines?
Alprazolam (Xanax)
Diazepam (Valium)
Lorazepam (Ativan)
Zolpidem (Ambien)- hypnotic agent.
91
What is the general dose usage for benzodiazepines?
Lower doses are typically anxiolytics while higher doses are hypnotics.
92
Explain GABAergic neurotransmission in homeostasis.
GABA is the main inhibitory NT in the brain. GABA is released from presynaptic vesicles and crosses synaptic cleft and binds to GABAergic receptors (GABA A receptor) on the post-synaptic membrane. Binding to the receptor causes a conformation change to receptor that allows chloride ions to flow into the cell therefore hyperpolarizing it. Hyperpolarization inhibits an action potential.
93
Where do the majority of sedative and hypnotic drugs like benzodiazepines and barbiturates work at?
They target GABA A receptors in the brain!
94
Describe the composition of the GABA A receptor.
The GABA A receptor has 6 different subunits; alpha, beta, and gamma. Each subunit has 4 more subunits within it. The second transmembrane subunit folds so it is lining the ion channel pore. Amino acids with a + charge line the pore which attracts those - charged chloride ions. Only GABA A receptors with a gamma subunit have activity with benzodiazepines.
95
What is the definition of a sedative?
Drugs that decrease activity, excitement, and produce a calming effect. The term anxiolytic is preferred.
96
What is the definition of a hypnotic?
Hypnotics are drugs that produce drowsiness and facilitate the onset and maintenance of sleep.
97
Explain the dose-dependent effects of benzodiazepines.
The CNS effects caused by barbiturates and benzodiazepines increase as dose increases.
At low doses, both drugs relieve anxiety. As the dose increases it makes you more tired. As dose continues to increase, the benzodiazepines only have so much effect and are generally safe drugs. Benzos are also NOT general CNS depressants However, the barbiturates are general CNS depressants and continuing to increase the dose will cause depression of the medullary centers controlling breathing.
98
Which drug, benzodiazepines or barbiturates, are generally safer?
Benzodiazepines are generally safer because they do not depress the CNS. However, if mixed with alcohol, these drugs are very dangerous. It is also dangerous when mixed with other sedative hypnotic drugs.
99
What are the benzodiazepines and barbiturates scheduled as?
Schedule 4 drugs
100
What is the MOA of benzodiazepines and barbiturates?
These drugs are allosteric modulators of the GABA A receptor. When these bind, they increase GABAs affinity for the GABA A receptor.
101
What are additive effects and cross tolerance regarding benzodiazepines and barbiturates?
Additive effects means that more substances can bind to the GABA A receptor as allosteric modulators to create greater CNS effects. This is how alcohol and benzodiazepine use work.
Cross tolerance is the idea that someone with an alcohol use disorder may need more of the drug to feel the effect compared to someone without an alcohol use disorder.
102
What are the main therapeutic uses for benzodiazepines.
1. Anxiety disorders
2. Sedation prior to surgical procedures
3. Insomnia
103
Why are benzodiazepines used to treat anxiety?
These drugs are effective immediately whereas antidepressants take a few weeks to work. Very quick onset of action due to high lipophilicity of the drug. These can also be taken on an 'as needed basis'.
104
What is pathological anxiety?
This is anxiety experienced by a person that is excessive for the situation and interferes with the daily functions of a person.
105
What are the top 3 anxiety disorders?
Generalized anxiety disorder (GAD).
Panic disorder.
Phobic disorders (included social anxiety)
106
What is the general pathophysiology involving GABA A receptors is seen in those with anxiety disorders?
There are deficits in GABA A receptors seen in those with anxiety disorders. Reduced GABA A inhibition leads to excessive excitation.
107
Tolerance to the ______________ of the benzodiazepines typically does not develop.
Anti-anxiety effects
108
Tolerance for benzodiazepines develops for which three things?
Hypnotic effects, muscle relaxing effects, and anti-convulsant effects.
109
Is physical dependence on benzodiazepines seen?
Yes. It occurs between 2-4 months for less potent benzodiazepines (Diazepam) and can occur in week for benzodiazepines that are more potent (Triazolam).
110
What are the 2 factors that impact the use of different benzodiazepines?
Age (lower in elderly) and drug potency!
111
What is the major fallback regarding the prescription use of benzodiazepines?
Concerns related to abuse and dependence.
