Exam 2 Flashcards
(161 cards)
1
Q
What is epilepsy?
A
This is recurrent disturbances of mental function and/or convulsions resulting for CNS seizures (abnormal + synchronized discharge of a group of neurons). Epilepsy is a chronic condition.
2
Q
What are the 3 types of seizures?
A
All seizures originate at a focus point within the brain where there are damaged neurons. Once a seizure begins, it spreads throughout the brain.
Generalized- This type of seizure is when the spread of the seizure is evenly distributed throughout the brain. This causes convulsions throughout the whole body.
Focal- This type of seizure is when the spread of the seizure is limited and typically effects one side of the body.
Unknown origin
3
Q
What are the different types of seizures included in the generalized seizure category?
A
Includes both tonic-clonic seizures and absence seizures.
Tonic-clonic seizure is the tonic phase (stiffening phase) followed by the clonic phase (jerking) with loss of consciousness.
Absence seizure is frequent but very brief seizure associated with brief loss of consciousness. No convulsions seen here.
Status epilepticus is a type of generalized seizure that is the most dangerous because it is prolonged and unceasing. This is a life threatening emergency.
4
Q
What are the two main ways anti-seizure medications help those with epilespy?
A
- Acute seizure termination
- Long-term prophylaxis
5
Q
What type of drug is Carbamazepine?
A
This drug is a highly selective Na+ channel blocker. This drug is specific for cells that are firing at a much more rapid rate than others. This is called a frequency-dependent block.
(Hopefully it leaves normal firing neurons alone, but sometimes it doesn’t which is where the sedation side effects come into play).
6
Q
What is the difference between the selective Na+ channel blockers and the non-selective Na+ channel blockers?
A
Non-selective Na+ channel blockers are a great poison that will kill whoever ingests it. Selective Na+ channel blockers can help prevent the propagation and spread of focal seizures.
7
Q
What is the only type of seizure that carbamazepine works well for?
A
Focal seizures
8
Q
How does carbamazepine effect CYP450 enzymes in the liver?
A
This drug is an enzyme inducer that increases the expression of those CYP450 enzymes in the liver. This means that the metabolism of other drugs is increased and blood concentration of the drug decreases more rapidly. That means this drug is prone to lots of drug-drug interactions.
9
Q
An addition side effect of carbamazepine is benign skin reactions like rashes etc. However, sometimes reactions with the skin can occur that are life-threatening. What is this side-effect called?
A
This is called Carbamazepine-induced toxic epidermal necrolysis. This condition means that the dermis and epidermis have separated due to desquamation. This leaves patients susceptible to infection.
10
Q
What anti-seizure drug has the broadest range of activity among all seizure types?
A
Valproic acid. This drug works well in treating tonic-clonic, absence, status epilepticus, and focal.
11
Q
What is a major side effect of valproic acid use in pregnant people?
A
Can induce neural tube defects that manifest as spina bifida and different variations of improper neural tube closure.
12
Q
What is the MOA of valproic acid?
A
This drugs blocks Na+ channels and thalamic Ca2+ channels. Blocking these channels prevent neuron depolarization therefore decreasing its hyperexcitability.
13
Q
What is the drug Topiramate?
A
This is newer anti-seizure drug with less issues. It is only available for oral use.
14
Q
What is the MOA of Topiramate?
A
It is known that this drug blocks Na+ channels however the other 2 mechanisms are only theorized. It is possible that Topiramate acts as an antagonist of the glutamate receptor subtypes and/or it enhances GABAergic neurotransmission.
15
Q
What are the seizure types that respond best to Topirmate?
A
Tonic-clonic and focal seizures respond best.
16
Q
What are important side-effects of Topiramate?
A
Associated with cleft lip/palate and weight loss.
17
Q
What is the drug ethosuximide used for?
A
This drug has a narrow range of use for absence seizures in children.
18
Q
What does an absence seizure look like on an EEG?
A
What is seen is a hyper-synchronized rhythm that is generated by a circuit where cortical and thalamocortical relay neurons repetitively stimulate each other.
19
Q
What is the MOA for Ethosuximide?
A
A neuron projects to a neuron within the thalamus called relay neuron. When relay neuron is stimulated, it sends signals to cortical neurons which sends signals back to the relay neurons and again and again and again like a cycle.
Ethosuximide binds and blocks the calcium channels on the relay neuron which dampers down the hyper-excitability of that loop.
20
Q
What is ethosuximide indicated for?
A
It is only indicated in absence seizures in children.
21
Q
What is the drug Levetiracetam?
A
Levetiracetam is a synaptic transmission modulator unlike the other anti-seizure medications that act on ion channels.
22
Q
What are the main types of seizures that Levetiracetam is used for?
