Exam 3 Flashcards
(186 cards)
1
Q
What was the 1906 Pure Food and Drug act?
A
This was the first law that required accurate labeling and restricted the sale of narcotics to pharmacies and doctors. This was basically the start of the FDA.
2
Q
Compared to other drugs, marijuana has less of a public health burden compared to tobacco, alcohol, and other illicit drugs. What burdens are included in marijuana use?
A
Acute psychomotor issues, increased motor-vehicle accidents, altered brain development, some dependence risk, worsened psychosis, pulmonary dysfunction, and more.
3
Q
What are important factors of listed within Canada’s Lower risk cannabis guidelines?
A
Cannabis is not for those under the age of 16. There should be a higher CBD to THC ratio (CBD can modulate THC response when binding to cannabinoid receptors). Synthetic THC should be avoided.
4
Q
What are the side effects of the new ‘synthetic’ marijuana that is laboratory made?
A
This is basically chemicals sprayed onto cardboard made to look like bud. It can induce psychosis (anxiety, confusion, paranoia, hallucinations), increase HR, vomiting, violent behavior, and suicidal thoughts.
5
Q
What issues arise when synthetic drugs are banned, like seen in the Synthetic Drug Abuse Prevention Act?
A
Because these drugs are made in a lab, when it is banned, labs can alter a small portion and a very similar drug becomes legal again.
6
Q
What is the medicinal cannabinoid called Dronabinol (Marinol)?
A
This is synthetic delta 9 THC. It is FDA approved. It is an antiemetic and an appetite stimulant.
7
Q
What is the difference between hemp and marijuana?
A
Hemp is derived from the trichome which is the dried non-root material from the cannabis plant. It contains less than 0.3% THC. Has higher levels of CBD which can help antagonize the THC.
Marijuana is the flower portion of the cannabis plant. It contains greater than 0.3% of THC (typically 5-18%).
8
Q
What are the different uses of hemp and marijuana?
A
Hemp is not psychoactive and is used in making fibers that are used for clothing, ropes, and more. It is also used to make cannabidiol (CBD) oil.
Marijuana is psychoactive and it uses are for recreation and medical.
9
Q
What does the current research show about the beneficial effects of cannabis?
A
It appears that cannabis can be beneficial for chronic pain and multiple sclerosis but not in movement disorders.
10
Q
What is the PK of inhaled Delta-9 THC?
A
Bioavailability of 10-35%
Max plasma conc. in minutes
Psychotropic effects in sec to mins
Max effect in 15-30 min.
Duration 2-3 hours
Metabolized by hepatic CYP2C
11
Q
What is the PK of orally taken Delta-9 THC?
A
Subject to first-pass metabolism so bioavailability is 6-7%
Psychotropic effects in 30-90 min
Max effect in 2-3 hours
Duration is 4-12 hours
Metabolized by hepatic CYP2C
12
Q
What is the PD of delta-9 THC?
A
Effects whole body: analgesia, immunosuppression, sedation, muscle relaxation, improved mood, appetite stimulation, antiemetic, lower intraocular pressure, and bronchodilator
Acute adverse effects: increased anxiety and HR
Chronic adverse effects: dependency, decreased reproduction, and exposure to burn products
(Centrally relaxed but peripherally excited)
Partial agonist of both CB1 and CB2
13
Q
Dronabinol (Marinol) is an FDA-approved oral version of delta-9 used for cancer patients. It has the typical PK and PD for orally taken delta-9 but can induce side effects. What are these side effects?
A
It has drug interactions with drugs that are also metabolized by CYP2C system meaning it can extend the half life of them. It also can potentiate the effects of alcohol, TCAs, sedatives, tranquilizers, barbituates, opioids, sleep aids, and muscle relaxers.
It also can’t be used in those who are pregnant, poor kidney, liver, and heart function, as well as those with a history of psychosis.
14
Q
What is the possible MOA of the CBD oil, Epidiolex?
A
It is unclear, but it is thought to interact with 5HT, TRPV1, and PPARs and may be a negative non-competitive allosteric modulator of CB1 by disrupting the recruitment of beta-arrestin to CB1. (Typically, the beta-arrestin pathway pulls in the receptor-ligand complex from the membrane into the cell. When this is disrupted, the CB1 receptor stays outside the cell for longer).
15
Q
What are the PK differences seen in the orally ingested version of CBD oil, also known as Epidiolex?
A
The bioavailability is around 13-19% and the half-life is 18-32 hours.
16
Q
What is the specific allergy condition in which these individuals cannot take Epidiolex?
A
Allergy to CBD and sesame oil
17
Q
What are the two main receptors of the endocannabinoid system (ECS) and where are they found?
A
CB1- inhibitory GPCR. Abundant in the brain (cortex and hippocampus). Not abundant in the periphery.
CB2- inhibitory GPCR. Lower levels in the brain and higher levels in the periphery are mainly associated with immune function.
Both use the beta-arrestin 2 pathway.
18
Q
Explain the CB1 receptor.
A
Higher levels in CNS and lower levels in PNS. Augments the VTA with reward and hypothalamus with feeding. Suppresses the PAG with pain and the amygdala with anxiety, stress, and affect regulation (chill out effect). Also highly expressed in cortex and hippocampus and can interfere with short-term memory especially when mixed with other drugs.
19
Q
Explain the CB2 receptor.
A
Lower levels in the CNS and higher levels in the PNS. It is mainly associated with immune function and is known to increase 100-fold following injury and inflammation.
20
Q
What is the endogenous ligand for the endocannabinoid system?