112
What is the typical therapeutic options for social anxiety disorder?
First line is anti-depressants. Benzodiazepines are not often prescribed here due to high prevalence of self-medicating with alcohol. Propranolol is also given to reduce the autonomic symptoms of anxiety.
113
What is the major difference in diagnostic criteria between anxiety and depression?
Time wise diagnosis for depression is 2 weeks due to suicidal ideation. Anxiety disorders have symptoms for at least 6 months.
114
Describe how serotonin is released in the brain.
Serotonin stored in presynaptic vesicles. Vesicles bind to wall and release serotonin into the synaptic cleft where they bind 5HT receptors. Some serotonin is sucked back into the presynaptic neuron to be stored and used again. The presynaptic cleft also has an autoreceptor. The autoreceptor is sensing how much serotonin is in the cleft.
115
What are the 4 classes of antidepressants?
1. SSRI
2. SNRI
3. Tricyclic antidepressants
4. Monamine oxidase inhibitors (MAOIs)
116
Why are tricyclic antidepressants and MAOIs not often used?
Tricyclic antidepressant have a lot of side effects and MAOIs have lots of drug food interaction.
117
What are the different hypothesis surrounding the pathology of depression?
1. Insufficient NE or 5HT NT (monoamine hypothesis)- decrease in dietary tryptophan induces relapse, low 5HT CSF levels in depressed people.
2. Loss of growth factors like BDNF- stress & pain lower BDNF levels which causes atrophy of the dendritic tree. Depressed people have lower CSF levels of BDNF. Electrotherapy shown to increase levels of BDNF.
3. Elevated cortisol levels
118
Depression is due to decreased levels of synaptic _______ and/or __________.
Serotonin
Norepinephrine
Research with reserpine (depletes catecholamine stores) caused depression.
119
All antidepressants _________ the synaptic concentration of serotonin or norepinephrine.
increase
120
What is responsible for the immediate effects of antidepressants?
Pre synaptic reuptake transporters are responsible for immediate effects.
Immediate effects include more NT in synapse, more inhibitory autoreceptors are stimulated which allows for greater feedback inhibition.
121
What is responsible for the delayed effects of antidepressants?
Presynaptic autoreceptors are responsbile for the delayed effect.
Delayed effects include down regulation of inhibitory autoreceptors due to excess NT binding to autoreceptor and therefore being down regulated. Allows for less feedback inhibition and increase NT and signaling.
With chronic therapy, the down regulation of presynaptic autoreceptors results in the increased firing of serotonin and norepinephrine neurons.
122
The delayed effects of antidepressants are correlated with the _______________ of presynaptic autoreceptors.
down regulation
123
What are the side effects involved with taking a tricyclic antidepressant?
Anticholinergic effects like blurred visions due to dilation of pupil, confusion, constipation, ventricular arrhythmia, orthostatic hypertension.
124
What are the more mild side effects of SSRIs?
GIT nausea and diarrhea. CNS activating properties like anxiety, tremors, and insomnia. Sexual dysfunction is high with SSRIs. Weight gain is also associated.
125
What type of depression responds best to monoamine oxidase inhibitors?
Atypical depression. Energy is so low often leads to paralysis.
126
What is the MOA for monoamine oxidase inhibitors?
Monamine oxidase is present in the presynaptic terminal. Normally, it functions as a safety valve to inactivate excess monoamines that could leak into the synapse.
MAOIs block this enzyme which results in the buildup of monoamines like NE and 5HT (and more but focus on these). These NTs then leak out into the synapse causing an increase in synaptic NTs.
127
Why can someone not eat foods containing tyramine if they are taking a monoamine oxidase inhibitor?
Mixing tyramine and MAOIs together results in a hypertensive crisis.
128
What is a non-pharmacological treatments for depression?
Bright Light Therapy- works by facilitating less reuptake of serotonin.
129
What type of treatment can be used for refractory depression?
Ketamine therapy. Works by blocking NMDA excitatory receptors which can be elevated in depression.
130
What is bipolar disorder?
This is also referred to as manic depression. It includes dramatic shifts in emotions, mood, and energy. BPD is considered a severe, life-threatening psychiatric disorder.
131
How long do symptoms need to show in order to be diagnosed with bipolar disorder?
At least 1 week of abnormal activity.
132
What are the characteristics of manic and depressive episodes?