A
Levetiracetam is best used in tonic-clonic, status epilepticus, and focal seizures.
23
Q
Explain the process of synaptic vesicles releasing neurotransmitters into the synaptic cleft.
A
- Vesicle is filled with NT
- Vesicle is docked at the pre-synaptic membrane
- Vesicles are primed for fusion with membrane
- Action potential arrives, triggers Ca2+ to enter cell, Ca2+ triggers vesicle fusion and NT release into synaptic cleft.
24
Q
What is the MOA of levetiracetam?
A
Levetiracetam binds to synaptic vesicle protein 2 (SV2). SV2 is a protein that sits on the membrane of synaptic vesicles and associated with the vesicles fusion to the presynaptic membrane. Levetiracetam binds to SV2 and partially disrupts its function so it no longer lets the vesicles fuse as well in response to the action potential releasing calcium. When there is not enough vesicle fusion, there is not enough NT release and therefore less hyper-excitability.
25
What is the most prominent side-effect of Levetiracetam?
Mood swings, agitation, irritability especially in children.
26
In an emergency setting, what is used to stop a status epilepticus seizure?
1st line- fast-acting benzodiazepines like lorazepam. Binds to GABA A receptors and enhances GABA inhibitory effects.
If the benzos do not work, move to 2nd line.
2nd line- Injectable valproic acid or levetiracetam
27
What is the MOA of the benzodiazepine Lorazepam?
Binds to BZ spot on the post-synaptic GABA A receptor. Enhances GABA inhibitory action by increasing the amount of Cl- into the cell therefor hyperpolarizing it.
28
What is chronopharmacology?
This is the study of drug actions in the context of the natural body rhythms.
29
What are the 3 types of biological rythms?
Circadian- Around 1 day. This would include the circadian rhythm of the body.
Ultradian- Greater than 1 hour but less than 1 day. This would include the sleep cycle.
Infradian- Greater than 1 day. This would be the menstrual cycle.
30
What is the main molecular clock of the body?
Genetic information converted to mRNA, carried to cytoplasm and translated to proteins that encode for circadian clock genes. These proteins bind to molecular clocks called E-boxes at the front of the circadian clock genes. Specifically, the BMAL1 and CLOCK proteins promote activation of the PER and mCRY genes while the PER protein inhibits activation of the PER and mCRY genes. The 24 hour cycling occurs due to BMAL1 and CLOCK proteins increasing the production of PER and CRY proteins but as PER and CRY proteins accumulate, they inhibit their own synthesis, and the levels of PER and CRY decline. PER and CRY proteins also inhibit the BMAL1 and CLOCK proteins before getting degraded.
31
Explain the increase and decrease of melatonin and corticosterone within the circadian rhythm.
Corticosterone ramps up during the day and decrease at night while melatonin decreases during the day and increases at night.
32
What are the 3 different types of molecular clocks?
1. Post-translational phosphorylation clock- 3 algae proteins in a test tube cyclically oscillating phosphorylating ATP on a 24 hr cycle.
2. Gene expression oscillator network- Handful of genes drive this rhythm within mammals. Seen within cells that have a nucleus
3. Redox clocks- in cells that have no nucleus like RBCs.
33
In multicellular organisms, endogenous clock behavior gets synchronized by signals from the ______ and ______ synchronizers. These synchronizers are sensitive to time cues called _________ to maintain rhythmicity.
Boss (suprachiasmatic nuceli in brain);
manager (other organs and tissues);
zeitgebers
34
What is the primary time cue/ zeitgeber?
Light
35
Explain how the 'boss' and the 'managers' work together to synchronize clock behavior.
The boss, suprachiasmatic nuclei (SCN) in the brain directly above the cross over of the eye nerves, is sensitive to light. When it senses light, it tells the managers to react to the light. These managers then slowly shift after the SCN picks up light cues quickly.
36
What is circadian stress?
This is when the organ systems are out of phase with the suprachiasmatic nuclei. It can be due to jet lag, shift work, and some diseases.
37
How does the suprachiasmatic nuclei react to light?
Within the retina of the eye, there are non-visual photoreceptor retinal ganglion cells (pRGCs) that respond to blue light. This information is sent to the SCN via the retinohypothalamic tract.
38
What is unique about the non-visual photoreceptor retinal ganglion cells (pRGCs) within the retina?
These cells can be destroyed experimentally and not affect vision.
Some blind patients still have light entrainment due to intact pRGCs.
39
What are the different things that can induce circadian disruption?
Jet lag, shift work
Major depressive disorder, dipolar, SAD, schizophrenia, PTSD, OCD
Alzheimer's, Parkinson's, MS, Epilepsy. (Sundowning in these diseases meaning as the sun sets, the symptoms get worse)
Cancerous cells are usually always out of sync.