A
Anandamide and 2-AG. Both are ligands produced from membrane lipids as a consequence of other signalling.
It works via retrograde neurotransmission meaning that when they bind to receptors, the post-synaptic cells send signals back to the pre-synapse.
21
Q
What is the signaling cascade when endogenous ligands bind to CB2 receptors?
A
Overall, it reduces cAMP, reduces calcium influx, and increases potassium efflux. Reduces excitability.
22
Q
What enzymes degrade anandamide?
A
FAAH and COX2
23
Q
What is 2-AG metabolized by and into what?
A
2-AG is metabolized by MGL and eventually into prostaglandins.
24
Q
Which part of the cannabis plant contains the highest concentration of cannabinoids?
A
The trichome
25
Does inhaled or orally taken marijuana have a higher bioavailability?
Inhaled has a greater bioavailability.
26
Where are CB1 receptors primarily located?
The brain
27
What are the endogenous ligands of the ECS?
2-AG and anandamide
28
The ligand-receptor synaptic signaling system is an example of ____________ neurotransmission.
Retrograde
29
What is the difference between prevention and treatment?
Prevention is an action taken to decrease the chance of getting a condition. Treatment is management and care to combat a condition. Prevention is harder than treatment, as prevention would be done within healthy populations.
30
What are the weaknesses of modeling in neurodegenerative disease?
We can't run experiments on humans; that is who we are looking at. We can get close to dogs and monkeys, but they are still very different in the number of neurons. There is also a long of age-related variability, meaning that as people get older, more issues arise that may not have been present when they were younger.
31
What is the survivor effect?
This bias occurs in research when studying only those who have survived thus far. For example, if you are looking at the long-term effects of a particular medication and you only look at survivors of that disease for the particular medication, you might wrongfully conclude that the treatment is more effective than it is because those who did not survive were not included in the analysis.
32
Distinguish environmental influences that can positively influence neurodegenerative disease.
Diets like Mediterranean and DASH. Exercise too.
33
Distinguish environmental influences that can negatively influence neurodegenerative disease.
High and low TSH levels in women, vitamin B and D deficiencies, obesity, type 2 diabetes, CVD, high BP, poor sleep, and more
34
What are the 3 Alzheimer's disease hypotheses currently being tested in clinical trials?
The amyloid hypothesis
The neurotransmitter hypothesis
the tau hypothesis
35
What is the definition of a traumatic brain injury?
This is a non-congenital insult to the brain caused by external impact and/or force, resulting in varying degrees of neurodegeneration and functional loss. Most cases are mild/minor, and most involve males.
36
What are the major factors that contribute to the heterogeneity of traumatic brain injury (TBI) clinical symptoms?
The diversity of factors that contribute to the symptoms seen within TBIs include the affected brain region, the severity, how much time has passed since the injury, the age and health of the victim, and injury history.
Clinical symptoms based on those 5 things!
37
What are the chronic neurodegenerative disorders that can arise from TBIs?
Chronic traumatic encephalopathy (CTE) can develop due to several TBIs seen in contact sports. Alzheimer's disease is also associated with TBIs.
38
What is CTE?
CTE is characterized by tauopathy, the progressive development of neurofibrillary tangles involving cytoskeletal filaments called tau. As tangles develop, the brain dies, which leads to brain atrophy and ventricular enlargement.
39
Why is Alzheimer's disease associated with TBIs?
TBIs are associated with increased expression of the amyloid precursor protein (APP), beta-secretase (BACE), and gamma-secretase.
APP is cleaved by BACE into C99 and s-APP beta.
NEED TO FINISH
40
List features of the primary injury cascade of TBIs.
The primary injury cascade is characterized as direct damage to the brain. It could be compression, stretching, steering, and more. Primary injuries are caused by anything that initially causes a TBI, such as fractures, hematomas, lacerations, contusions, penetration wounds, and more.
41
List features of the secondary injury cascade in TBIs.
The secondary injury cascade is characterized by damage to cells not initially injured at the time of injury. It arises hours, days, and weeks after the initial injury. Secondary injury cascade includes excitotoxicity, oxidative stress, neuroinflammation, vascular dysfunction, BBB dysfunction, and ion/h20 dyshomeostasis.
42
What are the advantages and disadvantages of targeting the primary injury cascade?
It would be best to be able to treat the primary injury cascade, but that happens right when the injury occurs, which makes it almost impossible and can only be treated prophylactically.
43
What are the advantages and disadvantages of targeting the secondary injury cascade?
Treating the secondary injuries is really the only treatment, but the sooner they are treated, the better. Pharmaceuticals have potential use, but only if used in the right time window.
44
What are the obstacles to developing successful TBI therapeutics?
TBIs vary from person to person in terms of severity and location. Additionally, TBIs are complex and can develop into chronic conditions. Also, the proper time window is important; some people do not come in with enough time.
45
What is the MOA of oxidative stress relating to the secondary injury cascade?
Oxidative stress is triggered by hypoxia, ischemia, and calcium overload. This leads to the breakdown of the mitochondrial membrane potential which creates reactive oxygen and nitrogen species. ROS and RNS at a greater level than normal cause oxidative stress and leads to breakdown of macromolecules like DNA, RNA, proteins, lipids, and more. This leads to cell disruption and eventually calcium dysfunction which leads to cell death.
46
What drug acts as a free radical scavenger in the oxidative stress secondary injury cascade?