Manic episodes- elevated mood, irritability, increased goal-directed activity, inflated self-esteem, poor judgement, excessive motor activity, lack of sleep
Depressive episodes- depressed mood, decreased interest, feelings of worthlessness, inability to concentrate, obsession with death, decrease activity, resembles typical depression with possibility of psychotic features.
133
What are the 4 episodes that bipolar disorder is characterized by?
Manic, depression, hypomanic, and mixed.
134
What is the difference between bipolar I and II?
Bipolar I is defined by the presence of overt manic episodes with range of manifestations including overconfidence, grandiosity, irritability, highly elevated mood, and decreased need for sleep.
Bipolar II is defined by episodes of depression but alternating with hypomania rather than full mania. 1 hypomanic episode in a lifetime is normal for those with bipolar II.
135
What is the pathophysiology regarding bipolar disorder?
MRI studies show that those with BPD have less gray matter in the frontal cortex which is involved in self-control. Thinning of those areas produces a lack of neuronal connectivity which impacts mood stability.
136
What is the goal of treatment when caring for someone with bipolar disorder?
Initially control of acute symptoms is needed to return to normal functioning. Then the goal is to prevent relapse and prevent suicide.
137
What are the 2 main categories of drugs used to manage bipolar disorder?
Mood stabilizers - lithium or anticonvulsant like valproic acid
Atypical antipsychotic
(antidepressants for depressive symptoms)
138
How are acute symptoms of bipolar treated based on symptoms present?
Acute manic or mixed episode SEVERE- Atypical antipsychotic + mood stabilizer
Acute manic or mixed episode MILD- Mood stabilizer
Acute bipolar depression SEVERE- Standard antidepressant + mood stabilizer
Acute dipolar depression MILD- mood stabilizer
139
What is the first line treatment for acute manic episodes?
Lithium and Valproic Acid
140
What is rapid cycling in bipolar disorder?
This is when someone experiences 4 or more episodes of depression and/or mania per year. They are often refractory to treatment.
140
What is the first line treatment for an acute bipolar depressive episode?
Lithium, valproic acid, and an SSRI.
141
What is the treatment plan for someone with rapid cycling bipolar disorder?
First line are the anticonvulsants like valproic acid. Lithium is avoided.
142
What is the MOA of the mood stabilizer, lithium?
Lithium is a monovalent cation that enters cells through Na+ channels. Lithium works by inhibiting IMPase and other enzymes in the normal recycling of membrane phosphoinositides, including conversion of IP2 to IP1 and IP1 to inositol. This block leads to the depletion of free inositol and ultimately PIP2 which is the membrane precursor for IP3 and DAG.
By reducing IP3 signaling, inositol is depleted. This cycle is the precursor for several important signaling molecules.
It also inhibits GSK-3 signaling which is associated with neuroprotection.
In conclusion, lithium suppresses inositol signaling and inhibits glycogen synthase kinase-3.
143
The method of action of the mood stabilizer, lithium, is understood. But how does the drug actually improve manic and depressive symptoms of bipolar disorder?
It is actually still a mystery on how this drug helps. There are several potential mechanisms including inhibition of excitatory NTs and promoting inhibitory NTs (GABA release more).
144
What is the MOA of the mood stabilizer, valproic acid?
Valproic acid blocks Na+ channels which blocks the ability for an action potential to be created. Therefore it block excitatory NTs from being released.
145
What is the MOA for antipsychotics?
Antipsychotics are antagonist of the D2 and 5HT2A receptors. Typical antipsychotics have higher affinity for D2 while Atypical (2nd gen) have a greater affinity for 5HT2A receptor.
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What is the MOA specifically for atypical (2nd gen) antipsychotics?
Atypical block both dopamine and serotonin receptors but have higher affinity for the 5HT2A receptors. By blocking the 5HT2A receptor, inositol and GSK3 signaling is inhibited. Blocking the the D2 receptor causes an increase in cAMP signaling.
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Is there a difference in how typical (1st gen) and atypical (2nd gen) antipsychotics work to treat positive and negative symptoms of bipolar disorder?
Both typical and atypical do well in reducing positive symptoms. Atypical (2nd gen) do better for controlling negative symptoms.
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Do antipsychotic drugs only work on serotonin and dopamine receptors?
No! They block multiple receptor types at different affinities.