40
What different aspect of pharmacokinetics is affected by the circadian rhythm?
1. Gastric pH which effects absorption
2. Xenobiotic metabolism pathway meaning how exogenous things are broken down
3. Excretion in the liver and kidney like changes in renal blood flow, GFR, reabsorption of drugs and more.
41
The more __________ a drug is, the more likely ________ is to matter.
Dangerous;
Rhythmicity
42
According to chronopharmacology, when is the best time to give anti-cancer medications?
Normal cells proliferative during rest and are acyclic during wake. However, cancer cells are always proliferating. This means the best time to give anti-cancer medication would be when normal cells are at rest so during wake is the best time. The concept is similar for other drugs like antibiotics, immunosuppressants, anti-seizures, cardiovascular medications, mood stabilizers, and more.
43
Explain the ultradian rhythm of the sleep cycle.
44
What is the sleep pressure system?
This is the idea that neurotransmitter buildup throughout the course of the day makes use tired. This is because neurotransmitters are released with ATP. Once ATP binds to postsynaptic membrane, it is dephosphorylated to adenosine. Adenosine itself drives the need for sleep.
45
What drugs effect deep sleep and how?
Diphenhydramine, barbiturates, benzodiazepines, and opioids lessen time spent in deep sleep.
Trazadone and GHB increase the amount of time spent in deep sleep.
46
What is narcolepsy?
This is a sleep disorder that is characterized by daytime sleep attacks, microsleep, sleep paralysis, hypnogogic hallucinations, cataplexy (loss of muscle tone due to surprise), and disturbed night time sleep.
Strong emotions can induce a thalamic shutdown.
47
How does hypocretin/orexin relate to sleep and narcolepsy?
These NTs and their receptors promote wakefulness. These receptors where located within the hypothalamus which projects to most cortical brain regions. It was found that those with narcolepsy had significantly less hypothalamic hypocretin/orexin positive nuceli.
48
How is narcolepsy treated?
This disorder is treated with the 'rock-star' lifestyle. This mens that stimulants are given during the day and sedatives are given at night.
49
What are some basic statistics about strokes in the US?
5th leading cause of death.
80% of strokes are preventable.
Stroke is the leading cause of long-term disability.
50
What are the different risk factors for a stroke?
Risk increases with age
Smoking
High BP
High Cholesterol
Obesity
Diabetes
51
What are the two different types of stroke?
Ischemic stroke- the pipe is clogged and there is no oxygen to the brain
Hemorrhagic stroke- the pipe bursts open and blood leaks into the brain where it should not be.
52
What is the FAST acronym for stroke?
F- face drooping
A- arm weakness
S- speech difficulty
T- time to call 911!
53
What is the general pathology of a stroke?
A stroke starts in a small brain area called the core. The region surrounding the stroke begins to be affected more and more and is called the penumbra. The penumbra is affected due to the decreased blood flow to other areas. Core area grows bigger with time and then eventually overtakes the penumbra.
When a stroke occurs, glutamate is released in high amounts which is toxic-excitotoxicity. This drives inflammation that damages brain cells which drives apoptosis making brain cells die.
Additionally, endothelial of the BBB begin to swell and express integrins which invites lymphocytes to come to the brain and promote inflammation. Astrocytes also begin to remove themselves from endothelial cells.
54
What is the only treatment for an ischemic stroke?
Tissue Plasminogen Activator (tPA). This needs to be given within 3 hours of stroke symptoms. TIME LIMITED FOR SURE!!!!!!
55
What is the MOA of tPA used to treat only an ischemic stroke?
In a normal clot, fibrinogen is converted to soluble fibrin via thrombin. The soluble fibrin is then cross-linked which is what normally happens when the body senses an injury. However, this is occurring in a BV and the cross-linked fibrin forms a clot. Things can attach to the clot and it can become really bad. Plasminogen is converted to plasmin and plasmin breaks down the clot. Plasminogen is activated by tPA.
tPA activates plasminogen which is converted to plasmin which dissolves the clot and resolves the ischemic stroke.
56
What are some issues that can arise when using tPA to treat an ischemic stroke?
It can cause excessive bleeding, pulmonary embolism, or reembolization.
57
Can tPA reverse the damage done by a stroke?
No, it can only break down the clot and prevent further brain damage.
58
What are the treatment options for someone suffering from an ischemic stroke and is past the 3-6 hour time limit to receive tPA?
They need to go into surgery. In surgery they can receive a balloon angioplasty, stent deployment, or endovascular mechanical thrombectomy.
59
What are the treatment option for a hemorrhagic stroke?
Hemorrhagic stroke can only be fixed by surgery. Surgery types include surgical clipping, coiling it, removing the BV, gluing it, or radiosurgery.
60
What type of disabilities appear after a stroke?