Tirilazad. This drug binds and neutralizes ROS and RNS. This drug is a steroid. It is non-specific, so it binds all free radicals, and we do need some. Also induces drowsiness, dizziness, and vasodilation.
47
What drug is a nuclear factor-like 2 activator that acts on oxidative stress in the secondary injury cascade?
Dimethyl Fumarate is the drug. It activates nuclear factor-like 2, a transcription factor that induces the expression of proteins with antioxidant properties.
48
What is the MOA of the secondary injury cascade symptom known as excitotoxicity?
Vicious feedback loop!
Severe head injuries can lead to seizures due to increased neuronal hyperexcitability. The neurons become excitable due to decreased blood flow resulting in hypoxia and lack of nutrients. Excessive neuronal firing increases glutamate activation which activates those AMPA and NMDA receptors which depolarizes more cells and tells them to fire and the neurons just keep activating more neurons in that injured brain region. With the overactivation of NMDA and AMPA receptors, the voltage-gated calcium channels that excite the cell are overactive and let in way too much, leading to calcium dysregulation. Calcium dysregulation leads to synapse dysfunction and activates glial cells and cell death pathways, eventually leading to cell death.
(EAAT reuptake transporters are also not working well and are the main things that help prevent excitotoxicity).
49
What drug is used to block NMDA receptors in excitotoxicity?
Eliprodil is used for this. However, it is not commonly used as NMDA receptors are very important. When the brain is recovering, it uses calcium and NMDA receptors to remodel. Magnesium is the endogenous version of this drug.
50
What drug is used to block voltage-gated calcium channels in excitotoxicity?
Nimodipine is the drug used. It works by stopping the influx of calcium into cells. Also, vasodilators which are bad in the early phases of TBIs.
51
What drug is used to activate EAAT transporters?
Riluzole is the drug used for this. Activates EAAT to slurp up glutamate and stop it binding. However, it is a dirty drug that acts on lots of other receptors.
52
What is the MOA of the seondary injury cascade known as neuroinflammation?
Vicious feedback loop!
NI is triggered by releasing nucleotides from dying cells, excess glutamate, ROS, RNS, myelin fragments, hypoxia, and ischemia. Glial cells (microglial and astrocytes) are the main mediators of NI. BBB also becomes weak, and peripheral immune cells get in and secrete prostaglandins, cytokines, and chemokines, which trigger glial reactivity. Too many of those chemical mediators (prostaglandins, cytokines, and chemokines) cause neuronal breakdown and calcium dysregulation, leading to cell death.
53
What drug acts on cytokines in the neuroinflammation secondary injury cascade?
Corticosteroids like dexamethasone. It is the dirtiest drug, though, as it has numerous long-term side effects. Prevent cerebral edema and intracranial swelling. The time window to give for TBIs needs to be quick.
54
What drugs act on COX2, stopping the production of prostaglandins in the neuroinflammation portion of the secondary injury cascade?
NSAIDs like celecoxib. These are good for minor TBIs, but long-term use is bad for GIT and liver.
55
What two drugs are cytokine inhibitors that block some of the main regulators of the inflammatory response in the neuroinflammation secondary injury cascade?
A. Anakira- IL-1 receptor antagonist (this is a protein)
B. Etanercept- TNF alpha receptor antagonist
It gets it main use in rheumatoid arthritis but may be too specific for TBIs as more than these cytokines are involved.
56
In terms of NI in the secondary injury cascade, what drug is a MAP kinase inhibitor?
Ralimetinib. These drug blocks MAP kinases which activate NFkB which is a key transcription factor in making macrophages. Overall it blocks NFkB activity by blocking MAP kinase.
57
In terms of NI in the secondary injury cascade, what drug is a JAK/STAT inhibitor (tyrosine kinases)?
Tofacitinib. This drug blocks JAK kinase, which is a tyrosine kinase that phosphorylates STAT. This stops JAK and STAT, which create cytokines.
58
What drug is a calcineurin inhibitor that acts on the NI secondary injury cascade?
Tacrolimus. Calcineurin is a phosphatase that activates NFAT (t cells). This drug inhibits the calcineurin.
59
What is the MOA of vascular dysfunction related to the secondary injury cascade?
TBIs cause the BBB to degenerate and dislodge from the vessels. First, dissociation of astrocyte feet and pericytes occurs, and the BBB leaks. This results in vasogenic edema (water in interstitial brain space) and the breakdown of iconic homeostasis, and this causes the brain to swell. When cells swell too, they die. With time, this leads to vasoconstriction leading to hypoxia and deficits in neuronal activity which leads to NI, excitotoxicity, oxidative stress, and ischemia leading to cell death.
60
Within vascular dysfunction, edema-reducing compounds actually target the primary injury cascade. What drug is used for this?
Corticosteriods. As well as any other dehydrating agent that pulls what from cells.
61
How can NO modulators be used in vascular dysfunction?
Sildenafil is the NO used typically. They are used to alleviate vasoconstriction. It works by stimulating cGMP and GTP which drive smooth muscle cell relaxation. Cannot give close to the injury, needs to be given later.
62
What are the symptoms associated with Parkinson's disease (PD)?
The main symptoms include resting tremors called pill-rolling, muscular rigidity, and bradykinesia, which is slow and restricted movement, as well as hunched posture and shuffling walk.
63
What are the risk factors for PD?
Risk factors include age, heredity, being male, and toxin use. Mostly idiopathic.
64
What is the pathology behind PD?