Disabilities could include paralysis, motor control issues, pain, aphasia, issues with memory, and more.
61
What does recovery and rehabilitation look like for a stroke?
1- hospital acute care
2- rehabilitation center
3- at-home health care
4- outpatient care
5- discharge
62
What are the two types of headaches?
Primary
AND
Secondary- headache is secondary to underlying pathology like meningitis, etc
63
What are the 3 types of primary headaches?
1. Tension- Most common type of headache. It can last a very long time. Pain is mild to moderate.
2. Migraine- Less common. Can be WITH or WITHOUT aura. More common for with aura. Typically has less duration of time but pain is moderate to severe.
A. With aura
B. Without aura
C. Retinal- just the aura and not actual headache.
3. Cluster- Very low prevalence of this. Very odd type of headache that comes on with different seasons.
64
What are general characteristics of migraines?
Idiopathic (do not know what the cause is), unilateral, pain is moderate to severe, pulsating pain. Attacks can last 4 to 72 hours. Migraines can be with aura, without aura, or retinal. Effects women more than men but become more even after menopause.
65
What is the diagnostic criteria for a migraine?
1. Headache limits function
2. Photophobic- pain increase with light/smell/sound
3. Nauseated
66
What percentage of headaches are tension or migraine?
90%
67
What are the 3 different hypotheses for migraine pathology?
1. Vascular hypothesis
2. Spreading depression hypothesis
3. Unifying sterile neurogenic inflammation hypothesis
68
What is the vascular hypothesis for migraine pathology?
States that an aura arise due to BVs in the occipital lobe being abnormally vasoconstrictive. This impairs neurons nearby. Other BVs respond to the constriction by pushing more blood into that area which resolves the aura but feeds the headache. Live human imaging showed the diameter of BVs do not change during migraine so likely not a correct hypothesis.
69
What is the spreading depression hypothesis for migraine pathology?
Sudden cortical depolarization of neurons on surface of cortex. When the neurons fire, the extracellular ion concentration changes which can cause neurons next to these neurons to fire as well. This is called cortical spread and it stimualtes the trigeminal nerve then that rolling wave of activity can release noxious agents into the CSF which sensitizes the meninges and causes pain.
70
What is the unifying sterile neurogenic inflammation hypothesis for migraine pathology?
Abnormal hyper-excitability occurs at the periaqueductal gray region (PAG) and/or the dorsal raphe somewhere near where the trigeminal nerve leaves the brain. This abnormal hyper-excitability drives the trigeminovascular system. The trigeminovascular system innervates BVs on outside of skull, side of face, and meninges. The hyper-excitability activates the trigeminovascular system which causes the trigeminal nerve to release inflammatory NTs like substance P and Calcitonin Gene Reactive Protein (CGRP). These substances rain down on vessels and cause them to become sensitized. They also stimulate NOX receptors in BVs that make them more sensitive to stretch.
71
Why does light amplify pain within headaches?
Non-image forming retinal ganglion cells (RGCs) sends light cues to the thalamus where the trigeminal nerve is activated. Blue light stimulation frequency matches the frequency of the stimulus of the trigeminal nerve. This causes pain where ever the trigeminal nerve innervates.
72
What are the different types of drugs used to treat acute migraines?
1. Ergot derivatives- dihydroergotamine (DHE) and ergotamine ***
2. Triptans- Sumatriptan is prototype ***
3. Gepants- Ubrogepant and Rimegepant ***
4. Barbiturates
5. Steroids
6. Non-opioid analgesics
7. Antiemetics
8. Opioids
73
What are Ergot derivatives?
Rye stored at bottom of barrel become wet and grew a fungus that made ergots. In large amounts they can cause vomiting, gangrene, hallucinations, miscarriages, and death.
74
Ergot derivatives do a good job at blocking what?
They block rebound headaches and are are good cycle breakers.
75
What is the prototype drug for ergot derivatives?
Ergotamine
76
What is the dosing like for Ergotamine?
Typically 1mg given with 100mg of caffeine to aid in absorption and vasoconstriction to stop stretching sensation.
CANNOT exceed 6mg in a day or 10mg in a week!!
77
What is the MOA of Ergotamine?
It binds to 5-HT1D receptors located in intracranial BVs which leads to vasoconstriction which can relieve migraine headaches. It also binds to 5-HT1D receptors on sensory nerve endings in the trigeminal nerves that stop the release of pro-inflammatory molecules. Dopamine receptor agonist which can cause nausea.
78
What are some complications involved with the use of Ergotamine?
It has a very narrow therapeutic index, variable absorption in GIT, several toxicities like hallucinations, gangrene, abortion, and more. Can overdose which is hard to reverse.
79
What is the drug dihydroergotamine (DHE) used for?
This is another ergot derivative drug. It is commonly seen in the ER to stop migraine cycling. A nasal spray version was used in the superbowl before FDA approval. Needs to be given as soon as the headache comes on. Side effects are similar to ergotamine but it is better tolerated than that drug.
80
What is unique about carotid arteriovenous anastomoses (basically capillaries)?
Capillary beds have branched points where precapillary sphincters are found that can close and shunt blood to other places. In the vascular hypothesis, it is argued that abnormal dilation of these capillaries pushes carotid blood flow from brain to surface. There are 5-HT receptors found on this capillary sphincters in the scalp and meninges.
81
What is the idea behind the drug class Triptans to treat acute migraines?
The idea is that Triptans bind to the 5HT receptors located on the carotid AVAs (capillaries). This binding will shunt blood from meninges and scalp to reduce nociceptive stimulus of pain for someone having a migraine.
82
What is the prototype Triptan drug?
Sumatriptan
83
What is the MOA for Sumatriptan?
Sumatriptan looks like serotonin. It binds to 5HT1B and 5HT1D receptors which helps divert blood flow from meninges (vasoconstrictor of meninges). It also inhibits serotonin release from neurons by acting on those 5HT receptors as they are autoreceptors. The latter is thought to be the major mechanism. It could also possible act on trigeminal nerve to reduce release from pro-inflammatory agents and facilitate anti-nociceptive input from brainstem to cortex.
84
What are the side effects associated with Sumatriptan?
It is usually well tolerated BUT can cause chest pressure and tightness. It is not to be given to patients with CAD or those on a MAOIs.
85
What type of Triptan drug has the longer half-life and is best for longer migraines?
Frovatriptan has a half-life of 26 hours.
86
What are the novel class of anti-migraine drugs called Gepants?
These are Calcitonin-gene-related peptide (CGRP) receptor antagonist. The two on the market include Ubrogepant (acute) and Rimegepant (acute & prophylactic).
87
What are rebound/ medication overuse headaches?
This is the 3rd most common form of secondary headaches. It occurs when analgesics are taken too frequently like ergotamine, triptan, opioids, or combos. Very difficult to treat.
88
What is serotonin syndrome?
This is medication-induced hyperthermic toxidrome that is triggered by excessive serotonergic activity via the 5HT1A and 5HT2 receptors. Diagnosis includes use of serotonin agent, 24hr onset, and 3 of the following: agitation, SHIVERING, tremor, diarrhea, sweating, and hyperreflexia.
89
How can migraines be treated prophlyatically?
If you have more than 1 headache per week then you need prophylaxis.
Rational agents-
Botox- blocks trigeminal nerve
Ditans- monoclonal antibodies that binds to CGRPs so less are floating around and cannot bind
Idiosyncratic agents-
B-blockers
Anti-epileptics- valproic acid
Anti-depressant- TCAs
90
In detail, we are the 4 main idiopathic drugs used for headache prophylaxis?
1. Beta Blocker-
1. TCAs- Amitriptyline
1. Anti-epileptic- Valproate
1. Monoclonal antibody- Erenumab (expensive)
91
What is diabesity?
This is the co-occurence of diabetes and obesity. Obesity is a risk factor for diabetes.
91
What is status migranosis and how is it treated?
Status migranosis is a migraine headache that is unresponsive to acute treatments. IV therapy given at ER can include NSAID, anti-emetic, anti-histamine, triptan or ergot derivative, opioids, and fluid.
92
What is the proposed pathological history behind diabetes?
Originally, the lipid hypothesis was used and it said that as you eat more saturated fat, you become more sick meaning more negative cardiovascular outcomes. At the end of the day though, it has much more to do with sugar intake.
93
Explain the Doug Coleman animal parabiosis experiments.
Parabiosis is the sharing of blood between mice.
db/db mice= no leptin receptors
ob/ob mice= no leptin
db/db mousee with normal mouse= normal mouse starved as it got signals it was not hungry
db/db mouse with ob/ob mouse= ob/ob mouse dies of starvation.
ob/ob mouse with normal mouse= ob/ob mouse and normal mouse survive
94
What is type 3 diabetes?
This is high sugar concentration in the brain with reduced intake of the sugar by brain cells. Type 3 diabetes makes the brain cells less sensitive to insulin and therefor less efficient in glucose intake. Type 3 could lead to AD.
95
How can type 3 diabetes lead to Alzheimer's and dementia?
Insulin degrading enzyme is present in the brain and breaks down amyloid beta and insulin. This leads to decreased insulin receptor signaling which increase tau protein phosphorylation. This is a sign of Alzheimer's disease.
96
What is the diagnostic criteria for metabolic syndrome?