PD is due to the loss of dopaminergic neurons in the substantia nigra. The striatum is where dopamine loss manifests as PD. Inside the substantia nigra there are things called Lewy bodies that are filled with alpha synuclein-containing inclusions. Over time these build up, and neurons die. There is an 80% reduction of dopaminergic neurons in this area before clinical symptoms emerge.
65
What is the difference between PD and PDD?
PD is less common, and the main complaint is tremors. PDD is more common, and the main complaint is imbalance and gait disorder. Comes with dementia as well. It has more Lewy bodies in the neocortex that can look like Alzheimer's.
66
How does dopamine signaling work?
DOPA is converted to dopamine via aromatic amino acid decarboxylase (AADC). Dopamine is packaged into vesicles and released. It is taken back up via dopamine transporter and broken down by MOAs and aldehyde dehydrogenase (ALDH).
67
What are the two types of dopamine receptors in the stratium?
D1- excitatory- increase cAMP and excitability
D2- inhibitory- Gi coupled- reduces cAMP and excitability.
68
What is the primary drug used for PD?
L-DOPA and DA agonists.
69
Where is L-DOPA converted into dopamine?
L-DOPA is converted to dopamine in the nigrostriatal tract, which starts in the substantial nigra and extends to the striatum.
70
What are the pharmacokinetics of L-DOPA?
Peak in blood in 1-2 hours.
1-3% gets in CNS.
Causes GIT disturbances
71
What is the adjunct therapy given with L-DOPA?
Adjunct therapy is another drug given to supplement the other drug. L-Dopa is given with carbidopa, which is a DOPA decarboxylase inhibitor that does not cross the BBB. This stops the production of dopamine in PNS, therefore limiting effects like nausea in PNS. Adjunct therapy increases L-DOPA delivery to the brain and reduces its use in PNS.
Another adjunct are COMT inhibitors. After too much LDOPA and carbidopa, the catechol-o-methyl transferase (COMT) enzyme rises up and turns LDOPA into 3OMD. COMT inhibitor stops LDOPA from being converted to 3OMD. Drug used here is called Entacapone and makes urine orange.
72
Dopamine agonists are also used for PD. What are some advantages and disadvantages of these drugs?
Advantages include not needing living substantia nigra neurons for the drug to help, longer duration of action, and can be monotherapeutic.
Disadvantages include off-target actions and worsened abnormal involuntary movements. It can also induce nausea, vomiting, postural hypotension, and amplified impulsive behavior. Contraindicated in those with psychosis, myocardial infarction, and PNS vascular disease.
73
What are the different D2 agonists used in PD?
Includes Bromocriptine, Pramipexole, Ropinirole, and Rotigotine.
74
What is the PD rescue drug that can temporarily get those with PD out of the stuck phase so they can move again?
Apomorphine. It is a non-selective DA agonist that also induces vomiting. It needs to be given with an antiemetic so the PD patient can tolerate it.
75
Why and what MAO inhibitor is given those with PD?
The thought is that inhibiting MAO-B is that it will not eat up the monamine like dopamine (not NE and epinephrine that is MAO-A) so there is more in the cleft that can bind.
The MAO-B inhibitor used is called Selegiline. It is an irreversible MAO-B inhibitor.
76
What is the the MAO-B drug called Selegiline and what is it often adjunctly given with?
An irreversible MOA-B inhibitor that covalently binds to it and is digested by the body. It is given with Amantadine, which reduces dyskinesia late in PD progression.
77
Is it usual for the substantis nigra to lose neurons with age?
Yes!
78
With PD, synapses in the ________ have reduced dopamine delivery.
Striatum
79
Alzheimer's disease is the leading cause of _________.
Dementia
80
What are the 3 diagnostic criteria for AD?
Amyloid pathology
Neurofibrillary tangle pathology
Neuronal degeneration and death
Can only be confirmed post-mortem
81
What is amyloid pathology in AD?
Amyloid precursor protein (APP) is cleaved by proteases called beta-secretase and gamma-secretase. Beta secretase is the first step and rate-limiting enzyme. Beta secretase cleaves APP into soluble APP fragment beta and CTF99. Gamma-secretase then cleaves CTF99 which releases abeta peptides. Amyloid monomers then stick together and aggregate into oligomers which is a toxic form of abeta peptides which then form plaques. The plaques are the amyloid pathology seen in post-mortuem analysis.
82
What is the neurofibrillary tangle pathology seen in AD?
Neurofibrillary tangles are formed by the aggregation of tau filaments. Hyperphosphorylated tau begins to tangle in the neurons.
83
What is the pathology of neuronal degeneration and loss in AD?
Advanced AD stages have a shrunken brain due to the brain expanding ventricles due to brain degeneration.
84
What are the secondary features of AD?
Excitotoxicity, NI, and oxidative stress.
85
What is the amyloid cascade hypothesis?
This is the idea that amyloid plaque formation produces a cascade that eventually leads to AD and dementia, which is called the amyloid cascade hypothesis. It is thought that excess amyloid arises due to mutations in the pathway or in proteins that clear them. When abeta aggregates, it leads to plaques which leads to neurofibrillary tangles, tau dysfunction, NI, ROS, and calcium dysregulation, and eventually cell death, causing dementia.
86
What evidence supports the amyloid cascade hypothesis?
1. Families with early onset of AD have mutation in the amyloid precursor protein (APP) and other genes involved in amyloid processing leading to higher levels of amyloid peptides
2. Those who carry the APOE4 allele have a higher risk of the onset of AD because APOE4 transports things out of the brain and binds abeta and clears it. People with this allele have reduced abeta clearance and increased risk of dementia.