Need 3 out of the 5:
Central obesity (waist circumference is large)
High triglycerides
Low HDL cholesterol
High BP
High fasting glucose
97
How can metabolic syndrome cause cognitive issues?
These are only associations!
- Those with greater peripheral insulin resistance showed increased negative clinical endpoints
-Overweight people show worse performance on test of learning, memory, and executive function compared to healthy individuals.
-Obesity in middle age increases risk for dementia
98
Most studies show a _________ x increase in dementia and AD in those with type 2 diabetes.
1.5-2 X
99
What are the different satiety signal going to the brain?
Includes the hormones released (leptin,ghrelin, CCK, glucagon, and more), stretch signals from stomach, and microbiome signals that travel to the hypothalamus. Specifically the ventromedial nucleus for satiety and the lateral hypothalamus area for hunger.
100
What are the different signals coming from the brain back to GIT?
Low blood glucose levels triggers sympathetic response from brain to liver and fat. Liver enters gluconeogenesis and glycogenolysis while fat enters lipolysis. Both sympathetic and parasympathetic work in gut motility while the enteric nervous system control the motility of the GIT.
101
What is the difference between nociception and pain?
Nociception occurs in the PNS when the sensory nervous system detects and encodes for noxious stimuli via chemical, thermal, or mechanical nociceptors.
Pain occurs in the CNS and is the physiological response and experience to the noxious stimuli
102
What is the difference between an anesthetic and an analgesic?
An anesthetic reduces all sensation.
An analgesic reduces pain without interfering with other sensory modalities.
103
Where do opioids work throughout the nociceptive pain pathway?
Opioids have an effect at the periphery, spinal cord, and supra spinal area.
Periphery nociceptors sense pain. Opioids reduce the firing of these nociceptive fibers.
These join the spinal cord at the dorsal horn where information is synaptically communicated. Opioids inhibit this signaling at the pre- and post-synaptic sites.
Signal then travels to thalamus and through disinhibition, opioids promote activity of outflowing pathways that stimulate the periaqueductal gray (PAG) area. The PAG has processes that extend down the spinal column and land on the same set of synapses for communication and inhibit them again.
104
What happens if electrodes were placed in the periaqueductal gray (PAG) area?
Electrodes in the PAG would cause a large amount of analgesia by activating its processes that work in the dorsal horn of spinal cord.
105
What are the short acting non-opioid analgesics? (also known as NSAIDs)
Aspirin, Ibuprofen, Diclofenac, Ketoprofen, and Indomethacin. Acetaminophen is included in the short-acting list but is not an NSAID.
106
What are the long-acting non-opioid analgesics?
Naproxen, Celecoxib, Meloxicam, Piroxicam, and Nabumetone.
107
What are the pharmacokinetics of the non-opioid analgesics?
Highly bioavailable, tightly bound to serum proteins (meaning more likely to hang out in circulation and diffuse to areas with low concentrations of the drug), low volume of distribution.
108
What are the pharmacodynamic properties of the non-opioid analgesics?
NSAIDs inhibit the activity of cyclooxygenase which stops the conversion of arachidonic acid to prostaglandins. Overall this decreases inflammation.
109
What are the side-effects of taking non-opioid analgesics?
Peptic ulcers can form.
110
What is a specific side-effect of taking acetominophen?
Hepatoxicity. More than 3 grams per day can lead to this.
111
What is the difference between opioids and opiates?
Opiates are made by the plant while opioids are derived from the plant.
112
How do opioids act at a cellular level?
Opioids bind to mu opioid receptors on synapses. At the presynaptic site, it blocks NT release and at post-synaptic site it makes receptors less sensitive to the NT.
Opioid receptors are GPCRs. When opioids binds to mu opioid receptors, they activate Gi (inhibitory) PCRS which causes a reduction in cAMP, making the cell less excitable. Additionally, they act on beta and gamma subunits of the mu opioid receptor which cause K+ ions to flow out of the cell and hyperpolarize it as well as reduced Ca2+ influx which disrupts vesicles merging with pre-synaptic cleft.
113
What is the opioid lifecycle with a cell?
Sometimes when opioids bind to their GPCR, they do not let go. Instead, the receptor and ligand are pulled into the cell which is called the internalized ligand receptor complex. While inside cell, this complex continues to signal.
114
What is the distribution of the 3 different opioid receptors?
Mu, Kappa, and Delta opioid receptors. All 3 can cause analgesia. There is 1 gene per receptor
All types are seen in the PNS, GIT, cerebral cortex, striatum, hippocampus, and dorsal horn of spinal cord.
Mu and kappa- midbrain periaqueductal gray region (PAG)
Delta- amygdala
115
What are endorphins?
Endorphins are endogenous opioids made by the body (endogenous opioids also include enkaphlins and dynorphins). There is more than one gene per ligand for endogenous opioids.
116
How are endorphins made?
Endorphins are made from POMC. POMC get cleaved into ACTH which enters bloodstream and stimulates adrenals to make glucocorticoids. Once the glucocorticoids enter the bloodstream, they make their way to pituitary. It changes composition of POMC and makes it cleave into beta-LPH which gets cleaved into gamma-LPH and beta-endorphins.
117
Is the body constantly secreting endogenous opioids?
No! The body produces these in response to different painful, stressful, or traumatic events.
118
What was naloxone found to do in healthy people?
Naloxone increases hormone secretion but does not alter pain threshold. It can reverse effect of acupuncture and nitrous oxide.
119
What is the prototype opioid drug?
Morphine
120
What are the different CNS effects that morphine induces?
Morphine must cross the BBB in order to induce analgesia, respiratory depression, antitussive (cough suppression), miosis in pinpoint pupils, tolerance, dependence, truncal rigidity, nausea and vomiting.
121
What are the different PNS effects that morphine induces?
Analgesia, constipation, and GI spasms.
122
What is the toxicity for morphine?
Death comes from profound respiratory depression. It can be reversed with an opioid antagonist like naloxone and mechanical ventilation.
123
What is the triad of symptoms that indicate opioid toxicity?
Miosis, decreased respiration, and coma.
Others signs include stupor, BP decline, and pupillary dilation.
124
Chronic toxicity of morphine is due to ___________ and ____________.
Tolerance;
Dependence
125
When does tolerance and dependence become relevant when taking morphine?
Tolerance develops within 1 week and becomes relevant after 2 weeks. Dependence is relevant when people try to withdraw from the drug.
126
What is diacetylmorphine?
Heroin
127
What is special about diacetylmorphine (heroin)?
This is a prodrug that is deacetylated to morphine within the CNS. It more rapidly penetrates the BBB compared to morphine.
128
What is special about the opioid, codeine?
This is another prodrug that is converted to morphine via demethylation by CYP2D6 within the liver. It has better survivability with 1st pass metabolism compared to morphine.
*Note; some people have CYP2D6 polymorphism not allowing for codeine conversion.
129
What is special about the opioids oxycodone and hydrocodone?
These drugs are semi-synthetic and their chemical modifications improve their 1st pass survivability. These drugs are more potent than morphine. Poppies are actually genetically modified to produce their precursor called thebaine.
130
What is Methadone?
This is a completely synthetic drug made in a lab. It has a high bioavaliablity and a long half life within the body. This drug is 'safe' in a controlled environment for helping people withdraw from more potent opioids. Methadone has same potency as morphine. Can be dosed once daily.
131
What are some characteristics about fentanyl?
It is a synthetic agent. It is 80-100x more potent than morphine. It is a highly lipophilic drug. Much shorter acting than morphine.
132
Even though fentanyl is abused, what is its main use in a controlled setting?
It is used as an IV analgesic in surgery. It is not an anesthetic though and needs to be given with a paralytic.
133
What is etorphine used for?
This is mainly a veterinary agent as it is 1000x more potent than morphine.
134
What is the purpose for mixed agonist opioids?
The idea is that people have analgesia without dependence or abuse. It is actually dysphoric at higher doses. Drugs include Pentazocine, Butrophanol, Nalbuphine, and more.
135
What is the one partial agonist of the opioid receptor discussed in class?
This is Buprenorphine. Produces physical dependence still.
136
What is the drug Tramadol?
This drug is an NE reuptake inhibitor, 5HT releaser, and weak agonist of mu opioid receptor. It is heavier duty than an NSAID but not as intense as an opioid.
137
What is the difference between nociceptive pain and neuropathic pain?
Nociceptive pain is what we are most familiar with. This is the acute pain caused by tissue injury that can be treated with opioids and NSAIDs. This is just the PNS telling the brain about an injury and telling you to do something about it. Everything in the CNS is fine but the pain signals make you uncomfy.
However, neuropathic pain is when their is something actually wrong with the nervous system. This is a pain that results from physical damage to the nervous system.
138
Explain the connections that occur with an injury stimulus happens.
1. Finger injury!
2. Pain sensed by primary afferent sensory neuron. Its cell body lives in the dorsal root ganglion next to spinal cord.
3. Pain travels down primary afferent sensory neuron via action potentials to the cell body in the dorsal root ganglion
4. From the cell body, the axon carries it into the actual spinal cord.
5. Primary afferent sensory neuron and dorsel horn projection synapse together at the dorsal horn.
6. The dorsal horn projection neuron then carries the pain signal to the brain.
139
What are the 4 most common neuropathic pain syndromes?
Diabetic neuropathy
Fibromyalgia
Post-herpetic neuralgia
Trigeminal neuralgia
140
What are the 3 describers for neuropathic pain?