3. APP is on chromosome 21, which is replicated in Down syndrome. Those with Down syndrome who live long enough always develop amyloid pathology and eventually dementia.
87
What evidence does not support the amyloid cascade hypothesis?
Post-mortuem, some people have a lot of amyloid pathologies but never developed AD.
Progression of amyloid pathology does not correlate to cognitive symptoms.
Reducing abeta pathology in humans does not improve cognition.
88
What are the FDA-approved drugs for treating AD symptoms?
Cholinesterase inhibitors
Weak NMDA receptor antagonists
Anti-abeta antibodies
89
What are the experimental drugs used for reducing amyloid pathology in AD?
Beta-secretase and gamma-secretase inhibitors
90
What are the three cholinesterase inhibitors used in AD?
Donepezil, Rivastigmine, and Galantamine
91
Why are cholinesterase inhibitors used in AD?
It is thought that AChE neurons in the septal area innervate the hippocampus and other areas important in cognition like memory and learning. Septal neurons are lost in AD. AChE metabolizes ACh, so inhibiting it should increase ACh to offset the loss of cholinergic neurons, so cognition is better.
92
What is the weak NMDA receptor antagonist used to treat symptoms of AD?
Memantine is the drug. Idea is to block NMDA receptors in early phase to prevent excitotoxicity to prevent calcium dysregulation and cell death.
93
What are the two monoclonal antibodies to Abeta that are FDA-approved?
Aducanumab and Lecanemab
94
How does Aducanumab and Lecanemab work?
These drugs bind to abeta oligomers and plaques and induce microglial CNS clearance of them from the brain. It works by halting the amyloid cascade.
95
What are the differences between Aducanumab and Lecanemab?
Aducanumab was rushed through the FDA. It clears Abta plaques but is less effective in clearing Abeta oligomers. There is a higher incidence of AREA-A.
Lecanemab is a disease-modifying drug. It significantly slows cognitive decline, which is not the case for the other. It is more effective at clearing Abeta oligomers. Lower incidence of AREA-A. Has full regular FDA approval. Better efficacy
96
What are the experimental beta-secretase inhibitors in the works?
Lanabecestat, Atabecestat, and Verubecestat
97
How do beta-secretase inhibitors work as a disease-modifying drug?
Beta-secretase is the rate-limiting enzyme in the formation of abeta oligomers and plaques. Drugs that stop the formation halt the amyloid case and prevent neurodegeneration and dementia. In humans, we see lower amyloid pathology but no improvement in cognition.
98
What are the gamma-secretase inhibitors currently in the works as a disease-modifying drug for AD?
Semagacestat and Tarenflurbil
99
How do gamma-secretase inhibitors work in preventing AD?
Gamma-secretase is the enzyme that cleaves CTF99 into abeta plaques. If we prevent this, we can prevent the amyloid oligomers and plaques. It works to reduce amyloid pathology but does not improve cognition.
100
Amyloid pathology precedes symptoms of AD by close to 15 years. This calls for what?
When people show up with symptoms, their abeta pathology has likely reached a max, and there is no way for us to fix it. This means we need to discover a biomarker that tells us who is at risk for cognitive decline.
101
Why do Abeta targeting strategies not work as well as anticipated?
1. People present with symptoms when abeta pathology is at maximum, and there is nothing that can be done
2. Abeta and APP modifying enzymes may have beneficial roles that are being blocked by these medications.
3. Other comorbid pathologies may be present that are contributing to dementia, too, like vascular pathology.
102
What is multiple sclerosis (MS)?
This is an autoimmune disease in which the immune system attacks the body. Specifically, immune cells attack the myelin sheath that covers the axons of neurons, resulting in slower communication throughout the brain.
103
What are the symptoms of MS?
Common symptoms include fatigue, depression, weakness, numbness presenting as pins and needles, balance and coordination problems, bladder and bowel problems, and visual loss.
104
When is the typical onset of MS?
Disease onset between 20 and 50 years old.
105
What are the genetic risk factors that contribute to the development of MS?
Being male, getting the disease over the age of 40, Asian or black, presentation of multiple symptoms, a large number of lesions at baseline MRI (lesions is myelin destruction).
HLA type increases SNPs in certain T-cells that are supposed to recognize foreign bodies. SNPs in vitamin D and estrogen receptors too.
106
What are the environmental risk factors that contribute to the development of MS?
Obesity, tobacco exposure, exposure to Mono, over-abundance of certain Gut microbiome bacteria, further away from the equator, and low vitamin D levels.
107
What are the key hallmarks of MS?
Neurodegeneration and neuroinflammation.
108
What are the four different types of MS?
1. Relapse-remitting MS- most common, episodes of flare-ups followed by complete or partial remission.
2. Primary-progressive MS- slowly worsening neurological function
3. Secondary progressive- steadily progressing disease with relapse-remitting MS.
109
Describe factors in the brain underlying MS and its progression.
Disease progression depends on the extent of myelin loss.
110
Describe how PNS immune cells can invade the brain and cause neuronal damage.
It is believed that neuroinflammation causes neurodegeneration. Sometimes, T-cells can gain access through the BBB and enter the brain. When in the brain, they release cytokines that cause direct inflammatory damage to myelin and the BBB. Now, there are large holes in the BBB and more T cells and B cells are recruited into the brain. B-cells form antibodies to the myelin and promote myelin breakdown. Macrophages also become overactive, digesting and clearing the myelin too much. Microglia from the brain also do this. Immune response it too intense for the oligodendrocytes to rebuild the myelin.