Hyperalgesia- exaggerated response to a low-intensity pain stimulus
Allodynia- sensations like touch are perceived as painful
Spontaneous pain- pain is present with no sensory input
141
What is the general pathophysiology behind neuropathic pain?
Damage to CNS can cause afferent sensory nerve hyper-excitability (peripheral sensitization) or dorsal horn hyper-excitability (central sensitization).
142
What are the 3 first-line treatments for neuropathic pain?
SNRIs, TCAs, and gabapentin
143
What is the common SNRI prescribed for neuropathic pain?
Duloxetine
144
What is the MOA of the SNRI, duloxetine?
Blocks reuptake of serotonin and NE by blocking the reuptake transporters. This drug enhances the effects of 5HT and NE.
145
How does the SNRI, duloxetine help with neuropathic pain though?
The picture is looking at the synapse between the primary afferent sensory neuron and the dorsal horn projection neuron.
Nuclei in the brain like locus coeruleus and rostroventral medulla send NE or 5HT NTs down the spinal cord (in green) where they reach the dorsal horn and synapse at the purple faded interneuron. This interneuron releases inhibitory NTs that decrease activity of the dorsal horn projection neuron. This acts like a break in a car to decrease pain signaling in that region. This tames down the pain sensation.
The SNRIs work because they act at the level of the synapse between the green spinal cord and purple interneuron. They increase 5HT signaling which leads to more inhibition of the dorsal horn projection.
146
What is the first line tricyclic antidepressant used to treat neuropathic pain?
Amytriptyline
147
What is the MOA for the TCA, Amitriptyline?
Inhibits breakdown of 5HT and NE. Helps neuropathic pain the same way the SNRIs do.
148
What is are the two Gabapentinoid drugs used as a 1st line treatment for neuropathic pain?
Gabapentin and pregablin
149
What type of neuropathic pain is gabapentin and pregabalin indicated for?
Gabapentin- post-herpetic neuralgia (also in focal seizures)
Pregabalin- post-herpetic neuralgia, diabetic neuropathy, fibromyalgia, and spinal cord injuries. (also in focal seizures).
150
What is the MOA of the gabapentinoids?
They inhibit neuronal excitability. The MOA is not fully understood but it is theorized that these bind and inhibit the alpha2delta subunit of the presynaptic calcium channel.
Typically, calcium channels on the presynaptic cleft are activated and release calcium to trigger NT release. However, when this drug binds the alpha2delta subunit, calcium entry is decreased, so NT release is decreased, so hyper-excitability of the next cell is decreased.
It may also decrease alpha2delta ability to serve as scaffolding proteins that bring synaptic proteins together at a synapse in dorsal horn.
151
Overall, how do gabapentin and pregabalin decrease neuropathic pain?
In the spinal cord, they decrease influx of calcium which decreases NTs and therefore hyperexcitabilty, and alter scaffolding protein function reducing pain synapses.
152
What is the drug carbamazepine?
This is a Na+ channel blocker that is typically used as an anti-seizure medication. It has limited use for chronic pain but works will in neuralgias, specifically trigeminal neuralgia.
153
Why does carbamazepine work well in helping trigeminal neuralgia?
An injury occurs to the trigeminal nerve it can begin to overexpress Na+ channels, extend its nerve fibers, or become demyelinated which induces cross talk with random nearby neurons. Carbamazepine blocks the hyperexcited Na+ channels in the trigeminal nerve which suppresses its hyper-excitability by blocking action potentials.
154
What is a local anesthetic?
This is a drug that produces a reversible nerve conduction block when applied to a limited area by blocking Na+ channels therefore suppressing neuronal activity.
155
What are the 4 different types of local anesthesia?
Topical
Infiltration
Nerve block
Epidural or spinal
156
What is the pecking order of sensory nerves that are blocked by local anesthetics?
Pain > temp > touch > pressure
Enough local anesthetics will block any nerve.
157
What is the indication for a lidocaine patch?
Used for post-herpetic neuralgia. There needs to be a specific spot of pain as you cannot apply lidocaine patch over the entire body.
158
What is post-herpetic neuralgia?
When someone gets chicken pox, they are infected with the varicella virus. After treatment, this virus hides in dorsal root ganglion cells bodies of primary afferent sensory neurons. It lays dormant until the immune system declines again. The virus then reemerges and shows up as pox following along the nerve that it was inhabiting. When this happens, neuronal damage is left behind to sensory neurons.
159
What type of pain perceptions are seen in post-herpetic neuralgia?
Persistant hyperalgesia or allodynia lasting longer than 4 months.
160
Peripherally, lidocaine patches block the alphadelta and C __________ neurons and the alphabeta _________ neurons.
pain; touch