111
What is the therapy for an acute attack of MS?
An acute attack is when a patient is currently experiencing a flare-up that lasts longer than 24 hours but no more than a month. The goal of acute therapy is to recover from the attack.
Glucocorticoids are used for this and can be given orally or in an IV. They work by reducing T and B cells invading CNS and those proinflammatory cytokines released by T cells. It increases regulatory T cells, which know invading from self cells.
112
What is the MOA of glucocorticoids?
Glucocorticoids diffuse across cell membranes and nuclear membranes and bind to DNA to induce the expression of anti-inflammatory genes and reduce inflammatory mediator genes. This reduces T and B cells and their chemical messengers in the brain while increasing regulatory T cells.
113
What are the 3 different categories of treatment for relapsing-remitting MS (most common)?
Safety
Convenience
Efficacy
Goal is to use chronic therapy to control symptoms and recurrence
114
What are the two safety drugs used in chronic therapy for MS?
Interferon B-1b (IV)
Glatiramer (IV)
Both reduce relapse rates and disease progression
115
What is the MOA of interferon B-1b?
Interferons are another type of cytokine released from T-cells that are anti-inflammatory. Interferon B is one of those. This drug helps to shift the off-balance in MS where more pro-inflammatory cytokines are present and make it more balanced by inducing anti-inflammatory cytokine (Tregs and Th2) response.
Interferon B-1b also decreases the ability of T-cells to adhere and penetrate the BBB.
116
What is the MOA of Glatiramer?
This drug also shifts t-cells from pro-inflammatory Th1 to anti-inflammatory Th2. It mimics a component of myelin and acts like a decoy mechanism and immune cells target the drug instead of the actual myelin.
117
What drug is used as the convenience approach in chronic therapy for MS?
Fingolimod (oral)
Decreases relapse rates and disease progression.
118
What is the MOA of fingolimod?
T-cells are made in lymph nodes and are released when sphingosine binds to receptors on these lymph nodes. Fingolimod blocks these sphingosine receptors and, therefore, blocks the efflux of B and T cells into circulation so they cannot even reach the BBB.
119
What drug is used as the efficacy approach for chronic therapy in MS?
Natalizumab
Most efficacious but most dangerous as it can predispose patients to fatal infections of white brain matter known as leukoencephalopathy.
120
What is the MOA of Natalizumab?
Blocks adhesion of T-cells to the BBB vessels. (similar to interferon B-1b in that sense)
121
What are critical illnesses?
These are life-threatening conditions that require sophisticated life support and intensive monitoring, usually in an intensive care unit (ICU). Includes heart attack, stroke, sepsis, kidney failure, respiratory failure, major surgeries, terminal cancers, major burns, end-stage aids, and more.
122
What is sepsis?
This is when the body gets an infection that is no longer contained within that site and begins to circulate in the bloodstream. The immune system responds to try to fight the infection, but both bacteria and immune cells lead to uncontrolled inflammation, which can lead to organ failure and death.
123
What percentage of ICU patients have sepsis?
30%
124
Sepsis is always characterized by __________ failure including the brain. In the brain, 70% of patients have ___________.
Multi-organ
Encephalopathy
125
What allowed clinicians to realize the development of cognitive issues from sepsis?
We got good at treating sepsis, and therefore, death rates decreased but were followed by intense cognitive decline in those patients.
126
What is the continuum of critical illness?
Acute critical illness can either lead to death, recovery, or chronic critical illness. Chronic critical illness is a result of modern medicine intervening and the body not knowing how to withstand the prolonged inflammation.
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What are the main features of chronic critical illness?
Profound weakness, loss of body composition, neuroendocrine changes, increased vulnerability to infection, respiratory failure, and especially brain dysfunction including coma and delirium.
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What are the general statistics around chronic critical illnesses?
5-10% of patients admitted to ICU require prolonged mechanical ventilation.
30-50% of chronically critically ill patients are discharged from the ICU
50% mortality rate after ICU
Only 10% of chronically critically ill patients achieve full autonomy
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How is the brain affected DURING critical illness?
Delirium is the most common effect. This includes confusion, lack of awareness, bad memory, and hallucinations. It has a rapid onset and happens to between 20-80% of ICU patients.
Additionally, effects include reduced consciousness, coma, seizures, and cerebral edema.
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How is the brain affected AFTER critical illness?
Neurocognitive impairments manifest as changes in memory, attention, and executive function. Depression and decreased social functioning are also seen.
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What is the main predictor of long-term impairment in critical illness?
Delirium
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What are the risk factors for critical illness-acquired brain dysfunction?
Older age, previous cognitive impairment, and arterial hypertension.
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What are the contributors to critical illness-acquired brain dysfunction?
The severity of critical illness, medication use (BZs, opioids, anticholinergics), pain, sepsis, fever, metabolic disturbances, sleep disturbances, and noisy environment.
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In terms of neuroimaging, what is seen in patients with in-hospital delirium and long-term cognitive impairment?
Cerebral atrophy is seen, meaning there is an increased ventricle-to-brain ratio. White matter lesions are also present.
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What are the proposed mechanisms in which acute brain dysfunction occurs?
1. Inflammation
2. Hypoxia
3. Glucose dysregulation
4. NT imbalance
5. Pharmacological neurotoxicity
6. Hostile ICU environment
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How is inflammation described in terms of acute brain dysfunction?
Cytokines and chemokines produced by the ongoing systemic inflammation cross the BBB and cause lots of damage including endothelial damage, thrombin formation, microvasular compromise, increased cerebral vascular permeability, decreased cerebral blood flow, altered NT synthesis, and disrupted neurotransmission. Also called the cytokine storm in which too much is a bad thing.
137
How does hypoxia influence acute brain dysfunction?
Hypoxia damages the brain by interrupting aerobic metabolism, causing prolonged ischemia (reduced blood flow) to tissues and cell death. Additionally, reperfusion of blood to low-blood areas can cause inflammation and oxidative stress due to too much calcium release.
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How does glucose dysregulation impact acute brain dysfunction?
Critical illness is often associated with hyperglycemia as it is a stress response. Patients then are given insulin resulting in hypoglycemia and then death. Both hypo- and hyper- are bad but cause different issues.
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How does NT imbalance impact acute brain dysfunction?
In critically ill ICU patients, Dopamine is in excess while acetylcholine is depleted. Due to muscle breakdown in these patients, proteins are released and broken down into amino acids, which the liver uses. Aromatic amino acid accumulation leads to an increase in dopamine.
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How do different aspects of pharmacological neurotoxicity impact acute brain dysfunction?
BZ administration is associated with an increased risk of brain dysfunction and delirium and a longer time on mechanical ventilation.
The level of deep sedation is associated with worse clinical outcomes.
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What are preventative therapies that can be used to prevent long-term neurological complications in acute critical illness patients?
Using sedative agents that do not impact GABA, such as opioids, may reduce the risk of delirium.
You can also target acquired muscle weakness and reduce the number of sedative days.
142
What is a side-effect, also known as an off-target effect?
An off-target effect is when a drug has an affinity for a receptor other than intended.
143
What antipsychotic is most selective for the D2 and D3 receptors?
Amisulpride
144
What are the general functions of the autonomic nervous system (ANS)?
This is the system that controls internal body homeostasis at a subconscious level. It controls respiration, circulation, digestion, body temperature, metabolism, and some endocrine secretions.
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Most organs are dually innervated with sympathetic and parasympathetic nerve fibers. Which functions are only innervated by the sympathetic nervous system though?
Blood pressure and sweat function
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The general idea is that the PNS and SNS oppose each other; however, we know that they often work together. How do the tonic and phasic activity of these systems work?
Tonic activity is long period of activity for the systems while phasic activity is short bursts of activity
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What are the 3 types of receptors in the ANS?
1. Ligand-gated (ionotropic or metabotropic)
2. Voltage-gated
3. G-protein linked receptors
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What NTs bind to nicotinic and muscarinic receptors?
Acetylcholine (Ach)
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What NT binds to Alpha and Beta Adrenergic receptors?
Epinephrine and Norepinephrine
150
Explain sympathetic innervation of the adrenal medulla.
The adrenal medulla releases acetylcholine (ACh), and it binds to the nicotinic receptors. Stimulates the adrenal medulla to release Epinephrine that binds to adrenergic receptors, which go on to affect the effector organs like the heart, lungs, eyes, glands, etc.
151
Explain sympathetic nervous system innervation.
The sympathetic nervous system releases acet6ylcholine (ACh), and it binds to nicotinic receptors. Nicotinic receptors than release Norepinephrine (NE) that binds to adrenergic receptors that eventually affect the effector organs like heart, lungs, eyes, and glands.
152
Explain Parasympathetic nervous system innervation.
The parasympathetic nervous system releases acetylcholine (ACh), and it binds to nicotinic receptors. These nicotinic receptors then release Acetylcholine (ACh) that binds to muscarinic receptors and go on to affect the effector organs like heart, lungs, eyes, glands, and more.
153
What is the difference in signaling between the ligand-gated nicotinic and muscarinic receptors?
Nicotinic acetylcholine receptors are IONOATROPIC, so much faster! Work with sodium and calcium efflux into the cell.
Muscarinic acetylcholine receptors are METABOATROPIC so they are much slower. Work with G-proteins.
154
How does Botox work in stopping acetylcholine signaling?
Botox prevents the vesicle carrying ACh from binding to the synaptic cleft and releasing it by cleaving the SNARE protein.
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What are the direct and indirect agonists that act on nicotinic and muscarinic acetylcholine receptors?
Nicotine- direct agonist
Neostigmine- indirect agonist
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What is the cholinergic antagonist of the NMJ?
Pancuronium
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What is the cholinergic muscarinic antagonist drug?
Atropine
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What is special about the direct agonist of the nicotinic receptor called nicotine?
Nicotinic receptors are easily desensitized, so when nicotine binds a lot to these, it can eventually become an antagonist.
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What is the MOA of the indirect agonist of the nicotinic receptor, Neostigmine?
Neostigmine is an acetylcholinesterase inhibitor, the enzyme that degrades ACh into acetate and choline. Allows for more ACh in cleft to bind. It does not cross the BBB. It is used to improve the tone of the GIT and bladder.
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What is the MOA of the non-depolarizing NMJ cholinergic antagonist called Pancuronium?
This drug completely blocks the nicotinic acetylcholine receptor in the NMJ.
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What are the characteristics of the muscarinic acetylcholine antagonist atropine?
Has a high affinity for all muscarinic receptors. It reduces pulmonary and salivary secretions and increases HR.
162
What are the effects of using a muscarinic antagonist (antimuscarinic) drug like atropine?
There is a lack of cholinergic tone, which induces blurred vision, confusion, mydriasis (large pupil), constipation, and urinary retention.
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Explain adrenergic neurotransmission.
Release of catecholamines like NE, E, and dopamine and taken back up by NETs into the presynaptic cells. The post-synaptic receptors include alpha 1 and 2 and beta 1, 2, and 3.
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How does the Alpha 1 adrenergic receptor work?
Alpha 1 is a Gq-protein-linked receptor. It increases the contractility of cells.
Located in vascular smooth muscle cells, eyes, and bladder. EPI=NE
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How does the Alpha 2 adrenergic receptor work?
Alpha 2 is a Gi-protein-linked-receptor. It inhibits adenylyl cyclase.
Located in central neurons and the eye. EPI=NE
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Beta receptors all work through cAMP and adenylyl cyclase. Which beta receptor has a higher affinity for epinephrine than NE?
Beta-2 receptor.
167
Even though sweating is mediated by the sympathetic nervous system, it is actually mediated through the activation of ___________ receptors.
Muscarinic
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The ANS system controls most functions through the activation of cholinergic receptors and adrenergic receptors. Which statements below are correct?
The nicotine receptors are always excitatory= YES
The adrenergic receptors are inhibitory= NO; they are g coupled, so they are neither.
The muscarinic receptor signal using ion channels= NO, use G-proteins
The alpha-adrenergic receptors are responsible for bronchdilation= NO, and beta receptors are.
The alpha-adrenergic receptors are responsible for decreasing HR=NO, muscarinic are
169
What are the characteristics of neuroinflammation in the brain?
Brain temperature and swelling can increase, which are both very bad. Sometimes there is a loss of function.
170
What are the cell types present in neuroinflammation?
This includes the microglia. It does not include the PNS immune cells like granulocytes, mast cells, natural killer cells, monocytes, and macrophages. However, if these enter the CNS, which can happen, it causes even more intense inflammation, and the brain can swell.
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What is the hallmark of neuroinflammation?
Morphological changes that are called glial activation and reactivity. These are mediated through transcription pathways.
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What are the main players in neuroinflammation?
Microglia and astroglia. Sometimes, peripheral immune cells sneak into the brain.
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What are the characteristics of microglia?
Microglia have a diverse morphology. During their macrophage state, they can develop more branches, become rod-like, hypertrophy, and amoeboid shape. Microglia act like innate immune cells that get right into plaques.
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What are the characteristics of astroglia/ astrocytes?
Astroglia are very different from microglia. These are metabolic cells that shuttle nutrients, remove toxins, and act like a metabolic hub. Active astrocytes begin to hypertrophy, sit on the edge of plaques, and form a glial scar representing a parameter.
175
What are the chemical mediators seen in neuroinflammation? (these are also seen in PNS inflammation)
Prostaglandins, chemokines, cytokines, and complement.
176
What creates arachidonic acid, and what does arachidonic acid create?
Phospholipids are hydrolyzed from the plasma membrane via phospholipase A into arachnoidic acid. Arachnoidic acid is converted by COX2 into prostaglandins.
177
What is the complement cascade?
The antibody binds to antigen cells and forms a coat around them, and then macrophages come and eat them up. That antibody-antigen complex has complement factors on it that help facilitate the macrophage clearance. This is called the opsonization of pathogens.
The other portion of this cascade involves different complement components. The rate-limiting enzyme, C3, is broken down and binds to the cell surface of antigen and antibody cells to form a non-selective complex channel pore. It allows ECF and ICF to flow rapidly and kills the cell by poking a hole in it.
178
What are the 5 different transcription factor families that regulate cytokine expression?
1. MAP kinase pathways
2. NFkB pathway
3. JAK/STAT pathway
4. Calcineurin/NFAT pathways (in T cells)
5. PPAR gamma pathways
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What is the main thing that activates MAP kinases?
Cytokines
180
Explain the NFkB pathway.
NFkB is a protein in the cytosol with inhibitory Kappa Bs stuck to it. When the cytokine receptors are activated, kinases phosphorylate Kappa Bs, and those let go, allowing NFkB to enter the nucleus and alter cytokine production.
181
Explain the JAK/STAT pathway.
When cytokine binds to receptors, JAK kinase phosphorylate STATs. When STATs are activated, they are transported to the nucleus and turn on cytokine production.
182
Explain the Calcineurin/NFAT pathway.
When calcineurin is activated by elevations in calcium levels, it dephosphorylates transcription factors called NFATs. NFATs translocate to the nucleus, and with NFkB, they regulate the expression of cytokines and other inflammatory molecules.
183
Explain the PPAR gamma pathway.
This pathway is generally anti-inflammatory, which is the opposite of the other pathways discussed. This pathway is activated by antioxidants, PUFAs, flavonoids, and good things for the body. PPAR game often inhibits transcriptional activity of the transcription factors NFkB and NFATs. Overall, PPAR game activation downregulates cytokines by antagonizing NFkB and NFATs.
184
Based on the previous lecture, we already know that ralimetinib inhibits the MAP/NFkB pathway, tofacitinib inhibits the JAK/STAT pathway, and tacrolimus inhibits the calcineurin/NFAT pathway. However, what other drug is used to inhibit the calcineurin/NFAT pathway?
Cyclosporine
185
Based on the previous lecture, we already know that ralimetinib inhibits the MAP/NFkB pathway, tofacitinib inhibits the JAK/STAT pathway, and tacrolimus and cyclosporin inhibit the calcineurin/NFAT pathway. What drugs activate the PPAR game pathway?
Rosiglitazone and Piaglitazone
186
Explain the range of drugs targetting neuroinflammation from low to high specificity.
Steroids, NSAIDs, Transcription factor modulators, and cytokine receptor inhibitors
